So much research work has been carried out on HIV this far and the studies are intensifying on a daily basis. HIV AIDS is still a mystery as it is one of the diseases which experience the greatest difficulties in treatment and cure despite sleepless nights of medical researchers worldwide. It is as a result of these difficulties that much emphasis is now laid on prevention rather than treatment.

The first and most common method of transmission of the virus is unprotected sexual intercourse with an infected person. The virus is easily passed across because of its extremely high survivability in body fluids. Dr William O’connor stated that nearly every fluid in the body can transmit the virus, including saliva, blood, sweat and tears

Recent findings about the HIV virus are even more frightful and present slim chances for an AIDS free tomorrow.

A recent study showed that the HIV virus can survive for up to seven days on dry surfaces out of the body and fourteen days on wet surfaces. This was confirmed by the Pasteur Institute though the media talks less of this.

Micro lesions are normally found in the mouth, and if blood in those tiny pores is infected then we can contract HIV virus through passionate kissing. It was observed on a survey that fifty percent of test group had blood in their saliva and the figure was even greater after brushing.

Blood transfusion presents a very high risk of contracting the virus. At least 10000 Americans have been infected as a result of blood transfusion though blood banks carry out their best, chances of AIDS free blood is never 100 percent

The risk of contracting the virus is so great and medical personnel are at the frontline.  The Medical world news mentioned more than 5000 doctors, dentists and health personnel infected with the virus. This is because medical equipments are no longer as safe as those who sterilize them emphasize. Studies by Dr Lewis and his team reveals that the HIV virus has some chases of escaping from the chemical disinfectant used to sterilize the dentists tools and so poses a risk almost similar to handling of an infected syringe.

Read the post title,  If the blood of one partner contains  HIV on web-articles.info

Che Elvis

Presented by Che elvis

BACKGROUND

There has been a general and rising interest among nation states on environmental issues, most especially environmental protection of water sources since after the United Nation’s Conference on Environment and Development (UNCED), which is also called the ‘Earth Summit”, held in Rio de Janeiro, Brazil in June 1992. It was the summit that sensitized most national governments, Municipal councils and city or towns worldwide to re-examine issues of the environment in general and water sources in particular along side with those of development. Theoretically this conference expected Nations and their citizens to recognize the rather complimentary relationship which exist between development and the environment. Practically, most nations even began to redefine national security to include the protection of water sources from both internal and external aggression (Chiras, 1994).

INTRODUCTION

River Ndongo as it is called locally is a stream that passes through Molyko in Buea down towards Mile 14. It joins others streams at Mutengene and probably heads towards the sea in Limbe. The water is used for vary purposes along its path; drinkable at its source, agriculture particularly tomatoes at UB gate, general cleaning and laundry water around the Dirty south parts of Molyko, car wash at Mile 14 and Mutengene

The River originates at Ndongo quarters(which is named after the river) as a clean underground spring which is “pure” and drinkable. The BOD at the source is less than 3mg per Litre and it is classified as class 1A, but the purity decreases significantly downstream. Ndongo quarter is around Boston, between Molyko and Bunduma, Buea.

The people there have no alternate source of water such as pipe borne water and have to use their underground spring despite some of the problems that occur.

WATER PROBLEMS FACED

Firstly the inhabitants of this locality have serious water problems as seasons change. During the dry season, strong winds carry a lot of dust that settles on the water even at the source and since the inhabitants are stereotyped on the fact that their parents drank it for generations, they do not filter before drinking. Where as in the heart of the rainy season on the other hand, dissolved greenhouse gases go into the stream as well as dirty water from runoff, giving the water a brown coluor and making it undrinkable.

The inhabitants themselves, especially children are the main sources of major problems faced. If some one defecates around the source for instance, the smell scares off those who come to fetch water giving the impression that the water is dirty.

Also inhabitants swim when they return from their farms just at the point where drinking water is carried, making the water contaminated at that point.

Apart from swimming, some inhabitants go as much as dumping refuge too close to the source which increases the concentration of microorganism close to the source that can lead to serious infection problems.

Being in a volcanic region, the purity of the underground spring can be accounted for by the heavy filtration processes taking place underneath facilitated by volcanic rocks, but during earth tremors like in Mt Fako eruptions, the water becomes very unsafe for drinking.

Very little scientific work is carried out in the river despite the close to 400 persons who depend on it for drinking. Previous work shows that the source has almost negligible traces of heavy metals which could be related to volcanic activity.

Another problem is risk of pandemics such as cholera due to pollution from various sources, both defined and undefined.

WHO IS RESPONSIBLE?

The first people to blame for the water problems are the inhabitants who do very little to maintain hygiene at the source. The inhabitants swim, do laundry and deposit refuge quite close to the source that can easily result in pollution problems.

Also, nature is responsible for the water problems faced at Ndongo quarter. The inhabitants only depend on the underground spring supplied by the aquifers which are water buried strata beneath the ground and cannot explain the purity of the aquifer at any specific point in time. Heavy leaching for instance can pollute and aquifer and hence springs.

Also nature causes changes in climate that go a long way in dirtying the water. Rain brings dissolved greenhouse gases as well as runoffs while winds carry dust that settles on the stream.

Another party to take responsibility for the water problems faced is the Government.

The locality is inhabited mainly by farmers and unfortunately is not supplied by pipe borne water probably because the inhabitants find it needless to complain to the Government, says an inhabitant. Inhabitants are therefore forced to rely uniquely on the underground spring even after the rains when the water appears slightly brown.

Also the Government has failed to do much research on the spring so as to publicly declare its purity or impurity in specific seasons. Inhabitants therefore survive on the hope of its purity.

SOLUTIONS PROPOSED

1 Sensitization

The inhabitants should be sensitized on how to keep their water source clean. Clean up campaigns should be organized on daily or weekly basis to cut grass around the source and remove all dirt dumped even several meters from the source. Individuals dumping refuge should be sanctioned by the quarter head and it should be a pleasant responsibility to maintain purity of the stream.

2 Filtration and purification

Inhabitants should be thought to use simple purification techniques such as sand and cotton in bottles such that pollution should be minimized despite the problems encountered as seasons change. Filtration and purification such as the use of Chlorine can greatly reduce or even avoid completely the chance of outbreak of a pandemic. Click here to learn a  simple filtering experiment

3 Introduction of pipe borne water

If pipe borne water is brought to this locality by the government a great deal of problems will be solved especially those that cannot be avoided at the local level as seasons change. In this way, at such periods inhabitants will simply run to their taps as the water has gone through several steps of filtration and purification.

Already, however, the local community has introduced community water at some points which is free for every one.

4 Scientific research

Research should be carried out such that purity of the water source should be documented. Research can also predict contamination right before time such as mountain tremors that release heavy metals to aquifers and consequently to springs.

CONCLUSION

The government of Cameroon was part of the ‘Earth Summit’ in 1992 and is taking great measures in environmental protection particularly water sources.

Ndongo is one of the neighbourhoods that benefit from underground water as unique source of consumable water and therefore deserves some protection as stipulated in the summit.

Ndongo river serves several purposes beyond drinking, ranging from agriculture to carwash.

Inhabitants face many problems including pollution due to seasonal changes, poor waste disposal near the stream and risk of possible outbreak of pandemics

Both nature, the inhabitants themselves and the government is responsible for the problems faced by the inhabitants drinking from the stream.

Some of the solutions proposed to counter the problems encountered include; sensitization of the general public on hygienic practices, filtration and purification before consumption, introduction of pipe borne water to supplement natural supply and improvement on research work to predict purity or possibility of pandem

REFERENCES

Inhabitants of Ndongo quarters

CHM 402 notes by Dr Lydia Lifongo and Dr Tening

Cornelius M, Lambi  2001,  Environmental issues: Problems and Prospects,  page 23

David Waugh, An Integrated Approach to Geography

LIST  OF  INHABITANTS INTERVIEWED

1. YONI NJIE
2. PETER AGBOR
3. MBAKO FRANCIS
4. EYAMBI PRISCILIQ
5. EPOSI  ANABEL
6. NDIFOR FRANK
7. ISAIAH CHE
8. FONJONG
9. ENGEMA

10. BAH DAMIEN

11. GWENDOLIE

12. MUH NOBERT ADAMU

13. EYONG SHU

UB  STUDENTS  DRINKING  FROM THE SOURCE

14. NELSON EYONG ARREY

15. TAKAN CHUNG HARRISON

16. ETAH TIKU

17. ZACH CHIDI

18. VICTOR ANJONEK

19. NEH MIRABEL

Presented by Tengmi Jespa

Abstract
The treatment of bacterial infections is increasingly complicated by the ability of bacteria to develop resistance to antimicrobial agents. Antimicrobial agents are often categorized according to their principal mechanism of action. Mechanisms include interference with cell wall synthesis (e.g.-lactams and glycopeptide agents), inhibition of protein synthesis (macrolides and tetracyclines), interference with nucleic acid synthesis (fluoroquinolones and rifampin), inhibition of a metabolic pathway (trimethoprim-sulfamethoxazole), and disruption of bacterial membrane structure (polymyxins and daptomycin). Bacteria may be intrinsically resistant to _1 class of antimicrobial agents, or may acquire resistance by de novo mutation or via the acquisition of resistance genes from other organisms. Acquired resistance genes may enable a bacterium to produce enzymes that destroy the antibacterial drug, to express efflux systems that prevent the drug from reaching its intracellular target, to modify the drug’s target site, or to produce an alternative metabolic pathway that bypasses the action of the drug. Acquisition of new genetic material by antimicrobial-susceptible bacteria from resistant strains of bacteria may occur through conjugation, transformation, or transduction, with
transposons often facilitating the incorporation of the multiple resistance genes into the host’s genome or plasmids. Use of antibacterial agents creates selective pressure for the emergence of resistant strains. Here in case histories one involving Escherichia coli resistance to third-generation cephalosporins, another focusing on the emergence of vancomycin-resistant Staphylococcus aureus, and a third detailing multidrug resistance in Pseudomonas aeruginosa—are reviewed to illustrate the varied ways in which resistant bacteria develop.

INTRODUCTION

Resistance to antimicrobial agent is a recognized health problem for past years. Bacterial where known to pose a lot of problems to antibiotics due to their resistance to the drugs. Resistance to drugs by bacterial is a means developed by bacterial to survive in the milieu within which there are found. Drugs are substance that modifies the response of a tissue to it environment. They bind to receptors to elicit a biological response. Antibiotic resistant bacterial has increased as many organisms (example; Staphylococcus aureus) have developed resistance to several antibiotics; hence the search of new antibiotics is mainly due to the worrying ability of bacterial to acquire resistance to modern drugs. According to the World Head Organisation (WHO), Staphylococcus aureus is responsible for many serious community and nosocomially acquired infections, being the most frequently isolated bacterial pathogen from patients with hospital-acquired infections, especially immunocompromised patients with implants or prostheses. Asymptomatic S. aureus colonization occurs intermittently in children and adults, most commonly in the anterior nasal vestibule, but occasionally on the skin, hair, nails, axillae, perineum, and vagina. Before the introduction of antimicrobials in the 1940s, the mortality rate of S. aureus invasive infection was about 90%. The initial success of antibiotherapy was rapidly countered by the successive emergence of penicillin-resistant, then methicillin-resistant S. aureus (MRSA) strains and, since 2002, by that of vancomycin-resistant strains. The development of antibiotic resistance in S. aureus is a strong incentive that spurs vaccine development.
Antibiotics have different site of action on the bacterial cell; this implies that, bacterial develop resistance depending on the site of action of the antibiotics. Nevertheless, some bacterial are resistant to many antibiotics by different mechanism of action, and it has become very difficult to fight such bacterial.
Bacterial have developed resistance to drug by many mechanism among which is drug resistance by mutation, drug resistance by genetic transfer, drug resistance by decrease permeability ability of the drug to the membrane of the bacterial, modification of the active site of the enzyme attack by the antibiotics and finally, the over production of enzyme that inactivate the antibiotics.
The enzymes that are involved in drug resistance include; penicillinases for the penicillin antibiotics, cephalosporinase for the cephalosporin antibiotics, the beta lactamases for the beta lactam antibiotics and many others.
The fight against bacterial resistance has brought many scientists together to develop strategies to combat the situation among which is the search for new antibiotics from natural product chemistry or other means but most important is the aspect of combination therapy which has brought more light to the fight against bacterial drug resistance.

Antibiotic resistance
Antibiotic resistance is the ability of a microorganism to withstand the effects of antibiotics. It is a specific type of drug resistance. Antibiotic resistance evolves via natural selection acting upon random mutation, but it can also be engineered by applying an evolutionary stress on a population. Once such a gene is generated, bacteria can then transfer the genetic information in a horizontal fashion (between individuals) by plasmid exchange. If a bacterium carries several resistance genes, it is called multiresistant or, informally, a superbug. The term antimicrobial resistance is sometimes used to explicitly encompass organisms other than bacteria.

Figure G: Effects of different antibiotics on growth of a Bacillus strain. The right-hand image shows a close-up of the novobiocin disk (marked by an arrow on the whole plate). In this case some individual mutant cells in the bacterial population were resistant to the antibiotic and have given rise to small colonies in the zone of inhibition.
Antibiotic resistance is not a recent phenomenon. On the contrary, this problem was recognized soon after the natural penicillin was introduced for disease control, and bacterial strains held in culture collections from before “the antibiotic era” has also been found to harbor antibiotic-resistance genes. However, in some cases the situation has now become alarming, with the emergence of pathogenic strains that show multiple resistance to a broad range of antibiotics. One of the most important examples concerns multiple-resistant strains of Staphylococcus aureus in hospitals. Some of these strains cause serious nosocomial (hospital-acquired) infections and are resistant to virtually all the useful antibiotics, including methicillin, cephalosporins and other beta-lactams that target peptidoglycan synthesis, the macrolide antibiotics such as erythromycin and the aminoglycoside antibiotics such as streptomycin and neomycin, all of which target the bacterial ribosome
Antibiotic resistance can also be introduced artificially into a microorganism through transformation protocols. This can aid in implanting artificial genes into the microorganism. If the resistance gene is linked with the gene to be implanted, the antibiotic can be used to kill off organisms that lack the new gene.
Why is resistance a concern?
There are a number of reasons why bacterial resistance should be a concern for physicians. First, resistant bacteria, particularly staphylococci, enterococci, Klebsiella pneumoniae, and Pseudomonas spp, are becoming common placein healthcare institutions. Bacterial resistance often results in treatment failure, which can have serious consequences, especially in critically ill patients. Inadequate empiric antibacterial therapy, defined as the initial use of an antibacterial agent to which the causative pathogen was not susceptible, has been associated with increased mortality rates in patients with bloodstream infections due to resistant Pseudomonas aeruginosa, Staphylococcus aureus, K pneumoniae, Escherichia coli, Enterobacter spp, coagulase-negative staphylococci, and enterococci. Prolonged therapy with antimicrobial agents, such as vancomycin or linezolid, may also lead to the development of low-level resistance that compromises therapy, but that may not be detected by routine susceptibility testing methods used in hospital laboratories.
Resistant bacteria may also spread and become broader infection-control problems, not only within healthcare institutions, but in communities as well. Clinically important bacteria, such as methicillin-resistant S aureus (MRSA) and extended-spectrum lactamase (ESBL) producing E coli, are increasingly observed in the community. Infected individuals, including children, often lack identifiable risk factors for MRSA, and appear to have acquired their infections in a variety of community settings. Community- associated MRSA strains are typically less resistant to antimicrobial agents than healthcare-associated MRSA, but are more likely to produce toxins, such as Panton–Valentine leukocidin. The spread of resistant bacteria within the community poses obvious additional problems for infection control, not just in long-term care facilities but also among sport teams, military recruits, and even children attending day care centers a task that is complicated by the increased mobility of our population. Finally, with respect to the cost-containment pressures of today’s healthcare environment, antibacterial drug resistance places an added burden on healthcare costs, although its full economic impact remains to be determined.
Causes and risk factors
Antibiotic resistance can be a result of horizontal gene transfer and also of unlinked point mutations in the pathogen genome and a rate of about 1 in 108 per chromosomal replication. The antibiotic action against the pathogen can be seen as an environmental pressure; those bacteria which have a mutation allowing them to survive will live on to reproduce. They will then pass this trait to their offspring, which will result in a fully resistant colony.
Several studies have demonstrated that patterns of antibiotic usage greatly affect the number of resistant organisms which develop. Overuse of broad-spectrum antibiotics, such as second- and third-generation cephalosporin, greatly hastens the development of methicillin resistance. Other factors contributing towards resistance include incorrect diagnosis, unnecessary prescriptions, improper use of antibiotics by patients, the impregnation of household items and children’s toys with low levels of antibiotics, and the administration of antibiotics by mouth in livestock for growth promotion.
Researchers have recently demonstrated the bacterial protein LexA may play a key role in the acquisition of bacterial mutations.

ORIGIN OF DRUG RESISTANCE
Human inability to respect the complete medication period given to them has mark a rapid increase in drug resistance by bacterial. When incomplete medication is carried out by a patient, it makes the bacterial to develop resistance against that drug, because the bacterial will develop new ways (factors) to prevent the conditions it is exposed to. By doing so, the bacterial cell wall may become impermeable to the drug, or produce enzymes that deactivate the drug and many others. So it is convenient to always take the complete medication given. Bacterial have become resistant to many drugs by developing certain factors which are explicitly given as follows;
Drug resistance by mutation:
Bacterial have the ability to multiply very rapidly, such rapid multiplication also pose a chance to the bacterial to undergo mutation which will render the bacterial cell resistance to a particular drug. The mutation can be the change in the bacterial structure, or the enzymes attacked by the drug changes it’s structure or composition. This works in line with the fact that patients do not always complete the course of their antibiotic treatment given that the symptoms of their illness have disappeared. To elaborate, the drug becomes foreign to its target due to mutation at the drug target.
Drug resistance by genetic transfer:
Genetic materials can be transferred from one bacterial cell to another by transduction or by conjugation. This therefore means that bacterial are capable of exchanging genetic materials and hence, a resistant bacterial cell can transfer the gene responsible for its resistance to a drug to a non resistant bacterial cell and this therefore cause the latter to be resistant to the same antibiotics.
In transduction, plasmids which are small segment of genetic information of a bacterial are transferred by means of bacterial viruses or bacteriophage. If the plasmid which contains the gene for resistance to a particular antibiotic agent leaves a resistant bacterial cell to a non resistant bacterial cell, then it will cause the latter to acquire resistance to that antibiotic. For example, the genetic information required to synthesize beta- lactamase can be pass on in this way and hence rendering bacterial resistance to beta- lactam antibiotic agent.
Conjugation is a method used mainly by Gram negative rod-shaped bacterial; it involves two bacterial cells building a sex bridge through which genetic information can pass. Hence, the bacterial cell passes genetic information directly to each other.
Change in permeability to bacterial cell:
Bacterial can undergo mutation which causes a decrease in permeability of the drug to the bacterial cell. Hence, causing the bacterial to be non susceptible to the attack of the drug. The mutation can be due to the change in polarity of the cell wall or cell membrane of the bacterial which repels the drug. The bacterial might develop a new protective coat which is impermeable to the drug. Many bacterial have developed resistance through this means.

Drug resistance by the production of drug deactivating enzymes:
Bacterial can produce enzymes that deactivate the antibiotics. These enzymes deactivate antibiotics by modifying them to inactive compounds.
Some of the enzymes produced by the bacterial include; penicillinase, cephalosporinase, beta- lactamase and much more. As an example, the beta- lactamases deactivates beta- lactam antibiotics by breaking the beta- lactam ring essential for activity.
Antibiotic usage in agriculture: creates a reservoir of resistance genes
One of the fiercest public debates at present concerns the use of antibiotics in agriculture and veterinary practice. The reason for concern is that the same antibiotics (or, at least, antibiotics with the same mode of action on bacteria) are also used for human therapy. Thus, it is possible that the irresponsible use of antibiotics for non-human use can lead to the development of resistance, which could then be passed onto human pathogens by transfer of plasmids. The greatest concern of all centres on the routine use of antibiotics as feed additives for farm animals – to promote animal growth and to prevent infections rather than to cure infections. It has been difficult to obtain precise figures for the amounts of antibiotics used in this way. But the scale of the potential problem was highlighted in a recent report by the Soil Association, which collated figures on the total usage of different types of antibiotic for humans and for animals:

Antibiotic resistance in genetically modified crops
A further source of concern is the widespread use of antibiotic-resistance genes as “markers” in genetically modified crops. Most of the companies insert antibiotic-resistance genes as “markers” during the early stages of developing their Genetically Modified( GM corps). This enables the scientists to detect when the genes that they are most interested in (herbicide-resistant genes or insecticidal toxin genes) have been inserted into the crop. The antibiotic-resistance genes then have no further role to play, but they are not removed from the final product. This practice has met with criticism because of the potential that the antibiotic-resistance genes could be acquired by microorganisms. In some cases these marker genes confer resistance to “front line” antibiotics such as the beta-lactams
Looking at penicillin, some bacterial develop resistance by producing enzymes called; amidases which slits off the R-side chain from the amino group of the 6-aminopenicilanic acid (6-APA). Also, metabolically inactive organisms are phenotypically resistant to penicillin but genotypically fully susceptible to penicillin. Such organism can act as “persisters” both in vitro and in vivo.
CASE STUDIES

E coli: Development of Resistance to Third-
Generation to penicillin

E coli is a common cause of urinary tract infections and bacteremia in humans, and is frequently resistant to aminopenicillin, such as amoxicillin or ampicillin, and narrow spectrum cephalosporins. Resistance is typically mediated by the acquisition of plasmid beta- lactamases which hydrolyze and inactivate these drugs. Some E coli strains develop resistance to third-generation cephalosporins and monobactams (aztreonam) commonly arising through mutation of the enzymes. Resistance to cephamycins and other lactams such as amoxicillin may arise as a result of changes in the porins in the outer membrane (proteins that form the water-filled channels through which drugs and other molecules enter the bacterial cell). Such changes decrease or eliminate the flow of small hydrophilic molecules like lactam drugs across the membrane. The following case illustrates the interaction of these mechanisms of resistance. A 4-year-old girl was admitted to an
Urban hospital in Atlanta with a plastic anemia and bacteremia. Blood cultures collected during her first week in the hospital were positive with E coli isolates that were resistant to ampicillin and narrow-spectrum cephalosporins but remained susceptible to third-generation cephalosporins. Over the next 3 weeks, the child received a variety of antimicrobial agents directed against E coli and other suspected bacterial pathogens in an attempt to treat her persistent fevers and bacteremia. The antibacterial agents included penicillins (ticarcillin, oxacillin, and mezlocillin), aminoglycosides (gentamicin), and third-generation cephalosporins.

