Treating the Diseases of Cardiovascular System | Essay | Medical Science

In this essay we will discuss about the drugs used for treating the diseases of cardiovascular system.

Essay # 1. Cardiac Glycosides:

Cardiac glycosides are the drugs that have inotropic action. They increase myocardial contractility and cardiac output in a hypo-dynamic heart without an increase in oxygen requirement and thus the overall myocardial efficiency as a pump is increased.

The cardiac glycosides are mainly obtained from the dried leaves of the foxglove plant, though they are also present in stropanthus and squill species and animals. Digoxin and digitoxin are the two principal glycosides obtained from Digitalis purpurea (digitoxin) and Digitalis lanata (digitoxin, digoxin). Digoxin is the only cardiac glycoside which is used and is being produced synthetically.

Pharmcokinetics:

Cardiac glycosides are well absorbed. They are cumulative drugs, because they are bound to heart muscle which accounts for the prolonged action. Digoxin is excreted by the kidneys and accumulation occurs in patients with poor renal functions. Digitoxin is metabolized by the liver.

Pharmacological Actions:

i. Effects on the failing heart:

Positive inotropic action:

Digoxin increases the force of contraction of the ventricular muscle by increasing both the velocity of muscle contraction and the maximum force that is developed without causing corresponding increase in the oxygen consumption. Thus overall myocardial efficiency is increased.

Cardiac glycosides do not prolong the duration of the contraction and they do not directly affect myocardial contractile proteins energy for contraction. This action is due to an increase in calcium ions in the heart muscle for interaction with contractile proteins. In large doses, digitalis causes increase excitability of the ventricles. The positive inotropic action of digoxin is observed only on the failing heart.

Heart rate:

Digoxin slows the heart rate (a negative chronotropic effect), partly due to increased activity of the vagus nerve and partly due to a direct action on the sinoatrial (SA) node.

A-V conduction:

Digoxin depresses conduction in the atrioventricular (AV) node and the bundle of His. This action does not affect the heart in sinus rhythm, but in atrial fibrillation, it decreases the number of impulses reaching the ventricles and thus decreases the rate of ventricular contraction.

The most important of these three actions is slowing of the ventricular rate, particularly in atrial fibrillation where the slower and more regular ventricular contractions allow the heart to function more efficiently leading to an increase in the cardiac output. The positive inotropic effect is less important and if the heart is in sinus rhythm the benefits are minimal.

ii. Extra cardiac effects:

Digoxin in congestive heart failure (CHF) causes a drop in peripheral resistance and veno-motor tone. Increased cardiac output and renal blood flow has a diuretic effect. Digoxin in higher doses causes stimulation of CTZ resulting in nausea and vomiting.

Therapeutic Uses:

a. Low-output cardiac failure:

The positive inotropic effect of digoxin is short lived and less important. The main use of digitalis lies in its slowing the pulse rate, in atrial fibrillation. Digoxin improves symptoms of heart failure and exercise tolerance, but it does not reduce mortality.

b. Cardiac arrhythmias:

Digoxin has great value in certain cardiac arrhythmias, even if they are unassociated with heart failure.

c. Atrial fibrillation:

Digoxin reduces the ventricular rate by prolonging the refractory period of conduction tissue.

d. Atrial flutter:

Digoxin may convert atrial flutter to atrial fibrillation. If digitalis is then stopped, normal sinus rhythm may be restored.

e. Paroxysmal atrial tachycardia:

It responds to digoxin, presumably as a result of reflex vagal stimulation.

Digitalization:

Digoxin is a cumulative drug and treatment is started with a full dose (loading dose) of the drug followed by the maintenance dose to replace the day-to-day loss. Loading dose. Rapid digitalization is done with digoxin 1-1.5 mg in divided doses over 24 hours and for less urgent digitalization 0.2-0.5 mg is given daily.

Maintenance dose is 0.125-0.25 mg daily, according to renal function. The toxic-therapeutic ratio is narrow and therapy should be followed by monitoring of plasma levels of digoxin, particularly in patients with unstable renal functions.

Adverse Effects:

i. Undue slowing of the heart:

A pulse rate below 60 indicates that the drug should be omitted for a day or two.

ii. Coupled beats:

These are due to ventricular extra-systoles following normal beats (double pulsation followed by a pause) and necessitate omission of the drug. Overdose may lead to paroxysmal tachycardia or even ventricular fibrillation a fatal complication.

iii. Nausea and vomiting:

Digoxin stimulates the vomiting centre in medulla, but heart failure itself can also produce vomiting. Visual disturbances (colour vision), headache, confusion, delirium and hallucinations are other symptoms of digoxin overdose. Concurrent use of certain diuretics may lower potassium levels in the blood resulting in increased digitalis toxicity.

The action of digoxin is increased by verapamil, diltiazem and amiodarone. Cardiac glycosides are contraindicated in intermittent heart block, second degree A-V block, supraventricular arrhythmias caused by Wolff-Parkinson-White syndrome, high output CHF and constructive pericarditis.

Treatment of digoxin Intoxication:

Lignocaine is the preferred antiarrhythmic drug for ventricular arrhythmias. Digoxin-specific antibody (digibind) is indicated in life threatening digitalis intoxication. Each 4.0 mg of digibind neutralizes approximately 0.6 mg of digoxin.

Essay # 2. Angiotensin Converting Enzyme (ACE) Inhibitors:

The renin-angiotensin system (RAS) is of primary importance in the control of blood pressure, body fluid volume and myocardial function. Renin controls the formation of angiotensin II. Angiotensin II is one of the most potent vasoconstrictors being 40 times more potent than noradrenaline. Angiotensin II interacts with the AT₁ receptor (angiotensin II receptor type I) and accelerates numerous cellular processes, which contributes to hypertension and end-organ damage.

