DIURETICS
DRUGS USED IN CARDIOVASCULAR DISEASES
DIURETICS
A diuretic is any substance that promotes the production of urine.. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way. The kidney play the major role in maintaining the volume and composition of extracellular fluid- this they do by selectively regulating solute or fluid reabsorption. To achieve significant diuresis, the most important solute that diuretics regulate is sodium, hence, diuretics inhibit renal sodium transport and thereby interfere with the normal regulatory activity of the kidney.
Diuretics are either used alone or in combination with other drugs. In some instances, administration of a diuretic drug is the primary treatment indicated e.g in oedema and premenstrual syndrome, while in others it is one of several drugs that are used as part of a treatment regimen e.g as seen in hypertension.
The term diuretic, however, is generally restricted to agents that act directly on the kidney. Thus, drugs that can enhance urine flow, for example- digitalis, by increasing cardiac output in the patient with congestive heart failure are generally not referred to as diuretics. From a therapeutic point of view, diuretics are considered to be substances that aid in removing excess extracellular fluid and electrolytes. In the main, they accomplish this by decreasing salt and water reabsorption in the tubules.
The classes of diuretics used clinically include the following
Carbonic anhydrase inhibitors
Thiazide diuretics
Loop diuretics
Potassium sparing diuretics
Osmotic diuretics
Carbonic anhydrase inhibitors
The prototype of this class of diuretics is acetazolamide, popularly known with the brand name- diamox. Other drugs in this group include dorzolamide, dichlorphenamide, and methazolamide. This class of diuretics works by inhibition of brush border carbonic anhydrase. Inhibition of proximal tubule brush border carbonic anhydrase decreases bicarbonate reabsorption, and this accounts for their diuretic effect. In addition, carbonic anhydrase inhibitors affect both distal tubule and collecting duct H+ secretion by inhibiting intracellular carbonic anhydrase. Renal excretion of Na+ , K+ , and HCO3- is increased by carbonic anhydrase inhibition. Diuresis following carbonic anhydrase inhibition consists primarily of Na+ and HCO3-
The main therapeutic use of carbonic anhydrase inhibitors is not for the production of diuresis but in the treatment of glaucoma. Because the formation of aqueous humor in the eye depends on carbonic anhydrase, acetazolamide has proved to be a useful adjunct to the usual therapy for lowering intraocular pressure.
ACETAZOLAMIDE
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Thiazide diuretics
The major thiazide diuretics are bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, and trichlormethiazide. Drugs similar to these, called thiazidelike diuretics include chlorthalidone, indapamide, metolazone, and quinethazone. Despite the structural distinctions, the drugs share the functional attribute of increasing sodium and chloride excretion by inhibiting Na+ – Cl- cotransport in distal convoluted tubules. Thiazide diuretics act in the distal convoluted tubule, where they block Na+ Cl- cotransport. The Na+ Cl- cotransport takes place on the luminal surface of distal convoluted tubules. Thus, to exert their diuretic action, the thiazides must reach the luminal fluid i.e they must be filtered at the glomerulus.
HYDROCHLOROTHIAZIDE
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Potassium sparing diuretics
The chronic use of some diuretics may require the oral administration of potassium supplements or potassium-sparing diuretics that reduce urinary K+ excretion. The presence or absence of clinical symptoms of hypokalemia is quite closely related to serum K+ concentrations, and even small changes in extracellular K+ can have marked effects. Most patients begin to show symptoms when serum K+ levels fall below 2.5 mEq/L (from a normal value of 3.5 - 5 mEq/L). Neurological symptoms include drowsiness, irritability, confusion, loss of sensation, dizziness, and coma. Other important symptoms of hypokalemia are muscular weakness, cardiac arrhythmias, tetany, respiratory arrest, and increased sensitivity of the myocardium to digitalislike drugs.
The three principal potassium-sparing diuretic agents (spironolactone, amiloride and triamterene) produce similar effects on urinary electrolyte composition. Through actions in the distal convoluted tubule and collecting duct, they cause mild natriuresis and a decrease in K+ and H+ excretion. Despite their similarities, these agents actually constitute two groups with respect to their mechanisms of action.
Spironolactone (Aldactone)- an aldosterone receptor antagonist, is structurally related to aldosterone and acts as a competitive inhibitor to prevent the binding of aldosterone to its specific cellular binding protein. Spironolactone thus blocks the hormone-induced stimulation of Na+ reabsorption and K+ secretion. Spironolactone, in the presence of circulating aldosterone, promotes a modest increase in Na+ excretion associated with a decrease in K+ elimination. Spironolactone acts only when mineralocorticoids ( aldosterone) are present.
Amiloride and triamterene are referred to as non- steroidal potassium sparing diuretics. Both agents appear to affect Na+ reabsorption in the cortical collecting duct and distal tubules. The reduced rate of Na+ reabsorption diminishes the gradient that facilitates K+ secretion. This is because K+ secretion by the collecting duct principal cells is a passive phenomenon that depends on and is secondary to the active reabsorption of Na+ .
SPIRONOLACTONE
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High ceiling or loop diuretics
The compounds known as high-ceiling or loop diuretics are the most efficacious agents available for inducing marked water and electrolyte excretion. They can increase diuresis even in patients who are already responding maximally to other diuretics.The drugs in this group available for use include furosemide (Lasix), bumetanide torsemide, and ethacrynic acid . Although these agents differ somewhat, they share a common primary site of action, which underlies their effectiveness.
