introduction

Effect of drugs on the heart

Positive inotropic agents - Increase force of contraction stimulate 1 adrenergic receptors increase Ca availability e.g. cardiac glycosides. Negative inotropic agents - 1 adrenergic blockers e.g propranolol (mixed), atenolol (selective 1). - Decrease Ca availability e.g. calcium channel blockers (verapamil, diltiazem)

Positive chronotropic effect Sympathomimetic agents Negative chronotropic effect Blockade at 1 receptors Ca channel blockers

Effect of drugs on the circulation

Direct vasodilators Organic nitrates e.g. nitroprusside Ca channel blockers e.g. nifedipine Hydralazine, minoxidil, diazoxide Drugs that block activity of vasoconstrictor 1 adrenergic receptor blockers e.g. prazosin Angiotensin II receptor blockers (ARB) e.g. losartan

Drugs that decrease production of vasoconstrictors - Angiotensin converting enzyme inhibitors (ACEIs) e.g. captopril, enalapril, lisinopril

positive inotropic agents

Mechanism of action: - Inhibit membrane Na/K ATPase, which is responsible for Na/K exchange across the muscle cell membrane. - This increases in intracellular Na which produces a secondary in intracellular Ca which s the force of myocardial contraction.

*The increase in intracellular Ca occurs because the decreased Na gradient across the membrane reduces the extrusion of Ca by the Na/Ca exchanger that occurs during diastole. *Digoxin and K ions compete for the receptor (Na/K ATPase) on the outside of the muscle cell membrane, so the effects of digoxin maybe dangerously increased in hypokalaemia; produced by, for example, diuretics.

Main effect - Increase force of contraction Other effects - ectopic pacemaker activity - impair AV conduction - vagal activity bradycardia ** K inhibits binding of glycosides to Na/K ATPase. A in plasma K enhances tendency of glycosides to cause dysrrthythmias.

Digoxin Widely used glycoside Uses: - ventricular rate in atrial fibrillation. - cardiac contractility in cardiac failure. Given orally or i.v in emergencies Renal elimination T is 36 hours, longer in renal impairment Narrow therapeutic window

Adverse effects - Nausea - Vomiting - Cardiac arrhythmias - Confusion Interactions - Interact with (i) drugs that reduce plasma K e.g. loop diuretics (ii) drugs which reduce excretion and tissue binding e.g. amiodarone, verapamil

Increase Ca intracellularly Have a positive inotropic effect Dobutamine Used for short-term improvement of cardiac fiunction, e.g. after cardiac surgery, in severe congestive cardiac failure or after myocardiac infarction (M.I). Effects: increase CO/stroke volume. Tolerance limits long term use.

Pharmacokinetics: Given by i.v infusion t = 2 mins Steady state in 10 minutes Conjugated to 3-O-methyldobutamine Side effects: may BP, HR during administration. May myocardial O demand. myocardial infarct

Dopamine An endogenous catecholamine Given as an i.v infusion at 2-10g/kg/min Has got positive inotropic effects through: (i) Stimulation of 1 receptors (ii) Increasing the release of norepinephrine from nerve terminals. Uses: treatment of shock cardiogenesis Side effects: nausea, vomiting, tachycardia, arrhythmias, angina pain, headache, BP during infusion. (effects disappear upon discontinuation due to the short t.

Amrinone and milrinone Have positive inotropic effects mechanism of action: Inhibit cGMP and cAMP phosphodiesterase Use: short term treatment of CCF

Block Ca entry into heart muscle and vascular smooth muscle. Phenylalkylamine: verapamil Dihydropyridines: nifedipine, amlodipine, felodipine Benzothiazapine: diltiazem

Verapamil : - Prolongs refractory period of heart muscle. - Reduces pacemaker activity - Negative inotropic effect. Nifedipine: - No negative inotropic effect Diltiazem: - Relatively selective to coronary arteries

Cardiovascular effects myocardial O delivery dilate coronary arteries and arterioles Reduce TPR decrease O requirements Slow AV & SA node conduction verapamil, diltiazem >nifedipine Nifedipine: - decrease preload reflex increase in HR Baroreceptor mediated sympathetic stimulation.

Pharmacokinetics: verapamil, diltiazem, nifedipine well absorbed orally; bound to plasma proteins Verapamil first pass metabolism Metabolites of all excreted in urine.