ACTION OF PENICILLIN
The antibacterial effect of penicillin was discovered by Alexander Fleming in 1929. He noted that a fungal colony had grown as a contaminant on an agar plate streaked with the bacterium Staphylococcus aureus, and that the bacterial colonies around the fungus were transparent, because their cells were lysing. Fleming had devoted much of his career to finding methods for treating wound infections, and immediately recognized the importance of a fungal metabolite that might be used to control bacteria. The substance was named penicillin, because the fungal contaminant was identified as Penicillium notatum. Fleming found that it was effective against many Gram positive bacteria in laboratory conditions, and he even used locally applied, crude preparations of this substance, from culture filtrates, to control eye infections. However, he could not purify this compound because of its instability, and it was not until the period of the Second World War (1939-1945) that two other British scientists, Florey and Chain, working in the USA, managed to produce the antibiotic on an industrial scale for widespread use.

Structure A showing Fleming’s slide

Structure of penicillin
Penicillin is a bicyclic compound consisting of a four membered beta- lactam ring fused to a five membered thiazoridine ring. The skeleton of the molecule reveal that it is derived from the amino acid valine and cysteine. The acyl side chain “R” varies depending on the make up of the fermentation as shown below;

Structure Activity Relationship

From the synthesis of great analogs of penicillin studies, reveals the following conclusion about the activity of the structure of penicillin;
• The strain beta lactam ring most be present
• The free carboxylic acid at position three is essential
• The bicyclic system is important because it confers strain of the beta lactam ring, the greater the strain the greater the activity and also the greater the instability of the molecule to other factors.
• The stereochemistry of the bicyclic ring
With respect to the acyl amino side chain is essential for activity.
From all the above observations, it is clear that very little variations can be done on the structure of the penicillin molecule. One of the penicillin analogs is penicillin G for which “R” is a benzyl group, as it is shown below;

Penicillin G

Why are there so few clinically useful antibiotics?
Several hundreds of compounds with antibiotic activity have been isolated from microorganisms over the years, but only a few of them are clinically useful. The reason for this is that only compounds with selective toxicity can be used clinically – they must be highly effective against a microorganism but have minimal toxicity to humans. In practice, this is expressed in terms of the therapeutic index – the ratio of the toxic dose to the therapeutic dose. The larger the index, the better is its therapeutic value.

It will be seen from the table above, that most of the antibacterial agents act on bacterial wall synthesis or protein synthesis. Peptidoglycan is one of the major wall targets because it is found only in bacteria. Some of the other compounds target bacterial protein synthesis, because bacterial ribosomes (termed 70S ribosomes) are different from the ribosomes (80S) of humans and other eukaryotic organisms. Similarly, the one antifungal agent shown in the table (griseofulvin) binds specifically to the tubulin proteins that make up the microtubules of fungal cells; these tubulins are somewhat different from the tubulins of humans
BRIEF PROPERTIES OF PENICILLIN G
The two natural penicillins obtained from culture filtrates of Penicillium notatum or the closely related species P. chrysogenum are penicillin G and the more acid-resistant penicillin V. They are active only against Gram-positive bacteria (which have a thick layer of peptidoglycan in the wall) and not against Gram-negative species, including many serious pathogens like Mycobacterium tuberculosis (the cause of tuberculosis). Nevertheless, the natural penicillins were extremely valuable for treating wound pathogens such as Staphylococcus in wartime Europe.
An expanded role for the penicillin came from the discovery that natural penicillin can be modified chemically by removing the acyl group to leave 6-aminopenicillanic acid and then adding acyl groups that confer new properties. This modern semi-synthetic penicillin such as Ampicillin, Carbenicillin and Oxacillin has various specific properties such as:
• Resistance to stomach acids so that they can be taken orally,
• a degree of resistance to penicillinase (a penicillin-destroying enzyme produced by some bacteria)
• extended range of activity against some Gram-negative bacterial.
Although the penicillin are still used clinically, their value has been diminished by the widespread development of resistance among target microorganisms and also by some people’s allergic reaction to penicillin.

ACID SENSITIVITY OF PENICILLIN
Penicillin is recognized to be acid sensitive in the stomach and this has made them to be inactive orally. There are three reasons which account for the acid sensitivity of penicillin.
Ring strain:
The bicyclic system of the penicillin molecule consists of a four membered ring and a five membered ring. As a result, penicillin suffers large angle torsional strain. Acid catalyzed ring opening relieved this strain by breaking open the high strain four membered ring.
A highly reactive beta- lactam carbonyl group:
The carbonyl group in the beta- lactam ring is highly susceptible to nucleophiles and as such does not behave as a normal tertiary amide which is usually quite resistant to nucleophlic attacks. This difference in reactivity is due to the fact that stabilization of the carbonyl is possible in the tertiary amide but impossible in the beta- lactam ring. The beta- lactam nitrogen is unable to feed its lone pair of electron into the carbonyl group since this would require the bicyclic ring to adopt an impossible strain plat system. As a result, the lone pair of electron is delocalized on the nitrogen atom and the carbonyl group is far more electrophilic than expected for a normal tertiary amine. A normal tertiary amine is far less susceptible to nucleophiles since resonance structure reduces the electrophilic character of the carbonyl group.
Influence of the acyl side chain:
The neighboring acyl group can actively participate in the mechanism of the beta- lactam ring opening by attacking the carbonyl group of the beta- lactam ring, hence it is self destructive.
Tackling the problem of acid sensitivity
It is then very necessary to solve the problem of acid sensitivity of penicillin. From the above factors, nothing can be done about the problem of ring strain and the problem of the highly reactive beta- lactam carbonyl. In this view, only the third factor can be solved by reducing the neighboring participation of the acyl amino side chain, which is to make it difficult if not impossible for the acyl amino side chain carbonyl group to attack the beta- lactam carbonyl which will lead to the breaking of the beta- lactam ring. This point is solved by introducing an electron withdrawing group to the carbonyl carbon of the acyl amino side chain. By inductive pulling effect, the electron withdrawing group pulls electrons from the carbonyl oxygen and reduces its tendency to act as a nucleophile. An example is penicillin V (pen V).
How penicillin is destroyed by beta- lactamase
Bacterial develop resistance to penicillin by secreting an enzyme (beta- lactamase) that hydrolysis penicillin before it can interfere with bacterial cell wall synthesis. Beta- lactamase destroy penicillin by breaking the beta- lactam ring which is necessary for the activity of penicillin.
Mechanism of action of penicillin.
Penicillin is a beta lactam anti biotic was inhibits bacterial cell wall synthesis.
In contrast to animal cells, bacterial posses a rigid outer layer, the cell wall which “corsets” the bacterial cell, which posses an unusually high internal osmotic pressure. Injury in the cell wall or inhibition of it formation can lead to lyses of the cell. In hypertonic environment, damaged cell wall, leads to formation of spherical bacterial “protoplast” limited by the fragile cytoplasmic membrane. In the environment of ordinary tonicity, the protoplast explodes, and the cell dies, meaning penicillin is bactericidal.
Beta-lactam antibiotics work by inhibiting the formation of peptidoglycan cross-links in the bacterial cell wall. The β-lactam moiety (functional group) of penicillin binds to the enzyme (DD-transpeptidase) that links the peptidoglycan molecules in bacteria, which weakens the cell wall of the bacterium (in other words, the antibiotic causes cytolysis or death due to osmotic pressure). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolysis and autolysins, which further digest the bacteria’s existing peptidoglycan.
Gram-positive bacteria are called protoplasts when they lose their cell wall. Gram-negative bacteria do not lose their cell wall completely and are called spheroplasts after treatment with penicillin.
Penicillin shows a synergistic effect with aminoglycosides, since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing its disruption of bacterial protein synthesis within the cell. This results in a lowered Minimum Bactericidal Concentration (MBC ) for susceptible organisms.
SIDE EFFECTS
Common adverse drug reactions (≥1% of patients) associated with use of the penicillins include diarrhea, hypersensitivity, nausea, rash, neurotoxicity urticaria, and/or super infection (including candidiasis). Infrequent adverse effects (0.1–1% of patients) include fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in epileptics), and/or pseudo membranous colitis.
Pain and inflammation at the injection site is also common for parenterally administered benzathine benzylpenicillin, benzylpenicillin, and, to a lesser extent, procaine benzylpenicillin.
Although penicillin is still the most commonly reported allergy, less than 20% of all patients who believe that they have a penicillin allergy are truly allergic to penicillin; nevertheless, penicillin is still the most common cause of severe allergic drug reactions.
Allergic reactions to any β-lactam antibiotic may occur in up to 10% of patients receiving that agent. Anaphylaxis will occur in approximately 0.01% of patients. It has previously been accepted that there was up to a 10% cross-sensitivity between penicillin-derivatives, cephalosporins, and carbapenems, due to the sharing of the β-lactam ring. However recent assessments have shown no increased risk for cross-allergy for 2nd generation or later cephalosporins. Recent papers have shown that a major feature in determining immunological reactions is the similarity of the side chain of first generation cephalosporins to penicillins, rather than the β-lactam structure that they share.
Fighting penicillin drug resistance
Chemist have developed new methods of fighting penicillin drug resistance, among this methods is;
• The development of drugs that inhibit beta-lactamases, an example is clavolanic acid, if such a drug is given alon side with penicillin, the antibiotics is not destroyed. This is an example of a prodrug that has no therapeutic effect but acts by protecting a therapeutic drug. A sulfone is also a beta-lactamase inhibitor which is obtained by oxidizing the penicillin sulfur atom with a peroxyacid.
• Another means of fighting resistance is by developing new targets.

CONCLUSION

References
: http://www.pharminfo.com/
PCH 362 therapeutic agents Dr. Akam 2007/2008.
McManus MC. Mechanisms of bacterial resistance to antimicrobial
agents. Am J Health Syst Pharm. 1997;54:1420 –1433.
Drlica K, Zhao X. DNA gyrase, topoisomerase IV, and the 4-quinolones.
Microbiol Mol Biol Rev. 1997;61:377–392.
Yao J, Moellering RJ. Antibacterial agents. In: Murray PR, Baron EJ,
Jorgensen JH, Pfaller MA, Yolken RH, eds. Manual of Clinical Microbiology,
8th ed. Washington, DC: ASM Press; 2003:1039 –1073.
Petri WAJ. Antimicrobial agents: sulfonamides, trimethoprim-sulfamethoxazole,
quinolones, and agents for urinary tract infections. In:
Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s The
Pharmacological Basis of Therapeutics, 11th ed. New York: McGraw-
Hill, 2006;1111–1126.
Storm DR, Rosenthal KS, Swanson PE. Polymyxin and related peptide
antibiotics. Annu Rev Biochem. 1977;46:723–763.
Carpenter CF, Chambers HF. Daptomycin: another novel agent for
treating infections due to drug-resistant gram-positive pathogens. Clin
Infect Dis. 2004;38:994 –1000.

Our Atoms which art in molecules  

Hallowed be thy compounds,

thy mixtures come

Thy electrons be associated with protons

as it is a mystery

Give us good reactions in our daily experiments

And forgive us, our unbalanced equations

As we forgive all electrons that trespass the continuum

And lead us not into explosions

But deliver us from killing

For thine is the power, in reactants and reagents

For ever and ever, Chemistry without end

Amen

http://elvizy.com

Presented by Shu Mabel Lum

University of Buea

Abstract

Herbal medicine, sometimes referred to as herbalism or Botanical Medicine is the use of herbs for their therapeutic or medicinal value .A herb is a plant or plant part valued for its medicinal, aromatic or savory qualities. Herbs produce and contain a variety of chemical substances that act upon the body and treat many diseases.

The use of plants in the treatment of diseases is more commonly used because medicinal plants are more efficient and less toxic. Plants also are of a natural source, hence are less costly when prepared. Medicinal plants also have an advantage over drugs because they can be consumed in their natural form, whereas drugs must first of all be prepared before consumption. Major pharmaceutical companies are presently conducting research on plant materials due to their potential medicinal value.

Introduction

The brain is made up of interrelated neural systems that regulate their own and each others activity. These divisions make it easier for the brain to function efficiently since it is responsible for carrying out many other activities. The sympathetic nervous system is vitally involved in the homeostatic regulation of a wide variety of functions such as heart rate, force of cardiac contraction, blood pressure and fatty acid metabolism. Stimulation of the sympathetic nervous system normally occurs in response to physical activity, physiological stress and other situations in which the organ is provoked. Because the functions that are mediated by the sympathetic nervous system are diverse, agents that mimic or alter its activity are useful in the treatment of several clinical disorders like shock, cardiac failure, hypertension and many others.

Drugs that affect the Central Nervous System may selectively relieve pain or fever, suppress disorder or movements or prevent seizures. They may as well induce sleep or arousal, reduce the desire to eat or reduce the tendency of vomiting and hence may be used to treat anxiety, mania, depression or schizophrenia without altering consciousness.

The major scientific challenge is an attempt to understand the way the brain functions and the major goals include:

1) To use drugs to dissect the mechanisms that operate in the normal Central Nervous System

2) To develop appropriate drugs to correct events in the abnormal Central Nervous System.

CHAPTER ONE

LITERATURE SURVEY

History of medicinal plants

Herbal medicine has a long and respected history. Many familiar medications of the twentieth century were developed from ancient healing traditions that treated health problems with specific plants. Today, science has isolated the medicinal properties of a large number of plants, and their healing components have been extracted and analyzed. Many plant components are now synthesized in large laboratories for use in pharmaceutical preparations. For example , vincristine (an antitumor drug), digitalis (a heart regulator) and ephedrine (a bronchodilator used to decrease respiratory congestion) were all originally discovered through research on plants.

Chemistry of medicinal plants

The use of plants in the treatment of diseases is attributed to their secondary compounds. They are called “secondary” compounds because they have no known functions in primary physiological processes like photosynthesis and respiration. Many classes of secondary compounds such as alkaloids and steroidal glycosides are found in medicinal plants.

i) Alkaloids are a chemically diverse group. They contain nitrogen which is usually found in rings although there are exceptions where the nitrogen atoms are not included in the rings e.g. epinephrine and ephedrine.

ii) Steroidal glycosides contain sugar molecules. The steroidal molecules are the same as those found in animal hormones produced by the pituitary glands and sex organs.

Advantages of medicinal plants over synthesized drugs

Herbs are medicinal plants (also called phytomedicals) that can be administered either as a whole plant or plant part while synthetic drugs are synthesized chemically in the laboratory to produce drugs not found in nature. Most of these drugs are derived from plants by extracting the active ingredients from the plant, replicating its structure in the lab and mass producing it.

Herbal medicines have three main advantages over synthetic drugs.

1) Their long term use already indicates that they provide a high degree of safety and efficacy for human consumption.

2) Plant materials are less costly to prepare.

3) With medicinal plants, there is a reduced incidence of adverse drug interaction which is common to most therapies using synthetic drugs.

Herbal drugs are considered less potent than prescribed medicines. Drugs contain one highly active ingredient while herbs may have several active ingredients that are chemically similar. Herbal ingredients work synergistically to contribute to the therapeutic effect of each individual ingredient.

Herbalism

Herbalism which is healing with plants is sometimes considered as a collection of home-made remedies to be applied to one symptom or another provided the ailment is not too serious. However, we often forget that herbal medicine provides a good system of healing and prevention of disease. It is the oldest and most natural form of medicine. When skillfully applied, herbal medicine offers very real and permanent solutions to very real problems. Herbalism should not be confused with Traditional medicine. Nowhere is the efficacy of herbalism more evident than in problems related to the nervous system. Stress, anxiety, tension, and depression are intimately connected with most illnesses. Because they are organic substances and not man-made synthetic molecules, they possess a natural affinity for the human organism. They are extremely efficient in balancing the nervous system, restoring a sense of well-being and relaxation is necessary for optimum health and for the process of self-healing.

Rather than using a whole plant, pharmacologists identify, isolate, extract and synthesize individual components, thus capturing the active properties. However, in addition to active ingredients, plants contain minerals, vitamins, volatile oils, glycosides, alkaloids, bioflavonoids and other substances that are important in supporting a particular herbs’ medicinal properties. These elements also provide an important natural safeguard. Isolated or synthesized active compounds can become toxic in relatively small doses; it usually takes a much greater amount of a whole herb, with all of its components to reach a toxic level.

What is a mental disorder?

According to the diagnostic and Statistical Manual of Mental Disorders-Fourth Edition, a mental disorder is any clinically significant behavioural or psychological syndrome characterised by the presence of distressing symptoms, impairments of functioning, a significantly increased risk of suffering death, pain, disability or loss of freedom.

Mental disorders are assumed to be the manifestation of behavioural or psychological dysfunction in the individual.

Types of mental disorders.

There are many different conditions that are recognized as mental illnesses. The more common types include;

Anxiety disorders: Responding to certain objects or situations with fear and dread, as well as with physical signs of anxiety and nervousness. They include panic disorder, social anxiety disorder and specific phobias

Mood disorders: Involve persistent feelings of sadness or periods of feeling too happy or fluctuation from extreme happiness to extreme sadness. Examples are mania and bipolar disorder.

Psychotic disorders: Involve distorted awareness and thinking. Symptoms include hallucinations and delusions e.g. schizophrenia.

Eating disorders: Involve extreme emotions, attitudes and behaviours involving weight and food e.g. anorexia nervosa, bulimia nervosa.

Impulse control and addiction disorders: Involve the inability to resist urges or impulses to perform acts that could be harmful to themselves and others e.g. pyromania (starting fires), kleptomania (stealing).

Personality disorders: Involve extreme and inflexible personality traits that are distressing to the person and/or problems in work, school or social relationships.

Some other very common illnesses include epilepsy , coma, dizziness, migraines, neurosis, amnesia, neuralgia.

Causes of mental illness

Although the exact cause of most mental illnesses is not known, it is becoming clear through research that many of these conditions are caused by a combination of biological, psychological and environmental factors;

i) Biological factors: Some mental illnesses have been linked to an abnormal balance of special chemicals in the brain called neurotransmitters. Neurotransmitters help nerve cells in the brain communicate with each other. If these chemicals are out of balance or are not working properly, messages may not make it through the brain correctly, leading to symptoms of mental illness. In addition, defects in or injury to certain areas of the brain have also been linked to some mental conditions. Other biological factors that may be involved in the development of mental illness include;

• Genetics: Susceptibility can be passed on in families through genes.
• Infections: Certain infections have been linked to brain damage
• Brain defects or injury: Defects in or injury to certain areas of the brain have been linked to some mental illness.
• Prenatal damage: Disruption of early fetal brain development or trauma that occurs at time of birth.
• Poor nutrition and exposure to toxins such as lead.

ii) Psychological factors:

• Severe psychological trauma suffered as a child, such as emotional, physical or sexual abuse.
• An important early loss, such as the loss of a parent
• Neglect
• Poor ability to relate to others.

iii) Environmental factors

• Death or divorce
• Living in poverty
• Feelings of inadequacy, low self-esteem, anxiety, anger or loneliness
• Changing jobs or schools
• Social or cultural expectations

Sometimes, mental problems may come as a result of excessive smoking of things like marijuana, tobacco, Indian hemp and many others.

Symptoms of mental disorders

Symptoms vary depending on the type and severity of the condition. They may also vary depending on the age group. Some general symptoms include:

In adults:

• Confused thinking
• Long-lasting sadness or irritability
• Excessive fear, worry or anxiety.
• Dramatic changes in eating or sleeping habits.
• Strong feelings of anger
• Delusions and hallucinations (seeing or hearing things that are not really there)
• Increase inability to cope with daily problems and activities
• Many unexplained physical problems
• Thoughts of suicide
• Denial of obvious problems

In older children and pre-teens

• Changes in sleeping and eating disorders
• Excessive complaints of physical problems.
• Intense fear of gaining weight
• Drug abuse and/or alcohol
• Frequent outbursts of anger
• Defying authority, skipping school, stealing or damaging property.

In younger children

• Changes in school performance
• Excessive worry or anxiety
• Persistent nightmares
• Persistent disobedience
• Hyperactivity

Classification of some medicinal plants used to treat mental disorders

Scientific name	Common name	Part of plant used	Major constituents	Diseases/uses	Side effects
Bocopa monnieri	Brahmi	Alcoholic extract of plant	Saponins, bacoside A, bacoside B, monnierin, hersoponin	Improvement of intelligence and memory Revitalizing of sense organs
Centella asiatica	Mandukoparni	Fresh leaves	Triterpenoid soponins, madecassides and asiaticoside and their aglycons Asiatic acid and madessic acid	Amnesia, hysteria, improves memory	Contact dermatitis
Valeriana officinalis	Valerian	Rhizomes	Volatile oil which includes valerianic acid, volatile alkaloids including chantinine and iridoids (valepotriates)	Tranquilizer, induces sleep and relieves anxiety	Gastrointestinal upset, contact allergies, headache, restless-sleep.
Withania somnifera	Ashwagandha	Roots, leaves		General debility, nervous exhaustion, brain-fatigue, andtidepressant, mood stabilizer
Piper methysticum	Kava	Water extracts	Kavapyrones Kavalactones	Antianxiety Sleeping pills	Oral and lingual dyskinesia, torticollis, painful twisting movements of the trunk, oculogyric crisis, increases Parkinson’s disease
Gingko biloba	Gingko	Leaves	Flavonoids, Terpenes	Fatigue, anxiety, depression, increases cerebral blood flow, Alzheimer’s disease	Headache, allergic, skin reactions, gastrointestinal upset
Panax ginseng	Ginseng			Maintains emotional balance, improves some aspects of mental function	Breast tenderness, postmenopausal, vaginal bleeding, menstrual abnormalities
Leonurus cardiaca	Motherwort			Increases blood circulation in the brain, anxiety, sleep, disorders, prevent melancholy	Diarrhoea, uterine bleeding, stomach, irritation.

Other herbs used in treatment of mental disorders include;

Platago asiatica, Scruphularia ningpoensis, Ilex pubescens which are traditional Chinese medicines prescribed for treating depression like ailments

Passiflora incarnata, Evolvulus alsinide, Scutellaria lateriflora are studied for their activity against irritation of the brain, nervousness, restlessness, sleeplessness.

Humulus lupulus, Convolvulus pluricaulis are considered for their activity against mild to moderate anxiety.

Celastrusa paniculatus, Acorus calamus, Piper longum are claimed as brain tonics.

Essential oils can be used in aromatherapy room diffuser to reduce depression and anxiety. The oils like that of Citrus bergamia (Bergamot), Juniperus virginiana (cedar wood), Anthemis nobilis (chamomile), Lavendula officinalis (lavender), Citrus lemon (lemon), Rosa centifolia (Rose), Santalum album (sandal wood) are mainly used in treatment of mild to severe depression, anxiety and stress. These oils are mainly used in the form of inhalation, bath, massage or steam treatments. However, their use is limited to external application. Some of them like Bergamot oil may cause phototoxicity, while others like lavender oil may result in skin irritation and rashes. Some like cedar wood oil and chamomile oil are restricted during pregnancy.

Even the layman can do much to reduce stress and sooth frayed nerves. Drinking chamomile , lemon balm or linden tea is preferable to coffee for anyone having sleeping difficulties or anyone who wishes to have a greater sense of inner calmness. Twenty minutes out-of-breath exercise (walking, swimming or cycling) will go a long way as a natural antidote to the tension that results from a stressful day at the office, and it will have the unexpected bonus of improving circulation, increasing metabolic rate and enhancing heart and liver function which are all associated with the nervous system.