The site of action of loop diuretics is the thick ascending loop of Henle, and diuresis is brought about by inhibition of the Na+ – K+ – 2Cl - transporter. This segment of the nephron is critical for determining the final magnitude of natriuresis. As much as 20% of the filtered Na_ may be reabsorbed by the loop of Henle. The importance of the loop is further emphasized by the realization that drugs that primarily inhibit proximal Na+ and fluid reabsorption have their natriuretic response reduced by the ability of the ascending limb to augment its rate of Na+ reabsorption in the presence of an increased tubular Na+ load. Thus, any agent that greatly impairs active reabsorption in the thick ascending limb may induce a very large Na+ and water loss.
FUROSEMIDE
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Osmotic diuretics
Osmotic diuretics owe their effects to the physical retention of fluid within the nephron rather than to direct action on cellular sodium transport. These compounds are not electrolytes, and they are freely filtered at the glomerulus and not reabsorbed to a significant extent. The prototype is mannitol, an unmetabolizable polysaccharide derivative of sucrose. Other clinically available osmotic diuretics include glycerin, isosorbide and urea Since these osmotic agents act in part to retard tubular fluid reabsorption, the amount of diuresis produced is proportional to the quantity of osmotic diuretic administered. Therefore, unless large quantities of a particular osmotic diuretic are given, the increase in urinary volume will not be marked.
The primary effect involves an increased fluid loss caused by the osmotically active diuretic molecules; this results in reduced Na+ and water reabsorption from the proximal tubule. An additional contributing factor to the diuresis induced by osmotic diuretics is the increase in renal medullary blood flow that follows their administration. Finally, there is an additional increase in electrolyte excretion due to impairment of ascending limb and distal tubule Na+ reabsorption; this occurs as a result of lowered tubular Na+ concentration.
MANNITOL
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USES OF DIURETICS
The ability of certain drugs to increase both fluid and electrolyte loss has led to their use in the clinical management of fluid and electrolyte disorders, for example, oedema. Regardless of the cause of the syndrome associated with oedema, the common factor is almost invariably an increased retention of Na+. The aim of diuretic therapy is to enhance Na+ excretion, thereby promoting negative Na+ balance. This net Na+ (and fluid) loss leads to contraction of the overexpanded extracellular fluid compartment.
Diuretics are used in the following underlisted conditions
Congestive heart failure
Hypertension
Hepatic diseases (such as cirrhosis) that causes ascites
Pulmonary oedema
Renal oedema e.g in nephritic syndrome, chronic kidney failure
Premenstrual oedema
Increased intracranial pressure osmotic diuretics (The parenteral administration of a hypertonic solution of one of the osmotic diuretics, urea or mannitol, can relieve the pressure through its osmotic effects).
DRUGS USED IN CONGESTIVE HEART FAILURE
Chronic CHF may be defined as the clinical condition in which an individual expels less than 40% of the blood from the left ventricle per heartbeat (ejection fraction [EF] < 40%).A normal individual expels about 55 to 65% of the blood from the left ventricle per heartbeat (EF =5565%). The rationale for choosing the 40% EF is based on clinical findings demonstrating progressive deterioration and early mortality in individuals who have an EF below 40%. It is remarkable that the therapeutic approach to a decreased EF is the same regardless of the etiology. The principles that guide the pharmacological management of CHF is the same for patients who had damage from a myocardial infarction (MI), viral infection, valvular disease, alcohol, and so on.
Pharmacological intervention for CHF due to left ventricular systolic dysfunction includes the following
Cardiac glycosides
Diuretics
Angiotensin converting enzyme inhibitors (ACEIs)
Vasodilators
β – adrenoceptor blocking drugs
Cardiac glycosides
Drugs that belong to this group are referred to as digitalis, of which digoxin and digitoxin are examples. Digitalis has the unique characteristic of increasing contractility (positive inotropy) while decreasing heart rate (negative chronotropy). This pharmacological profile results from indirect as well as direct effects of digitalis glycosides on the heart. Digitalis is a fat-soluble steroid that crosses the blood-brain barrier and enhances vagal tone, thus inhibiting the sympathetic nervous system and causing arterial vasodilation. It produces symptomatic improvement, improves exercise tolerance and reduces hospitalisations.
Digitalis remains notorious today for its very narrow dosage window for therapeutic efficacy without toxicity. A unique process, digitalization, for dosing digitalis has been widely accepted over the years as a means of minimizing toxicity. This process is to start patients on several repeated doses of digitalis over 24 to 36 hours before establishing a lower daily maintenance dose.
DIGOXIN
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Diuretics
One cannot discuss the management of heart failure without including comments about the kidney. The relationship between the heart and the kidney makes intuitive sense when one considers the importance of the kidney in maintaining an appropriate volume status throughout the body. The diminished renal perfusion makes the kidney to elaborate hormones designed to retain fluid.
Many of the problems in CHF result from an inappropriate neurohormonal activation by the kidney in response to perceived volume depletion from hemorrhage. Mechanisms that result in vasoconstriction are normally compensatory in the short term for acute bleeding. These same adaptive mechanisms (RAAS response) become damaging in chronic heart failure.