These include:

i. Aldosterone secretion from adrenal gland leading to salt and water retention.

ii. Vasoconstriction due to:  

(a) Peripheral vasoconstriction,

(b) Vascular hypertrophy,

(c) Production of superoxide anions and other reactive oxygen species that inactivate nitric oxide, thereby inhibiting endothelium-dependent vasodilatation, and

(d) Augmentation of both central and peripheral sympathetic nervous system leading to excessive stimulation of adrenergic receptors in peripheral blood vessels.

iii. Cardio-toxic action due to: 

(a) Hypertrophy of cardiac musculature and

(b) Aldosterone induced collagen deposition leading to cardiac fibrosis.

Mechanism of Action:

ACE inhibitors inhibit the enzyme responsible for the conversion of angiotensin I to angiotensin II in the circulation and prevent the deleterious actions of angiotensin II on the cardiovascular system. However, the beneficial effects of ACE inhibitors may not be entirely explained by the inhibition of formation of angiotensin II.

ACE inhibitors also enhance the actions of kinins (e.g. bradykinin, vasodilatory prostaglandins); kinin potentiation contributes importantly to the actions of ACE inhibitors. Bradykinin is a potent endothelial-dependent vasodilator.

The effects of ACE inhibitors on the cardiovascular system are greater than angiotensin II receptor blocking drugs, which do not enhance the action of kinins. ACE inhibitors, by inhibiting the formation of angiotensin II, reduce aldosterone secretion which leads to a mild natriuretic and a decrease in K⁺ secretion.

Pharmacokinetics:

ACE inhibitors are well absorbed orally; they differ in their onset and duration of action. Most of them are pro-drugs (except lisinopril) which are converted into active forms in the liver. They are eliminated by the kidneys. Fosinopril is unique in that 50% of the drug is eliminated by the liver under normal conditions, but (this) percentage increases in the presence of renal inefficiency.

Pharmacological Actions:

ACE inhibitors cause a fall in blood pressure and may actually improve the structure of thickened arteries. They also reduce proteinuria in diabetic patients with kidney disease and slow the decline in renal functions. Despite the vasodilating effects, ACE inhibitors do not cause significant reflex tachycardia, perhaps due to resetting of the baroreceptor reflex.

In heart failure, ACE inhibitors decrease left ventricular chamber size, lower the resistance to blood flow from the heart due to dilatation of the arterioles (afterload), improve the left ventricular ejection fraction, reduce cardiac work and raise cardiac output. ACE inhibitors can reduce hypokalemia, hypercholesterolemia, hyperglycemia, and hyper-uricemia caused by diuretic therapy.

Therapeutic Uses:

Large numbers of ACE inhibitors (captopril, enalapril, lisinopril, ramipril, quinapril, perindopril, cilazopril, fosinopril, imidapril, moexipril, and trandolapril.) are available with similar actions and uses.

a. Heart failure:

ACE inhibitors are considered to be amongst first line agents for the treatment of heart failure due to left ventricular systolic dysfunction, and have a valuable role in all grades of heart failure, combined when appropriate with a diuretic, β blocker and digoxin. In chronic heart failure, they cause an increase in cardiac output, reduction in peripheral and pulmonary vascular resistance, and reduction in the retention of salt and water. ACE inhibitors relieve dyspnea, prolong exercise tolerance, and reduce the need for emergency care for worsening heart failure.

Because fluid retention can attenuate the effects of ACE inhibitors, they should not be used before or instead of diuretics in patients with a history of fluid retention. There is evidence that they not only control symptoms of heart failure but also reduce the mortality rate in heart failure (Digitalis does not reduce mortality). A marked fall in blood pressure occurs occasionally with the first dose of ACE inhibitor, especially if the patient is already taking a diuretic. For this reason the initial dose in heart failure should be low and taken before going to bed.

The starting dose of captopril is 6.5 or 12.5 mg to minimize any hypotensive effect and maintenance dose is 25 or 50 mg three times daily. The initial dose of enalapril is 2.5 mg and maintenance dose 10 or 20 mg twice daily. Trandolapril is long acting and is given once daily (initial dose 0.5-1.0 mg and maintenance dose 4 mg).

b. Hypertension:

ACE inhibitors, because of their low side effect profiles and beneficial effects on the heart are recommended as first-line treatment for hypertension either as a single drug or combined with other antihypertensive drugs such as diuretics and β blockers. They are particularly useful if hypertension is complicated by diabetic nephropathy, non-diabetic renal insufficiency and heart failure.

They can be used in patients with mild or moderate degree of renal impairment, although, serum creatinine and potassium need to be monitored in all patients receiving ACE inhibitors. Except for captopril (given thrice daily), they require only once a day administration.

Adverse Effects:

Adverse effects associated with the use of ACE inhibitors are infrequent. They do not cause levels of lipids, glucose or uric acid to increase. The adverse effects of ACE inhibitors are those related to blockade of the actions of angiotensin II or to, those related to the effects of kinin potentiation.

i. Adverse effects due to blockade of angiotensin:

ACE inhibitors can precipitate acute renal failure in patients with bilateral renal artery stenosis or hypovolemia. After correction of hypovolemia, ACE inhibitors can be restarted safely at a lower dose. Potassium retention may occur if the patient is receiving potassium supplements or potassium-sparing diuretics, which can be avoided by making changes in these background medicines. Catopril, which contains a sulfhydryl group, may cause taste disturbances, leucopenia and a glomerulopathy with proteinuria.

ii. Adverse effects due to kinin potentiation:

The common side effect of ACE inhibitors is a nonproductive cough (up to 20% of patients) and is probably due to inhibition of bradykinin breakdown. The most serious adverse effect is angioedema, which occurs in less than 1% of patients and may be life threatening. Bronchospasm (5%) and skin rashes are additional side effects. The adverse effects due to kinin potentiation require withdrawal of ACE inhibitors and its replacement with angiotensin II receptor blocking drugs. These drugs are contraindicated in pregnancy because they are teratogenic.