The B-vitamins as found in whole-wheat bread, wheat germ, brewer’s yeast and liver (organically produced) provide ideal nourishment for the nervous system and can be wisely substituted for the stimulant foods such as white flour, sugar, junk foods and their harmful chemical additives.

Methods of preparation of medicinal plant extracts

Medicinal plants can be prepared in many different ways depending on the part of the plant being used, the illness being treated and the major constituents of the plant. Some methods used in preparing medicinal plants for use include;

1) Tinctures: They contain alcohol. In a tincture, alcohol is employed to extract and concentrate the active properties of the herb. Alcohol is also a very effective natural preservative. Because a tincture is easily assimilated in the body, it is a very effective way to administer herbal compounds. The full taste of the herb comes through very strongly in a tincture. Children and adults too may find the taste of some herbs unpleasant. Goldenseal for example is bitter-tasting

In order lesson, the amount of alcohol in a tincture, mix the appropriate dose with one -quarter cup of very hot water. After about five minutes, most of the taste of the alcohol will have evaporated.

2) Extracts: Extracts can be made with alcohol, like tinctures, or the essence of the herb can be leached out with water. Extracts offer essentially the same advantages and disadvantages that tinctures do. They are the most concentrated form of herbal treatment and therefore the most cost-effective. They are easy to administer, but have a strong herbal taste.

3) Capsules and tablets: They contain a ground or powdered form of raw herbs. In general, there are little differences between the two in terms of clinical results. Because finely milled herbs degrade quickly, it is important that herbs be freshly ground and then promptly encapsulated or tableted, within twenty four hours of being powdered. With the exception of certain herbal concentrates in capsule from, both capsules and tablets tend to be much less strong and potent than tinctures and extracts.

4) Decoctions: This involves boiling the plant parts in water for about 15-20 minutes

5) Infusions: Infusions make use of dried or fresh herbs in boiled water.

6) Pills: The dried and powdered drug is mixed thoroughly with honey and cooked.

7) Syrups: Cane sugar is dissolved in boiling water and the decoction fluid is added .

Poultice or paste: The plant material is ground with little oil, water and honey.

9) Juices: The fresh plant material is pounded, filtered and then squeezed to extract the juice.

Toxic effects of medicinal plants

Over the past decade, there have been certain cases of adverse effects produced by these plants which are sometimes life threatening. These toxic effects may come as a result of contamination with excessive use of banned pesticides during treatment and collection of plant materials, microbial contamination, heavy metals, chemical toxins. Chemical toxins may come from unfavourable or wrong storage conditions or chemical treatment due to storage.

Toxic effects may also come as a result of unprofessional practice of the manufacturer. Since plants contain many active ingredients, if not used properly, they can provoke adverse reactions.

CHAPTER TWO

EXPERIMENTAL

CASE STUDY: Bombe Health Centre for Mental Problems and other Chronic

Illnesses.

This is a centre run by Dr. Zack Maghang who is responsible for the treatment of people suffering from mental problems and other chronic diseases. He keeps his mental patients in a house which is divided into different sections depending on the intensity of the problem. Those whose cases are chronic are usually chained since they are very aggressive and dangerous while those with milder cases are kept in different rooms.

Treatment

Generally, treatment here is the same for all the patients irrespective of the cause of the illness and the intensity. The only thing that varies is the duration of treatment. If a patient is brought to the centre as soon as the problem starts, he can be treated within a week.

When a patient is first brought to the centre, he is given some snuff-like medicine to inhale. The purpose of this is to clear the patients brain. After a period of about 2 hours, the patient is administered some droplets through the nose in order that all the liquid in the patients head goes out. This liquid leaves through both the mouth and the nostrils. This calms down the patient and he is then allowed to sleep. The following morning , as soon as the patient wakes up, his hair is shaved to let it cool. Some leaves are boiled in water and then used to bath the patient. The patient is rubbed with some medicinal oil which is made up of a mixture of palm oil and some medicinal plant. This process is carried out every morning. The essence of this is just to let the patient to be conscious of the fact that he must take a bath every morning.

The patient is then given malaria and typhoid drugs alongside the other drugs that are being administered. The malaria medicine is prepared using tree bark and it is boiled with some other leaves. The patient receives this medicine in the morning while he is given a valium-like medication in the evening to allow the patient to sleep. This treatment goes on daily till the patient recovers.

Sometimes, these patients have nightmares and are unable to sleep. In this case, some dried leaves are burnt to produce incense. This causes them to sleep very well. The medications given to the patients are usually given through the ears, the eyes, the nose or the mouth. This is the ensure that when the patient recovers, he regains all his senses. This is because when the brain is affected, the various senses could also be affected. When a patient starts complaining of body pains and aches it implies that the patient is recovering. While the patients are receiving treatment, they are being taken care of by their relatives who provide food and clothing . sometimes, those who have recovered and are able to reason help in taking care of the others. When not treated at the early stage, like any other illness, it becomes chronic and more difficult to treat.

CHAPTER THREE

RESULTS

Analysis show that the majority of mad people are women. Women are the weaker sex and are generally less resistant to pain than men. When a woman undergoes a lot of stress or pain, the probability of having mental problems is greater than in men who are more resistant. An example is during child birth.

Results have shown that these medicinal plants are very effective in the treatment of mental problems because they are less toxic and have not produced any cases of death so far. All the patients receiving this treatment have been able to regain consciousness. Also, it is worth mentioning that when the patients are recovering, they are able to tell what led to the madness and sometimes they are able to tell at what time and place, though most of them feel very ashamed after recovery.

In cases where the problem was as a result of excessive smoking, most of the patients after recovery still desire going back to continue with the smoking.

Conclusion

Some of the most common causes of mental disorders are excessive smoking and drug abuse and the teenage age group are more exposed to these problems since most of these activities are carried out by teenagers.

As soon as it is discovered that an individual is showing any of the symptoms mentioned, he should immediately be taken for check up. This reduces the risk of the person’s situation becoming chronic and more difficult to treat.

Recommendations

There is need for a rigorous study of various traditionally but not scientifically proven herbs at the pre-clinical and clinical levels.

The environmental related factors can be controlled by implementing standard operating procedures which will lead to good agricultural practice, good laboratory practice, good supply practice and good manufacturing practice for producing these medicinal products from their natural sources.

Since mental illnesses are diverse and individual patients are biochemically unique, a larger number of drugs will increase the probability of finding a beneficial medication

References

http://www.skepticsfiles.org/weird/nerveshr.htm

http://www.webmd.com/anxiety-panic/mental -health-causes-mental-illness

The illustrated Encyclopedia of Natural Remedies, Norman Shealey

A consumer’s guide to avoiding Drug Induced Death or Illness, Sidney M. Wolfe

Presented by Mbakwa Terence,

University of Buea

INTRODUCTION

1.1 Origin of Hypertension

The vascular system in animals ends up in arterioles and veins which supply and take blood to and from the individual tissues respectively. The normal flow of blood (pressure) in these vessels might be altered, being reduced (hypotension) or increased (to cause hypertension). Thus, hypertension is a disease of the vascular-system, particularly of the arterioles and veins. Hypertension could result from an increase in blood volume or an increase in cardiac output, and also from the resistance to blood flow caused by vaso constriction of veins and arterioles.

Hypertension or elevated blood pressure can result from a number of variable causes, which could be known or unknown. Depending on whether causes are known or unknown, hypertension can be divided into two:

1. Essential or primary hypertension which is hypertension originating from unknown causes, and accounts for 90 – 95% of all hypertensive cases. It occurs mostly in adults, at age of above 40 years.
2. Secondary hypertension which accounts for 5 – 10% of all hypertensive cases. By definition, it is hypertension that can be attributed to an identifiable cause; for example, renovascular disease which elevates blood pressure by activating the rennin-angiotensin – aldosterone system. It can also be caused by a variety of endocrine diseases (e.g. pheochromocytoma) and excessive secretion of adrenaline.

In essential hypertension, it does not follow that the lowering of blood pressure with drugs is thus accomplished by reversing the disease process that caused it. But, if blood pressure is lowered by any mechanism, great benefit result.

1.2 Problem Set

Hypertension in patients is of different varying degrees. By this, both primary and secondary hypertension can be classified by the degree of increased cardiovascular risk and the extent to which blood pressure is elevated.

In most patients, treatment of hypertension is a lifetime project to reduce cardiovascular risk. In some patients with marked elevated blood pressure, it is necessary to decrease blood pressure in hours or days. These uncommon situations are referred to as hypertensive emergencies or urgencies respectively. Blood pressure normally increases progressively over months or years. As such, an increase risk of cardiovascular disease develops gradually over the said period. Chronic hypertension then results from the resultant loss of vascular elasticity and compliance. Therapy in this condition requires a longer term control of blood pressure.

Hypertensive emergencies with larger increase in blood pressure pose an immediate life-threat on target organs such as the heart, aorta, brain, kidney etc. The pharmacotherapeutic objective here is to control blood pressure within minutes or hours. This can be achieved by quick intravenous drug administration, but carefully end in stages.

The degree of hypertension is based on the level of blood pressure.

Category	Systolic (mmHg	Diastolic (mmHg)	Stages
Normal	<130	<85	(moderate) 160-179 100-109
High-normal	130-139	85-89	Stage 5 (severe) 180-209 110-119
hypertension			Stage 4
Stage 1 (mild)	140-159		Very severe ≥210 ≥120

Table as presented by the Joint National Committee 1993.

OBJECTIVE

The aim for the treatment of hypertension is to reduce the cardiac output and blood volume, and also to reduce the peripheral and/or vascular resistance.

The primary sign of hypertension is high-blood pressure. Thus, the treatment of this sign itself, (by reducing it) is a primary objective in the treatment. This can be achieved by drugs whose mechanism of action is to alter;

v blood volume,

v cardiac output,

v peripheral resistance as well as vascular resistance

There is an expectation that a reduction of blood pressure will limit the development of subsequent organ pathology.

The tissue targets for antihypertensive drugs are:

v The sympathetic nerves, which release the vasoconstrictor, norepinephrine.

v The kidney, which regulates blood volume.

v The heart, which generate cardiac output

v The arterioles, which determine peripheral vascular resistance.

v The endothelial cells, which regulate circulating levels of the endogenous hypertensive and hypotensive agents, such as angiotensive II and nitric oxide, respectively.

v The central nervous system, (CNS) which senses the blood pressure and controls its set point by regulating some systems involved in blood pressure control.

2.0 CLASSES OF DRUGS FOR TREAMENT

2.1 Non – Drug Treatment

Though not dependent on drugs, non drug treatment is the first-choice therapy. Patients are advised to avoid activities that predispose to cardiovascular diseases and to do the following recommendations:

v To exercise,

v To reduce body weight, in case of overweight

v In some cases, to restrict dietary salt in take

v Stop smoking

v Restrict ethanol intake

v Treat lipoprotein disorders carefully

2.2 Drug Treatment Classes

Hypertension is a disease affecting targets that are controlled by the nervous system. As such, drugs that can act on the nervous system, whether sympathetic or parasympathetic are useful, in addition to others which may not affect the nervous system. Thus, the available classes of drug treatment include:

v Diuretic/Thiazides

v Sympatholytics

v Direct – acting vasodilators

v Calcium antagonists

v Renin-angiotensin cascade inhibitors (also with the angiotensin II receptor antagonists, losartan).

Essential hypertension is a process of variable causes, course and severity, with the treatment intensity being correspondingly variable. In contrast with the treatment of other diseases, the variation in the intensity of treatment is not achieved by simply increasing the dose of the drug(s) used. Rather, it can be achieved by stepwise addition of drugs as required to return blood pressure to normal. Different patients have specific needs, thus the drug addition will depend on the patient.

2.3 DIURETICS.

Diuretics are useful antihypertensive but their benefits may not be related to diuresis. Diuretic (and/or thiazides) are often used to initiate treatment invariably. Three types of diuretics are used in treating hypertension:

v Thiazides

v Loop diuretics

v Potassium – sparing agents

Though are all diuretics, their effects vary, since their hypotensive effects are not due to diuresis.

2.3.1 Thiazides/Thiazide Diuretics

Thiazides are relatively effective antihypertensives but are only moderately effective diuretics. The thiazides do not lower blood pressure in normotensive humans (humans with normal blood pressure) but will reduce blood pressure in patients with essential hypertension, to about 10% or even more. It has been suggested recently that diuretics (especially thiazides) may produce their effects in hypertension by modulating the activity of potassium ion (K⁺) channels.

The ATP – regulated K⁺ channels in resistance – arterioles may be activated by thiazides. This molecular action leads to membrane hyperpolarization, which opposes smooth muscle Ca²⁺-entry and contraction and, at the system level, reduces peripheral vascular resistance.

Thiazide diuretics (e.g bendrofluazide and hydrochlorothiazide (HCT)), and thiazide – like drugs which are sulfonamide derivative such as chlorthalidone are actively transported by a probenecid – sensitive secretary mechanism into the proximal renal tubule. As diuretic, this group of agents acts on the luminal membrane of the cortical dilating segment of the distal convuluted tubule, to bring about a reduction in blood pressure. Thiazides may cause male sexual dysfunction and an increase in sodium ion (Na⁺) concentration in the distal convuluted tubule which impairs K⁺ absorption, (leading to an increase in K⁺ excretion), called kaliuresis and possibly hyperkalemia.

The potassium – sparing diuretics may be used to avoid hyperkalemia. This group of drugs act at the cortical collecting duct, to alter the exchange of Na⁺/K⁺ and H⁺ as controlled by endogenous aldosterone.

2.3.2 Thiazide diuretics in combination with other drugs

The administration of a thiazide on its own causes only a slight decrease (about 10%) in blood pressure. Their effect is boosted when they are administered with another hypertensive drug, possibly from amongst drugs discussed here below. With this combination, the thiazide acts to reduce the amount of the potent drug necessary.

3 SYMPATHOLYTICS

These are a heterogeneous group of antihypertensive drugs that have a variety of actions in the cardiovascular system. The activity of the sympathetic nervous system plays a pivotal rule in acute regulation of blood pressure. The sympatholytic drugs act by inhibiting one or more component of this activity. This system mechanism can be achieved in a variety of different ways:

v Action on the vasomotor center in the brain to reduce the sympathetic system tone, centrally.

v Peripheral action on adrenergic neurotransmission at pre- or postsynaptic sites or on receptors activated by circulating epinephrine and neurally released norepinephrine.

Most sympatholytic agents posses both direct and indirect tissue mechanism of action, since they may directly affect nervous tissue function. Other drugs such as β adrenoceptor antagonists act directly on norepinephrine and epinephrine receptors in the cardiovascular system.

v The selective sympatholytics are used recently. The noneselective are rarely used because of their adverse effects.

3.1 Beta (β) Adrenoceptor Antagonists

These are the second most widely used antihypertensives; The mechanism of action of these drugs as a class, in the treatment of essential hypertension is not known, for certainty. But with each, the molecular and tissue effects and benefits will depend upon specific properties of the drug.

v The molecular mechanism of action is generally regarded to be competitive antagonism of adrenoceptors, although β adrenoceptor antagonism may also contribute to the benefit achieved with some drugs.

v The cellular mechanism is not known in general but known for β₁ and β₂ antagonists.

v The tissue mechanism is likewise unclear. β adrenoceptor antagonists may act in the central nervous system (CNS) to reduce sympatholytic tone, in the heart to reduce heart rate and cardiac output and in the kidney to reduce rennin production. They commonly reduce peripheral resistance, but it is not clear how the effect occurs.

3.1.1 β₁ Adrenoceptor Antagonists e.g Atenolol and metoprolol

Historically, the β₁ adroneceptor antagonists have been described as ‘cardioselectives, although these agents will affect any tissue that expresses β₁ adrenoceptors. The β₁ adrenoceptor antagonists antagonize the effects of norepinephrine and ephinephrine on heart rate. They have a less effect on the airway which also posses or express β₁ adrenoceptors. Nonetheless, β₁ and β₂ selectivity is only relative. Thus, these drugs are not safe enough for patients with asthma, except under special circumstances (when no other antihypertensive is tolerated but some form of drug therapy is essential).

3.1.2 β₁ Adrenoceptor partial agonist: e.g. pindolol

Some partial agonists of β₁ adrenoceptors are used in the treatment of hypertension (e.g. pindolol). These drugs inhibit excess β₁ adrenoceptor activity during sympathetic hyperactivity, but achieve an overall β₁ agonist effect when sympathetic tone is low. Historically, these drugs have been described as β₁ blockers with intrinsic sympathomimetic activity. However, this description is not precise as the agents are quite specifically partial agonists. They reduce blood pressure to a similar degree as β₁ adrenoceptor antagonists, but evoke less reduction in resting heart rate.

3.2 ₁ Adrenoceptor antagonists

Prazosin was the first selective agent with the molecular mechanism of postsynaptic ₁ adrenoceptor antagonism. Prazosin and newer drug analogues such as terazosin and doxazosin act directly on the effector component of the sympathetic neuroeffector junction, namely ₁ adrenoceptors. They are expressed in abundance in arteriole resistance – vessels where they mediate a vasoconstrictor tone. The tissue mechanism of ₁ adrenoceptor antagonists is therefore the inhibition of this tone. Norepinephrine normally limits its own neural release by acting on presynaptic ₂ receptors (negative feedback).

Drugs that block ₂ receptors therefore tend to increase norepinephrine release from the sympathetic nerve terminals. Unrestricted norepinephrine release in the heart causes excess stimulation of postsynaptic β₁ adrenoceptors and tarchyardia. Consequently, nonselective  (₁ and ₂) antagonists are not useful antihypertensives. Because prazosin has selectivity for ₁ receptors, the negative feedback mechanism remains in tact. This means that the drug’s therapeutic effectiveness is not compromised by tarchycardia.

3.3 ₂ Adrenoceptor agonists: E.g Clonidine;

Centrally acting ₂ adrenoceptor agonists such as clonidine and  – methyldopa mimic the autoinhibitory effects of norepinephrine on sympathetic activity without producing sympathomimetic effects. This is due to their relative selectivity for ₂-receptors. The mechanisms of action are as follows:

v The molecular mechanism of action is ₂ adrenoceptor agonism.

v The direct tissue mechanism of action is reduction in the activity of the vasomotor center in the brain, leading to a fall in sympathetic nervous activity. This leads to a secondary tissue mechanism of action; a reduction in peripheral resistance as a result of arteriolar relaxation.

Clonidine is a widely used ₂ agonist whereas -methyldopa is a pro-drug which is metabolized via a two-step enzymatic process in the CNS to -methylnorepinephrine which is an ₂ agonist. In the CNS, -methylnorepinephrine stimulates the vasopressor centers in the brainstem, which results in a reduction of sympathetic outflow. Renal blood flow is well maintained with -methyldopa. As such, it has been widely used in hypertensive patients with renal insufficiency or, cerebrovascular disease. -methyldopa is also recommended in hypertensive pregnant women because it has no adverse effect on fetus, despite crossing the blood-placenta barrier.

It should be noted that this class of drug is generally not preferred for the treatment of hypertension.

3.4 Reserpine

Reserpine has adrenergic neuron blocking actions resulting in arteriolar vasodilation and a reduced cardiac output. Though being a reduced-hypotensive drug on its own, reserpine is extremely useful in combination with a thiazide diuretic or a postural hypotensive agent.

Reserpine is an alkaloid of the genus Rauwolfia and is usually purified from snakeroot, most often, from Rauwolfia (Serpentine rauwolfia).

3.4.1: Mechanism of action

Reserpine is transported into peripheral sympathetic nerve terminals by uptake (which is the same mechanism of norepinephrine reuptake into nerves) and its mechanism of action are as follows:

v Its molecular mechanism of action is inhibition of the norepinephrine pump (an-ATP- and Mg²⁺- dependent uptake molecule) located on the storage vesicles for norepinephrine in the neural cytoplasm

v Its cellular mechanism of action is a reduction of the norepinephrine (and other amines) content of neuronal storage vesicles, which can also be regarded as amine depletion from storage vesicles. These storage vesicles are often within sympathetic nerves, blood vessels and the hypothalamus in the brain. The depletion of the amines from the storage sites implies an initial rise in the circulation of these amines.

v Its direct tissue mechanism of action is a reduction of the nerve action potential – mediated release of norepinephrine from sympathetic nerve terminals.

v Its indirect tissue mechanism of action is arteriolar vasodilation and reduced cardiac output.

3.6 Guanethidine:

Guanethidine and related guanethidine compounds including guanadrel, bethanidine, and dibrasoquin are, like reserpine, transported into peripheral sympathetic nerve terminals by uptake. However, their molecular and cellular mechanisms of action differ from those of reserpine. Two molecular and cellular mechanisms act in parallel to reduce the activity of the sympathetic nervous system.

3.6.1 Mechanism of action

v One molecular mechanism is competition with norepinephrine for the intracellular norepinephrine pump. The drugs are actually taken up and stored in the adrenergic vesicles in preference to norepinephrine. They are said to act like false – transmitters since a stimulation of these nerves will result to their release, instead of norepinephrine. This is the associated molecular mechanism and the direct tissue mechanism of action is a reduction of nerve action potential – mediated release of norepinephrine from the sympathetic nerve terminals.

v The second molecular mechanism is binding to the inner surface of the neurolemma. The associated cellular mechanism is the reduction of fusion between storage vesicles and the neurolemma, known as the true “adrenergic neuron blocking” action. The associated tissue mechanism of action is a reduction of nerve action potential – mediated release of norepinephrine from sympathetic nerve terminals. The tissue mechanism is a reduction in cardiac output as a result of a reduction in heart rate.

There are two consequences that result from the common path way used by the uptake of Guanethidine as well as reserpine and the reentry of norepinephrine.

1. Sympathomimetics agent such as ephedrine, phenoxybenzamine, cocain, and antipsychotics that block the reentry of norepinephrine can prevent or reserve the action of Guanethidine and reserpine.
2. A transient initial sympathometic effect arises following the blockage of norepinephine by guanethidine. This effect is often apparent in humans after intravenous administration.

Both Guanethidine and reserpine analogs share two common adverse effects:

v Postural hypotension which is a sudden fall in blood pressure on suddenly standing up. It results from a loss of sympathetic mediated reflex. There is also venous pooling of blood in the lower limb, and a fall in cardiac output which may cause fainting.

v A generalized block of sympathetic neurotransmission. The existence of these adverse effects and newer safer drugs has led to the use of Guanethidine only in patients with severe hypertension, who are unresponsive to other drugs.

3.7 Calcium channel blockers (CCB).

The ca²⁺ antagonists are increasingly being used in the treatment of hypertension. These drugs fall into three main groups, based on their chemical structure, with two mentioned here.

3.7.1: The 1, 4 – dihydropyridines, nifedipine, nicardipine and amlodipine are the most vascular – selective group and most effective antihypertensive ca²⁺ channel blockers (or antagonists). Nifedipine however is a slow CCB that also inhibits and binds to intracellular calcium binding proteins.