Diuretics used in CHF are majorly the thiazides, loop diuretics and potassium sparing diuretics. They are used alongside other CHF drugs.
ACEIs
These are drugs that prevent the conversion of angiotensin I to angiotensin II ( a potent arterial vasoconstrictor which increases peripheral resistance) by blocking the activity of the enzyme, angiotensin converting enzyme. As discussed above, the kidney initiates the RAAS system in response to perceived depletion in plasma volume, which is inappropriate in CHF because this response only worsens the heart failure via increased peripheral resistance and aldosterone mediated fluid retention. It was recognized that the way to improve survival in heart failure was not by directly addressing the weakened heart pump but rather by reversing the inappropriate peripheral vasoconstriction that results from neurohormonal activation. This factor singles out ACEIs as first line drugs in the treatment of CHF.
The prototype ACEI is captopril. Other drugs in this group include enalapril, lisinopril etc.
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Vasodilators
These are drugs that either help to dilate arteries, veins or both. Both arterial dilation and venous dilation are useful in heart failure. Arterial dilation leads to decreased peripheral resistance which amounts to a decrease in afterload. Venous dilation leads to reduced venous return to the failing heart, thereby reducing ventricular preload, helping to improve symptoms of pulmonary congestion and dyspnoea.
An example of a drug that causes arterial vasodilation is hydralazine while isosorbide dinitrate (nitroglycerin) causes venous dilation.
HYDRALAZINE
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NITROGLYCERINE
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β – adrenoceptor blocking drugs
β-Blockers are adrenoceptor antagonists that bind to the β-receptor at the same site as do endogenous β-adrenergic agonists, such as norepinephrine. Norepinephrine binds to the adrenergic receptor, which activates a G protein, which participates in the conversion of ATP to cAMP via adenylyl cyclase. cAMP subsequently leads to increased calcium, increased heart rate, conduction, and contraction. β-Blockers bind to the same receptor as does norepinephrine but do not facilitate G protein coupling. Occupation of the binding site by the β-blocker prevents norepinephrine from binding to it and stimulating cAMP formation. Not all β-blockers are useful in CHF, use of some has produced improvements in survival, others have produced no improvements at all. An example of β-blocker used in CHF is carvedilol and metoprolol.
DRUGS USED IN HYPERTENSION
Hypertension is described as a persistent elevated rise in blood pressure. It is basically of two types, primary and secondary. The actual level of pressure that can be considered hypertensive is difficult to define; it depends on a number of factors, including the patients age, sex, race, and lifestyle. As a working definition, a diastolic pressure of 90 mm Hg or higher or a systolic pressure of 140 mm Hg or higher represents hypertension.
Hypertension is considered to be stage I, or mild, if diastolic pressure is 90 to 99 mm Hg and/or systolic pressure is 140 to 159 mm Hg. Stage II, or moderate, hypertension is diastolic pressure of l00 to 109 mm Hg and/or systolic pressure of 160 to 179 mm Hg. Stage III, or severe, hypertension exists when diastolic pressure is 110 mm Hg or greater and/or systolic pressure is 180 mm Hg or greater.
There are three general approaches to the pharmacological treatment of primary hypertension. The first involves the use of diuretics to reduce blood volume. The second employs drugs that interfere with the reninangiotensin system, and the third is aimed at a drug-induced reduction in peripheral vascular resistance, cardiac output, or both. A reduction in peripheral vascular resistance can be achieved directly by relaxing vascular smooth muscle with drugs known as vasodilators or indirectly by modifying the activity of the sympathetic nervous system. Therefore, the classes of drugs used include the following:
Diuretics
Angiotensin converting enzyme inhibitors
Calcium channel blockers
Vasodilators
Drugs that impair sympathetic nervous system------ β-adrenoceptor antagonist, α-adrenoceptor antagonist, drugs that interfere with norepinephrine synthesis, release and storage.
Centrally acting sympathoplegics.
Of the above drugs, first line regimen include the use of diuretics (thiazides in particular), ACEIs and β-adrenoceptor antagonists.
N.B -- It should be noted that blood pressure is mathematically defined as the product of cardiac output and peripheral resistance i.e B.P = C.O × P.R . This informs the fact that any factor that either increases C.O or P.R or both will lead to an increase in blood pressure. Therefore, pharmacological therapy is usually directed towards the reduction / elimination of these factors.
Diuretics
The value of diuretics lies in their ability to reverse the Na_ retention commonly associated with many antihypertensive drugs that probably induce Na_ retention and fluid volume expansion as a compensatory response to blood pressure reduction. The type (s) of diuretics used include thiazides, loop diuretics and potassium sparing diuretics.
Angiotensin converting enzyme inhibitors
As discussed above, these drugs prevent the conversion of angiotensin I to angiotensin II ( a potent arterial vasoconstrictor which increases peripheral resistance) by blocking the activity of the enzyme, angiotensin converting enzyme. Therefore, the absence of adequate amounts of angiotensin II to stimulate increased peripheral resistance leads to reduced blood pressure. Examples already discussed above.