Essay # 3. Angiotensin-Receptor Blockers (ARBs):

Angiotensin II is an extremely powerful vasoconstrictor that acts on specific angiotensin II receptors on the blood vessel wall and on the renin-angiotensin system. Antagonist drugs bind to angiotensin II receptor and block the vasoconstrictor actions and the secretary effects on the zona glomerulosa of angiotensin II at the angiotensin II type 1 receptor. These actions result in decreased peripheral vascular resistance.

Candesartan, irbesartan, losartan, telmisartan, valsartan and olmesartan are ARBs available for clinical use. ARBs have approximately comparable pharmacological actions similar to that of ACE inhibitors. In contrast to ACE inhibitors, they do not cause accumulation of kinins.

The side effect profile of ARBs is similar to ACE inhibitors, except that they do not cause adverse effects related to kinins. ARBs should not be used as substitutes for ACE inhibitors, but only as an alternative in patients who cannot tolerate ACE inhibitors. Losartan differs from other ARBs in two ways: a shorter duration of action requiring twice-daily dosing if used as mono-therapy, and a uricosuric effect, which may be beneficial in patients with hyperuricemia.

Essay # 4. Diuretics:

Diuretics are drugs which cause a net loss of sodium ions and water from the body, resulting into an increase secretion of urine from the kidneys. Diuretics are not used in patients who cannot empty their bladder (e.g. prostatic hyperplasia leading to urinary retention).

Classification:

Diuretics are classified according to their site of action in the kidney tubule and their relative effects on sodium and potassium excretion.

They belong to three main groups:

a. Thiazides and related drugs.

b. “Loop” (high ceiling) diuretics, and

c. Potassium sparing diuretics.

In addition, less often used diuretics are the carbonic anhydrase inhibitors and osmotically active drugs. Mercurial diuretics, because of their serious cardiac and renal toxicity are no longer used.

a. Thiazides:

These are moderately potent diuretics, and with few exceptions are equally effective at equivalent doses. Bendroflumethiazide (bendrofluazide) is the most widely used thiazide in doses of 2.5-5 mg daily. Other thiazide drugs chlorothiazide, clopamide, cyclo-penthiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, and polythiazide do not offer any significant advantage over bendrofluazide.

Mechanism of action:

Thiazides are medium potency natriuretic drugs. They inhibit sodium reabsorption, particularly in the cortical portion of the ascending tubule of loop of Henle and at the beginning of the distal convoluted tubule, where less than 10% of the filtered sodium load is reabsorbed and cause excretion of only 5-10% of the total sodium load. Refractoriness to their action does not occur. Thiazides also increase excretion of potassium by the kidney. Thiazides may also produce mild vasodilatation by inhibiting sodium entry into vascular smooth muscles. Indapamide in particular has pronounced vasodilating effect.

Pharmacokinetics:

All thiazides are given orally and are well absorbed. They produce diuresis within 2 hours, but the duration varies between 12 hours or less (bendrofluazide) and 48 hours or longer (polythiazide). They are mainly excreted unchanged by kidneys. Long acting thiazides cause profound hypokalemia.

Pharmacological actions:

Thiazides increase the renal excretion of Na⁺, CI, HCO₃^– and K⁺. Thiazides have a direct vasodilator effect.

Therapeutic uses:

i. Congestive heart failure: 

Thiazides are used to treat mild to moderate edema of heart failure.

ii. Hypertension:

Thiazides are first-line drugs for the management of hypertension in patients with normal renal functions. Bendrofluazide in small doses (2.5 mg daily) lowers the blood pressure and rarely causes postural hypotension or biochemical disturbances. Addition of a p blocker or ACE inhibitor to thiazide treatment usually obviates the need for potassium supplements.

iii. Cirrhosis of liver with ascites:

Thiazides will produce diuresis with reduction in the ascites and edema. Mental changes with disorientation may occur due to potassium deficiency produced by these drugs.

iv. Hypercalciurea:

Thiazides increase calcium retention and may reduce stone formation and the frequency of renal colic.

Adverse effects:

Thiazides, especially long acting (e.g. polythiazide, chlorthalidone), may result in biochemical disorders such as hypokalemia, hypomagnesemia, hyperuricemia, gout, hyperlipidemia (with increase in low density lipoproteins and triglyceride levels) and hyperglycemia. Serum potassium monitoring may be necessary when used with digitalis, in cirrhosis of liver and in acute myocardial infarction. Other side effects include weakness, muscle cramps and impotence. Thiazides are contraindicated in refractory hypokalemia and renal and hepatic impairment.

Thiazide related drugs:

Chlorthalidone has a longer duration of action than thiazides and may be given on alternate days to control edema. Indapamide produces minimal diuresis but lowers blood pressure as effectively as a thiazide. In contrast to thiazides, indapamide has little or no apparent influence on concentrations of serum potassium, urate, glucose or lipoproteins.

Xipamide has pronounced diuretic action but causes profound hypokalemia. Metolazone, unlike other thiazides, exerts its action at the proximal as well as the distal tubule and may be useful in combination with a loop diuretic, even in patients with renal failure. Severe electrolyte disturbances have been reported and it should be reserved for resistant edema.

b. Loop Diuretics:

The loop or “high ceiling” diuretics are powerful diuretics and act by inhibiting the reabsorption of sodium from the ascending limb of the loop of Henle in the renal tubule, where normally about 20% of the filtered sodium load is reabsorbed. The loop diuretics have the advantage of inducing diuresis despite volume and electrolyte depletion.

Pharmacokinetics:

Loop diuretics are rapidly absorbed after oral administration and have a characteristically rapid onset (30-60 minutes) and brief duration (4—6 hours) of action.

Pharmacological actions:

Loop diuretics cause greater excretion of chloride than sodium. Hypochloraemic alkalosis can occur but it does not produce a refractory state. They increase renal blood flow without increasing glomerular filtration rate. Large doses promote uric acid excretion.