3.7.2: The phenethylakylamine, verapamil, and the benzothiazepine, are less vascular selective and may also affect the arteroventricular (AV) node, causing AV block. They are therefore associated with cardiac conduction problems especially when given with B₁ adrenoceptor antagonists.

Elderly hypertensive patients respond well to CCB. However, people of African origin are less responsive. The CCB have a rapid onset of action and reduce blood pressure within half an hour after administration. They reduce muscle tension in arteries, expanding them and creating more room for flow. They also relax the heart muscles.

It should be noted that, despite their ability to control hypertension, there is growing awareness that ca²⁺ antagonists may actually increase mortality in patients with hypertension. The mechanism by which this occurs is not known.

4 DIRECT – ACTING VASODILATORS

Agents that dilate arterioles by a molecular mechanism that is not ₁ adrenoceptor antagonism or L-type ca²⁺ channel blockage are called direct acting vasodilators. These agents are increasingly being used in the treatment of hypertension. An example is Hydralazine.

4.1 Hydralazine

Hydralazine is the only direct-acting vasodilator in treating mild to moderate hypertension, usually as a second – or third – line drug. It is also still used as a parenteral treatment in hypertensive emergencies and in hypertensive pregnant women, because of a long safety record in this setting.

Mechanism of action

The molecular and cellular mechanisms of action are to increase cyclic Guanine monophosphate (cGMP) following activation of guanylyl cyclase, resulting in relaxation of smooth muscle in precapillary resistance-vessels. This thus leads to a reduction in blood pressure due to a reduction in peripheral resistance.

4.2 Minoxidil

Minoxidil is highly effective in reducing blood pressure, especially in severe hypertension and also when there is renal failure. This drug is more effective than hydralazine and produces dilation of resistance – vessels. It works at the molecular level by activating ATP- sensitive potassium (K⁺) channels leading to the hyperpolarisation of smooth muscle sarcolemma. The ca^{2+ _} influx via the L-type ca²⁺ channels is subsequently reduced. Like hydralazine, it should be given in combination with diuretics and adrenoceptor antagonists, to prevent reflex increase in cardiac output and fluid retention which may be profound in some patients. A common adverse effect of minodixil is facial hair growth, which limits the use of this drug in women but has resulted in its use to treat male pattern baldness.

5 The Angiotention converting Enzyme (ACE) Inhibitors / Antagonists.

The Angiotensins are peptides found in humans, with angiotensin I being an inactive decapeptide which is converted into the active octapeptide, Angiotensin II. This conversion is done by the Angiotensin converting enzyme (ACE).The effects of Angiotensin II are numerous, all of which contribute to elevating blood pressure. It constricts arterioles and stimulates aldosterone release from the adrenal cortex; in turn, aldosterone stimulates Na⁺ re-absorption in the kidney.

Thus, the use of ACE inhibitors to block the ACE activities will lead to a reduction in blood pressure. The use of Angiotensin II receptor antagonists will also result to a reduction in blood pressure.

5.1 Mechanism of action

The ACE inhibitors have the following mechanisms of action:

v The molecular mechanism of action is the inhibition of the ACE activity, by direct blockade.

v The resultant cellular Mechanism of action is a reduced Angiotensin II synthesis and reduced metabolism of some vasodilating kinins e.g Braddykinin.

ACE inhibitors are useful for all types and severity of hypertension, and are widely used. They reduce mortality and are classified into chemical classes depending on whether they contain phosphinyl, carboxyl or sulfhydryl moieties. An example of an ACE inhibitor that contains the sulfhydryl moity is captopril. It causes vasodilation and reduces Na⁺ retention.

Other ACE inhibitors which are commonly used include; lisinoprie which is the most commonly used ACE inhibitor in the USA, enalapril and benazepril. These drugs contain the carboxyl moiety. These have slower onset and longer duration of action compared to captopril. The inhibitor fosinopril has the phosphinyl moiety.

The tissue respond to ACE inhibitors include:

v A reduction in peripheral resistance with little change in heart rate or cardiac output.

v A reduction in Na⁺ retention, secondary to altered aldosterone levels.

6.0 OTHER ASPECTS

6.1 COMBINATION TREATMENT

Useful in the pharmacotherapy approach of controlling elevated blood pressure is the combination of two or more drugs.

It should be noted that the diuretics are often used invariably to treat or initiate treatment of hypertension. As such, they are suitable for combination with most drugs to enhance control/treatment. The adrenoceptor antagonists/-diuretic combination is the most common.

With the diuretics aside, other combinations can still hold; the β adrenoceptor antagonists and the Ca²⁺ antagonists (dihydropyridine Ca²⁺ antagonists only) are usually well tolerated, provided they are combined in right dosage.

Note should be taken in that the β₁ antagonists in combination with nondihydropyridine Ca²⁺ antagonists is dangerous. An example of such drug is verapamil. It has been noticed that this combination causes asystole, severe bradycardia and hypotension.

6.2 Drugs in Progress

Renin inhibitors are a new class of drugs that reduce angiotensin II levels. Several rennin inhibitors have been developed with high potency and long duration of action. However, the oral bioavailability of currently available agents is too slow to achieve effective plasma concentrations in humans.

6.3 Treatment for hypertensive emergencies

Hypertensive emergencies are the results of extensive and acute damage of hypertension on some target organs. This condition puts the patient’s life in great danger, and no particular level of blood pressure provides the diagnosis, but only dependent on the clinical presentation. An example of hypertensive emergency is pulmonary edema.

An example of a drug that can be used in the treatment of hypertensive emergencies is sodium nitroprusside which is a directly acting vasodilator, and is administered intravenously. It has a rapid onset of action and efficiency. This drug can cause an abrupt fall in blood pressure. Thus, it is important to monitor the blood pressure constantly.

7. CONCLUSION

Drug treatment of essential hypertension has gone a long way in relieving pain in patients with this illness. The level of relief will vary between individuals and with the class of drug used. If a class of a drug does not act well in a patient, then, the drug has to be switched to another drug. Care and precaution should be taken in switching as individual drugs have certain steps to follow before switching is done. The degree of hypertension varies from mild through moderate to hypertensive emergencies. There are classes of drugs that best fit with each condition. In cases where it might be necessary, combination treatment is recommended in order to achieve a greater effect of the drugs.

Reference

Curtis sutter, Walter, Hoffmann: Integrated pharmacology, 2^nd edition, 2004.

F.H meyers, Jawltz, Goldfien: Review of medical pharmacology, 6^th edition, 1978.

Google Images http://images.google.com

PRESENTED BY: CHE ELVIS

ABSTRACT

The Nervous system contains millions of neurons that transmit impulses through out the body in fractions of seconds.

There are different types of neurons and a variety of neurotransmitters are produced at the pre-synaptic end of the neurons.

This neurotransmitters are released in the synapse in response to potential or stimulus.

They bind to receptors and elicit biologic responses at the post synaptic neurons.

Termination of action is by removal of neurotransmitter from synapse.

The process however seems but not necessarily occurs so easily. The slightest modification results in disease condition. A handful of them will be discoursed in this document as well as a remedy for some of them

Also, some substances are neurotoxic due to structural similarity with neurotransmitters.

In this document most chemical neurotransmitters will be touched but the major emphasis on disease will be the Glutamate transporters.

TABLE OF CONTENT

Abstract……………………………….……………………………………………………i

Table of content …………………………………………………………………………..ii

Chapter 1 General introduction

1.1 Basic definitions……………………………………………………………1

1.2 Brief review of the nervous system…………………………………………2

1.3 Neurons and their functions………………………………………………..2

1.4 Types of neurotransmitters………………………………………………….3

Chapter 2 Chemical Neurotransmission Steps

Schematic illustration of a synapse………………………………………….……4

2.1 Synthesis of neurotransmitter………………………………………….……5

2.2 Storage in synaptic vesicles………………………………………….……..5

2.3 Release of neurotransmitter………………………………………….……..5

2.4 Binding to the receptor………………………………………………….….5

2.5 Elicidation of biological response………………………………………….5

2.6 Termination of action……………………………………………………….5

Chapter 3 Neurotoxicity and disease

3.1 Alzheimer’s disease…………………………………………………………..6

3.2 Huntington’s disease…………………………………………………………6

3.3 Parkinson’s disease………………………………………………………….7

3.4 Epilepsy……………………………………………………………………..7

3.5 Cerebral ischemia……………………………………………………………8

3.6 Other neurological disorders…………………………………………………8

3.7 Neurotoxicity by other substances………………………………………….8

Chapter 4 Health

4.1 Reversal of transporter actions…………………………………………….10

4.2 Treatment of neurological disorders………………………………………..11

4.3 Treatment of poisoning with antidotes…………………………………….11

Chapter 5 Conclusion……………………………………………………….12

References

CHAPTER 1

GENERAL INTRODUCTION

1.1 BASIC DEFINITIONS

Health: Can be defined as soundness of any living organism

Disease: Disturbed or abnormal structure or physiological action in the living organism as a whole, or in any of its parts

Neurotransmission (or synaptic transmission) is communication between neurons as accomplished by the movement of chemicals or electrical signals across a synapse.

Neurones a neurone is a nerve cell; it has a cell body, a very long axon sheathed in myelin, and many tiny branches called dendrites. There are three kinds of neurones: sensory, intermediate and motor neurones.

Axons: these are long cytoplasmic tubes, they carry electric impulses from one part of the body to another. They are insulated from each other by their myelin sheathes.

Dendrites: these are tiny branches on the cell body and at the ends of all neurones. The dendrites of one cell do not actually touch the dendrites of any other cell. There are very tiny gaps between them called synapses.

Synapses: these are the gaps between the dendrites of one neurone and the cell body of another one. There is no electrical connection between nerve cells. when one neurone stimulates another it does so by secreting a chemical into the synapse. Many drugs work by interfering with these chemical transmitters

1.2 BRIEF REVIEW OF THE NERVOUS SYSTEM

The nervous system is concerned primarily with the reception of stimuli, transmission of impulse, interpretation of sensation and intergration of sensory information arising from within or out of the body.

It is organized into the central nervous system (CNS) and the Peripheral nervous system (PNS)

CNS consists of the brain and spinal cord. It contains millions of neurons and has white and gray matter

PNS consists of all the sensory nerves containing sensory neurons (this feed information into the spinal cord and brain) and motor nerves ( these carry messages to other parts of the body from the brain and spinal cord)

1.3 STRUCTURE AND FUNCTION OF NEURONES

The function of a neuron is to receive INPUT “information” from other neurons, to process that information, then to send “information” as OUTPUT to other neurons.

A “typical” neuron has four distinct parts (or regions). The first part is the cell body (or soma). This is not only the metabolic “control center” of the neuron, it is also its “manufacturing and recycling plant.” (For instance, it is within the cell body that neuronal proteins are synthesized.) The second and third parts are processes — structures that extend away from the cell body. Generally speaking, the function of a process is to be a conduit through which signals flow to or away from the cell body. Incoming signals from other neurons are (typically) received through its dendrites. The outgoing signal to other neurons flows along its axon. A neuron may have many thousands of dendrites, but it will have only one axon. The fourth distinct part of a neuron lies at the end of the axon, the axon terminals.

1.4 TYPES OF NEUROTRANSMITTERS

Acetylecholine	Choline	CNS, parasympathetic nerves
Serotonin 5-hydroxyphane (5-HT)	Tryptophane	CNS, chromatin cells of the gut, enteric cells
GABA	Glutamine	CNS
Glutamate		CNS
Aspartate		CNS
Glycine		Spinal cord
Histamine	Histidine	Hypothalamus
Epinephrine Synthesis pathway	Tyrosine	Adrenal medulla, some CNS cells
Norepinephrine Synthesis pathway	Tyrosine	CNS, sympatheic nerves
Dopamine	Tyrosine	CNS
Adenosine	ATP	CNS, peripheral nerves
ATP		Sympathetic, sensory, enteric nerves
Nitric oxide,NO	Arginine	CNS, gastrointestinal tract

CHAPTER 2

STEPS OF CHEMICAL NEUROTRANSMISSION

Schematic illustration of a synapse.

	Step 1. The neurotransmitter is manufactured by the neuron and stored in vesicles at the axon terminal.
	Step 2. When the action potential reaches the axon terminal, it causes the vesicles to release the neurotransmitter molecules into the synaptic cleft.
	Step 3. The neurotransmitter diffuses across the cleft and binds to receptors on the post-synaptic cell. Step 4. The activated receptors cause changes in the activity of the post-synaptic neuron.
	Step 5. The neurotransmitter molecules are released from the receptors and diffuse back into the synaptic cleft.
	Step 6. The Neurotransmitter is re-absorbed by the post synaptic neuron. This process is known as Reuptake.

CHAPTER 3

NEUROTOXICITY AND DISEASE

The general point of focus in this section will be the role of Glutamate transporters in neurodegenerative Diseases. How ever it is worth nothing that all transporters have diseases

3.1 ALZHEMER’S DISEASE (AD)

Glutamate toxicity plays a role in neurodegeneration in AD. Reduced glutamate transporter expression and uptake are associated with (AD). Experiments reveal the uptake is reduced in patients with AD.

3.2 HUNTINGTONS’ DISEASE (HD)

HG is a genetic disease arising from expansion of CAG codons for glutamine, resulting in a polyglutamine (PolyQ) of at least 30 residues in the protein Huntington. This mutation leads to deep cortical layers and degeneration of the striatum. The hippocampus and hypothalamus are also affected.

There are a variety of ways the mutant Huntington could result in neurodegeneration such as formation of protein aggregates, effects on endocytosis and exocytosis and interaction with other proteins.

Mutant Huntington with the poly Q expansion displays decreased binding to post synaptic density protein 95(PSD-95) , freeing PSD-95 to bind NMDA receptors to the cell surface, thereby stabilizing NMDA receptors and increasing receptor activation

In summary, mutant Huntington may decrease glutamate transporter levels, resulting in decreased glutamate uptake and exacerbating excitotoxicity

3.3 PARKINSON’S DISEASE (PD)

The hallmarks of PD are striking degeneration of dopaminergic nigrostriatal neurons and the presence of lewey bodies; the loss of nigrostriatal neurons leads to motor dysfunction including tremor rigidity and bradykinesia

One hypothesis is that the over activation of glutamate receptors on nigrostriatal neurons may contribute to excitotoxic death.

Drugs that increase glutamate uptake have beneficial effects in models of PD. NMDA antagonists provide short term protection after N-methyl-1,4-phenylpyridium administration in rat.

3.4 EPILEPSY

Epilepsy is a common neurologic disorder; by 20years of age, 1% of the population will have developed epilepsy, and the incidence increases to 3% by 75years of age.

In addition to perturbations to the GABA-ergic system, alterations in the glutamatergic system have been hypothesized to play a role in the development of seizures and epilepsy.

Studies have shown results suggesting that impaired glutamate homeostasis maybe a factor contributing to patient’s epilepsy (JEN, et al 2005)

In contrast to decreased levels of glutamate transporters, increased levels of glutamate transporters have also been described in animal models of epilepsy. Given that glutamate transporter knockout or knockdown leads to seizures, it seems likely that increases in glutamate transporters might represent a compensatory neuroprotective mechanism, rather than contribute to epileptogenesis.

3.5 CEREBRAL ISCHEMIA

Stroke is the third leading cause of death in the U.S, and the predominant type of stroke is cerebral ischema. There is reasonable evidence that glutamate-mediated excitotoxicity, imflammation, and cell death contribute to the neurodegeneration observed after death.

In humans that experience stroke, the concentration of glutamate in the plasma and cerebrospinal fluid is significantly elevated in patients with a large cerebral infarct. However, glutamate concentrations do no necessarily correlate with initial stroke severity, suggesting that there may be some glutamate susceptibility that is unique among individuals.

3.6 GLUTAMATE TRANPORTERS AND OTHER DISORDERS

Decreased levels of glutamate transporters seem to be a common observation in many neurodegenerative diseases. Nieman-Pick disease symptoms range from ataxia and dystomia to dementia, and are due to mutations in genes for proteins that affect intracellular transport of cholesterol leading to accumulation of cholesterol in the lysosomes, neural swelling and neural death.

Glutamate transporter dysfunction may also contribute to HIV-associated dementia (HAD). Transporter alterations have also been implicated in different models of CNS injury, psychiatric illnesses, including schizophrenia.

3.7 NEUROTOXICITY BY OTHER SUBSTANCES

Chronic dosing of isoniazid in experimental animals causes degeneration of the peripheral nerves. Peripheral neuropathy in man due to isoniazid in ma n is influenced by acetylator phenotype being predominantly found in slow acetylators.

6-Hdroxydopamine is a selectively neurotoxic compound which damages the sympathetic nerve endings this is due to structural similarity to dopamine and noradrenaline. It is thus actively taken up into the synaptic system along with other catecholamines. Once localized in the synapse it destroys the nerve terminal.

Neurotoxicity is also caused by neurotransmitter inhibition. For example the inhibition of cholinesterase, the enzyme responsible for hydrolyzing acetylcholine results in accumulation. The toxic effects can be divided into three types as the accumulation of acetylcholine leads to symptoms which mimic the muscarinic, nicotinic CNS actions of acetylcholine.

CHAPTER 4

HEALTH

4.1 REVERSAL OF TRANSPORTER ACTIONS

Studies have been carried out to investigate if treatment targeted towards up regulating glutamate transporters offer neuroprotection and if there are any possible deleterious side effects of over expression of glutamate transporters.

Excitatory neurotransmission at many CNS synapses depends upon AMPA-type glutamate receptors. Derangements in AMPA receptor-mediated synaptic transmission may be a contributing factor in neurological and neurodegenerative diseases and could be a target for therapeutic intervention. Drugs that positively modulate AMPA receptors by reducing AMPA receptor desensitization and/or slowing AMPA receptor deactivation, such as thiazide derivatives (cyclothiazide, diazoxide, IDRA 21) and benzoylpiperidine derivatives (1-BCP, CX516, aniracetam), facilitate AMPA receptor-mediated processes and may have beneficial therapeutic effects. For example, AMPA modulators facilitate long-term potentiation, which may be important for memory storage, and facilitate memory encoding in behavioral experiments. Thus, AMPA modulators might ameliorate memory deficits that occur in dementia, such as Alzheimer’s disease. However, AMPA receptor-mediated excitotoxicity may occur with excessive AMPA receptor activation such as in seizures or ischemia, and positive AMPA modulators would promote neuronal injury under those conditions. Regardless of the ultimate clinical utility of positive AMPA modulators, their discovery and study have already provided significant insight into the physiology and structural determinants of important AMPA receptor properties.

4.2 TREATMENT OF NEUROLOGICAL DISORDERS

Manipulations of glutamate transporters may have pharmacologic effects but it is very likely to t have some unwanted non specific side effects

Although treatment for AD designed to target glutamate glutamate for upregulation are not currently in use, one treatment option acts to decrease glutamergic activation of NMDA receptors. Memantine is an NMDA receptor partial antagonist and protects against glutamate-induced neurotoxicity without physiological activation of NMDA receptors, and has been shown to significantly reduce functional and cognitive decline in patients with AD.

It is therefore conceivable that treatment aimed at upregulating glutamate transporters could also have beneficial effects for AD patients by decreasing excitotoxicity

The major treatment of Parkinsons disease is L-3,4-Hydroxyphenyla mine (L-DOPA), to replace the progressive loss of dopamine; however repeated L- DOPA treatment leads to motor complications.

4.2 TREATMENT OF POISONING

Poisoning by organophosphorus compounds can be treated, and although the acute symptoms can be alleviated, the delayed neuropathy cannot.

1) The compound pralidoxine is administered in order to degenerate the acetycholinesterase. This forms a complex with the organophosphorus moiety.

Pralidoxime must be administered quickly as if the phosphorylated enzyme is allowed to age then it will no longer be an effective antidote.

2) The physiological effects of the accumulation of acetylcholine can be antagonized by the administration of atropine and the symptoms alleviated.

Atropine and pralidoxime have a synergistic effect and are usually taken together.

CHAPTER 5

CONCLUSION

So many conclusions can be drawn;

The neurotransmission process does not always occur so easily as expected.

The slightest change in a step leads to a disease condition.

Also there are many substances that are neurotoxic amd influence chemical neurotransmission either directly or indirectly.

REFERENCES

Richard S. Snell Clinical neuroanatomy for medical students 3^rd edition

J.A. Timbrell Principles Of Biochemical toxicity 2^nd edition

Donald Voet and Judith G. A Textbook of Biochemistry with clinical Relations

3^rd ed

Neil A Campbell, Biology 4^th edition year 1996 pg 994 to 996

PCH 362 notes of 2007/08 academic year in UB by Prof Efange

Neurobiology of Disease
Volume 5, Issue 2, August 1998, Pages 67-80

Neurotransmitters Dr. C. George Boere

Neurons, Synapses, Action Potentials, and Neurotransmission Neurons, synapse Action Potentials, and Neurotransmission by Robert Stufflebeam

Carlos G. Finlay and Michael R. Markham, Synaptic transmission in diagrams

Molecular and chemical neuroscience, vol 17 issue 5 Watanabe, Hiroshi Takeshima, Toshiya Manabe Masahiko

Standard dictionary of the English language volume one

Google image results for neurons

PRESENTED BY CHE ELVIS NKWENTI (ELVIZY)

www.elvizy.com

info@elvizy.com

elvizy@gmail.com

ABSTRACT

In the introductory part of this document, the various types of alcohols are reviewed; methanol is the simplest of them while ethanol is the alcohol with an agreeable odor and characteristic taste found in most alcoholic beverages.

The amount of alcohol in the body is measured using the Blood Alcohol Concentration, the higher the value, the greater the effects which range from 0.02%, mild alteration of feeling to 0.5%, death.

Alcohol enters the mouth and follows a path similar to other drugs and it is metabolized in the liver to Carbon dioxide and Water through a series of steps

Alcohol, just like any other substance, when taken in excess has serious toxic effects; starting from the liver where it is metabolized, the entire nervous system involving the brain where the damage is most felt. Alcoholism also has social effects.

Consuming alcohol in moderation on the other hand has countless beneficiary effects than excessive drinking or abstaining. It helps improve memory and thinking. It prevents many diseases and even reduces risk of stroke, Demantia and High Blood Pressure.

Some alcoholics are unable to moderate drinking so a way forward is to produce non alcoholic drinks with alcohol flavor. Studies have shown that some people drink just to feel drunk and they consume such no alcoholic drinks and act drunk.

CHAPTER ONE

INTRODUCTION TO ALCOHOL

1.1 TYPES OF ALCOHOL

Alcohols are a class of organic compounds containing the hydroxyl group, OH, attached to a carbon atom. Alcohols have one, two, or three hydroxyl groups attached to their molecules and are thus classified as monohydric, dihydric, or trihydric, respectively. Methanol and ethanol are monohydric alcohols. Alcohols are further classified as primary, secondary, or tertiary, according to whether one, two, or three other carbon atoms are bound to the carbon atom to which the hydroxyl group is bound. Alcohols, although analogous to inorganic bases, are neither acid nor alkaline. They are characterized by many common reactions, the most important of which is the reaction with acids to form substances called esters, which are analogous to inorganic salts. Alcohols are normal by-products of digestion and chemical processes within cells and are found in the tissues and fluids of animals and plants.