Calcium channel blockers
Also called calcium entry blockers, the available Ca2+ channel blockers exert their effects primarily at voltage-gated Ca2+ channels of the plasma membrane. It should be recalled that Ca2+ influx occurs during membrane depolarisation, making Ca2+ ion a very important ion and second messenger that underlies the process of excitation- contraction coupling in the cardiovascular system. Calcium currents in cardiac tissues serve the functions of inotropy, pacemaker activity (sinoatrial (SA) node), and conduction at the atrioventricular (A-V) node. In essence, calcium channel blockers prevents influx of Ca2+ into the myocardial cells leading to slowing of the heart rate, strong depression of conduction at the A-V node, and inhibition of contractility.
These drugs also exert vascular effects. Vascular tone and contraction are determined largely by the availability of calcium from extracellular sources (influx via calcium channels) or intracellular stores.
Drug-induced inhibition of calcium influx via voltagegated channels results in widespread dilation and a decrease in contractile responses to stimulatory agents. Ingeneral, arteries and arterioles are more sensitive tothe relaxant actions of these drugs than are the veins.
Examples include nifedipine and its analogues( e.g amlodipine, isradipine, felodipin), verapamil and diltiazem.
NIFEDIPINE
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VERAPAMIL
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Vasodilators
These drugs produce a direct relaxation of vascular smooth muscle and thereby their actions result in vasodilation. This effect is called direct because it does not depend on the innervation of vascular smooth muscle and is not mediated by receptors, such as adrenoceptors, cholinoreceptors, that are acted on by classical transmitters and mediators such as norepinephrine and acetylcholine. The vasodilators decrease total peripheral resistance and thus correct the hemodynamic abnormality that is responsible for the elevated blood pressure in primary hypertension. In addition, because they act directly on vascular smooth muscle, the vasodilators are effective in lowering blood pressure, regardless of the etiology of the hypertension. Unlike many other antihypertensive agents, the vasodilators do not inhibit the activity of the sympathetic nervous system; therefore, orthostatic hypotension and impotence are not problems. Also, they mediate decreased preload and afterload as discussed above.
However, the lack of sympathetic nervous system inhibition produced by the vasodilators, which is advantageous in some ways ( absence of orthostatic hypotension and impotence), can also be a disadvantage in that reflex increases in sympathetic nerve activity will lead to hemodynamic changes that reduce the effectiveness of the drugs. Therefore, the vasodilators are generally inadequate as the sole therapy for hypertension. However, many of the factors that limit the usefulness of the vasodilators can be obviated when they are administered in combination with a β-adrenoceptor antagonist, such as propranolol, and a diuretic. Propranolol reduces the cardiac stimulation that occurs in response to increases in sympathetic nervous activity, and the large increase in cardiac output caused by the vasodilators will be reduced. Propranolol also reduces plasma renin levels, and that is an additional benefit. The reduction in Na+ excretion and the increase in plasma volume that occurs with vasodilator therapy can be reduced by concomitant treatment with a diuretic.
Examples of vasodilators include hydralazine and minoxidil ( both are effective when administered orally) and are used for the chronic treatment of primary hypertension. Other drugs, diazoxide and sodium nitroprusside, are effective only when administered intravenously. They are generally used in the treatment of hypertensive emergencies or during surgery. All these drugs exert their effect primarily on arteries/arterioles except sodium nitroprusside which exerts its effect on arteries and veins.
SODIUM NITROPRUSSIDE
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Drugs that impair sympathetic nervous system
β-adrenoceptor antagonist – Discussed above
α-adrenoceptor antagonist- Examples include phenoxybenzamine, phentolamine, doxazosin and prazosin. These drugs block α-adrenoceptors on cardiac and smooth muscle thereby preventing norepinephrine from stimulating these receptors, the resultant effect of which is reduced blood pressure.
Drugs that interfere with norepinephrine storage e.g reserpine. Reserpine is the prototypical drug interfering with norepinephrine storage. Reserpine lowers blood pressure by reducing norepinephrine concentrations in the noradrenergic nerves in such a way that less norepinephrine is released during neuron activation.
Drugs that interfere with norepinephrine release. Also called adrenergic neuron-blocking drugs, these drugs are antihypertensives because they prevent the release of transmitters from peripheral postganglionic sympathetic nerves. The contraction of vascular smooth muscle due to sympathetic nerve stimulation is thereby reduced, and blood pressure decreases. Guanethidine is the prototypical member of this class.
Drugs that interfere with norepinephrine synthesis. Metyrosine is an example of this class of drugs. Chemically, metyrosine is α-methyl tyrosine. The drug blocks the action of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines. The ultimate action of the drug is to decrease the production of catecholamines.
Centrally acting sympathoplegics.
Two important antihypertensive agents, α-methyldopa and clonidine, act predominantly in the brain. Although the details of their actions may differ in some respects, their antihypertensive activity is ultimately due to their ability to decrease the sympathetic outflow from the brain to the cardiovascular system.
α-METHYLDOPA
Current evidence suggests that for α-methyldopa to be an antihypertensive agent, it must be converted to α-methylnorepinephrine; however, its primary site of action appears to be in the brain rather than or to a lesser extent, in the periphery. Systemically administered α-methyldopa rapidly enters the brain, where it accumulates in noradrenergic nerves, is converted to α-methylnorepinephrine, and is released. Released α-methylnorepinephrine activates CNS α- adrenoceptors whose function is to decrease sympathetic outflow.
