EXAMPLES OF DRUGS THAT AFFECT HOMEOSTASIS

OVERVIEW The term homeostasis is used by physiologists to mean maintenance of nearly constant conditions in the internal environments. Essentially all organs and tissues of the body perform functions that help maintain these constant conditions. For instance, the lungs provide oxygen to the extracellular fluid to replenish the oxygen used by the cells, the kidneys maintain constant ion concentrations, and the gastrointestinal system provide nutrients. In this paper we will discuss the pharmacodynamic effects of some drugs that affect particularly the homeostatic mechanisms that are important in maintaining arterial blood pressure and cardiac functions.

MECHANISMS FOR CONTROLLING BLOOD PRESSURE Arterial blood pressure is regulated within a narrow range to provide adequate perfusion of the tissues without causing damage to the vascular system, particularly the arterial intima. Arterial blood pressure is directly proportional to the product of the cardiac output and the peripheral vascular resistance. In both normal and hypertensive individuals, cardiac output and peripheral resistance are controlled mainly by two overlapping control mechanisms : the baroreflexes mediated by sympathetic nervous system, and the renin-angiotensin-aldosterone system. Most antihypertensive drugs lower blood pressure by reducing cardiac output and/or decreasing peripheral resistance.

The nervous system controls the blood circulation almost entirely through the autonomic nervous system. The most important part of the autonomic nervous system for regulating the circulation is the sympathetic nervous system. An especially important characteristic of nervous control of arterial pressure is its rapidity of response, beginning within seconds and often increasing pressure to two times normal within 5 to 10 seconds. Conversely, sudden inhibition of nervous cardiovascular stimulation can decrease the

arterial pressure to as little as one half normal within 10 to 40 seconds. Therefore, nervous control of arterial pressure is by far the most rapid of all mechanisms for pressure control. Baroreflexes involving the sympathetic nervous system are responsible for the rapid moment-to-moment regulation of blood pressure. A fall in blood pressure causes pressure-sensitive neurons ( baroreceptors in the aortic arch and carotid sinuses) to send fewer inhibitory impulses to cardiovascular centres in the spinal cord. This results in a reflex response of increased sympathetic and decreased parasympathetic output to the heart and vasculature, resulting in vasoconstriction and increased cardiac output. These changes result in a compensatory rise in blood pressure. The renin-angiotensin-aldosterone system acts synergistically with the

sympathetic nervous system. It also stimulates aldosterone secretion and plays a central role in the control of Na+ excretion and fluid volume as well as vascular tone. Renin is a proteolytic enzyme that is secreted by the juxtaglomerular apparatus. It is secreted in response to various physiological stimuli, including a fall in Na+ concentration in the distal tubule, and a fall in renal perfusion pressure. Renal sympathetic nerve activity, beta-adrenoceptor agonists and PGI2 all stimulate renin secretion directly, whereas angiotensin II causes feedback inhibition. ANP (atrial natriuretic peptide) also inhibits renin secretion. Renin acts on angiotensinogen splitting off a decapeptide called angiotensin I. Angiotensin I has no appreciable activity per se but is converted by ACE (angiotensin converting enzyme) to an octapeptide called angiotensin II, which is a potent vasoconstrictor. Angiotensin II can be broken down further by enzyme (aminopeptidase A and N) , giving rise to angiotensin III and angiotensin IV. These had been regarded as of little importance, but it is now known that angiotensin III stimulates aldosterone secretion and involved in thirst. Angiotensin IV also has distinct actions, probably via its own receptors, including release plasminogen activator inhibitor-1 (PAI-1) from the endothelium. ACE is a membrane-bound enzyme on the surface of endothelial cells and is particularly abundant in the lung, which has a vast surface area of vascular endothelium. The common isoform of ACE is also present in other vascular tissues including heart,

brain, striated muscle and kidney and is not restricted to endothelial cells. Consequently, local formation of angiotensin II can occur in different vascular beds, and it provides local control independent of blood-borne angiotensin II. ACE inactivates bradykinin and several other peptides. This may contribute to the pharmacological actions of ACE inhibitors (ACEI) as discussed below.