Uses: Angina pectoris Prinzmetalis (variant) angina [coronary vasospasm]. Arrhythmias; verapamil, diltiazem Hypertension; nifedipine Route: oral, i.v for emergencies (verapamil) S.E: headaches, arrhythmias, leg oedema, HR

Esters of nitric acid Organic nitrites esters of nitrous oxide - Nitroglycerin (glyceryl trinitrate), amyl nitrite, isosorbide dinitrate. Nitroglycerin: effect on heart relaxes vascular smooth muscle - Venodilation in venous capacitance venous return - peripheral resistance - myocardial O demand due to: - afterload - preload - coronary flows

Extra-cardiac effect Cerebral vasodilation (can cause headaches). Skin vasodilation (flushing). Relax bronchial and biliary smooth muscle.

Pharmacokinetics - Absorbed through mucous membrane, skin, GIT, lungs - Sublingual rapid onset (2-5min) - short duration of action (<30min) - Oral sustained release (often) - Hepatic metabolism by glutathionedependent organic nitrate reductase and excreted in urine

Uses: Treat acute attacks of angina pectoris (primary use). Prophylaxis Relief of pulmonary congestion

Administration: Sublingual, nitroglycerine (GTN) p.o or transdermal (ointment or patch) for longer lasting effects. i.v for emergencies **keep nitroglycerin tablets in a dark glass container. Potency is lost when in contact with cotton, paper or plastic.**

Side effects: Headache (decrease with time, decreasing dose maybe beneficial, temporary cessation for a few days recurrent of headaches on readministration). Dizziness, weakness, cerebral ischemia due to postural hypotension occur occasionally. Circulatory collapse, respiratory failure; due to acute nitrate poisoning Tolerance

DIURETICS

drugs that act on the kidney to increase urine flow. Most work by reducing the re-absorption of electrolytes by the tubules. Diuretics are used to reduce oedema in congestive cardiac failure, some renal diseases and hepatic cirrhosis. Some, notably the thiazides, are widely used in the treatment of hypertension

E.gs, furosemide, bumetanide, ethacrynic acid, torsemide Most effective diuretics Have a very rapid onset and fairly short duration of action. Are very powerful and can cause serious electrolyte imbalances and dehydration Effective in patients with diminished renal function, unlike thiazides. Are given intravenously to patients with pulmonary oedema that results from acute ventricular failure.

They inhibit NaCl reabsorption in the thick ascending loop of Henle. *this segment has a high capacity for absorbing NaCl thus the drugs which act on this segment/site produce the greatest diuresis. Act on the luminal membrane where they inhibit the co-transport of Na/K/2Cl. Their specificity is due to their high local concentration in the renal tubules. At high doses they may induce changes in electrolyte composition of the endolymph and cause deafness.

Adverse effects Hyperuricaemia Hyperglycaemia Hypokalaemia Hypotension Idiosyncratic blood dyscrasias Carbohydrate intolerance can occasionally be observed. Overenthusiastic use of loop diuretics (high doses, i.v administration) can cause deafness which may not be reversible.

Drug interactions: NSAIDs oppose diuretic effect and inhibit tubular secretion of furosemide. Probenicid delays the renal secretion of loop diuretics, thereby retarding their effect. Reduce lithium excretion. Potentiate ototoxic effects of aminoglycosides.

Clinical uses: Moderate to severe heart failure (main indication); to reduce peripheral and pulmonary oedema. Renal failure with fluid overload and hypertension. Acute treatment of hypercalcemia

Hydrochlorothiazide, metolazone, chlorthalidone, indapamide, chlorothiazide Are safe, orally active, but relatively weak diuretics. Moderate diuretic effect. Have been shown to reduce the incidence of stroke. Widely used in the treatment of mild heart failure and hypertension.

Mechanism of action Act mainly on the early segments of the distal tubule and inhibit the active reabsorption of Na and accompanying Cl by inhibiting the Na/Cl co-transport. Excretion of Cl, Na and accompanying water is increased. Relax smooth muscle and cause vasodilation. The increased Na load in the distal tubule stimulates Na exchange with K and H increasing their excretion and causing hypokalemia and metabolic alkalosis.

Other effects: Decrease uric acid and Ca excretion Increases Mg excretion Hypochloremic alkalosis can occur. Paradoxical effect in diabetes insipidus where they reduce the volume of urine can cause hyperglycaemia.

Pharmacokinetics: Given orally Highly tissue and plasma bound Excretion is by tubular secretion Variable metabolism: HCT 95% excreted unchanged, bendfluazide is 30% excreted unchanged i.e. 70% metabolised.