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DIURETICS
A diuretic is any substance that promotes the production of urine.. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way. The kidney play the major role in maintaining the volume and composition of extracellular fluid- this they do by selectively regulating solute or fluid reabsorption. To achieve significant diuresis, the most important solute that diuretics regulate is sodium, hence, diuretics inhibit renal sodium transport and thereby interfere with the normal regulatory activity of the kidney.
Diuretics are either used alone or in combination with other drugs. In some instances, administration of a diuretic drug is the primary treatment indicated e.g in oedema and premenstrual syndrome, while in others it is one of several drugs that are used as part of a treatment regimen e.g as seen in hypertension.
The term diuretic, however, is generally restricted to agents that act directly on the kidney. Thus, drugs that can enhance urine flow, for example- digitalis, by increasing cardiac output in the patient with congestive heart failure are generally not referred to as diuretics. From a therapeutic point of view, diuretics are considered to be substances that aid in removing excess extracellular fluid and electrolytes. In the main, they accomplish this by decreasing salt and water reabsorption in the tubules.
The classes of diuretics used clinically include the following
Carbonic anhydrase inhibitors
Thiazide diuretics
Loop diuretics
Potassium sparing diuretics
Osmotic diuretics
Carbonic anhydrase inhibitors
The prototype of this class of diuretics is acetazolamide, popularly known with the brand name- diamox. Other drugs in this group include dorzolamide, dichlorphenamide, and methazolamide. This class of diuretics works by inhibition of brush border carbonic anhydrase. Inhibition of proximal tubule brush border carbonic anhydrase decreases bicarbonate reabsorption, and this accounts for their diuretic effect. In addition, carbonic anhydrase inhibitors affect both distal tubule and collecting duct H+ secretion by inhibiting intracellular carbonic anhydrase. Renal excretion of Na+ , K+ , and HCO3- is increased by carbonic anhydrase inhibition. Diuresis following carbonic anhydrase inhibition consists primarily of Na+ and HCO3-
The main therapeutic use of carbonic anhydrase inhibitors is not for the production of diuresis but in the treatment of glaucoma. Because the formation of aqueous humor in the eye depends on carbonic anhydrase, acetazolamide has proved to be a useful adjunct to the usual therapy for lowering intraocular pressure.
ACETAZOLAMIDE
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Thiazide diuretics
The major thiazide diuretics are bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, and trichlormethiazide. Drugs similar to these, called thiazidelike diuretics include chlorthalidone, indapamide, metolazone, and quinethazone. Despite the structural distinctions, the drugs share the functional attribute of increasing sodium and chloride excretion by inhibiting Na+ – Cl- cotransport in distal convoluted tubules. Thiazide diuretics act in the distal convoluted tubule, where they block Na+ Cl- cotransport. The Na+ Cl- cotransport takes place on the luminal surface of distal convoluted tubules. Thus, to exert their diuretic action, the thiazides must reach the luminal fluid i.e they must be filtered at the glomerulus.
HYDROCHLOROTHIAZIDE
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Potassium sparing diuretics
The chronic use of some diuretics may require the oral administration of potassium supplements or potassium-sparing diuretics that reduce urinary K+ excretion. The presence or absence of clinical symptoms of hypokalemia is quite closely related to serum K+ concentrations, and even small changes in extracellular K+ can have marked effects. Most patients begin to show symptoms when serum K+ levels fall below 2.5 mEq/L (from a normal value of 3.5 - 5 mEq/L). Neurological symptoms include drowsiness, irritability, confusion, loss of sensation, dizziness, and coma. Other important symptoms of hypokalemia are muscular weakness, cardiac arrhythmias, tetany, respiratory arrest, and increased sensitivity of the myocardium to digitalislike drugs.
The three principal potassium-sparing diuretic agents (spironolactone, amiloride and triamterene) produce similar effects on urinary electrolyte composition. Through actions in the distal convoluted tubule and collecting duct, they cause mild natriuresis and a decrease in K+ and H+ excretion. Despite their similarities, these agents actually constitute two groups with respect to their mechanisms of action.
Spironolactone (Aldactone)- an aldosterone receptor antagonist, is structurally related to aldosterone and acts as a competitive inhibitor to prevent the binding of aldosterone to its specific cellular binding protein. Spironolactone thus blocks the hormone-induced stimulation of Na+ reabsorption and K+ secretion. Spironolactone, in the presence of circulating aldosterone, promotes a modest increase in Na+ excretion associated with a decrease in K+ elimination. Spironolactone acts only when mineralocorticoids ( aldosterone) are present.
Amiloride and triamterene are referred to as non- steroidal potassium sparing diuretics. Both agents appear to affect Na+ reabsorption in the cortical collecting duct and distal tubules. The reduced rate of Na+ reabsorption diminishes the gradient that facilitates K+ secretion. This is because K+ secretion by the collecting duct principal cells is a passive phenomenon that depends on and is secondary to the active reabsorption of Na+ .
SPIRONOLACTONE
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High ceiling or loop diuretics
The compounds known as high-ceiling or loop diuretics are the most efficacious agents available for inducing marked water and electrolyte excretion. They can increase diuresis even in patients who are already responding maximally to other diuretics.The drugs in this group available for use include furosemide (Lasix), bumetanide torsemide, and ethacrynic acid . Although these agents differ somewhat, they share a common primary site of action, which underlies their effectiveness.