Methyl alcohol, or methanol, CH₃ OH, is the simplest of all the alcohols, made from hydrogen and carbon monoxide. Methanol is used as a denaturant for grain alcohol, as an antifreeze, as a solvent for gums and lacquers, and in the synthesis of many organic compounds, particularly formaldehyde. When taken internally, by either drinking the liquid or inhaling the vapors, methanol is extremely poisonous.

Ethyl alcohol, or ethanol, C₂ H₅OH, is a clear, colorless liquid, with a burning taste and characteristic, agreeable odor. Ethanol is the alcohol in such beverages as beer, wine, and brandy.

Ethanol has been made since ancient times by the fermentation of sugars. All beverage ethanol and more than half of industrial ethanol is still made by this process. Starch from potatoes, corn, or other cereals can be the raw material. The yeast enzyme, zymase, changes the simple sugars into ethanol and carbon dioxide. The fermentation reaction, represented by the simple equation

C₆H₁₂O₆→ 2C₂ H₅OH + 2CO₂

is actually very complex because impure cultures of yeast produce varying amounts of other substances, including fusel oil, glycerin, and various organic acids. The fermented liquid, containing from 7 to 12 percent ethanol, is concentrated to 95 percent by a series of distillations.

Higher alcohols, those of greater molecular weight than ethyl alcohol, have many specific and general uses. Isopropyl alcohol is used extensively as a rubbing alcohol, butyl alcohol is a base for perfumes and fixatives, and others are important flavoring agents and perfumes. Polyhydric alcohols, those containing more than one 8OH group, are also important-as, for example, the trihydric alcohol known as glycerol.

1.2 ALCOHOLIC BEVERAGES

Beer

Alcoholic beverage made from cereal grains, usually barley, but also corn, rice, wheat, and oats. Beer is made using a process called fermentation, in which microscopic fungi called yeast consume sugars in the grain, converting them to alcohol and carbon dioxide gas. This chemical process typically produces beer with an alcohol content of 2 to 6 percent.

Four basic ingredients are used to brew beer: grain, hops, yeast, and water. Grain contains the natural sugars required for fermentation. It also provides beer with flavor, color, body, and texture. Hops are small, green, cone-shaped flowers from the hop plant, a vine related to the nettle plant. Two species of yeast used to make beer, called brewer’s yeast, are Saccharomyces cerevisiae and Saccharomyces uvarum.

Wine

Alcoholic beverage made from the juice of grapes. During fermentation, microscopic single-celled organisms called yeasts digest sugars found in fruit juice, producing alcohol and carbon dioxide gas in the process.

Wine is also made from the fermented juice of pears, apples, berries, and even flowers such as dandelions. Wine naturally contains about 85 to 89 percent water, 10 to 14 percent alcohol, less than 1 percent fruit acids, and hundreds of aroma and flavor components in very small amounts.

While the basic production elements of wine are simple, manipulation of the grapes, juice or must, and wine to produce the desired combination of flavors and aromas is very difficult, and many recognize this process as an art form.

Champagne

sparkling wine produced by a traditional method in the Champagne region around Reims and Épernay in northeastern France. The word is derived from the Latin campagna, meaning countryside, a name for this area of France since the Middle Ages

While defined as a white sparkling wine, there are varieties of champagne. The three grapes used in champagne production are white Chardonnay and the red varieties Pinot Noir and Pinot Meunier. Wine-makers must be careful to acquire clear juice from the red grapes for standard champagne

Brandy

Alcoholic beverage produced by the distillation of grape wine and matured by aging in wooden casks. When freshly distilled, the brandy is clear and colorless and will remain so if kept in glass containers.

The most famous brandy is cognac. In the United States, liquors made from fruits other than grapes are also called brandies, but are more correctly termed cordials or liqueurs.

Whiskey

Liquor distilled from the fermented mash of cereal grains and containing about 40 to 50 percent ethyl alcohol by volume. Whiskeys are broadly divided into two categories, straight and blended.

The principal whiskey types are Scotch, distilled primarily from barley; Irish, from a mixture of five different grains, including malted barley; American, primarily from rye or corn; Canadian, from a blend of cereal grains; and Japanese, from various blended grains, sometimes including small amounts of rice, but seldom wheat or rye.

All whiskeys are made from grain or malt (sprouted grain), or from both, and water. Certain other substances, such as sherry wine and caramel (burned sugar), may be added to blended whiskey in small amounts.

1.3 BLOOD ALCOHOL CONCENTRATION (BAC)

Blood Alcohol Concentration (%)

Effects

0.02	Mild alteration of feelings, slight intensification of moods.
0.05	Feelings of relaxation, giddiness, lowered inhibitions. Judgment and motor skills are both slightly impaired.
0.08	Muscle coordination and reaction time impaired. Face, hands, arms, and legs may tingle and then feel numb. Legally intoxicated in Canada and some U.S. states.
0.10	Clumsiness, uncoordinated behavior. Impairment of mental abilities, judgment, and memory. Legally intoxicated in most U.S. states.
0.15	Irresponsible behavior, euphoria. Some difficulty standing, walking, and talking.
0.20	Motor and emotional control centers measurably affected. Slurred speech, staggering, loss of balance, and double vision can all be present.
0.40	Drinker is usually unconscious.
0.45	Respiration slows and can stop altogether.
0.50	Death can result.
Source: National Safety Council and California Department of Alcohol and Drug Programs

What affects the amount of alcohol in your blood?

The amount of alcohol in the blood is known as the blood alcohol concentration or BAC. Your BAC depends on how much you’ve drunk and how quickly you drank it. Other important factors affecting BAC are:

Your size and weight
If you’re small, your blood alcohol volume is obviously less than that of someone who is larger. So the same amount of alcohol will probably affect you more.

Your sex
Women can’t drink as much as men. That’s not a male conspiracy but a biological fact! Women are generally smaller. They also have proportionately less body water and more body fat – and alcohol doesn’t dissolve easily in fat. That’s why, drink for drink, women end up with more alcohol in their blood than men.

Your water level
If you’re dehydrated, alcohol will have a greater effect than if your body’s water concentration is normal. That’s why drinking alcohol in summer or after exercise affects you more.

The amount you’ve eaten
If you drink a unit of alcohol on an empty stomach, almost all of it will be absorbed in an hour. But if there’s food in your stomach, the process will be slower and the alcohol reaches your brain and the rest of your body more slowly.

1.4 THE PATH OF ALCOHOL IN THE HUMAN SYSTEM

1. Mouth: alcohol enters the body.
2. Stomach: some alcohol gets into the bloodstream in the stomach, but most goes on to the small intestine.
3. Small Intestine: alcohol enters the bloodstream through the walls of the small intestine.
4. Heart: pumps alcohol throughout the body.
5. Brain: alcohol reaches the brain.
6. Liver: alcohol is oxidized by the liver at a rate of about 0.5 oz per hour.
7. Alcohol is converted into water, carbon dioxide and energy.

1.5 METABOLISM OF ALCOHOL

The first step in the metabolism of alcohol is the oxidation of ethanol to acetaldehyde catalyzed by alcohol/dehydrogenase containing the coenzyme NAD⁺. The acetaldehyde is further oxidized to acetic acid and finally CO₂ and water through the citric acid cycle. A number of metabolic effects from alcohol are directly linked to the production of an excess of both NADH and acetaldehyde.

CH₃CH₂OH + NAD⁺ —> CH₃CH=O + NADH + H⁺

The red box shows the above reaction.

(Adapted from C.S. Lieber, Sci. Am. 234(3), 25(1976)

Metabolic Fates of NADH:

1. Pyruvic Acid to Lactic Acid:

The conversion of pyruvic acid to lactic acid requires NADH:

Pyruvic Acid + NADH + H⁺ —> Lactic Acid + NAD⁺

This pyruvic acid normally made by transamination of amino acids, is intended for conversion into glucose by gluconeogenesis. This pathway is inhibited by low concentrations of pyruvic acid, since it has been converted to lactic acid. The final result may be acidosis from lactic acid build-up and hypoglycemia from lack of glucose synthesis.

2. Synthesis of Lipids:

Excess NADH may be used as a reducing agent in two pathways–one to synthesize glycerol (from a glycolysis intermediate) and the other to synthesis fatty acids. As a result, heavy drinkers may initially be overweight.

3. Electron Transport Chain:

The NADH may be used directly in the electron transport chain to synthesize ATP as a source of energy. This reaction has the direct effect of inhibiting the normal oxidation of fats in the fatty acid spiral and citric acid cycle. Fats may accumulate or acetyl CoA may accumulate with the resulting production of ketone bodies. Accumulation of fat in the liver can be alleviated by secreting lipids into the blood stream. The higher lipid levels in the blood may be responsible for heart attacks.

CHAPTER TWO

TOXIC EFFECTS OF ALCOHOL

2.1 ALCOHOL AND LIVER DAMAGE

Chronic heavy drinking can cause the liver to become fatty. Fat deposits in the liver block the liver cells from their blood supply, depriving them of oxygen and other nutrients, eventually killing them. As the name implies, the liver performs so many vital functions that we cannot live without it. The liver filters all of the blood in our bodies, breaking down and eliminating toxins, converting excess blood sugar to glycogen, and many other crucial functions. When liver cells die from lack of fresh blood, they are replaced with scar tissue, which can’t perform the functions of a liver cell – a condition is called cirrhosis.

Cirrhosis, the main liver affliction of many alcohol abusers, results in a multitude of health problems as well as reduced ability to tolerate alcohol. Genetic make-up can play a big role in a drinker’s susceptibility to this condition. For instance, some alcohol users develop symptoms of cirrhosis after just a few years of consuming 3 to 4 drinks a day, while other heavy drinkers never suffer from this potential killer. Warning signs of cirrhosis include jaundice (yellowing of the skin and the whites of the eyes), fatigue, and a swelling of the abdomen and lower extremities.

2.2 ALCOHOL AND THE NERVOUS SYSTEM

Alcohol is a central nervous system depressant. It acts at many sites, including the reticular formation, spinal cord, cerebellum and cerebral cortex, and on many neurotransmitter systems. Alcohol is a very small molecule and is soluble in “lipid” and water solutions. Because of these properties, alcohol gets into the bloodstream very easily and also crosses the blood brain barrier. Some of the neurochemical effects of alcohol are:

• Increased turnover of norepinephrine and dopamine
• Decreased transmission in acetylcholine systems
• Increased transmission in GABA systems
• Increased production of beta-endorphin in the hypothalamus

Chronic drinking can lead to dependence and addiction to alcohol and to additional neurological problems. Typical symptoms of withholding alcohol from someone who is addicted to it are shaking (tremors), sleep problems and nausea. More severe withdrawal symptoms include hallucinations and even seizures.

2.3 EFFECTS ON THE BRAIN

Chronic alcohol use can:

• Damage the frontal lobes of the brain
• Cause an overall reduction in brain size and increase in the size of the ventricles

Schematic drawing of the human brain, showing regions vulnerable to alcoholism-related abnormalities.

2.3.1 FETAL ALCOHOL SYNDROME

Drinking during pregnancy can lead to a range of physical, learning, and behavioral effects in the developing brain, the most serious of which is a collection of symptoms known as fetal alcohol syndrome (FAS). Children with FAS may have distinct facial features (see illustration). FAS infants also are markedly smaller than average. Their brains may have less volume (i.e., microencephaly). And they may have fewer numbers of brain cells (i.e., neurons) or fewer neurons that are able to function correctly, leading to long-term problems in learning and behavior.

2.3.2 WERNICLE-KORSAKOFF SYNDROME

Up to 80 percent of alcoholics have a deficiency in thiamine, and some of these people will go on to develop serious brain disorders such as Wernicke-Korsakoff syndrome (WKS). WKS is a disease that consists of two separate syndromes, a short-lived and severe condition called Wernicke’s encephalopathy and a long-lasting and debilitating condition known as Korsakoff’s psychosis.

The symptoms of Wernicke’s encephalopathy include mental confusion, paralysis of the nerves that move the eyes (i.e., oculomotor disturbances), and difficulty with muscle coordination. For example, patients with Wernicke’s encephalopathy may be too confused to find their way out of a room or may not even be able to walk. Many Wernicke’s encephalopathy patients, however, do not exhibit all three of these signs and symptoms

Approximately 80 to 90 percent of alcoholics with Wernicke’s encephalopathy also develop Korsakoff’s psychosis, a chronic and debilitating syndrome characterized by persistent learning and memory problems. Patients with Korsakoff’s psychosis are forgetful and quickly frustrated and have difficulty with walking and coordination (17). Although these patients have problems remembering old information (i.e., retrograde amnesia), it is their difficulty in “laying down” new information (i.e., anterograde amnesia) that is the most striking. For example, these patients can discuss in detail an event in their lives, but an hour later might not remember ever having the conversation.

2.3.3 BLACKOUTS AND MEMORY LAPSES

Alcohol can produce detectable impairments in memory after only a few drinks and, as the amount of alcohol increases, so does the degree of impairment. Large quantities of alcohol, especially when consumed quickly and on an empty stomach, can produce a blackout, or an interval of time for which the intoxicated person cannot recall key details of events, or even entire events.

• Drinkers who experience blackouts typically drink too much and too quickly, which causes their blood alcohol levels to rise very rapidly. College students may be at particular risk for experiencing a blackout, as an alarming number of college students engage in binge drinking. Binge drinking, for a typical adult, is defined as consuming five or more drinks in about 2 hours for men, or four or more drinks for women

2.4 CARDIOMYOPATHY

Large-quantity consumption of alcohol can lead to alcoholic cardiomyopathy, commonly known as “holiday heart syndrome.” Alcoholic cardiomyopathy presents in a manner clinically identical to idiopathic dilated cardiomyopathy, involving hypertrophy of the musculature of the heart that can lead to a form of cardiac arrythmia. These electrical anomales, represented on an EKG, often vary in nature, but range from nominal changes of the PR, QRS, or QT intervals to paroxsysmal episodes of ventricular tachycardia. The pathophysiology of alcoholic cardiomyopathy has not been firmly identified, but certain hypotheses cite an increased secretion of epinephrine and norepinephrine, increased sympathetic output, or a rise in the level of plasma free fatty acids as possible mechanisms.

]

CHAPTER THREE

THERAPEUTIC EFFECTS OF ALCOHOL

This section explains the beneficiary effects of moderate alcohol consumption

MODERATION

Medical researchers generally describe moderation as one to three drinks per day. It appears that consuming less than about half a drink per day is associated with only very small health benefits. Four or five drinks may be moderate for large individuals but excessive for small or light people. Because of their generally smaller size and other biological differences, the typical woman should generally consume 25 to 30 percent less than the average man. And, of course, recovering alcoholics, those with any adverse reactions to alcohol, and those advised against drinking by their physicians should abstain.

3.1 MENTAL FUNCTIONING

Older people who drink in moderation generally suffer less mental decline than do abstainers, another study finds.

Over a thousand persons age 65 and older in Pennsylvania were studied over a period of seven years. Their mental functioning was measured at the beginning of the study and then periodically every two years thereafter. The study took into consideration such factors as age, sex, education, depression, smoking, general mental status.

Overall, light and moderate drinkers experienced less mental decline than did non-drinkers. These findings are consistent with other research.

Alcohol might lead to better mental function by improving cardiovascular health, in turn leading to better blood circulation in the brain. It might also have a beneficial effect on the neurotransmitters or chemical messengers in the brain.

The study adds to the growing evidence that drinking in moderation helps reduce the risk of dementia and Alzheimer’s disease. It was funded with grants from the National Institute on Aging and published in Neurology, the journal of the American Academy of Neurology.

3.2 MEMORY AND THINKING

Women who consume alcohol moderately on a daily basis are about 20% less likely than abstainers to experience poor memory and decreased thinking abilities, according to recent research. The senior author of the study explains that “Women who consistently were drinking about one-half to one drink per day had both less cognitive impairment as well as less decline in their cognitive function compared to women who didn’t drink at all.”

Researchers at Harvard School of Public Health and Brigham and Women’s Hospital analyzed data from 12,480 women age 70 to 81 who participated in the Nurses’ Health Study beginning in 1980.The study was twice as large as any earlier study and also investigated the effects of different forms of alcohol on cognition and memory.

It didn’t matter whether the women drank beer, wine, or liquor (distilled spirits). The positive effects of the alcoholic beverages were all the same.

Although the study only examined women, previous research indicates that men benefit from substantially higher levels of alcohol consumption – one to two drinks each day.

3.3 PREVENTION OF STROKE

While increased levels of high density lipoprotein cholesterol (HDL) or “good” cholesterol clearly protects against heart disease, its role in stroke prevention has not yet been extensively documented. New findings published in The Journal of the American Medical Association add to the growing evidence that HDL protects against stroke.

Dr. Ralph Sacco of Columbia University and colleagues compared levels of HDL, LDL and triglycerides in over 500 patients who had experienced strokes with those of about 900 individuals of similar age and race who had never experienced strokes.

Only high HDL level was found to be a predictor of lower stroke risk, especially among older people. Moreover, increased levels of HDL were even linked with fewer strokes among people with high blood pressure, heart disease, and diabetes. And the higher the HDL level, the greater the protection against risk.

Stroke or “brain attack” is a major health problem with few therapies. Therefore, more emphasis needs to be placed on prevention, according to Dr. Sacco. He explains that “Physical activity, healthy diet, and moderate alcohol consumption, as well as medicines, are sone of the ways that HDL can be increased.

3.4 REDUCE RISK OF ALZHEMER’S DISEASE

Another study has found evidence that elderly people who drink lightly or moderately (less than two drinks per day) are less likely to develop Alzheimer’s or other forms of dementia.

The study examined over 400 people who were at least 75 years old and tracked their health for a period of six years. Researchers found that drinkers were only half as likely to develop dementia as similarly-aged abstainers from alcohol . Abstainers were defined as people who consumed less than one drink of alcohol per week.

The lead researcher pointed out that light to moderate drinking is associated with reduced risk of atherosclerosis, cardiac, and cerebrovascular diseases. Alzheimer’s and other forms of dementia have been linked with these diseases. Therefore, it’s logical that anything reducing cardic and cerebrovascular disease would also help prevent congnitive impairment and dimentia.

3.5 REDUCED DEMANTIA RISK

Drinking alcohol (beer, wine or liquor) in moderation is one of the strategies that can reduce the risk of cognitive decline and dementia in later life.

That’s the conclusion of researchers from the School of Aging Studies at the University of South Florida (Drs. Ross Andel and Tiffany Hughes) and the University of Alabama at Birmingham (Dr. Michael Crowe). They carefully analyzed the existing research to identify how dementia can be reduced.

Abstaining from alcohol and abusing alcohol are both risk factors for cognitive decline and dementia.

Reducing the risk of dementia would help contain health care costs and reduce the emotional burden of care giving. It would also promote enhanced wellness and quality of later life.

The study is published in the inaugural issue of Aging Health.

3.6 HYPERTENSION OR HIGH BLOOD PRESSURE

A Harvard University study found the lowest levels of hypertension among young adults who consumed one to three drinks per day.

A study of alcohol consumption and subsequent high blood pressure for eight years among over 7,000 women found that those who consumed an average of about half a drink a day had a 15% lower chance of developing high blood pressure than did women who abstained from alcohol. This is very important because it’s one of the few risk factors over which a person has control.

3.7 PROSTATE ENLARGEMENT

Consuming alcoholic drinks daily reduces risk of benign prostate hyperplasia (BPH) or enlarged prostate. Consuming 3 or more alcoholic drinks per day reduces risk 33% compared to alcohol abstainers or teetotalers.

3.8 IMPROVE LUNG FUNCTION

Research has found that alcohol consumption of up to six drinks of beer, wine or liquor each day reduces the risk of lung disease and poor lung function or breathing problems, according to a large study of over 178,000 members of Kaiser Permanente health plan.

3.9 KIDNEY CANCER

The moderate consumption of alcoholic beverages (beer, wine or spirits) appears to lower the risk of developing kidney cancer about 40% according to a report in the British Journal of Cancer of a large population-based case-control study of adult Swedish men and women without previously diagnosed renal cell cancer.

3.10 CORONARY VASCULAR DISEASE

Moderate drinking has been found to reduce the risk of angina pectoris. In heart attack patients, treated with alcohol, the tissues affected by low blood flow are healthier and stronger, than those who receive no alcohol, because of alcohol’s positive effects on artery walls. Drinking alcoholic beverages in moderation may help patients recover from coronary stenting, as healing appears to be promoted by its anti-inflammitory effects.

3.11 PERIPHERAL ARTERIAL DISEASE

“Moderate alcohol consumption appears to decrease the risk of PAD in apparently healthy men. In a large population-based study, moderate alcohol consumption was inversely associated with peripheral arterial disease in women but not in men. Residual confounding by smoking may have influenced the results. Among nonsmokers an inverse association was found between alcohol consumption and peripheral arterial disease in both men and women.

CHAPTER FOUR

THE WAY FORWARD

Here is a section of an interview with Dr Heath

“Dr. Hanson–

You raise a significant point: what people think and believe about alcohol influences their drinking behavior. Could you elaborate?

Dr. Heath–

Yes. Expectations — what people expect alcohol either to do to or for them — influence how they behave when drinking. There is overwhelming cross-cultural evidence that people learn how to be affected by drink — how they are to feel and act. Additionally, numerous experiments conducted under strictly controlled conditions (double-blind, with placebos) on a wide range of subjects and in different cultures have demonstrated that both mood and actions are affected far more by what people think they have drunk than by what they have actually drunk. That is, when people consume a non-alcoholic beverage that they think contains alcohol, then they tend to become “intoxicated.” But when they consume an alcoholic beverage that they think is non-alcoholic, they tend to act “sober.”

Furthermore, if people think that drinking leads to violence, then they tend to become violent when drinking. If they think that it makes people sexy, they tend to become amorous. And if they think that alcohol disinhibits, then they tend to become disinhibited when drinking. Because behavior reflects expectations, a society gets the kind of intoxicated behavior that it expects of intoxicated people.”

Hence a way forward to those who cannot consume alcohol in moderation is alcohol free drinks with alcohol flavors. And non alcoholic beverages with alcohol for abstainers.

PREPARATION OF ALCOHOL-FREE DRINK WITH YEAST AROMA

To prepare alcohol-free drinks with a yeast aroma, such as alcohol-free beer, an aqueous starting liquid containing nutrients and/or flavor substances is used. The starting liquid can be prepared by mixing a nutrient and/or flavor substance concentrate with water. A yeast is removed from a fermentation process and is freed from the fermented liquid. The starting liquid and the yeast are brought into contact with one another, and in particular at such low temperatures that virtually no alcoholic fermentation occurs. The starting liquid and the yeast are left in contact with one another until the aroma substances of the yeast have diffused from the cell into the liquid and the yeast has exerted its reducing effect.

