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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.

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