The site of action of loop diuretics is the thick ascending loop of Henle, and diuresis is brought about by inhibition of the Na+ – K+ – 2Cl - transporter. This segment of the nephron is critical for determining the final magnitude of natriuresis. As much as 20% of the filtered Na_ may be reabsorbed by the loop of Henle. The importance of the loop is further emphasized by the realization that drugs that primarily inhibit proximal Na+ and fluid reabsorption have their natriuretic response reduced by the ability of the ascending limb to augment its rate of Na+ reabsorption in the presence of an increased tubular Na+ load. Thus, any agent that greatly impairs active reabsorption in the thick ascending limb may induce a very large Na+ and water loss.
FUROSEMIDE
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Osmotic diuretics
Osmotic diuretics owe their effects to the physical retention of fluid within the nephron rather than to direct action on cellular sodium transport. These compounds are not electrolytes, and they are freely filtered at the glomerulus and not reabsorbed to a significant extent. The prototype is mannitol, an unmetabolizable polysaccharide derivative of sucrose. Other clinically available osmotic diuretics include glycerin, isosorbide and urea Since these osmotic agents act in part to retard tubular fluid reabsorption, the amount of diuresis produced is proportional to the quantity of osmotic diuretic administered. Therefore, unless large quantities of a particular osmotic diuretic are given, the increase in urinary volume will not be marked.
The primary effect involves an increased fluid loss caused by the osmotically active diuretic molecules; this results in reduced Na+ and water reabsorption from the proximal tubule. An additional contributing factor to the diuresis induced by osmotic diuretics is the increase in renal medullary blood flow that follows their administration. Finally, there is an additional increase in electrolyte excretion due to impairment of ascending limb and distal tubule Na+ reabsorption; this occurs as a result of lowered tubular Na+ concentration.
MANNITOL
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USES OF DIURETICS
The ability of certain drugs to increase both fluid and electrolyte loss has led to their use in the clinical management of fluid and electrolyte disorders, for example, oedema. Regardless of the cause of the syndrome associated with oedema, the common factor is almost invariably an increased retention of Na+. The aim of diuretic therapy is to enhance Na+ excretion, thereby promoting negative Na+ balance. This net Na+ (and fluid) loss leads to contraction of the overexpanded extracellular fluid compartment.
Diuretics are used in the following underlisted conditions
Congestive heart failure
Hypertension
Hepatic diseases (such as cirrhosis) that causes ascites
Pulmonary oedema
Renal oedema e.g in nephritic syndrome, chronic kidney failure
Premenstrual oedema
Increased intracranial pressure osmotic diuretics (The parenteral administration of a hypertonic solution of one of the osmotic diuretics, urea or mannitol, can relieve the pressure through its osmotic effects).
DRUGS USED IN CONGESTIVE HEART FAILURE
Chronic CHF may be defined as the clinical condition in which an individual expels less than 40% of the blood from the left ventricle per heartbeat (ejection fraction [EF] < 40%).A normal individual expels about 55 to 65% of the blood from the left ventricle per heartbeat (EF =5565%). The rationale for choosing the 40% EF is based on clinical findings demonstrating progressive deterioration and early mortality in individuals who have an EF below 40%. It is remarkable that the therapeutic approach to a decreased EF is the same regardless of the etiology. The principles that guide the pharmacological management of CHF is the same for patients who had damage from a myocardial infarction (MI), viral infection, valvular disease, alcohol, and so on.
Pharmacological intervention for CHF due to left ventricular systolic dysfunction includes the following
Cardiac glycosides
Diuretics
Angiotensin converting enzyme inhibitors (ACEIs)
Vasodilators
β – adrenoceptor blocking drugs
Cardiac glycosides
Drugs that belong to this group are referred to as digitalis, of which digoxin and digitoxin are examples. Digitalis has the unique characteristic of increasing contractility (positive inotropy) while decreasing heart rate (negative chronotropy). This pharmacological profile results from indirect as well as direct effects of digitalis glycosides on the heart. Digitalis is a fat-soluble steroid that crosses the blood-brain barrier and enhances vagal tone, thus inhibiting the sympathetic nervous system and causing arterial vasodilation. It produces symptomatic improvement, improves exercise tolerance and reduces hospitalisations.
Digitalis remains notorious today for its very narrow dosage window for therapeutic efficacy without toxicity. A unique process, digitalization, for dosing digitalis has been widely accepted over the years as a means of minimizing toxicity. This process is to start patients on several repeated doses of digitalis over 24 to 36 hours before establishing a lower daily maintenance dose.
DIGOXIN
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Diuretics
One cannot discuss the management of heart failure without including comments about the kidney. The relationship between the heart and the kidney makes intuitive sense when one considers the importance of the kidney in maintaining an appropriate volume status throughout the body. The diminished renal perfusion makes the kidney to elaborate hormones designed to retain fluid.
Many of the problems in CHF result from an inappropriate neurohormonal activation by the kidney in response to perceived volume depletion from hemorrhage. Mechanisms that result in vasoconstriction are normally compensatory in the short term for acute bleeding. These same adaptive mechanisms (RAAS response) become damaging in chronic heart failure.