CHAPTER FIVE

CONCLUSIONS

Consuming alcohol in moderation is associated with better health and greater longevity than is either abstaining or drinking heavily.

FREQUENTLY ASKED QUESTIONS

DOES ALCOHOL HAVE NUTRITIONAL VALUE?

By David J. Hanson, Ph. D.

It’s often said that alcohol has “empty calories” and no nutritional value.

That’s technically true but very misleading. That’s because no one drinks pure alcohol — they consume alcoholic beverages. And alcoholic beverages not only have nutritional value, but they have little or no fat carbohydrates (carbs), cholesterol, or sodium (salt). In addition, alcoholic drinks tend to have fewer calories than most non-alcoholic drinks.

Although most alcohol beverages contain fewer calories than most non-alcohol beverages, some people are still concerned about gaining weight from consuming them. However, numerous scientific research studies have demonstrated that consuming alcohol tends not to increase weight and, among women, it is often associated with slight losses in weight

DOES DRINKING ALCOHOL KILL BRAIN CELLS?

By David J. Hanson, Ph. D.

The idea that alcohol kills brain cells has long been promoted. The early temperance writers made this assertion and also insisted that the alcohol in their blood could cause “drunkards” to catch fire and burn alive. This combustion argument against drinking was dropped long ago but many anti-alcohol writers continue to promote the idea that even moderate drinking causes brain cells to die.

Scientific medical research has actually demonstrated that the moderate consumption of alcohol is associated with better cognitive (thinking and reasoning) skills and memory than is abstaining from alcohol. Moderate drinking doesn’t kill brain cells but helps the brain function better into old age. Studies around the world involving many thousands of people report this finding.

Of course, years of alcohol abuse can cause serious neurological damage, including Wernicke-Korsakoff syndrome. Harm can be done to message-carrying dendrites on neurons in the cerebellum, a part of the brain involved in learning and physical coordination. But even in such extreme cases, there’s a lack of evidence that alcohol kills brain cells.

However, abstinence after chronic alcohol abuse enables brains to repair themselves, according to new research involving rats.

During simulated alcohol “binges,” rats’ ability to create new brain cells was reduced. But after the animals no longer consumed alcohol they had a “huge burst” in new brain cell development. The study is the first to demonstrate that brain cell production can return after abstinence from alcohol abuse.

People who drink too much and are thinking about either reducing or eliminating their drinking should find these findings encouraging, although humans have not yet been tested directly for the positive brain effects.

HOW DOES ALCOHOL AND DRUGS INTERACT

A drug generally must travel through the bloodstream to its site of action, where it produces some change in an organ or tissue. Alcohol behaves similarly, traveling through the bloodstream, acting upon the brain to cause intoxication, and finally being metabolized and eliminated, principally by the liver. Alcohol can influence the effectiveness of a drug by altering its availability.

First, an acute dose of alcohol (a single drink or several drinks over several hours) may inhibit a drug’s metabolism by competing with the drug for the same set of metabolizing enzymes. This interaction prolongs and enhances the drug’s availability, potentially increasing the patient’s risk of experiencing harmful side effects from the drug.

Second, in contrast, chronic (long-term) alcohol ingestion may activate drug-metabolizing enzymes, thus decreasing the drug’s availability and diminishing its effects. After these enzymes have been activated, they remain so even in the absence of alcohol, affecting the metabolism of certain drugs for several weeks after cessation of drinking. Thus, a recently abstinent chronic drinker may need higher doses of medications than those required by nondrinkers to achieve therapeutic levels of certain drugs.

Third, enzymes activated by chronic alcohol consumption transform some drugs into toxic chemicals that can damage the liver or other organs.

Fourth, alcohol can magnify the inhibitory effects of sedative and narcotic drugs at their sites of action in the brain. To add to the complexity of these interactions, some drugs affect the metabolism of alcohol, thus altering its potential for intoxication and the adverse effects associated with alcohol consumption.

REFERENCE

Antilla, Tiia, et al. Alcohol drinking in middle age and subsequent risk of mild cognitive impairment and dementia in old age: a prospective population based study. British Medical Journal, 2004, 329

Ganguli, M., et al. Alcohol consumption and cognitive function in late life: A longitudinal community study. Neurology, 2005, 65, 1210-12-17.

Stampfer, M.J., et al. Effects of moderate alcohol consumption on cognitive function in women. New England Journal of Medicine, 2005, 352, 245-253;

Heslam, Jessica. Women age better with a fine wine: Study: Alcohol helps memory. Boston Herald, January 20, 2005; Stein, Rob. Study: Moderate drinking good for cognitive health. Washington Post, January 20, 2005.

Huang, W., et al. Alcohol consumption and incidence of dementia in a community sample aged 75 years and older

USF researchers focus on strategies to reduce dementia risks. University of South Florida report, August 9, 2005

Statistic from the National Institute on Alcohol Abuse and Addiction, Alcohol Alert, 58:1-4, 2002

NIAAA, National institute for Alcohol Abuse and Alcoholism, number 63 of Oct 2004

Harvard Medical School Guide to Healthy Eating

Journal of the American Medical Association

American Heart Association’s journal

Research work by Dwight B. Heath, Ph.D. and by David J. Hanson, Ph. D.

Presented by

Che Elvis

University of Buea

PRESENTED BY NGOMBA NARA

UNIVERSITY OF BUEA

ABSTRACT

Local Anesthetics exist in hundreds but a handful has been found clinically useful. The term paper will be laying emphasis on some of the following pertinent subjects: definition of some fundamental terms, classes, type, general pharmacology, properties desirable in local anesthetics, techniques for the application of local anesthetics, clinical applications, toxicity, the maximum recommended dose and fate of local anesthetics.

Several clinical advantages attend the use of local anesthetics over general anesthetics especially in high- risk surgery patients as most local synthetic anesthetics show low levels of toxicity.

INTRODUCTION

Anesthetic means loss of sensation or without loss of consciousness. Anesthetic drugs are given to prevent pain and promote relaxation during surgery, childbirth, and some diagnostic test and treatment procedures .They interrupt the conduction of painful nerve impulse from a site of injury to the brain. The are two basic types of anesthesia; general and local .

Local anesthetics are drugs that prevent the patient from feeling pain when they are applied to parts of the peripheral nervous system. Depending on which portion of this system’s nerve roots and fibers is affected, the loss of sensation may be limited to a small part of the body or involve quite a large area. However, unlike the general anesthetics, the se drugs are not used clinical to cause unconscious.

The effects of local anesthetics are not necessarily limited to the sensory fibers alone. When these drugs are brought into direct contact with other parts of mixed spinal nerves, they can also affect the functioning of somatic motor and sympathetic efferent nerve fibers. This can then interfere with the tone of the skeletal and smooth muscles innervated by these nerves.

In addition, local anesthetics that are systematically absorbed from the site of their application may be carried by the bloodstream to the brain, heart, liver, and other organs. The effects of these drugs on the central nervous system and the circulatory system can then cause serious toxic reactions.

Thus, the anesthesiologist employs special techniques of administration. These are intended to:[1]place the local anesthetic solution at some precise local point along the

course of the peripheral nerves ;and[2]to keep the drug’s systemic absorption at a rate so slow that it goes up to toxic levels.

DEFINITION OF FUNDAMENTAL TERMS

1) Apgar Scores:A score that is given after assessing the condition of a new baby in the five areas of heart rate,breathing,skin colour,muscle tone and reflex response.

2) Anesthesiologist: Some one in charge of quantitizing and administering local anesthetics.

3) Analgesia: The lack of sensation to pain while somebody is conscious.

4) Antihistamine:A drug that blocks the action of histamine,used to control allergy.

5) Arrhythmias: Irregularity in a rhythmic action such as heart beat.

6) Axoplasm: Cytoplasm of a nerve cell extension.

7) Bradycardia: Slowness of heart rate.

8) Catecholamine: A compound that acts as a neurotransmitter or hormones.

9) Cessation: permanent discontinue.

10) Euphoria: Extreme happiness.

11) Gangrene: Local death and decay of soft tissues of the body as a result of lack of blood to that area.

12) Ischemia: Lack of blood supply to parts of the body to the area caused by partial or total blockage of artery.

13) Local Anesthesia: A drug that prevent a patient from filling pain when applied to part of the peripheral nervous system.

14) Meconium: The greenish faeces that have collected in the intestines of an unborn baby and are released shortly after birth.

15) Potentiation: Increase effectiveness of a chemical substance such as a drug.

Suppository: A medicated mass that melts at body temperature designated to be inserted into the rectum, vagina, or urethra.

CHAPTER ONE

1.1 TYPES OF LOCAL ANESTHESIA

There basically seven known types of local anesthesia which are describe as follows:

i) Local Infiltration: Occurs when the nerve endings in the skin and subcutaneous tissues are blocked by direct contact with a local anesthetic, which is injected into the tissue. Local infiltration is used primarily for surgical procedures involving a small area of tissue (for example, suturing a cut).

ii) Topical Block: It is accomplished by applying the anesthetic agent to mucous membrane surfaces and in that way blocks the nerve terminals in the mucosa. This technique is used during examination procedures involving the respiratory tract. The anesthetic agent is rapidly absorbed to the blood stream. For topical application, the local anesthetic is always used without epinephrine. The topical block easily anesthetizes the surface of the cornea and oral mucosa.

iii) Surface Anesthesia: This is accomplished by applying the local anesthetic to the skin or mucous membranes. Surface anesthesia is used to relieve itching, burning, and surface pain(example as seen in minor sunburns).

iv) Nerve Block: Local anesthetic is injected around a nerve that leads to the operative site. Usually more concentrated forms of the local anesthetic solutions are used for type of anesthesia.

v) Epidural Anesthesia: This type of anesthesia is accomplished by injecting a local anesthetic into the epidural space. The epidural space is one of the covering of the spinal cord.

vi) Spinal Anesthesia: This type is accomplished by injecting the local anesthetic into the subarachnoid space of the spinal cord.

vii) Vasoconstrictors: These are agents that cause the narrowing of blood vessels and therefore decrease in blood flow. Decrease the rate of vascular absorption which allows more anesthetic to reach the nerve membrane and improves the depth of anesthesia

1.2 CLASSIFICATION OF LOCAL ANESTHETICS

Hundreds of chemicals have the ability to interfere with the conduction of impulses in nervous tissue. However, only relatively few of these compounds have proved clinically useful. Those that are available differ in several of their pharmacological properties and in their suitability for use in different clinical situations. Thus; the doctor tries to select the local anesthetic that seems most suitable for each surgical procedure or medical disorder. In our course of discussion, we shall briefly mention some significant differences in the properties of individual drugs.

It should be noted that there two main classes of local anesthetics based on the functional groups they possess: Esters and amides respectively.

a) ESTERS: These include; cocaine, procaine, tetracaine, and chloroprocaine.They are hydrolyzed in plasma by pseudo-cholinesterase. One of the by-products of metabolism is paraaminobenzoic acid, the common cause of allergic reactions seen with these agents.

b) AMIDES: These include Lidocaine, mepivacaine; prilocaine, bupivacaine, and etidocaine.They are metabolized in the liver to inactive agents. True allergic reactions are rare (especially with lidocaine).

1) Benzocaine[Americaine]

Benzocaine is hydrolysed very rapidly by plasma esterases to para-aminobenzoic acid,and this presumably accounts for its low toxicity.Poorly water soluble and poorly absorbed; thus anesthetic effects are relatively prolonged and systematic absorption is minimal; available in many prescription and preparation including aerosol sprays,, lotions, and ointments.

Its main use : topical

2) Bupivacaine (Marcaine)

It is given by injection; has a relatively long duration of action, may produce systematic toxicity

- its main use is infiltration and conduction on the maximal dose is 15 – 25mg

3) Cocaine

This alkaloid obtains from the coca shrub was the first clinically important local anesthetic. Cocaine is used mainly for producing topical anesthetic when applied to mucus membrane. It may be sprayed in to the throat. Dropped into the eye, it produces prompted surface anesthesia, and vasoconstriction.

Dose and administration of cocaine: For topical application to the nasal and pharyngeal mucosa 5 to 10 percent solution are employed. The maximal dose is 150mg.

4) Dimethisoquin (Quotane).Applied only to the surface and is not given by injection.

Main use: Topical

5) Etidocaine (Duranest) A derivative of lidocaine that is both more potent and more toxic than lidocaine; long duration of action

6) Lidocaine (xylocaine)

It is given topically and by injection; more rapid in onset intensity; and duration of action than procaine, also more toxic; acts as an antiarhythmic drug by decreasing myocardial irritability. It is one of the most widely used local anesthetic drugs today.

Injections are made with 1 to5 percent solutions in amounts that vary widely depending upon the procedure. Total doses of solutions administered without epinephrine; the maximum recommended dose is 500mg.

7) Mepivacaine (carbocaine)

Chemically and pharmacologically related to Lidocaine: action slower in onset and longer in duration than Lidocaine; effective only in large doses; not used topically

Main use: Infiltration and conduction

Maximal dose: 100-400mg

Procaine (Novocain)

Most widely used local anesthetic for many years, but it has largely been replaced by lidocaine and other newer drugs .It is rapidly metabolized, which increases safety but shortens duration of action.

Dosage and Administration; Local infiltration and field block is carried out with solution of 0.5 to 1percent in amounts up to 1000mg or 300mL. The total doses for spinal anesthesia is 50 to 200mg injected intrathecally.For intravenous anesthesia, a 0.1 percent or 0.2percent solution is infused slowly at a rate of 10 to 15mL per minute for several hours.

9) Tetracaine [Pontocaine]

Applied topically or given by injection. This is a potent, long-acting spinal anesthetic that is particularly useful for prolonged [two-to. three-hour] surgical operations. Because an algesia may last as long as five or six hours, its use reduces the need for potent narcotic analgesics post-operatively. The onset of anesthesia is relatively low about 15 to 45 minutes. This local anesthetic may also be used for infiltration and for peripheral nerve blocks, as well as for epidural, including caudal, anesthesia and as a surface anesthetic in the eye, nose, and throat or on the skin.

CHAPTER TWO

2.1 PROPERTIES DESIRABLE IN LOCAL ANESTHETICS

A good local anesthetics should combine several properties. It should not be irritating to the tissue to which it is applied nor should it cause any permanent damage to the nerve structure; most local anesthetics in common use fulfill these requirements.

Its systemic toxicity should be low because it is eventually absorbed from its site of application. Therefore, the therapeutic index is an important factor in evaluating the efficacy and safety of local anesthetic agents .Since this can vary greatly among local anesthetics, the constant search for new, more effective and safer agents is eminent.

The ideal local anesthetic must be effective regardless whether it is injected into the tissue or whether it is applied locally to mucous membranes.

It is usually important that the time required for the onset of anesthesia should be as short as possible.

Furthermore the action must last long enough to allow time for the contemplated surgery, yet not so long as to entail an extended period of recovery. There are many agents that satisfy this latter requirement.

Occasionally, a local anesthetic action lasting for days or even weeks or months is desirable, for example, in the control of chronic pain. Unfortunately the compounds employed for anesthesia of such long duration have high local toxicity.

2.2 GENERAL PHARMACOLOGY OF LOCAL ANESTHETICS

The local anesthetics have many actions in common, and before discussing the pharmacology of the individual members these general properties will be considered.

i) Chemistry and Structure-Activity Relationship

The structures of most of the useful local anesthetics contain hydrophilic and hydrophobic domains that are usually separated by an intermediate alkyl chain. The hydrophilic group is usually a tertiary amine, but it may also be a secondary amine ;hydrophobic domain is an aromatic residue.

In almost all cases linkage to the aromatic group is of the ester or amide type and the nature of this bond is a determinant of the certainty of the pharmacological properties of these reagents .The ester link is important because this bond is readily hydrolyzed.during metabolic degradation and inactivation in the body. Procaine is typical of local anesthetics with the esteratic link.

The molecule is divided into three main portions: the aromatic acid (paraaminobenzoic), the alcohol (ethanol), and the tertiary amino group (diethylamino)

Changes in any part of the molecule after the anesthetic potency and the toxicity of the compound, an observation that provides the basic for the vast number of available local anesthetics. Increasing the length of the alcohol leads to a greater anesthetic potency. It also leads to decrease toxicity so that compounds with an ethyl ester, such as procaine, exhibit the least toxicity. The length of the two terminal groups on the tertiary amino nitrogen is similarly important. The structure of procaine and tetracaine are examples.

ii) Mechanism of Action

Local anesthetics prevent both the general and the conduction of impulses. Their main site of action is the cell membrane, and there is seemingly little direct action of physiological important on the axoplasm.

Local anesthetics and other classes of agents such as alcohols and barbiturates, block conduction by depressing or preventing the large transient increase in the permeability of the membrane to sodium ions that is produced by a slight depolarization of the membrane.

As the anesthetic action progressively develops in a nerve, the threshold for electric excitability gradually increases and the safety factor for conduction decreases; when this action is well developed, block of conduction is produced.

Raising the calcium concentration in the medium bathing a nerve tends to relieve the conduction block produced by local anesthetics. This relief occurs because calcium alters the surface potential on the membrane and hence the transmembrane electrical field. This in turn reduces the degree of inactivation of sodium channels and the affinity of the local anesthetic molecules.

The local anesthetics also reduce the permeability of resting nerve to potassium as well as to sodium ions. This accounts for the observation that the block in the conduction is not accompanied by any large or consistent change in the resting potential.

iii) Differential Sensitivity of Nerve Fibers to local anesthetics

As a general rule, small nerve fibers seem to be more susceptible to the action of local anesthetics than are large fibers. This was clearly established for the myelinated a fibers. The small mammalian nerve fibers are non-myelinated and on the whole, are blocked more readily than the myelinated fiber. Thus, some myelinated A delta fibers are blocked earlier and with lower concentrations of anesthetic, than are more of the C fibers.

The sensitivity to local anesthetics is not determined only by fiber size alone, therefore, but also by the anatomical fibers of varying sizes is of great practical importance and may explain why there is a definite order in which the sensory functions of a nerve are affected by local anesthetics.

iv) Effect of pH

The local anesthetics in the form of the unprotonated amine tend to be only slightly soluble. This makes them to be marketed in the form of their water -soluble salts, usually hydrochlorides. For the fact that local anesthetics are weak bases, these salts are quite acidic, a condition that fortunately increases the stability of the local anesthetic and any accompanying vasoconstrictor substance.

However, alkaline solutions of the drugs are not more effective clinically because under conditions usually encounter in clinical use, the pH of the local anesthetic is rapidly brought that of the intracellular fluids, regardless of the pH of the solution in which it is injected.

It should be noted that all the commonly used local anesthetics contain a tertiary (or secondary) nitrogen atom and therefore can exist either as the uncharged tertiary amine or as the positively charged substituted ammonium cat ion, depending on the dissociation constant (pKa) of the compound and the pH of the solution.

v) Frequency -Dependence and Use- Dependence

The degree of block produced by a given concentration of local anesthetics depends markedly on how much and how recently the nerve has been stimulated. Thus a resting nerve has been recently and repeatedly stimulated: the higher the frequency of receding stimulation, the greater is the degree of block obtained to a test shock.

Local anesthetics exhibit these properties to different extent, depending for example, on their pka and lipid solubility. .

vi) Prolongation of Action by Vasoconstrictor

The duration of action of a local anesthetic is proportional to the time during which it is in actual contact with nervous tissues. Consequently, procedures that maintain the localization of the drug at the nerve greatly prolong the period of anesthesia. For instance cocaine constricts blood vessels, probably by potentiating the action of norepinephrine.

In general the concentration of constrictor agents such as epinephrine, norepinephrine and phenylephrine should be kept at the minimal effective level. The epinephrine performs a dual service. By decreasing the rate of absorption, epinephrine not localizes the anesthetic at the desired site but allows the rate at which it is destroyed in the body to the pace with the rate at which it is absorbed into the circulation. This reduces its systematic toxicity.

vii)Pharmacological Actions

For the fact that local anesthetic block conduction in the nerve axons in the peripheral nervous , local anesthetics also interfere with the function of all the organs in which conduction or transmission of impulses occurs. Thus they have very important effects on the central nervous system, the automatic ganglia, the neuromuscular junction and all forms of muscle fiber.

In general, the more potent the anesthetic, the more readily convulsions may be produced. The function of the critical centers that control respiration and vasomotor tone may be impaired quickly, depriving neurons that are involved in the apparently stimulation effects of local anesthetics of oxygen and glucose. Diazepam is the drug of choice for both the prevent an arrest of convulsion.

Lidocaine may produce euphoria and muscle twitching at a blood concentration of 5ug/mL.Cocaine seems to be unique in that it has a particularly powerful action on the cortex. This property of cocaine and its potential for abuse is very crucial. The synthetic local anesthetics, in contrast, are less stimulating to the higher cerebral centers and are not abused.

In the cardiovascular system due to systemic absorption, local anesthetics act on the cardiovascular system. The primary site of action is the myocardium, where decreases in electrical excitability, conduction rate, and force of the contraction occur.

viii) Hypersensitivity to Local Anesthetics

Rare individuals exhibit a hypersensitivity to local anesthetics. This may manifest itself as an allergic dermatitis, a typical asthmatic attack, or a fatal anaphylactic reaction. Hypersensitivity seems to occur most prominently in response to local anesthetics of ester type benzocaine, cocaine, tetracaine and frequency extends to chemically related compounds. For example, individual sensitive to procaine may also react to structurally similar compounds (for example, tetracaine).Agents of the amide type are essentially free of this problem and substitution of such a compound to avoid group specificity is usually possible. Certain antihistamines are occasionally used as local anesthetics for local anesthetics for individuals who have become hypersensitive to all the conventional agents. These antihistamines presumably have the general structural features necessary for local anesthetic activity without sharing the specific antigenic determinants of the conventional drugs.

2.3 GUIDELINES FOR ADMINISTRATION OF A LOCAL ANESTHTIC

1) When local anesthetic solutions are injected, some guidelines for safe use include the following:

a).Local anesthetic solution must not be injected into blood vessels because of the risk of serious adverse reactions involving the cardiovascular and the nervous systems. To prevent accidental injection into the blood vessel, needle placement must be verified by aspirating before injecting the local anesthetic solution .If blood is aspirated into the syringe, another injection site must be selected.

b) Local anesthetics given during labor cross the placental barrier and may depress muscle strength, muscle tone, and rooting behavior in the newborn.Apgar scores is usually normal. If excessive amount are ,are used in parcervical block, for example, local anesthetics may cause fetal bradycardia ,increased movement , and expulsion of meconium before birth and marked depression after birth. Dosage used for spinal anesthesia during labor is too small to depress the fetus or the newborn.

c) For spinal or epidural anesthesia, use only local anesthetic solutions that have been specially prepared for spinal anesthesia and are in single-dose container. Multiple dose containers are not used because of the risk of injecting contaminated solution.

d) Use of local anesthetic solutions containing epinephrine require some special considerations, such as the following:

i)This combination of drugs should not be used for nerve blocks in the areas supplied by end arteries,(fingers,ears,nose ,toes and penis) because it may produce ischemia and gangrene.

ii) This combination of drugs should not be given IV in excessive dosage because both the local anesthetic and epinephrine can cause serious systemic toxicity, including cardiac arrhythmias.

iii) The combination should not be used with inhalation anesthetic agents that increase myocardial sensitivity to catecholamines.Severe ventricular arrhythmias may result.

iv) These drugs should probably be used in people who have severe cardiovascular disease or hyperthyroidism.