The main actions of angiotensin II are mediated via receptors AT1 and AT2. AT1 is a specific membrane-bound G-protein-coupled receptor. These actions include : generalised vasoconstriction, especially marked in efferent arterioles of the kidney increased release of noradrenaline from sympathetic nerve terminals, reinforcing vasoconstriction and increasing the rate and force of contraction of the heart stimulation of proximal tubular reabsorption of Na+ secretion of aldosterone from the adrenal cortex cell growth in the heart and in arteries

AT2 receptors have also been cloned. They are expressed during fetal life and in distinct brain regions. Studies of mice suggest that it may be involved in growth, development and exploratory behaviour. Cardiovascular effects of AT2 receptors (inhibition of cell growth and lowering of blood pressure) appear to be relatively subtle and oppose those of AT1 receptors. The renin-angiotensin-aldosterone pathway is important in the pathogenesis of heart failure, and several very important classes of therapeutic drug act by inhibiting it at various points.

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACEI)

Captopril and other drugs in this class inhibit the converting enzyme that hydrolyzes angiotensin I to angiotensin II and (under the name plasma kininase) inactivates bradykinin, a potent vasodilator, which works by stimulating the release of nitric oxide (NO) and prostacyclin. The hypotensive activity of captopril results both

from an inhibitory action on the renin-angiotensin-aldosterone system and a stimulating action on the kallikrein-kinin system. Enalapril is an oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies. Lisinopril is a lysine derivative of enalaprilat. Benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril are other long-acting members of the class. All are prodrugs, like enalapril, and are converted to the active agents by hydrolysis, primarily in the liver. Although ACE Inhibitors are most effective in conditions associated with high plasma renin activity, there is no good correlation among subjects between plasma renin activity and antihypertensive response. Accordingly, renin profiling is unnecessary. ACE Inhibitors have a particularly useful role in treating patients with chronic kidney disease because they diminish proteinuria and stabilize renal function. They benefits probably result from improved intrarenal hemodynamics, with decreased glomerular efferent arteriolar resistance and a resulting reduction of intraglomerular capillary pressure. ACE Inhibitors have also proved to be extremely useful in the treatment of heart failure, and after myocardial infarction, and there is recent evidence that ACE Inhibitors reduce the incidence of diabetes in patients with high cardiovascular risk.

ANGIOTENSIN RECEPTOR BLOCKERS ( ARB)

Losartan and valsartan were the first marketed blockers of the angiotensin II type 1 (AT1) receptor. More recently, candesartan, eprosartan, irbesartan, and telmisartan have been released. They have no effect on bradykinin metabolism and are therefore more selective blockers of angiotensin effects than ACE Inhibitors. They also have the potential for more complete inhibition of angiotensin action compared with ACE Inhibitors because there are enzymes other than ACE that are capable of generating angiotensin II. Angiotensin receptor blockers provide benefits similar to those of ACE inhibitors in patients with heart failure and chronic kidney disease. The adverse effects are similar to those of ACE Inhibitors, including the hazard of use during pregnancy.

Cough and angioedema can occur but are less common with angiotensin receptor blockers than with ACE Inhibitors.

PHARMACODYNAMIC HYPERTENSION

EFFECTS

OF

OTHER

DRUGS

USED

IN

Hypertension is the most common cardiovascular disease, which presents a unique problem in therapeutics. It is usually a lifelong disease that causes few symptoms until the advanced stage. For effective treatment, medicines must be consumed daily. Therefore, the physician must establish with certainty that hypertension is persistent and requires treatment and must exclude secondary causes of hypertension that might be treated by definitive surgical procedures. A useful classification of antihypertensive agents categorizes them into : 1) diuretics, 2). Sympathoplegic agents, 3) direct vasodilators, and 4) agents that block production or action of angiotensin.

Diuretics lower blood pressure primarily by depleting body sodium stores. Initially, diuretics reduce blood pressure by reducing blood volume and cardiac output; peripheral vascular resistance may increase. After 6-8 weeks, cardiac output returns toward normal while peripheral vascular resistance declines. Sodium is believed to contribute to vascular resistance by increasing vascular stiffness and neural reactivity, possibly related to increased sodium-calcium exchange with a resultant increase in intracellular calcium. These effects are reversed by diuretics or sodium restriction. Thiazide diuretics (eg. HCT, chlorthalidon) are appropriate for most patients with mild or moderate hypertension and normal renal and cardiac function. More powerful diuretics (eg. furosemide, ethacrynic acid) are necessary in severe hypertension, when multiple drugs with sodium-retaining properties are used, in renal insufficiency, and in cardiac failure or cirrhosis, where sodium retention is marked. In the treatment of hypertension, the most common adverse effect of diuretics (except for potassium-sparing diuretics) is potassium depletion. Although mild degrees of hypokalemia are tolerated well by many patients, hypokalemia may be hazardous in persons taking digitalis, those who have

chronic arrhytmias, or those with acute myocardial infarction or left ventricular dysfunction. Other adverse effects of diuretics include hypomagnesaemia, impaired glucose tolerance, and increased serum lipid concentration.