Diuretics used in CHF are majorly the thiazides, loop diuretics and potassium sparing diuretics. They are used alongside other CHF drugs.
ACEIs
These are drugs that prevent the conversion of angiotensin I to angiotensin II ( a potent arterial vasoconstrictor which increases peripheral resistance) by blocking the activity of the enzyme, angiotensin converting enzyme. As discussed above, the kidney initiates the RAAS system in response to perceived depletion in plasma volume, which is inappropriate in CHF because this response only worsens the heart failure via increased peripheral resistance and aldosterone mediated fluid retention. It was recognized that the way to improve survival in heart failure was not by directly addressing the weakened heart pump but rather by reversing the inappropriate peripheral vasoconstriction that results from neurohormonal activation. This factor singles out ACEIs as first line drugs in the treatment of CHF.
The prototype ACEI is captopril. Other drugs in this group include enalapril, lisinopril etc.
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Vasodilators
These are drugs that either help to dilate arteries, veins or both. Both arterial dilation and venous dilation are useful in heart failure. Arterial dilation leads to decreased peripheral resistance which amounts to a decrease in afterload. Venous dilation leads to reduced venous return to the failing heart, thereby reducing ventricular preload, helping to improve symptoms of pulmonary congestion and dyspnoea.
An example of a drug that causes arterial vasodilation is hydralazine while isosorbide dinitrate (nitroglycerin) causes venous dilation.
HYDRALAZINE
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NITROGLYCERINE
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β – adrenoceptor blocking drugs
β-Blockers are adrenoceptor antagonists that bind to the β-receptor at the same site as do endogenous β-adrenergic agonists, such as norepinephrine. Norepinephrine binds to the adrenergic receptor, which activates a G protein, which participates in the conversion of ATP to cAMP via adenylyl cyclase. cAMP subsequently leads to increased calcium, increased heart rate, conduction, and contraction. β-Blockers bind to the same receptor as does norepinephrine but do not facilitate G protein coupling. Occupation of the binding site by the β-blocker prevents norepinephrine from binding to it and stimulating cAMP formation. Not all β-blockers are useful in CHF, use of some has produced improvements in survival, others have produced no improvements at all. An example of β-blocker used in CHF is carvedilol and metoprolol.
DRUGS USED IN HYPERTENSION
Hypertension is described as a persistent elevated rise in blood pressure. It is basically of two types, primary and secondary. The actual level of pressure that can be considered hypertensive is difficult to define; it depends on a number of factors, including the patients age, sex, race, and lifestyle. As a working definition, a diastolic pressure of 90 mm Hg or higher or a systolic pressure of 140 mm Hg or higher represents hypertension.
Hypertension is considered to be stage I, or mild, if diastolic pressure is 90 to 99 mm Hg and/or systolic pressure is 140 to 159 mm Hg. Stage II, or moderate, hypertension is diastolic pressure of l00 to 109 mm Hg and/or systolic pressure of 160 to 179 mm Hg. Stage III, or severe, hypertension exists when diastolic pressure is 110 mm Hg or greater and/or systolic pressure is 180 mm Hg or greater.
There are three general approaches to the pharmacological treatment of primary hypertension. The first involves the use of diuretics to reduce blood volume. The second employs drugs that interfere with the reninangiotensin system, and the third is aimed at a drug-induced reduction in peripheral vascular resistance, cardiac output, or both. A reduction in peripheral vascular resistance can be achieved directly by relaxing vascular smooth muscle with drugs known as vasodilators or indirectly by modifying the activity of the sympathetic nervous system. Therefore, the classes of drugs used include the following:
Diuretics
Angiotensin converting enzyme inhibitors
Calcium channel blockers
Vasodilators
Drugs that impair sympathetic nervous system------ β-adrenoceptor antagonist, α-adrenoceptor antagonist, drugs that interfere with norepinephrine synthesis, release and storage.
Centrally acting sympathoplegics.
Of the above drugs, first line regimen include the use of diuretics (thiazides in particular), ACEIs and β-adrenoceptor antagonists.
N.B -- It should be noted that blood pressure is mathematically defined as the product of cardiac output and peripheral resistance i.e B.P = C.O × P.R . This informs the fact that any factor that either increases C.O or P.R or both will lead to an increase in blood pressure. Therefore, pharmacological therapy is usually directed towards the reduction / elimination of these factors.
Diuretics
The value of diuretics lies in their ability to reverse the Na_ retention commonly associated with many antihypertensive drugs that probably induce Na_ retention and fluid volume expansion as a compensatory response to blood pressure reduction. The type (s) of diuretics used include thiazides, loop diuretics and potassium sparing diuretics.
Angiotensin converting enzyme inhibitors
As discussed above, these drugs prevent the conversion of angiotensin I to angiotensin II ( a potent arterial vasoconstrictor which increases peripheral resistance) by blocking the activity of the enzyme, angiotensin converting enzyme. Therefore, the absence of adequate amounts of angiotensin II to stimulate increased peripheral resistance leads to reduced blood pressure. Examples already discussed above.