2) For topical anesthesia of mucous membranes of the nose, mouth, pharynx, larynx, trachea, bronchi, and urethra, local anesthetics are effective but should be given in reduced dosage .Because drug absorption from areas is rapid, no more than one fourth to one third of the dose used for infiltration should be given to minimize systemic adverse reaction.

2.4 TECHNIQUES OF ADMINISTRATION

Three general procedures are employed to bring local anesthetics into contact with nerve

endings, nerve roots, or along the nerve fibers or truncks, that run between the nerve’s root and its ending. These are:

1) Topical application to nerve endings in mucous membranes or broken skin.

2) Infiltration along the line of a surgical incision or deep into the structures within the wound. (This affects local nerve endings but not nerve trunks).

3) Regional or conduction anesthesia is carried out, not in the surgical field itself, but by injections made into or around the nerve or group of nerves that supply the area in which the operation is to be performed.

Nerve blocks of this kind differs depending upon the autonomic point at which the solution of the local anesthetic is injected. Some are called peripheral nerve blocks, because specific nerves such as the sciatic-femoral, ulnar or intercostal nerves or the brachial plexus are blocked. Others are called central nerve blocks, because injections are made close to the spinal cord portion of the cerebrospinal axis-central nervous system an example is spinal anesthesia.

CHAPTER THREE

3.1 ANESTHETIC PROCEDURES

On the basis of anatomic considerations, regional anesthesia may be divided into five categories: topical, infiltrative, IV regional anesthesia, peripheral neural blockade, and central neutral blockade.

i) Topical Anesthesia

Local anesthetic agents have been applied topically to such diverse sites as the skin, eye, tympanic membrane, gingival mucosa, tracheobronchial tree, gastrointestinal tract genitourinary tract, and rectum.

The composition of topical anesthesia preparation varies markedly, depending on the intended site of application. For example, lidocaine is prepared in the following forms for topical anesthesia use.

ii) Infiltration Anesthesia

This regional anesthesia is produced by intradermal and subcutaneous injection of local anesthetics in the area of intended surgery. It is primary useful for minor superfacial surgical procedures. Any local anesthetic may be employed for infiltration anesthesia. Onset of action is almost immediate for all agents following subcutaneous administration. Epinephrine markedly prolongs the duration of anesthesia of all anesthetic agents. This effect is most pronounced when epinephrine is added to lidocaine.

This dosage of local anesthetic required for adequate infiltration anesthesia depends on the extent of the area to be anesthetized and the expected duration of the surgical procedure when large areas must be anesthetized, large volumes of dilute anesthetic solutions should be used

iii)Intravenous Regional Anesthesia

This procedure involves the intravascular administration of a local anesthetic agent into tourniquet-occluded limb. An inflatable tourniquet is placed around the upper arm over a gauge bandage. A 23-gauge needle or catheter is placed into the vein on the dorsum of the hand and secured to the skin. The arm is exsanguinated by applying an elastic bandage from hand to the tourniquet.

.Lidocaine has been the most frequently utilized for intravenous regional anesthesia.Appromately 3mg/kg (40mL of 0.5 percent solution) of preservative free lidocaine without epinephrine is used for upper extremity procedures. For surgical procedures on the lower limbs, 50 to 100mL of 0.25 percent lidocaine been used.

iv)Peripheral Nerve Blockade

Regional anesthetic procedures involving the inhibition of condition in nerve fibers of the peripheral nervous system can be grouped together under the general category of peripheral nerve blockade. This form of regional anesthesia has been subdivided arbitrarily into minor and major nerve blocks.

Minor nerve blocks: These procedures involve the blockade of a single nerve entity such as the ulnar or radial nerve.A needle is passed percutaneously in the area of the nerve to be blocked. The nerve may be identified either by eliciting a anesthesia or by use stumulator.

Major nerve blocks: This involve the blockade of major nerve truncks or plexus. An intercostal nerve block is performed by injecting 2 to 4 mL of a local anesthetic solution around individual intercostal nerves. In essence, the block consists of a series of multiple minor nerve blocks.Intercostal blocks have a rapid onset of act and a long duration of analgesia.

v) Central Neural Blockade

There are two main types of central neural blockade: Epidural anesthesia and Spinal anesthesia.

Epidural Anesthesia is usually subdivided into four categories, according to the site of injection: cervical epidural, thoracic epidural, lumbar epidural and caudal anesthesia. Lumbar epidural is the most common epidural anesthetic. Lumbar blockade requires injection of 15 to 25mL of anesthetic solution to achieve satisfactory analgesia.

The onset of epidural anesthesia occurs within 5 to 15 minutes following the administration of chloroprocaine, lidocaine, mepivacaine, prilocaine and etidocaine; whereas bupivacaine generally have a slower onset of action. The duration varies depending on the local anesthetics.

Spinal Anesthesia is probably the most commonly used regional anesthetic technique. The density of the local anesthetic can be decreased or increased, by mixing the local anesthetic with distilled water or 10 percent dextrose, respectively.Baricity is the ratio of the density of local anesthetic solution to the density of the cerebrospinal fluid. Thus, a local anesthetic mixed with distilled water becomes hyperbaric; whereas a local anesthetic mixed with 10 percent dextrose becomes hyperbaric. Undiluted plain local anesthetic solution is essentially isobaric.

3.2 CLINICAL APPLICATIONS OF LOCAL ANESTHETICS

a) Topical Blocks (SURFACE ANESTHESIA)

The skin, when damaged or diseased, permits penetration of topically applied local anesthetics. The drugs act on nerve endings then deadens pains and itch sensations. Thus, drugs such as Dimethisoquin, pramoxine, benzocaine offer effective relief in many dermatological disorders that are marked by minor or annoying symptoms.

Pain and itching of the anogenital area may also be relieved by application of local anesthetic creams, ointments, jellies or suppositories. However, allergic reactions can occur in patients who have become sensitized to topically applied local anesthetics. . If signs such as redness, swellings, oozing. And pain developed during use of a topical anesthetic, treatment is discontinued.

Simple surgical procedures such as opening of a small sty, or eyelid tumor (chalazon), can be carried out after topical application of a soluble anesthetics. More complicated ocular surgery such as cataract removal requires retrobulbar injection of local anesthetics; such injections are made only after the conjunctiva and cornea are first desensitized by surface anesthesia.

The anesthesiologist may also have the nurse keep a record of the actual amount of anesthetic (in milligram) that has been administered in the fine spray or instilled as a solution.

b) Local Infiltration and Field Blocks

The injection of local anesthetics can also result in pharmacological effects that are not limited to local sites. Solutions injected into or under the skin and into muscles to anesthetize the nerve fibers in these tissues are, before long, absorbed into the systemic circulation. If the plasma level rises too rapidly, the anesthetic can adversely affect the functioning of the heart, brain, and other tissues.

Precautions employed to prevent rapid systemic absorption from the skin, subcutaneous tissues, fascia, and muscles, or accidental intravenous injection, include the following:

1. Injecting only the least amount of the most dilute solution that is effective for anesthesia.

2.Aspiration is performed in several injection planes to be sure that the needle has not enter a blood vessel, or the needle and syringe are kept moving back and forth constantly during field block or local infiltration. To ensure against the needle’s staying in any vein that it may accidentally enter.

3. Injections are not made haphazardly, but solutions are instead placed systematically in intradermal, then subcutaneous, and finally intrafascial and intramuscular sites.

4. A record is kept of the total amount of solution that has been injected, and the actual number of milligrams that have been administered is calculated. Thus, the total dose is kept constantly within safe limits for the particular anesthesia that is being employed.

5. Enough time is allowed to elapse the drug’s local action to take effect and for any systematically absorbed drugs to be largely eliminated before further injection are made.

6. Observations are made of the patient’s behavior, and pulse, blood pressure and rate of respiration are carefully watched.

7.Vasoconstrictor drugs such as epinephrine are added in low concentrations to local anesthetic solutions in order to:(1)reduce the rate of systemic absorption and toxicity.(2)to prolong the local block of nerve conduction.

c) Central nerve Block

Regional anesthesia of extensive area can be obtained by injecting local anesthetic solutions at points close to where the spinal nerve emerge from the cord. Conduction anesthesia of this kind includes; spinal, saddle, epidural and caudal blocks-terms that refer mainly to the anatomical sites at which the injections are made.

d) Spinal Anesthesia

It is induced by introducing the needle between the two lumbar vertebrae, puncturing the Dural and subarachnoid membranes, and injecting the local anesthetic solution into the spinal fluid in the subarachnoid space. The drug blocks conduction quickly in spinal nerve roots but has little effect on the spinal cord itself. For emergency surgery in patients who have eaten recently and have a full stomach, spinal anesthesia is indicated.

e) Saddle Block

It is a form of spinal anesthesia in which the local anesthetic solution is brought into contact with the sacral nerves that runs to the perineal area. The resulting loss of sensations limited to the perineum, buttocks, and thighs without affecting feeling or movement in the legs, it is useful for carrying out gynecological, urological, and rectal surgery.

f) Epidural (PERIDURAL) Anesthesia

It is induced by inserting the needle in the same way as spinal anesthesia but without breaking through the spinal membranes. The space between the Dura and spinal canal’s peritoneal lining is then flooded with local anesthetic solution. This results in block of conduction in the spinal nerves without some of the complications that can occur when the Dura is penetrated in spinal block.

g) Caudal Anesthesia

It is a form of epidural block in which the local anesthetic solution is deposited in which is continuous with the epidural space at a low level. The block that results can be prolonged by making repeated injections through a needle or catheter that is left in place in the canal.

Continuous caudal anesthesia is used in obstetrics to prevent labor pains and to relax the perineal musculature. It does not affect contractions of the uterus or abnormal. The breathing of the newborn baby is not ordinarily depressed.

CHAPTER FOUR

4.1 TOXICITY OF LOCAL ANESTHETICS

The systemic toxicity of local anesthetics involves the central nervous system (CNS) and the cardiovascular system. But we will discuss on some general points before delving into the specifics.

Toxic effects associated with local anesthetic usually result from excessively high plasma concentrations; single application of topical lidocaine preparations are not generally caused systemic side-effects. Effects initially include a feeling of inebriation and lightheadedness followed by sedation circumoral paraesthesia and twistching.Convulsion can occur in severe reactions. On intravenous injections and cardiovascular collapse may occur very rapidly.

For the Central Nervous System: Because local anesthetic drugs cross the blood -brain barrier, toxic levels can produce central nervous system excitation and depression. Initially, toxicity is manifested by light-headedness and dizziness, followed by auditory and visual disturbances. Drowsiness, disorientation, and a temporary loss of consciousness may follow. Slurred speech, shivering, muscle twitching, and tremors precede a generalized convulsive state. Further increases in local anesthetic dose during the excitation period result in cessation of convulsive activity, respiration arrest and flattering of the brain wave pattern, consistent with the generalized CNS depression. Such motor stimulations are best counteracted by the careful intravenous administration of an ultrafast-acting barbiturate such as thiopental. The antidote is best given repeatedly in small doses that control the convulsions but do not depress respiration.

For Cardiovascular system: Local anesthetic agents can produce profound cardiovascular changes by direct cardiac and peripheral vascular effects, and indirectly by conduction blockade of autonomic nerve fibers. Cardiovascular toxicity is manifested by myocardial depression and peripheral vasculation.This pattern is similar to for local anesthetic agents. Inadvertent, rapid intravenous injection or administration of an excessive dose may cause significant depression of myocardial contractility and peripheral vasodilatation, resulting in profound hypotension and circulatory collapse. Bupivacaine is particular potent in this regard and has been reported to produce severe ventricular arrhymias leading to ventricular fibrillation and sudden cardiovascular collapse.

The anesthetic technique itself may cause cardiovascular changes due to sympathetic nerve blockade. For example, high levels of spinal anesthesia (fifth thoracic dermatome) may be associated with decreased cardiac output (CO) and a significant fall in the mean arterial blood pressure (MABP).Hypotension follows epidural anesthesia may be related to the levels of anesthesia, local anesthetic agent, concomitant use of vasoconstrictor drugs, and the physical status of the patient.

Local anesthetic systemic toxicity primarily results from accidental intravascular injection or injection of an excessive dose and must always be anticipated during regional anesthesia.

4.2 MAXIMUM RECOMMENDED DOSAGES

To avoid systemic toxicity, the operator must be aware of the toxic doses of the various local anesthetics. The manufacture’s maximum recommended dosages for some local anesthetics is shown in the table below. Adherence to these recommendations is helpful in decreasing the likelihood of a systemic toxic reaction but it is not an absolute guarantee, particularly if an accidental intravascular injection occurs.

DRUG	Concentration (percent)	mg/70kg Plain(+Epi)	mg/70kg Plain(+Epi)	mg/70kg Plain(+Epi)
Chloroprocaine	3	11(14)	770(980)	25(33)
Lidocaine	1	4(7)	280(490)	28(50)
Lidocaine	1.5	4(7)	280(490)	19(33)
Mepivacaine	2	4(7)	280(490)	14(25)
Bupivacaine	0.75	2.5(3.2)	175(225)	23(30)
Etidocaine	1	6(8)	420(560)	42(56)
Etidocaine	1.5	(8)	(560)	(34)

4.3 Toxicity Management of Central Nervous System and Cardiovascular

1. For cardiac arrest, if the patient cannot be adequately ventilated, 20 to 40mg of succinylcholine given intravenous may allow insertion of an oral airway, and successful ventilation by mask. Should mask ventilation not be possible or if the patient has full stomach tracheal intubation should be performed.

2. CNS excitability is treated with small amounts of barbiturate (Thiopental, 25 to 50mg), or benzocaine (midazodam, 1 to 2) or diazepam 5 to 10mg).

3. Hypotension is treated with alpha- and beta-antagonists (ephedrine, 5 to 10mg, 40 to 80microgram).

4.Also resuscitative equipment( oxygen , airways, bag and mask , suction)central nervous system depressant drugs ( ephedrine, phenylephrine, epinephrine ,lidocaine).Should therefore be made readily available.

5. An intravenous infusion should always be .initiated before a major regional anesthetic is started.

4.4 CLINICAL USES OF LOCAL ANESTHETICS

Ø Dentistry (surface anesthesia, infiltration anesthesia, during restorative or extractions, regional nerve blocks during extractions and surgeries.

Ø Eye surgery (topical anesthesia with topical; retrobulbar (back of eyeball) blocks.

Ø Head and neck surgery (infiltration anesthesia, field blocks, peripheral nerve blocks.

Ø Heart and lung surgery (epidural anesthesia combined with general anesthesia).

Ø Abdominal surgery (epidural/spinal anesthesia).

Ø Gynecological, obstetrical and urological operations (spinal/epidural).

Ø Bone and joint surgery of the pelvis hip and leg (spinal and epidural)

Ø Surgery of skin and peripheral blood vessels (topical anesthesia, field blocks, peripheral nerve blocks, spinal epidural anesthesia

4.5 FATE OF LOCAL ANESTHESIA

The metabolic fate of local anesthetics is of great practical importance because their toxicity depends largely on the balance between their rate of absorption and their rate of destruction. It should be noted that, the rate of absorption of anesthetic agents can be reduced considerably by the incorporation of a vasoconstrictor agent in the anesthetic solution.

However, the rate at which they are destroyed varies greatly, and this is a major factor indetermining the safety of a particular anesthetic agent,

Furthermore, binding of the anesthetic to tissues reduces the amount that appears in the systemic circulation and consequently, reduces toxicity. For example, in intravenous regional anesthesia of an extremity, about half of the original anesthetic dose is still tissue bound 30 minutes after release of the tourniquet.

Many of the common local anesthetics such as procaine and tetracaine are esters, and their toxicity is usually lost as a result of hydrolysis, which occur in both the liver and the plasma.

Animals with experimentally produced hepatic damage are much more susceptible to the toxic actions of local anesthetics, so that the extensive use of a local anesthetic in patients with severe hepatic damage should be avoided.

However, the ester type of local anesthetic is degraded not only by the liver esterase but also by the plasma esterase, probably plasma cholinesterase.

Metabolic degredation by plasma esterase is particularly important in man, whose plasma can hydrolyze local anesthetics of the ester type 4 to 20 times faster than can the plasma of any other animal.

The metabolism of the amide-linked local anesthetics is more complex.Lidocaine is degraded by hepatic microsomes, the initial reactions involving N- dealkylation and subsequent hydrolysis .The general features of the metabolism of mepivacaine and prilocaine similar. Those anesthetic agents that are slowly destroyed by the liver are in small part eliminated in the urine.

REFERENCES

1) Clinical Pharmacology in Nursing by RODMAN SMITH (pages 171-188,189-199)

2) Clinical Drug Therapy by ANNE COLLINS ABRAMS. (Rationales for nursing practice ,2^nd Edition.pages; 123-136).

3) The Pharmacological Basis of Therapeutics by GOODMAN and GILMAN (6^th Edition;pages 300-310,311-320).

4) Principles and Procedures in Anesthesiology by PHILIP L.LIU and J.B LIPPINCOTT( pages 191-206).

5)Textbook of Dental Pharmacology and Therapeutics by JOHN G. WALTON,JOHN W.THOMPSON AND ROBIN A. SEYMOUR.

Malaria drugs sell the most in African Pharmacies because it is still the most deadly disease in sub Saharan Africa. Treatment is mostly combination therapy. For less complicated cases, single therapeutic doses are administered. Type and duration of treatment varies with the level of complication. Most complete doses are now limited to 3 days.

The drug forms range from Tablets, Powder, Dribs and injections, syrups and suspensions.

COMBINATION THERAPY

Coartem®

It contains artemether and lumefantrin. Artemeter is a sesquiterpene lactone isolated from the plant Artemissia annua, while lumefantrin is a synthetic racemic fluorine mixture. The mixture 20/120 is effective against both drug sensitive and drug resistant Plasmodium falciparum, and the combine effect enhances treatment to a greater effect than that of an individual drug.

Artefan® is another drug that contains artemeter and lumefantrin.

Both drugs are not administered during the first trimester of pregnancy and during breast feeding.

SINGLE THERAPEUTIC DOSE

E.g Maloxine®, Amalar® and Combimal®.

They are as well combination drugs comprising of Sulfadoxine and pyrimethamine.

The combination acts by reciprocal potentiation of its two components achieved by sequential blockage of the two enzymes involved in the biosynthesis folic acid in the parasites

The use of these medications is progressively declining since it is not very effective when the malaria is fully established. However it is used in cases where the symptoms are mild or in cases of pregnancy to prevent malaria

Other combination drugs in tablet form include; Co-Arinate, Artequin, Coarsucam, Quinine sulphate.

POWDERS

Co-Artesiane®

It contains artemeter and lumefantrin, in ratio 180/1080

The powder is diluted to form a 60ml solution. It is mostly administered to children. The full dose is taken in 3 days.

Malacur®

Powder contains 90mg Dihydroartemisinin (DHA) and 720mg Piperaquine phosphate. It is diluted to 60ml suspension. The solution can be stored for 14 days I refrigerator but only 7 days at room temperature. It is a 3day treatment for infants and children under the age of 6years.

Other powders for malaria are Artemediam® and Camoquin plus®.

DRIBS AND INJECTABLES

Quinimax®

It is administered through slow intravenous infusion deep intramuscular injection. It can effectively be administered during pregnancy. It contains 770.23mg quinine gluconate, 21.18mg quinidine gluconate and its excipients.

Other injectables include; Paluther, and Artenam.

Presented by Mbuahme Margaret

University of Buea

Abstract

Tuberculosis (TB) is the leading cause of mortality due to a single infectious agent. The currently used combination drug regimens produce cure rates that exceed 95%, given good patient adherence during the multiple months treatment period. However the recent surge in HIV infections and the synergy between HIV and TB as well as the emergence of resistance resulted in an unforeseen increase in the number of TB cases, including multi-drug resistant (MDR) and extensively-drug resistant (XDR) forms of TB. Consequently, there is an urgent need to develop novel, fast acting antituberculosis drugs with high potency that can provide treatment options for all forms of TB. It is well known that the current TB drugs exhibit differences in their in vivo activity profile and these differences are largely determined by their pharmacodynamics (PD), i.e. intrinsic antibacterial activity, biopharmaceutical properties such as solubility and permeability, and pharmacokinetic (PK) properties such as drug exposure, tissue distribution, and protein binding. An understanding of the relationships among these properties is considered key for a rational use of antituberculosis therapeutics. The current review provides a comprehensive summary of physicochemical/biopharmaceutical, PK, and PD properties of currently used anti tuberculosis drugs and novel agents under development. Also, a brief review of PK/PD parameters of current TB drugs is given and properties of a desirable TB drug target and drug molecule are outlined. The information provided herewith may be useful in the optimization of biopharmaceutical and PK/PD characteristics in the development of novel TB therapeutics and in the design of optimal treatment regimens.

Introduction

Tuberculosis (TB) is a contagious disease caused by Mycobacterium Tuberculosis and occasionally by opportunistic microbacterial. It affects mostly areas in the body that are rich in blood and oxygen such as the lungs as pulmonary tuberculosis and can also affect other parts of the body such as the skin or other organs as extrapulmonary tuberculosis. Its primary reservoir host is in humans and occasionally in cattle within incubation of 4 to 12 weeks TB is also associated with HIV/AIDS which is the leading killer of HIV positive patients. TB can also manifest as primary or reactivated infection

Primary infection which is asymptomatic, is initiated by inhaling droplet of nuclei that contain tubercle bacilli which passes through the bronchiole tree and implants in the respiratory bronchiole beyond the mucocillary. It is engulfed by microphages and after entering the lungs, a Ghon’s complex could be formed later. The immune response also provide protection against additional tubercle bacilli that maybe inhaled at later time, but people with HIV infection are more likely to acquire activated TB which is also known as latent tuberculosis infection.

Reactivated TB, results from the activation of previously healed primary lesion that develops because of impaired body’s defense mechanism.

OBJECTIVES

· To identify the first line drugs employed in the treatment of tuberculoses.

· Identify the genetic factors that can affect the action of the drugs.

· To understand the pharmacokinetics and pharmacodynamics of antitubercular drugs in the treatment of tuberculosis.

· Identify the drug interactions that are associated with anti-tubercular drugs.

· Identify the adverse reaction of these drugs.

· Teach the patient with a mycobacterial infection about the disease and drug therapy.

· To know how to apply the nursing processes when caring for a patient who is receiving anti tubercular drugs.

SOME DEFINITIONS

Drug: It is a chemical substance that modifies the response of a tissues to its environment

Pharmacokinetics: It is the study of the factors that determine the concentration of a drug at its site of action at any given time after administration into the system by any route. In short pharmacokinetics is the study of what the body does to the drugs. The pharmacokinetic phases of drug actions are;

- Absorption: it is the transfer of chemicals from site of exposure into the systemic circulation.