Sympathoplegic agents lower blood pressure by reducing peripheral vascular resistance, inhibiting cardiac function, and increasing venous pooling in capacitance vessels. The latter two effects reduce cardiac output. It should be noted that all of agents that lower blood pressure by altering sympathetic function can elicit compensatory effects through mechanisms that are not dependent on adrenergic nerves. Thus, the antihypertensive effect of any of these agents used alone may be limited by retention of sodium by the kidney and expansion of blood volume. For these reasons, sympathoplegic antihypertensive drugs are most effective when used concomitantly with a diuretic. Centrally acting sympathoplegic drugs (eg.methyldopa, clonidine, guanabenz, guanfacine) reduce sympathetic outflow from vasopressor centers in the brainstem but allow these centers to retain or even increase their sensitivity to baroreceptor control. Accordingly, the antihypertensive and toxic actions of these drugs are less dependent on posture than are the effects of drugs that act directly on peripheral sympathetic neurons. Antihypertensive action of methyldopa appears to be due to stimulation of central presynaptic 2-adrenoceptor by alfa-methylnorepinephrine or alfa-methyldopamine. Studies of methyldopa and clonidine suggest that normal regulation of blood pressure involves central adrenergic neurons that modulate baroreceptor reflexes. Clonidine and alfa-methylnorepinephrine bind ore tightly to 2 than to 1 adrenoceptors. It is possible that clonidine and methydopa act in the brain to reduce norepinephrine release onto relevant receptor sites. Finally, clonidine also binds to a nonadrenoceptor site, the imidazoline receptor, which may also mediate antihypertensive effects. Guanabenz and guanfacine are centrally active antihypertensive drugs that share the central alfaadrenoceptor-stimulating effects of clonidine. They do not appear to offer any advantages over clonidine.

Propranolol is a prototype and the first beta-blocker shown to be effective in hypertension and ischaemic heart disease. The other beta blockers that are available in the market include atenolol, oxprenolol, bisoprolol, metoprolol, nadolol, labetalol, carvedilol, pindolol, acebutolol and timolol. In hypertensive patients beta-blockers gradually lower the arterial pressure by a mechanism that involves reduction in cardiac output, reduction of renin release from the juxtagomerular cells of the kidney. Labetalol and carvedilol are mixed - and -adrenoceptor blockers, although clnically they act predominantly on -adenoceptors. Carvedilol is used mainly to treat hypertension and heart failure; labetalol is used occasionally to treat hypertension in pregnancy.

Alpha1-blockers

(eg.

prazosin,

terrazosin,

doxazosin)

produce

their

antihypertensive effect mostly by selectively blocking 1-receptors in arterioles and venules. Alpha-blockers reduce arterial pressure by dilating both resistance and capacitance vessels. As expected, blood pressure is reduced more in upright than in the supine position. Retention of salt and water occurs when these drugs are administered without a diuretic. The drugs are more effective when used in combination with other agents, such as a beta-blocker or a diuretic.

Vasodilators include the oral vasodilators (eg. hydralazine, minoxidil) which are used for long-term outpatient therapy of hypertension; the parenteral vasodilators (eg. nitroprusside, diaxozide, and fenoldopam) which are used to treat hypertensive emergencies; and the calcium channel blockers (eg. nifedipine, amlodipine, diltiazem, verapamil), which are used in both circumstances. All of the vasodilators useful in hypertension relax smooth muscle of arterioles, thereby decreasing systemic vascular resistance. Hydralazine directly relaxes smooth muscle of the arterioles by an unknown mechanism, while minoxidil and diaxozide produce their vasodilating effects by acting as a potassium channel opener, which stabilizes the membrane at its resting potential and makes the contraction is less likely. Sodium nitroprusside is a powerful parenterally administered vasodilator that is used in

treating hypertensive emergencies as well as severe heart failure. Nitroprusside dilates both arterial and venous vessels, resulting in reduced peripheral ascular resistance and venous return. The action occurs as a result of activation of guanylyl cyclase, either via release of nitric oxide or by direct stimulation of the enzyme. The result is increased intracellular cGMP, which relaxes vascular smooth muscle. Fenoldopam is a peripheral arteriolar dilator used for hypertensive emergencies and postoperative hypertension. It acts primarily as an agonist of dopamine D1-receptors, resulting in dilation of peripheral arteries and natriuresis. Calcium channel blockers reduce peripheral resistance and blood pressure. The mechanism of action in hypertension is inhibition of calcium influx into arterial smooth muscle cells.