Therapeutic uses:

Loop diuretics are useful in acute pulmonary edema, edema associated with chronic heart failure, cirrhosis, and renal disease. High dose intravenous furosemide has been used to treat elevated intracranial pressure and in hypercalcaemia of malignancy. Furosemide (lasix) is the most widely used loop diuretic. Its bioavailability is poor, perhaps as low as 20%. It can be administered intramuscularly and more often intravenously. The dose is 20-40 mg.

Bumetanide is 40 times more potent on a weight basis than furosemide and its bioavailability is much higher because of better oral absorption. It is more ‘potassium sparing’ than furosemide and is less likely to impair glucose tolerance or cause urate retention. It is preferred for those patients who fail to respond to oral furosemide.

Ethacrynic acid is a loop diuretic which also possesses uricosuric action but it is now little used because of high incidence of adverse reactions. However, it is used in sulfa-sensitive patients as an alternative to furosemide and bumetanide, which are sulfa derivatives.

Adverse effects:

Loop diuretics cause biochemical disturbances as seen with thiazides except on lipids.. They may precipitate acute urinary retention in patients with prostatism and cause mild or asymptomatic thrombocytopenia and ototoxicity. Loop diuretics are contraindicated in precomatose states associated with cirrhosis or renal failure with anuria.

Drug interactions:

Thiazide and loop diuretics can cause nephrotoxicity when combined with NSAIDs or aminoglycoside antibiotics. Thiazides increase lithium toxicity. Concurrent use of steroids increases potassium loss.

c. Potassium Sparing Diuretics:

Triamterene, amiloride and spironolactone are potassium sparing diuretics. These are only weak natriuretics but potentiate the action of thiazides and loop diuretics and cause retention of potassium. Triamterene and amiloride block the specific sodium channels in the distal renal tubule, and thus prevent the active sodium reabsorption at the expense of potassium. This results in excretion of sodium and in prevention of potassium loss.

Triamterene and amiloride are usually combined with thiazides and loop diuretics:

Co-amilozide — Hydrochlorothiazide + Amiloride

Dyazide — Hydrochlorothiazide + Triamterene

Co-amilofruse — Frusemide + Amiloride

Therapeutic uses:

Potassium sparing diuretics are mainly used to conserve potassium rather than for their diuretic and antihypertensive actions. Amiloride, by inhalation, is used to treat lung disease associated with cystic fibrosis.

Adverse effects:

Hyperkalemia can occur in patients with impaired renal functions and those taking ACE inhibitors, especially in treatment of hypertension. Triamterene (usually in combination with hydrochlorothiazide) can cause renal tubular damage and renal calculi.

Spironolactone:

Spironolactone inhibits the increase in numbers of sodium channels and activity of Na⁺/K⁺ pump, which drives the exchange process under the influence of aldosterone. It is a competitive antagonist of aldosterone. Spironolactone causes diuresis as well as retention of potassium and magnesium. It also causes some fall in blood pressure.

Eplerenone:

Eplerenone is a selective aldosterone receptor antagonist that does not possess the hormonal side effects of spironolactone. It is used as an alternative to spironolactone and has been found to reduce mortality in patients with heart failure associated with acute myocardial infarction.

Therapeutic uses:

Spironolactone is at times used in the treatment of heart failure. It has an additional benefit in improving myocardial function in heart failure, which is independent of its effect on renal transport mechanism. Serum potassium must be monitored closely after its initiation, since the potential for development of life-threatening hyperkalemia exists with the use of potassium-sparing diuretics.

Concomitant use of ACE inhibitors and NSAIDs and the presence of renal insufficiency increase the risk of hyperkalemia. Spironolactone should not be used for hypertension because long term therapy carries a remote risk of carcinogenicity.

Adverse effects:

Spironolactone may cause hyperkalemia (especially when used alone), metabolic acidosis, rashes and estrogenic effects such as gynaecomastia, testicular atrophy and menstrual disorders which may limit its use. Unlike thiazides, potassium sparing and loop diuretics do not cause adverse lipid effects.

Drug interactions:

ACE inhibitors promote potassium retention by inhibiting the release of aldosterone and pose a major risk of hyperkalemia when combined with potassium sparing diuretics. NSAIDs in combination with potassium sparing diuretics may precipitate acute renal failure. Spironolactone increases digoxin plasma concentration as a result of its reduced clearance.

Other Diuretics:

Carbonic Anhydrase Inhibitors:

Mechanism of action:

Carbonic anhydrase inhibitors inhibit carbonic anhydrase enzyme, which reduces the number of H⁺ ions available for Na⁺-H⁺ exchange and thus leads to decrease Na⁺ reabsorption. Carbon dioxide (CO₂) reabsorption from glomerular filtrate is suppressed and HC0₃^–excretion is increased. Increase urinary excretion of Na⁺, K⁺ and HCO₃^– results in an alkaline urine leading to metabolic acidosis. The acidosis eventually induces a refractory state (i.e. decreased diuresis). Carbonic anhydrase inhibitors also reduce the rate of aqueous humor and spinal fluid formation.

Therapeutic uses:

Carbonic anhydrase inhibitors are no longer used as diuretics because of development of metabolic acidosis which limits their diuretic effect.

Acetazolamide (Diamox) is given orally (250 mg-1 g daily in divided doses) for following conditions:

i. Glaucoma to reduce rate of aqueous humor formation.

ii. Petit mal epilepsy, in which they act as an anticonvulsant and decrease the rate of spinal fluid formation.

iii. Mountain sickness to increase ventilation at altitude.

iv. Salicylate or barbiturates poisoning to alkalinize the urine and increase their excretion.

Adverse effects:

Side effects are not common. Acetazolamide is an aromatic sulphonamide and rarely can cause blood dyscrasias and allergic skin reactions. Large doses may cause drowsiness and parasthesias.

Osmotic Diuretics:

Mechanism of action:

Osmotic diuretics are filtered at the glomerulus but are poorly reabsorbed because of their molecular size. The presence of osmotic diuretics in the proximal tubule decreases reabsorption of Na⁺ and water resulting in marked diuresis.