Weakness, impotence and occasionally rashes Hypokalemia and hypomagnesemia Hyponatremia (maybe severe in the elderly). Hyperuricaemia; compete with uric acid for secretion in proximal tubule, which may precipitate gout. Glucose intolerance; contraindicated in patients with non-insulin dependent diabetes (risk is increases with age and obesity and is dosedependent). Increase plasma cholesterol levels at least during the first 6 months of administration.

Interactions: - Useful combination with; - adrenoceptor antagonists - adrenoceptor antagonists - ACEI For the treatment of moderate to severe hypertension. - Reduce lithium excretion.

Clinical uses: Hypertension (main indication). Heart failure (seldom potent enough). In severe resistant oedema, together with loop diuretics. Idiopathic hypercalciuria to prevent recurrent stone formation. Nephrotic diabetes insipidus; paradoxically reduce urine volume by preventing formation of hypotonic fluid in the distal tubule.

Act on the aldosterone responsive segments of the distal nephron, where K homeostasis is controlled. Reduce Na reabsorption by either antagonising aldosterone (spironolactone) or blocking Na channels (amiloride, triamterene). Weak when used alone Cause K retention. Often given with thiazides or loop diuretics to prevent hypokalaemia.

Clinical uses: With K losing diuretics to prevent K loss In primary hyperaldosteronism. In secondary hyperaldosteronism due to hepatic cirrhosis. In complicated ascites.

Adverse effects: - Hyperkalaemia - Metabolic acidosis - Skin rashes - Spironolactone GIT disturbances, gynaecomastia, menstrual disorders and testicular atrophy. **hyperkalaemia is also likely to occur if patients are also taking ACEIs (e.g. captopril, enalapril), because these drugs reduce aldosterone secretion (and therefore K excretion).

Examples, mannitol Are compounds that are filtered in glomerulus but partially or not reabsorbed. Are excreted with an osmotic equivalent of water Reduce passive water reabsorption. Usually given intravenously.

Clinical uses: - Cerebral oedema - Acutely raised intracellular and intracranial pressure. - To maintain a diuresis during surgery. Adverse effects: - headache, nausea, vomiting, transient expansion of ECF.

example, acetazolamide Depress HCO reabsorption in the proximal tubule by inhibiting the catalysis of CO hydration and dehydration reactions. Thus, the excretion of HCO, Na and HO is increased. Increase flow of alkaline urine The loss of HCO causes a metabolic acidosis

Clinical uses: Treatment of glaucoma, to reduce the intraocular pressure, which it does by reducing the secretion of HCO and associated water into the aq humour. Also used as a prophylactic agent for mountain (altitude) sickness.

Agents which increase urinary pH: Na/K citrate or other salts (acetate, lactate) Cations are excreted with HCO to give alkaline urine. May have antibacterial effects as well as decreasing inflammation in the urinary tract. Can be used to increase excretion of drugs which are weak acids (e.g. salicylates and some barbiturates) by alkalinising the urine.

Agents which decrease urinary pH: Ammonium chloride, rarely used clinically.

Drugs that alter the excretion of organic molecules (uric acid, penicillin) Probenicid, sulphinpyrazone Sulphinpyrazone: Inhibits uric acid reabsorption in proximal tubule Absorbed orally Highly protein bound

Probenicid: Lipid soluble derivative of benzoic acid Well absorbed orally, peak conc in 3hrs. 90% bound to plasma albumin, free drug filtered at the glomerulus Increase urate excretion ( reabsorption in proximal tubule) Inhibits penicillin secretion into the tubules

Inhibit secretion of uric acid at therapeutic doses may exacerbate gout arthritis

Most diuretics plasma uric acid. Research is aimed at developing diuretics with uricosuric properties. Indacrinone is one such agent.

 SUMMARY

Contractility : +ve inotropic agents (digoxin, dobutamine) -ve inotropic agents (1blockers, CCBs) Heart Rate: +ve chronotropic agents (sympathomimetics) -ve chronotropic agents ( blockers, CCBs) Circulation: Vasodilators direct vasodilators vasoconstrictor blockers (ARBs) drugs that production of vasoconstrictors (ACEIs).

Loop diuretics (frusemide, torsemide) - Inhibit the Na/K/2Cl co-transporter in the ascending loop of Henle. Thiazides (HCT, indapamide, chlorthalidone) - Inhibit the Na/Cl transport on the early segments of the distal tubules K sparing (spironolactone, amiloride) - Act on the distal tubules, on the aldosterone responsive segments.

Osmotic diuretics (mannitol) - Filtered in the glomerulus and excreted with an osmotic equivalent of water. Carbonic anhydrase inhibitors (acetazolamide) - Act on the proximal tubules by inhibiting the enzyme carbonic anhydrase.