CARDIAC FAILURE

The underlying abnormality in cardiac failure is a cardiac output that is inadequate to meet the metabolic demands of the body during exercise and ultimately also at rest. It may be caused by disease of the myocardium itself (most commonly ischaemic heart disease), or by circulatory factors such as volume overload (eg. leaky valves, or arteriovenous shunts caused by congenital defects) or pressure overload overload (eg.hypertension). When cardiac output decreases, an increase in fluid volume occurs, partly because increased venous pressure causes increased formation of tissue fluid, and partly because reduced renal blood flow activates the renin-angiotensinaldosterone system, causing sodium and water retention. Non-drug measures, including dietary salt restriction, are important but drugs are needed to improve symptoms of oedema, fatigue and breathlessness and to improve prognosis.

DRUGS USED IN CARDIAC FAILURE

1. Diuretics (eg.furosemide) are important in increasing salt and water excretion, especially if there is pulmonary oedema. Their major mechanism of action in heart failure is to reduce venous pressure and ventricular preload. This results in reduction of oedema and its symptoms, and reduction of cardiac size, which leads to improved pump efficiency. Spironolactone and eplerenone, the aldosterone antagonist diuretics, have the additional benefits of decreasing morbidity and mortality in patients with severe cardiac failure who are also receiving ACE Inhibitors and other standard therapy. 2. The renin-angiotensin-aldosterone system is inappropriately activated in patients with cardiac failure, especially when they are treated with diuretics. The ACE Inhibitors (eg. captopril) counteract this. By blocking the formation of angiotensin II, they reduce vascular resistance, thus improving tissue perfusion and reducing cardiac afterload. They also cause natriuresis by inhibiting secretion of aldosterone and by reducing the direct stimulatory effect of angiotensin II on reabsorption of sodium and water in the proximal tubules. Most important of all, ACE Inhibitors prolong life. 3. Beta-adrenoceptor blockers. Most patients with chronic heart failure respond favorably to certain beta-blockers inspite of the fact that these drugs can

precipitate acute decompensation of cardiac function. Studies with bisoprolol, metoprolol, and carvedilol showed a reduction in mortality in patients with stable severe heart failure but this effect was not observed with another betablocker , bucindolol. A full understanding of the beneficial action of beta-blocade is lacking, but suggested mechanisms include attenuation of the adverse effects of high concentration of catecholamines (including apoptosis), up regulation of betareceptors, decreased heart rate, reduced remodeling through inhibition of the mitogenic activity of catecholamines. 4. Glyceryl trinitrate is used to treat acute cardiac failure, especially if there is associated ischaemic pain. Its venodilator effect reduces venous pressure , and its effects on arterial compliance reduce cardiac work. The combination of hydralazine (to reduce cardiac afterload) with a long-acting organic nitrate (to

reduce preload) in patients with chronic heart failure improves survival, although less well than treatment with ACE Inhibitor. This combination is useful in patients in whom ACEI are contraindicated or are not tolerated. 5. Cardiac glycosides (eg. digoxin) are mainly used either in patients who also have chronic rapid atrial fibrillation or in patients who remain symptomatic despite treatment with diuretic and ACEI. Digoxin does not reduce mortality in this latter group of patients but does improve symptom and reduces the need for hospital admission. Dobutamine ( a 1-selective adrenoceptor agonist) is used intravenously when a rapid response is needed in the short term, for example following heart surgery.

REFERENCES AND FURTHER READING 1. Brunton, L.L., Lazo,J.S., Parker,K.L. (2006). Goodman & Gilmans The Pharmacological Basis of Therapeutics, 11th Edition, McGraw-Hill Medical Publishing Division, USA. 2. Harvey,R.A; Champe,P.C. et al.(2000). Lippincotts Illustrated Reviews, 2nd Edition, Lippincott Williams & Wilkins, A Wolters Kluwer Company, USA. 3. Katzung,B.G. (2007). Basic And Clinical Pharmacology, 10th Edition, McGrawHill Companies,Inc., Singapore. 4. Rang, H.P., Dale,M.M.; Ritter,J.M., Moore,P.K. (2003). Pharmacology, 5th Edition, Churchill Livingstone, Bath Press, U.K.

10

11