Therapeutic uses:

Mannitol is used in cerebral edema by intravenous infusion in a dose of 50-200 g as a 20% solution over a period of 24 hours.

Adverse effects:

Chills and fever may occur. Mannitol infusion is contraindicated in CHF and pulmonary oedema.

Essay # 5. Calcium Channel Blockers:

In the myocardium and vascular smooth muscle, an essential step in the process of contraction is the entry of calcium ions in the cells. Calcium channel blocking drugs or calcium antagonists act by selective blockade of the slow inward calcium channels into the myocardium and the vascular smooth muscles. Thus, myocardial contractility is reduced (negative inotropic effect), the formation and propagation of electrical impulses within the heart is depressed (decreased AV conduction) and coronary and systemic vascular tone is diminished (vasodilatation).

On the basis of chemical structure and differential effects on the heart and blood vessels, calcium antagonist can be divided into three groups (Table 5.2):

Dihydropyridines include nifedipine, nicardipine, amlodipine, felodipine, isradipine lacidipine and nisoldipine.

Pharmacokinetics:

Calcium antagonists are well absorbed after oral administration. Most of them undergo extensive first pass metabolism in the liver. They differ in their duration of action.

a. Short-Acting:

Nifedipine, nicardipine, isradipine and diltiazem. These need to be administered twice or three times daily.

b. Long-Acting:

Amlodipine, lacidipine, felodipine, nisoldipine and verapamil. These drugs are usually administered once daily. They are highly bound by serum proteins and are excreted as metabolites in the urine.

Pharmacological Actions:

i. CVS effects:

Calcium antagonist suppresses cardiac contractility and slow cardiac conduction. They are potent vasodilators. Verapamil and diltiazam have more pronounced action on heart while dihydro­pyridines are more potent vasodilators.

ii. Extra-Cardiac effects:

Verapamil produces nonspecific sympathetic antagonism and has a local anesthetics action. Calcium antagonists have no significant effects on glucose tolerance, electrolytes or lipid profiles.

Therapeutic Uses:

a. Angina:

Calcium antagonists are used in lieu of a β blocker (when contraindicated or not tolerated) or in conjunction with β blocker, if β blockers are not fully effective at relieving angina symptoms. Calcium antagonist lower the oxygen requirements of the ischemic myocardium by reducing myocardial contractility and by decreasing the cardiac work by dilating the peripheral blood vessels and lowering left ventricular pressure (after load) and by decreasing the venous return (preload) due to a decrease in venous tone.

In addition, they relieve coronary artery spasm and therefore are very useful in treating angina. Unlike, β blockers, they do not greatly reduce the heart rate. Calcium antagonist has a synergistic action with β blockers. Given alone, they are generally less potent than β blockers, but may prove very useful when β blockers are contraindicated.

All calcium antagonists except isradipine and lacidipine are indicated for prophylaxis of angina. Verapamil and diltiazem are highly negative inotropic calcium channel blockers and may precipitate heart failure and should not be used with β blockers.

b. Supraventricular tacchycardia:

Verapamil is used to slow the ventricular rate in many supraventricular arrhythmias and may sometimes prevent or abolish them. It is not useful in managing ventricular arrhythmias.

c. Hypertension:

Calcium antagonists qualify to be first line drugs for treatment of hypertension, especially when diuretics or β blockers are contraindicated or may produce unfavorable metabolic effects. Calcium antagonists relax arterial muscles and so reduce raised blood pressure. Their hypotensive effect is more striking when combined with a β blocker (amlodipine and atenolol, a popular combination in use). Dihydropyridine calcium antagonists are usually more potent hypotensives than verapamil. Nifedipine has been used successfully in combination with methyldopa in the long term treatment of severe hypertension.

d. Raynaud’s syndrome:

Nifedipine is useful for reducing the frequency and severity of vasospastic attacks, particularly the idiopathic variety rather than that secondary to collagen vascular disorders.

e. Subarachnoid haemorrhage:

Nifedipine acts preferentially on cerebral arteries and is used for prevention and treatment of ischaemic neurological defects following subarachnoid haemorrhage.

f. Non-Cardiac chest pain:

Nifedipine decreases the pressure in the lower oesophageal sphincter and is useful in patients with diffused oesophageal spasm and “nutcracker” oesophagus, which is a common cause of non-cardiac chest pain.

g. Migraine:

Nifedipine and verapamil have been reported to reduce the frequency of migrainous headache.

h. Cardiomyopathy:

Verapamil, particularly reduces cardiac symptoms and improves tolerance to exercise in hypertrophic cardiomyopathy, even in patients who have not responded to β blockers. Calcium antagonists, unlike diuretics and β blockers, have not been found to be associated with particular problems in managing patients who have concomitant peripheral vascular disease, gout or asthma.

Adverse Effects:

Headache, flushing, ankle oedema (which may respond only partially to diuretics) and GIT disturbances can occur with all calcium antagonists, but is more common with dihydropyridines. Drug induced allergic reactions with hepatitis may occur rarely.

Dihydropyridines should not be used in cardiogenic shock, unstable angina, advanced aortic stenosis and pregnancy. Verapamil particularly causes constipation. Verapamil and diltiazem are cardiac depressants and are contraindicated in heart failure, or significantly impaired left ventricular function, second or third degree AV block and sick sinus syndrome. Calcium antagonists enhance the action of digoxin, theophylline and carbamazepine by increasing their steady state blood concentrations.

Essay # 6. Nitrates and Antianginal Drugs:

Nitrates are the principal drugs for the treatment of acute attacks of angina pectoris and in anticipation of attacks, to prevent their occurrence.