- Distribution: Movement of drug from blood to the tissues.

- Metabolism: It is the Biotransformation of drugs to more hydrophilic molecules for easy passage through membranes.

- Excretion: It is the elimination of metabolic waste substances from the body.

Pharmacodynamics: It is the study of the interaction between the drug and the target (site of action) of the drug to bring about a biochemical responds. In simple terms it is the study of what the drug does to the body.

Causes of Tuberculosis

You can catch TB by breathing droplets in the air that contain the bacterium M. tuberculosis. These are spread through the air when someone with TB coughs or sneezes. TB is only infectious when it affects the lungs (See Symptoms). Although it is spread through the air, you need to be closely exposed to a person with TB for some time before you catch it. People most commonly catch TB from people they live or work with.

You are more likely to get TB if you:

• already have a weakened immune system (e.g. from HIV/AIDS or from taking medicines that suppress your immune system)
• have diabetes
• regularly come into contact with people who have TB lung infection
• are young or elderly
• are malnourished
• smoke or drink alcohol excessively
• live in overcrowded housing
• travel to, or come from, places where TB is common

Signs and Symptoms of Tuberculosis

Many people who become infected with TB don’t realize they have been exposed to the infection because their immune system successfully fights it off. When this happens, the bacteria become coated in tiny tubercles (round lesions), usually in the lungs. These can sometimes be seen on a chest X-ray. The bacteria are still in the body, but there are no symptoms and it can’t be passed on to other people. This is called latent TB. Depending on how effectively your immune system fights the infection, you may have:

• no symptoms at all
• minor symptoms for a few weeks, which then go as you fight the infection off
• no symptoms at first, but symptoms and active TB develop in the following weeks or months

If your immune system successfully fights the infection, you will be immune to TB. Sometimes latent tuberculosis becomes active years later. This is known as post-primary

TB, and is more likely to happen if your immune system is weakened by other problems such as HIV, poorly controlled diabetes, or if you are underweight. About one in 10 people infected with TB bacteria go on to develop active TB at some point in their life.

Active TB bacteria are not contained in tubercles, and a person with active TB will have symptoms, which may include:

• a persistent cough – there may also be lots of phlegm, sometimes containing blood
• fever
• swollen glands, especially in the neck
• tiredness
• loss of appetite
• weight loss
• night sweats
• chest pain when you breathe in, caused by inflammation of the membranes lining your lungs (pleurisy)

At first, a TB infection normally affects the lungs. This is called pulmonary TB. However, TB often spreads to the lymph nodes (glands throughout your body that are part of your immune system). It can also affect your bones, joints and kidneys, as well as cause meningitis (inflammation of the membranes surrounding the brain and spinal cord).

Diagnosis

The most common test for TB is the tuberculin test. The test detects latent TB and is also used as part of vaccination programmes.

There are two ways to do the test.

The most common one is called the Heaf test. A small device with six small needles is pressed onto the skin of your forearm. The needles carry tiny amounts of tuberculin protein, which comes from the bacteria that cause TB. One week later, a doctor or nurse will examine the skin at the site of the test to see if there has been a reaction.

An alternative, the Mantoux test involves injecting the tuberculin protein into your skin. You will get the results 48 hours after the test.

In either case, the doctor or nurse is looking for a raised red reaction on your skin. This is a positive result, meaning you have been exposed to the TB bacteria. The reaction is then graded.

A weak reaction suggests that you have developed some immunity to the disease. A strong reaction means the problem may need further investigation and diagnosis.

If you have no reaction, you haven’t been exposed to TB, which means you can be immunized (see Immunisation).

The test for active TB involves analysis of a sample of your phlegm. This can also identify which combination of drugs is likely to treat it successfully. A chest X-ray can also diagnose active TB.

Treatment

People with either active or latent TB are treated with a combination of antibiotic tablets to kill the bacteria. Treating latent TB prevents the infection becoming active.

You may need to go to hospital for the first week or so, especially if you are very ill or thought to be very infectious. However, some people can be treated at home.

Unlike most antibiotics antituberculosis drugs may need to be administered over many months or even years. This creates problems such as patient non compliance, the development of bacterial resistance and drug toxicity.

You will usually need to take antibiotics for six months. You may need a longer course of treatment if the bacteria are resistant to one or more of the antibiotics (See Drug resistant TB).

It’s very important to take the full six-month course of antibiotics and to take them regularly; otherwise the bacteria may develop resistance to the antibiotics. Treatment with antibiotics is usually effective, provided that the full course of medication is taken as prescribed. Some people may get side-effects from the antibiotics. These can include:

• visual disturbances
• nausea, vomiting or diarrhea
• dizziness
• skin flushes
• fever
• jaundice (yellowing of the skin and eyes)
• pins and needles
• depression or other mental disturbances

If you notice any of these symptoms, don’t stop taking the medication, but talk to your doctor as soon as you can – an alternative treatment may be needed.

Prevention

Immunization

In the UK, a large-scale immunisation programme is run to help prevent TB. Immunisation is given as the BCG (Bacillus Calmette-Guérin) vaccination. This protects between 70 and 80 percent of people who receive it. It lasts for at least 15 years. The vaccination strategy in the UK targets people who are most at risk of getting TB, such as:

• babies born in areas where TB is common
• people who have immigrated from a country where TB is common, or their children
• healthcare workers and laboratory staff
• people who intend to travel to a country where TB is common

The vaccination is not usually recommended for people over 45 unless they are in a high-risk group such as healthcare workers. Once you have had the immunization, you won’t need to have it again.

Before giving the vaccination, your doctor or nurse must first check whether you are already immune to TB. This is done with the tuberculin test (see Diagnosis).

If the test is positive, this means you have been exposed to the TB bacteria and you are already immune. You will not be given the BCG vaccination. Depending on the size of the skin reaction, you may be referred for more tests, such as an X-ray and a phlegm test, and possibly treatment for TB.

People who are not already immune are given the vaccination either as a single needle injection, or with a multiple needle device similar to the one used for the Heaf test. The injection is given to the top of the left arm (or the right arm in left-handed people).

It is rare to get a strong reaction to the vaccination, but a small ulcer on the skin of the arm often forms. This may take several weeks to heal properly. A flat scar often develops later. This is normal and a sign of successful immunisation.

ANTIMYCOBACTERIAL AGENTS (DRUGS)

Antitubercular And Antileprotic Agents

These are agents used to treat mycobacterial infections: tuberculosis which is caused by Mycobacterium tuberculosis and Hansen’s disease (previously called leprosy), which is caused by Mycobacterium leprae. These agents are also effective against less common mycobacterial infection caused by M. kansasii, M. aviun, M. fortuitun, M. intracellulare and other related organisms. These agents are not always curative but can halt the progression of a mycobacterial infection. Unlike most antibiotics, antitubercular and antiaprotic agents are administered over many months or even years. They create problems such as patient non compliant, development of bacterial resistance and drug toxicity. To help reduce these complications to the patient during long therapy, the nurse must be aware of these and other problems.

1. Antitubecular Agents

The most used antitubercular agents are ethambutol hydrochloride, isoniazid, rifampin and streptomycin sulfate. Other antitubercular agents which are less commonly used include amino salicylic acid, capreomycin sulfate, cycloserine, ethionamide and pyrizinamide. These agents are less commonly used because they are less effective and more toxic. They are used only when hypersensitivity, intolerance or bacterial resistance to the first line agent exist.

2. Antileprotic Agents

The primary agent used to treat Hansen’s disease (leprosy) is dapsone, a sulfa drug. However, refampin and clofazimine are also used. Clofazimine ane dapsone are mostly used. Ethonamides, an antitubercular agents is used to treat dapsone resistant Hansen’s disease and is usually combined with refampin or clofazimine.

Tuberculosis Treatment; Drug Therapy

The first line drug in the treatment of tuberculosis:

- The first option is a four drug regimen consisting of isoniazides, refampin, pyrazinamide and either ethambutol or streptomycin. This therapy may be given daily or two or three times weekly if directly observed. Ethambutol or streptomycine may be continued if susceptibility to isoniazide and refampin is documented. Pyrazinamide should be discontinued after eight weeks.

- The second option for treatment is to administer isoniazide, refampicin, pyrazinamide and streptomycin or ethambutol daily for two weeks followed by directly observed twice weekly administration of the same drug for six weeks, and followed by directly twice weekly administration of isoniazide and refampin for sixteen weeks.

- The third option is directly observed twice administration of ioniazide, refampin, pyrazinamide and ethambutol for six months.

Treatment of Special Cases of Tuberculosis

1. HIV infection cases: for patients with HIV infection, any of the three options can be used but therapy should be continued for nine months and at least six months after culture conversion.

2. Extrapulmonary Tuberculosis: treatment is the same as for pulmonary tuberculosis. However nine months of therapy is advised. Treatment of skeletal tuberculosis is enhanced by early surgical drainage and debridement of necrotic bone. Corticosteroids therapy is indicated in tuberculus pericardiatis and tuberculos meningitis.

3. Pregnancy case: it is treated with an initial regimen of isoniazide, refampin and ethambutol. Pyrazinamide should be used only if resistance to other drugs is document or likely and susceptibility to pyrazinamide is also likely. This is because the risk of theratogenecity with pyrazinamide has not been determined. Streptomycin is contraindicated in pregnancy because is causes congenital deafness.

A Table Showing The First Line Drugs And Other Anti Mycobacterial Agents

Used In The Treatment Of Tuberculosis.

DRUGS	ACTION	ROUTE AND ADULT DOSAGE	ADVERSE EFFECT
Isoniazid	Unknown, may block mycolic acid synthesis in mycobacterium buberculoses, resulting in either bacterostatic or bactericidal effect depending on dose	Oral or intramuscular 5mg/kg/dayin single dose with a maximum of 300mg daily for the treatment of active tuberculoses.	Peripheral neuritis, irritability, seizure, hyperglycemia, metabolic acidosis, allegic reactions, hypertoxicity
Rifampin	Inhibit bacteria RNA formation (bactericidal)	Oral 600mg once daily, 1hour before or 2hours after meal.	Gastrointestinal tract distress, central nervous system effects, hypertoxicity with intermittent therapy fever, chills, nausea, vomiting, trumbocitopemia, henolitic anemia, acute renal failure.
Ethambutol	Unknown, only effective against mycobacteria (bactericidal)	Oral 15microgram/kg single dose daily as initial treatment. Real treatment is 25mg/kg as a single oral dose every 24hours.	Retrobulbar neuritis, GI tract upset, allergic reaction, central nervous effect, acute gout peripheral neuritis.
Para aminosalicyclic acid	Blocks the synthesis of folic acid in mycobacterium tuberculoses (bacteriostatic)	Oral’ 10-12g/day in 2 or 3 divided doses.	GI irritation, allergic reactions, blood dyscrasias, fluid retention.
Cycloserine	Compete with alanine for use by bacteria thus preventing cell wall formation	Oral; 12mg/kg/day. 25mg every 4days until therapeutic serum levels are reached.	Central nervouse system toxicity.

Pharmacodynamics Of Antitubercular Agents

These agents are specific for mycobacteria. At usual doses, ethambutol and isoniazides are tuberculostatic inhibiting growth of mycobacterium tuberculosis bacteria. In contrast, refampin is tuberculocidal destroying the bacterial. Because bacterial resistance to isoniazide and refampin can rapidly develop, they are usually used with other antituberbacular agents.

Mechanism of action

Ethambutol is most active against mycobacterium tuberculosis and mycobacterium Kansasii but acts to varying degree against all mycobacteria. Although mycobacterial rapidly takes up ethambutol, the drug does not inhibit their growth significantly for approximately 24 hours. The exact mechanism of action remains unclear but may be related to inhibition of cell metabolism, arrest of multiplication and cell death. Ethambutol acts only against replicating bacteria.

Isoniazide mechanism of action is not exactly known but evidence suggest that the drug inhibits the synthesis of mycolic acid, an important component of the mycobacterium cell wall.

This inhibition alters the fastness of the cell and disrupts the cell wall. Because mycolic acid synthesis is unique to mycobacteria, this mechanism explains the high degree or specificity of isoniazides. Only isoniazide sensitive bacteria takes the drug and only replicating not resting bacteria are inhibited.

Rifampin inhibits ribonucleic acid (RNA) synthesis in susceptible organisms by acting on the beta subunit of the enzyme RNA polymerase. The drug is effective primarily in replicating bacteria but may have some effect on resting bacteria as well.

Para-Aminosalicylic Acid is structurally similar para-aminobenzoic acid.Its mechanism of action is claimed to be similar to that ofsulfanamide in that it prevent the synthesis of folic acid. however sulfonamide are insensitive in treating M.tuberculosis and PAS is inactive against sulfonamide sensitive bacteria.

Clocyrine is structurally similar to the amino acid alanine. By competing with alanine in the bacteria, it is believed to prevent the formation of bacteria cellwall.

Capreomycin sulfate is a polypeptide antibiotic whose mechanism of action isunknown. It is absorbed by the GI tract thus administered intra-muscularly.It half life is four to six hours unchanged in urine.

Pyrazinamide is a niacinamide derivative.It is highly specific for M.Tuberculosis. Mechanism of action isunknown.

Ethionamide(trecator-SC), aderivative of isonicotinic acid is use to treat tuberculosis and Hansen’s disease especially useful in dapsone-resistance M leprae. It mechanism of action is unknown

Streptomycin sulfate is the first egent recognized to effectively treat tuberculosis

It appear to enhance the activity of oral anti-tubercular agents and is of great value in the early weeks to month of therapy.

PHARMACOKENITIC

Antitubercular agents almost exclusively are administered orally. Isoniazid is commercially available parentarally. When this agent are administered orally they are absorbed well from the gastrointestinal tract and distributed through out the body. This drugs are metabolized primarily by the liver and excreted by the kidney.

Absorption, Distribution, Metabolism and Excretion of drugs.

Ethambutol

- After oral dose of ethambutol is administered, about 75 – 80% is absorbed rapidly from the GI tract.

- The drug is distributed widely into more body tissues and fluids and about twice as much appears in erythrocytes as that in the plasma. The erythrocytes can serve as a reservoir that slowly releases the drug into the circulatory system.

- Ethambutol crosses the placenta and appears in the breast milk in concentrations equal to those of plasma concentration.

- 50% of the drug is metabolized in the liver and the kidney excretes almost all of it primarily as an unchanged drug.

Isoniazids

- It is readily absorbed from the GI tract and the intra muscular injection site as it is administered both orally and intramuscularly.

- It is distributed into all body tissues and fluids and readily crossed the blood brain barrier and the placenta. It distributes into blood milk in concentration level similar to that of the maternal plasma concentration.

- It is metabulised almost completely by enzymatic acetylation and hydrolises in the liver. The rate of the acetylation is determined by race-linked genetic factors that produce significant variations in the rate of isoniazid elimination. Despite this, the drug is still effective when administered two of three times a week. It’s effectiveness is reduced for some patients (fast acytelators), when administered once weekly.

- About 75 -95% of isoniazid is excreted in the urine as metabolite and unchanged drug within 24hours after administration. Small amounts are excreted in the saliva, sputum and feaces.

Rifampin

- It is absorbed well from the GI tract although food in the stomach can reduce its rate and extend of absorption. The drug difusses freely into most body tissues and fluids such as the cerebrospimal fluids in concentrations of 10-20% that of the plasma.

- It crosses the placenta and appears in breast milk.

- Metabolism take place in the liver and is excreted primarily in the feaces, urine and bile.

- Aminosalicycylic acid is readily absorbed in the GI tract, distributed widely to the tissues and metabolized rapidely by the liver and excreted by the kidneys.

Capreomycin Sulphate

- It is absorbed by the GI tract thus administered intramuscularly. Its half life is four to six hour

- It is excreted unchanged in the urine.

Cycloserine

- After oral administration, it’s absorbed well in the GI tract, distributed widely and excreted by the kidney

Ethionamide

- It is absorbed well after oral administration and distributed widely. It is extensively metabolized in the liver and excreted in the urine.

Pyrazinamide

- It is absorbed well and distributed widely. It is metabolized by the liver.

Streptomycin Sulphate

- It is administered only intramuscularly and this limits its usefulness and long term therapy.

- It is rapidly absorbed from the IM injection site.

- It is excreted by the kidney as unchanged drug.

Onset, Peak and Duration of action of drug.

- After and oral dose of ethambutol, the plasma concentration peaks in 2-4hours in proportion to the size of the dose. The half life in a patient with normal renal function is three hours whereas that for a patient with renal impairment is longer an those the dosage is adjusted.

- Isoniazid after oral administration reaches a peak plasma concentration in 1-2hours. The half life of this drug ranged from 4-5hours but may be longer for patients with renal or hepatic impairment.

- Rifampin reaches a peak plasma concentration kin 2-4hours. Initially, it half life ranges from 1-5 as an averages 3hours but because of biliary excretion of rifampin increases during the first two weeks of therapy, the half life gradually decreases to about 2hours. Its plasma concentration is higher and more prolonged in patients with hepatic dysfunction but unaffected in patients with renal dysfunction.

DRUG INTERACTION

Anacids that contain aluminum hydroxide or other aluminum salts may decrease the GI absorption of ethambutol slightly. Some evidence suggest that isonaizid, cycloserine and ethionamide may produce additive CNS effect such as drowsiness, dizziness, heahach, lethargy, depression, tremor, anxiety, confusion and finnitus. Therefore this drugs should be administered cautiously in combination.

Isoniazid may increase plasma concentration of phenytoin, who are slow acetylators Aluminum hydroxide a common ingredient in antacid, significantly decreases isoniazids absorption. Isoniazid should be administered at least one hour before aluminum anacid. INH’s administration with a corticosteroid decreases its effect and increases the corticosteroid effect. Psychotic episodes and difficulty incordination have occurred when INH’s has be give with disufiram. Concomitant administration should be avoided.

Refampin can increase the rate of metabolism and consequently decreases the plasma concentration of some drugs including oral contraceptives. Ketoconazole, quinidine, cyclosporine, chloramphenicol estrogens, corticosteroids, methadone, oral hypoglycemics, warfarine, cardiac glycosides and dapsone. The dosage of these agents may need to be increased during refampin therapy. Aminosalicylic acid may inhabit refampin reaction.

ADVERSE DRUG REACTION

Adverse drug reaction to anti tubercular agent primarily occur in the GI tract, the peripheral nervous system and the hepatic system. Fortunately this reaction seldom are severe enough to necessitate interruption of tuberculosis therapy.

Optic neuritis is the significant reaction to ethambutol. Signs and syntoms include decrease visual aquity, lost of red-green colour discrimination visual field constriction, and central and peripheral scotomas. This adverse reaction occur in only 0.8% of patients receiving 15mg/kg, but its incidence increases in patients who receive higher dosage or who have renal dysfunction. Discontueing ethambutol usually reverses the optic neuritis, but if vision impairment is severe, recovering may be incomplete. Occasionally ethambutol therapy increases serom uric acid levels and precipitate and acute gouts episode. The most common hypersensitivity reaction to ethambutol are rash and fever.

Peripheral neuritis occurs in 20% of the patient receiving isoniazid daily and higher doses increase the incidence of this reaction. Usually preceded by paresthesia of the feet and hands. Peripheral neuritis is more likely to affect and alcoholic, a diabetic or a malnourished individual or one who is predisposed to peripheral neuritis.

Drug Resistant TB

The bacteria that causes TB can, in rare cases, become resistant to antibiotics, making it extremely difficult to treat. According to the World Health Organisation (WHO), multi drug resistant tuberculosis (MDR TB) has been found in most countries surveyed. Drug resistant TB is more likely to develop if you don’t finish your antibiotic treatment course for TB.

Some Common Nursing Diagnosis And Related Intervention

For Each Anti Tubercular Drug Class

Planning and Implementation

- Monitor the patient closely for hypersensitivity reaction.

- Monitor the patient’s liver function test for abnormalities with NIH or rifampin therapy, serum uric acid levels with ethambutol therapy and white blood count with rifampin and ethambutol therapy.

- Monitor hydration if the patient experiences nausea, vomiting, and anorexia, or diarrhea during rifampin ore ethaambutol therapy. Obtain a prescription for an antirnetic or anti diarrheal agent as needed.

- Administer an analgesic as prescribed if the patient experience a headache during ethambutol therapy of joint pain or muscle aches or cramps during rifampin therapy.

- Take safety measures if the patient experiences adverse CNS reactions such are confusion or coordination. For example, place the patients bed at a lower position, keep the bed rails raised, and supervise ambulation.

- Take seizure precaution when administering INH’s to a patient with a seizure disorder.

- Administer rifampin one hour before of two hours after the meal because food affect the rate and extent of absorption.

- Administer INH at least one hour before administering aluminum antacid to prevent a drug interaction.

- Monitor the patient closely for additive central nervous system effect during concomitant therapy with INH and cycloserine or ethionamide.

- Expect to increase the dosage of oral contraceptive, corticosteroids and warfarin because rifampin is not to accelerate their metabolism.

- Notify the physician if adverse reaction of drug interaction occur.

- Monitor the patient closely for peripheral neuritis when administering 6mg/kg of INH daily of higher.

- Administer pyeridozine concurrently with INH as prescribed to prevent peripheral neuritis.

- Monitor the patient closely for optic neuritis when administering INH of 50mg/kg or higher doses of ethambutol.

- Test the patient visual acuity before INH or ethambutol theraphy begins and monthly thereafter when the ethambutol dose excite 15mg/kg and throughout INH therapy.

- Notify the physician if visual disturbances occur.

CONCLUSION

Various chemically unrelated agents are used to treat myco bacterial infections. Although this agents show relatively high bacteria specificity and inhibition, myco bacterium tuberculosis and mycobacterium leprae require long term treatment. In almost all compliant patients, combination therapy can control this diseases effectively. Isonicotinic acid hydroxide (INH), streptomycin and PAS where formerly termed first line drugs but this phase now include ethambutol and rifampin with the later two drugs and isoniazids serving as a trio of powerful first line oral drugs suitable, for initial therapy for treating TB. Their low level of toxicity make them more acceptable to the patient than PAS with its gastrointestinal upset of the painful injection of streptomycin or its ototoxicity. Although this drugs vary in terms of specific regimens and length of treatment required, they produce similar therapeutic results. Anti tubercular agents have a favorable benefit to risk ratio. Significant adverse reaction do occir however usually produces neurotoxin of hypertotoxic effect. The development of bacteria resistance to this drugs is a constant threat but aggressive combination therapy can minimize it greatly.

Finally, the nurse must instruct the patient anf family in the administration effect of and possible adverse reaction to anti mycobacterial agents monitoring the patient throughout therapy and notify the physician it adverse reaction occur.

Reference

- Mackie and McCartney Medical Microbiology Volume 1: Microbial Infections, 13^th Edition. J.P DUGUID ET AL

- Chemotherapy of Infections W. B Pratt , Oxford Press (1977)

- The Choice of Anti Microbacterial drugs, The medical letter (24,21-28, March 5^th, 1982)