Calcium channel blockers
Also called calcium entry blockers, the available Ca2+ channel blockers exert their effects primarily at voltage-gated Ca2+ channels of the plasma membrane. It should be recalled that Ca2+ influx occurs during membrane depolarisation, making Ca2+ ion a very important ion and second messenger that underlies the process of excitation- contraction coupling in the cardiovascular system. Calcium currents in cardiac tissues serve the functions of inotropy, pacemaker activity (sinoatrial (SA) node), and conduction at the atrioventricular (A-V) node. In essence, calcium channel blockers prevents influx of Ca2+ into the myocardial cells leading to slowing of the heart rate, strong depression of conduction at the A-V node, and inhibition of contractility.
These drugs also exert vascular effects. Vascular tone and contraction are determined largely by the availability of calcium from extracellular sources (influx via calcium channels) or intracellular stores.
Drug-induced inhibition of calcium influx via voltagegated channels results in widespread dilation and a decrease in contractile responses to stimulatory agents. Ingeneral, arteries and arterioles are more sensitive tothe relaxant actions of these drugs than are the veins.
Examples include nifedipine and its analogues( e.g amlodipine, isradipine, felodipin), verapamil and diltiazem.
NIFEDIPINE
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VERAPAMIL
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Vasodilators
These drugs produce a direct relaxation of vascular smooth muscle and thereby their actions result in vasodilation. This effect is called direct because it does not depend on the innervation of vascular smooth muscle and is not mediated by receptors, such as adrenoceptors, cholinoreceptors, that are acted on by classical transmitters and mediators such as norepinephrine and acetylcholine. The vasodilators decrease total peripheral resistance and thus correct the hemodynamic abnormality that is responsible for the elevated blood pressure in primary hypertension. In addition, because they act directly on vascular smooth muscle, the vasodilators are effective in lowering blood pressure, regardless of the etiology of the hypertension. Unlike many other antihypertensive agents, the vasodilators do not inhibit the activity of the sympathetic nervous system; therefore, orthostatic hypotension and impotence are not problems. Also, they mediate decreased preload and afterload as discussed above.
However, the lack of sympathetic nervous system inhibition produced by the vasodilators, which is advantageous in some ways ( absence of orthostatic hypotension and impotence), can also be a disadvantage in that reflex increases in sympathetic nerve activity will lead to hemodynamic changes that reduce the effectiveness of the drugs. Therefore, the vasodilators are generally inadequate as the sole therapy for hypertension. However, many of the factors that limit the usefulness of the vasodilators can be obviated when they are administered in combination with a β-adrenoceptor antagonist, such as propranolol, and a diuretic. Propranolol reduces the cardiac stimulation that occurs in response to increases in sympathetic nervous activity, and the large increase in cardiac output caused by the vasodilators will be reduced. Propranolol also reduces plasma renin levels, and that is an additional benefit. The reduction in Na+ excretion and the increase in plasma volume that occurs with vasodilator therapy can be reduced by concomitant treatment with a diuretic.
Examples of vasodilators include hydralazine and minoxidil ( both are effective when administered orally) and are used for the chronic treatment of primary hypertension. Other drugs, diazoxide and sodium nitroprusside, are effective only when administered intravenously. They are generally used in the treatment of hypertensive emergencies or during surgery. All these drugs exert their effect primarily on arteries/arterioles except sodium nitroprusside which exerts its effect on arteries and veins.
SODIUM NITROPRUSSIDE
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Drugs that impair sympathetic nervous system
β-adrenoceptor antagonist – Discussed above
α-adrenoceptor antagonist- Examples include phenoxybenzamine, phentolamine, doxazosin and prazosin. These drugs block α-adrenoceptors on cardiac and smooth muscle thereby preventing norepinephrine from stimulating these receptors, the resultant effect of which is reduced blood pressure.
Drugs that interfere with norepinephrine storage e.g reserpine. Reserpine is the prototypical drug interfering with norepinephrine storage. Reserpine lowers blood pressure by reducing norepinephrine concentrations in the noradrenergic nerves in such a way that less norepinephrine is released during neuron activation.
Drugs that interfere with norepinephrine release. Also called adrenergic neuron-blocking drugs, these drugs are antihypertensives because they prevent the release of transmitters from peripheral postganglionic sympathetic nerves. The contraction of vascular smooth muscle due to sympathetic nerve stimulation is thereby reduced, and blood pressure decreases. Guanethidine is the prototypical member of this class.
Drugs that interfere with norepinephrine synthesis. Metyrosine is an example of this class of drugs. Chemically, metyrosine is α-methyl tyrosine. The drug blocks the action of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines. The ultimate action of the drug is to decrease the production of catecholamines.
Centrally acting sympathoplegics.
Two important antihypertensive agents, α-methyldopa and clonidine, act predominantly in the brain. Although the details of their actions may differ in some respects, their antihypertensive activity is ultimately due to their ability to decrease the sympathetic outflow from the brain to the cardiovascular system.
α-METHYLDOPA
Current evidence suggests that for α-methyldopa to be an antihypertensive agent, it must be converted to α-methylnorepinephrine; however, its primary site of action appears to be in the brain rather than or to a lesser extent, in the periphery. Systemically administered α-methyldopa rapidly enters the brain, where it accumulates in noradrenergic nerves, is converted to α-methylnorepinephrine, and is released. Released α-methylnorepinephrine activates CNS α- adrenoceptors whose function is to decrease sympathetic outflow.
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