Mechanism of action:

Nitrates relieve the pain of angina in two ways:

a. By venodilation which is their main action. This decreases the venous return of blood to the heart and thus reduces the heart work and demand for myocardial oxygen by decreasing left ventricular volume, filling pressure and to a lesser extent afterload.

b. By increasing the supply of oxygen by causing redistribution of coronary blood flow (dilatation occurs only in normal vessels) and increasing collateral flow particularly to ischemic regions. The primary action of nitrates is due to release of nitric oxide which is the “endogenous nitrate” (endothelial derived relaxant factor) and plays an important part in mediating vasodilatation by lowering intracellular free calcium concentration.

Pharmacokinetics:

Nitrates are readily absorbed from the buccal mucous membranes, the skin, the gastrointestinal tract, and the lungs. The nitrates undergo extensive first pass metabolism in the liver and need sufficiently large doses (to offset first pass metabolism) to be pharmacologically active. Nitrates differ in their potency and onset and duration of action (Table 5.4).

Pharmacological Actions:

Heart:

The major effect of the nitrates on the heart is to reduce myocardial oxygen requirements.

Extra Cardiac:

Nitrates dilate the cerebral vessels, which may result in an increase in cerebral pressure and headache and skin vessels resulting in flushing. They relax bronchial muscles and biliary tract smooth muscles with a reduction of biliary pressure.

Therapeutic Uses:

The main use of nitrates is in the prophylaxis and treatment of an acute attack of angina. They can be used in several ways for the management of angina. Sublingual glyceryl trinitrate (nitroglycerine) is the best drug for providing rapid symptomatic relief of an acute attack of angina. Nitroglycerine is also available as a metered dose aerosol, which is sprayed onto the oral mucosa.

The aerosol spray has the advantage of chemically stable, may produce even more rapid relief from angina in some patients and may also be useful in patients affected by dry mouth, who find difficulty in dissolving sublingual tablet.

Isosorbide dinitrate (sorbitrate) is also active sublingually and is a more stable preparation for those who require nitrates infrequently.

Nitroglycerine and sorbitrate are also absorbed from skin, but more slowly than from the sublingual mucosa, bypassing the liver and are available as transdermal impregnated skin patches. These and other long acting nitrates can be given for prophylaxis, but development of tolerance limits their use on routine basis. Nitroglycerine and sorbitrate can be used intravenously in patients with severe angina or myocardial infarction for the relief of pain and control of hypertension.

Tolerance:

Tolerance to the action of nitrates occurs when taken regularly for prophylaxis. Mechanisms involved for development of tolerance include the down regulation of receptors after continuous use of nitrates or increased liver metabolism. Tolerance is due to depletion of reduced sulphydryl groups in vascular smooth muscle. Lower doses of nitrates combined with a calcium antagonist or beta blockers may obviate the nitrate tolerance.

Adverse Effects:

These are related to vasodilatation and include throbbing headache, flushing, postural hypotension and reflex tachycardia. Nitrate ions in large amount can oxidize hemoglobin to methaemoglobin to result in hypoxia.

Other Antianginal Drugs:

Calcium antagonist, β blockers and potassium channel activator are used for prevention of an attack of angina.

Potassium channel activators:

Nicroandil, a potassium channel activator has actions like nitrates and calcium antagonists. It causes both arterial and venous dilatation and is reserved for the prevention and long-term treatment of angina, in patients who remain symptomatic despite management with other drugs. Side effects are like nitrates and include headache, flushing, nausea, and vomiting. Nicroandil is contraindicated in cardiogenic shock, left ventricular failure and hypotension.

Essay # 7. Anticoagulants:

The anticoagulant drugs are used in the prophylaxis of venous thrombosis, where the thrombus consists of a fibrin web enmeshed with platelets and red cells. Anticoagulants are generally ineffective in the treatment of arterial (white) thrombi which are composed mainly of platelets with little fibrin.

Heparin:

Heparin is a complex mixture of acidic substances. It occurs naturally, and is stored in mast cells and basophils. It is a very potent anticoagulant. It is derived from porcine intestinal mucosa or bovine lung tissue.

Mechanism of action:

Heparin inhibits coagulation both in vivo and vitro. Normally, factor Xa formed by the clotting cascade, when activated converts pro-thrombin to thrombin. Thrombin reacts with soluble fibrinogen to form fibrin strands, which enmeshes the platelets to form a clot.

Heparin inhibits coagulation by inactivation of factor Xa and thrombin by binding to antithrombin III. Therefore, heparin prolongs the activated partial thromboplastin time (aPTT) and the thrombin time (TT). Factor VIIa is unaffected. Because the anticoagulant effects of heparin administration normalize within hours of discontinuation and heparin is reversible by protamine sulphate, it is the therapy of choice for patients with increased risk of bleeding. Heparin suppresses the rate of aldosterone secretion and cell- mediated immunity and slows wound healing.

Pharmacokinetics:

Heparin is not absorbed orally because of its highly negated charge and large molecular size. It is usually given by intravenous or sometimes by subcutaneous injection. It is not given by intramuscular injection because of formation of painful hematomas. Heparin is metabolized in liver by heparinase. The anticoagulant effect of heparin is seen with a minute or two of injection and passes off within a few hours. Heparin does not cross the placental barrier.

Therapeutic uses:

Heparin is given as an intravenous loading dose (5,000 units), followed by subcutaneous injection of 15,000 units every 12 hours along with warfarin for 3 days (the period until oral anticoagulant becomes effective) for the treatment of deep vein thrombosis, pulmonary embolism, management of myocardial infarction, unstable angina and acute peripheral arterial occlusion.

Low dose heparin by subcutaneous injection is used prophylactically in orthopaedic surgery (particularly, if the pelvis or hip is involved) to prevent postoperative deep vein thrombosis and pulmonary embolism. Heparin therapy is monitored by measurements of activated partial thromboplastic time (aPTT) which should be kept between 1.5 and 2.5 times the control value.

Adverse effects:

Hemorrhage is the most common side effect, which requires withdrawal of heparin. In emergency, protamine sulphate, a specific antidote, shall reverse the effects of heparin.

Other side effects of heparin include thrombocytopenia, hyperkalemia (due to inhibition of aldosterone secretion), hypersensitivity reactions and osteoporosis after prolonged use.

Heparin is contraindicated in hemophilia and other hemorrhagic disorders, peptic ulcer, recent cerebral hemorrhage, severe hypertension, severe liver disease and hypersensitivity to heparin.

Low molecular weight heparin (LMWH):

Heparin is a large molecule that can be broken down into a number of fragments, which also have anticoagulant properties and are known as low molecular weight heparins. Dalteparin, enoxaparin, tinzaparin and certoparin are low molecular weight heparin preparations.

They offer certain advantages over un-fractioned heparin:

i. LMWH inactivates factor Xa to a greater extent than it does thrombin; therefore, the aPTT is minimally prolonged and the patients may not need the same degree of monitoring.

ii. LMWH subcutaneously is as effective as intravenous unfractioned heparin.

iii. LMWH does not cross placental barrier and can be used during pregnancy.

iv. LMWH is long acting than unfractioned heparin.

v. LMWH can be used in lower doses for prevention of thrombosis.

vi. LMWH is less likely to cause thrombocytopenia and osteoporosis than unfractioned heparin.

vii. LMWH without laboratory monitoring of anticoagulant effect is safe and efficacious.

viii. LMWH is the first choice for long-term anticoagulation in pregnant women with thrombosis, and it is an alternative for patients who have clearly failed oral anticoagulation or have unacceptable INR liability.

Fondaparinux:

It is a synthetic pentasaccharide, which is a selective inhibitor of factor Xa. It is structurally similar to the region of the heparin molecule that binds anti-thrombin and is used by SC route for deep vein thrombosis (DVT) prophylaxis. Unlike heparin and LMWH, it does not cause thrombocytopenia.

Protamine sulphate:

Protamine sulphate, a basic protein, reverses the action of heparin. It is a specific antidote for the acidic heparin and is given intravenously. It may cause a fall in blood pressure.

Hirudin:

Hirudin was, originally obtained from leeches. It is now made synthetically using recombinant technology. It differs from heparin in its mode of action, being a specific inhibitor of thrombin. It is used in patients with heparin-induced thrombocytopenia (HIT) and associated thrombosis by intravenous infusion. No reversal agent is available for hirudin. Lepirudin and desirudin are two recombinant hirudins available for therapeutic use.

Argatroban:

It is a synthetic direct thrombin inhibitor, and is used by intravenous infusion for the treatment of thrombosis in HIT patients. The actions of argatroban are like hirudin and cannot be reversed by any agent.

Oral Anticoagulants:

The Coumarins:

Warfarin and phenindione are the oral anticoagulants. They act by inhibiting the reduction of vitamin K to its active form. Consequently, administration of coumarins leads to depletion of the vitamin-K dependent clotting factors II (prothrombin), VII, IX, and X and proteins C and S. Warfarin is well absorbed orally, but requires 4-5 days before the full anticoagulant effect is achieved and for immediate effect, heparin is given concomitantly. Phenindione is a short acting anticoagulant and is seldom used.

Therapeutic uses:

Warfarin is used for prophylaxis of embolism in rheumatic heart disease and atrial fibrillation and after insertion of prosthetic heart valve. It is used with heparin for the treatment of venous thrombosis and pulmonary embolism.

The pro-thrombin time should be measured before starting treatment, then daily in the early days of treatment, then up to every 12 weeks to maintain INR between 2 and 3.5 depending on the clinical situation. INR (International Normalized Ratio) is the patient’s pro-thrombin time divided by normal pro-thrombin time. The pro-thrombin time (PT) is the time taken for clotting to occur in a sample of blood to which thromboplastin and calcium have been added. (Thromboplastin is formed naturally during the early stages of coagulation, and it converts the inactive prothrombin to thrombin.).

Adverse effects:

The main adverse effects are:

a. Hemorrhage

b. Skin rashes, fever and jaundice (phenindione)

c. Teratogenic effects (fetal abnormalities)

Coumarin-induced skin necrosis is a rare complication that can occur during initiation of warfarin therapy because of rapid depletion of the anticoagulant factor protein C. Hemorrhage is the most important side-effect, which may result from over dosage. It is best treated by withdrawal of the drug. If necessary an infusion of fresh frozen plasma or phytomenadione (vitamin K) is given intravenously. Warfarin is contraindicated in active peptic ulcer, severe liver disease, and renal failure and during pregnancy.

Drug interactions:

The anticoagulant activity of warfarin is increased by antibiotics, NSAIDs, antiplatelet drugs, lipid lowering drugs, alcohol, cimetidine, anabolic hormones, antimalarials and phenytoin. Barbiturates and oral contraceptives decrease the activity of warfarin.

Ximelogatran:

Ximelogatran is an oral direct thrombin inhibitor that is currently being evaluated in clinical trials for prophylaxis and therapeutic anticoagulation. Unlike warfarin, it does not require monitoring of coagulation studies.

Essay # 8. Antiplatelet Drugs:

Antiplatelet drugs reduce platelet “stickiness” (aggregation) and are helpful in inhibiting arterial thrombosis, where thrombi are formed partly by platelet aggregation and where anticoagulants have little effect.

The main indications for the use of antiplatelet drugs are:

i. Angina pectoris

ii. Myocardial infarction

iii. Peripheral arterial disease

iv. Cerebrovascular disease (stroke prevention)

v. Coronary angioplasty

Among the various antiplatelet drugs, aspirin is the most widely used. The use of aspirin for stroke prevention has become controversial since a meta-analysis of controlled clinical trials of the use of low dose aspirin-a-day was found to increase the risk of hemorrhagic stroke by 69 percent in males.

Aspirin:

Aspirin is unique in that it causes irreversible inhibition of platelet cyclooxygenase leading to depletion of thromboxane for the life of the platelets. Thromboxane is responsible for platelet aggregation and its depletion by aspirin results in inhibition of platelet ‘stickiness’ to athermanous plaques in arteries and thus prevents formation of arterial thrombus or its extension. Aspirin does not block all the pathways to platelets clumping.

Therapeutic uses:

Aspirin within the dose range of 75-300 mg daily is taken regularly for the prophylaxis of vascular diseases and for the secondary prevention of thrombolic cerebrovascular episodes in cardio­vascular diseases (myocardial infarction, stable angina, atrial fibrillation, and intermittent claudication) and following bypass surgery. Aspirin may have a place in preventing eclampsia in pregnancy and in slowing the progress of diabetic retinopathy. The use of aspirin is contraindicated in children under 15 years and in breast-feeding (Reye’s syndrome), active peptic ulceration, hemophilia and other bleeding disorders.

Dipyridamole:

Dipyridamole inhibits the uptake of adenosine into erythrocytes and other tissues. It allows metabolically released adenosine to accumulate in the plasma, which decreases coronary vascular resistance and increases coronary blood flow and coronary sinus oxygen saturation.

Dipyridamole also prevents platelet aggregation. It is not very effective when given alone and is used as an adjunct to oral anticoagulation for prophylaxis of thromboembolism associated with prosthetic heart valves. It can also be used alone or with aspirin for secondary prevention of ischemic stroke and transient ischemic attacks.

Glycoprotein IIb/llla (GPIIb/IIIa) Receptor Antagonists:

The final step in the platelet aggregation is mediated by the binding of fibrinogen to the functionally active receptor (GPIIb/IIIa) on the platelet surface. Drugs inhibit platelet aggregation by competing with fibrinogen for occupancy on the platelet surface receptor GPIIb/IIIa, leading to blocking of all the pathways to platelet aggregation.

Ticlopidine and clopidogrel are orally active GPIIb/IIIa receptor inhibitors that are used for long-term prophylaxis of thrombo­embolic episodes. Abciximab, tirofiban and eptifibatide are GPIIb/IIIa inhibitors that are available for IV administration in patients undergoing percutaneous coronary interventions (PCI), and tirofiben and eptifibatide in patients with unstable angina and non S-T segment elevation myocardial infarction.

Ticlopidine:

Ticlopidine, though more effective than aspirin in reducing stroke in patients with transient cerebral ischemia, is not suitable for long-term use due to its many important side effects, which include hypercholesterolemia, aplastic anemia, and thrombolic thrombocytopenia purpura (TTP).

Clopidogrel:

Clopidogrel has replaced ticlopidine because it is equally effective and has a better safety profile. It is absorbed and metabolised rapidly, and the onset of platelet aggregation inhibition is more rapid than ticlopidine. Inhibition of platelet is detectable 90 minutes after an oral loading dose of 300 mg, which is maintained by administration of low doses (75 mg) daily. Clopidogrel is more effective than aspirin in patients who have experienced a recent stroke or recent myocardial infarction and in patients presenting symptomatic peripheral arterial disease.

The combination of clopidogrel and aspirin is more effective than aspirin alone in patients with unstable angina and non-ST segment elevation myocardial infarction. Side effect is mainly hemorrhage. GIT, CNS, hepatic and biliary disorders have also been reported. It is contraindicated in active bleeding and breast-feeding.

Essay # 9. Fibrinolytic Drugs:

Fibrinolysis, normally, takes place to digest a blood clot. Plasminogen, a naturally occurring plasma globulin protein, is deposited on the fibrin strands. Plasminogen activators convert plasminogen into another protein called plasmin, which digests fibrin and fibrinogen amongst other proteins. With the advent of plasminogen activators, it has become possible to use them as fibrinolytic drugs to dissolve the thrombi. They, therefore, complement the use of anticoagulants, which prevent the formation of clots in the first place.

The fibrinolytic drugs in use include:

Agents without fibrin specificity: 

Streptokinase

Agents with fibrin specificity: 

ii. Alteplase (rt-PA)

iii. Reteplase (r-PA)

iv. Tenecteplase (TNK-tPA)

Agents without Fibrin Specificity: 

Streptokinase:

Streptokinase is a nonselective plasminogen activator that induces a generalized fibrinolytic state characterized by extensive fibrinogen degradation. It is a streptococcal exotoxin and is isolated from β-hemolytic streptococci. It is antigenic in humans and leads to the development of antibodies, which restricts its further use and requires the use of an alternate fibrinolytic drug, if the treatment is warranted. Prior treatment with IV antihistamine (chlor­pheniramine) and hydrocortisone is required to prevent anaphylactic reactions.

Agents without Fibrin Specificity: 

i. Alteplase:

Alteplase is a recombinant tissue plasminogen activator (rt-PA). It is a more clot selective and does not cause adverse effects (allergy or hypotension) as compared to streptokinase.

ii. Reteplase (r-PA):

Reteplase has reduced fibrin specificity but has a longer duration of action than alteplase. Its efficacy equals to streptokinase and alteplase.

iii. Tenecteplase (TNK-tPA):

Tenecteplase is a genetically engineered variant of alteplase with slower plasma clearance, better fibrin specificity and high resistance to plasminogen-activator inhibitor-I.

Fibrinolytic Therapy:

All plasminogen activators are given intravenously either as perfusion or bolus administration. Concomitant use of IV heparin reduces the risk of subsequent coronary occlusion. Fibrinolytic therapy is most effective if given within 12 hours of the onset of symptoms, but can be administered unto, but not beyond, 24 hours. If angina symptoms or ischemic changes on the ECG persist at 60-90 minutes after the initiation of fibrinolytic therapy, patients should be considered for urgent invasive strategy coronary angiography and subsequent revascularisation, as warranted.

Bleeding complications are the most common adverse effects of fibrinolytic therapy, which may be of concern with intracranial hemorrhage. The contraindications of fibrinolytic therapy include active bleeding, defective hemostasis, recent major trauma, stroke/ transient ischemic attacks, surgical procedures, acute pericarditis and Gl/genitourinary bleeding.