Anti-Ischemic Drugs

1. Anti-Ischemic Drugs Betablockers Nitrates Calcium Channel Blockers

2. Partial agonism of beta-blockers Most bblockers are pure antagonists: the occupancy of a Beta receptor by the drug causes no activation of the receptor Some are partial agonists: they cause partial activation of the receptor, albeit less than that caused by the full agonists epinephrine and isoproterenol Partial agonists inhibit the activation of beta receptors in the presence of high catecholamine concentrations but moderately activate the receptors in the absence of endogenous agonists

3. Receptor affinity of betablockers

4. Potency of Betablockers Potency can be measured by the ability of beta blockers to inhibit the tachycardia produced by isoproterenol. All durgs are considered in reference to propranolol which is given a potency of 1 Atenolol 1 Metoprolol 1 Labetalol 0.3 Bisoprolol 10 Betaxolol 4 Carvedilol 10 Esmolol 0.02

5. Pharmacokinetics of betablockers Most drugs are well absorbed. Peak concentrations occur 1-3 hours after ingestion Lipophilic agents (propranolol, penbutolol) cross the blood-brain barrier Extensively metabolized by the liver: propranolol, metoprolol Not metabolized at all in the liver: nadolol: excreted unchanged in the urine

7. Effects on the cardiovascular system Reduction in inotropism Reduction in chronotropism Reduction of renin release Reduction of blood pressure Mechanisms include effect on the heart, blood vessels, renin-angiotensin system, effect on central nervous system The acute effects of bb may include a rise in peripheral resistance by blocking ß2 mediated vasodilatation; their chronic utilization however, results in a reduction in peripheral resistance. How this adjustment occurs is not yet clear

8. Other effects of betablockers Effects on the respiratory system Increase in airway resistance by blocking ß2 receptors in bronchial smooth muscle No currently available ß1 selective antagonist is sufficiently specific to completely avoid interaction with ß2 receptors Effects on the eye Decrease aqueous humor production and decrease in intraocular pressure

9. Metabolic and endocrine effects of betablockers Glycogenolysis in the liver is at least partially inhibited after ß2 blockade Glucagon is the primary hormone to combat hypoglycemia It is thus unclear to what extent betablockers impair recovery from hypoglycemia Increase plasma levels of VLDL and decrease of HDL. Occur with selective or non selective betablockers, but less often with betablockers possessing intrinsic sympathomimetic activity The mechanisms of these effects are not well understood; a change in the sensitivity to insulin may be incriminated

10. Local anesthetic effect of betablockers Also called membrane stabilizing action Not all betablockers possess this effect Local anesthetic blockade of sodium channels and can be demonstrated experimentally in isolated neurons, heart muscle, and skeletal muscle membrane This effect is unlikely to occur after systemic administration of these drugs because the concentration in plasma is too low for the anesthetic effects to be evident

11. Specific betablockers Nadolol has the longest half-life Timolol is a nonselective agent with no local anesthetic activity. It has excellent ocular hypotensive effects when administered topically in the eye Labetalol blocks ß1, ß2 and is a selective a1 blocker. Its ß blocking potency is however less than propranolol Carvedilol is a more potent ß than a blocker. It also attenuate oxygen free radical-initiated lipid peroxidation and inhibit vascular smooth muscle mitogenesis independently of adrenoceptor blockade Esmolol is an ultra-short-acting ß1 antogonist. Its structure contains an ester linkage; esterases in red blood cells rapidly metabolize esmolol (half life 10 min).

12. Dosage of Beta-blockers The resting heart rate should be decreased to between 50-60 beats/minute An increase of less than 20 beats/minute should occur with modest exercise (e.g., climbing one flight of stairs)

13. Nitrates and Nitrites

14. Mechanism of action of nitrates on smooth muscle Nitroglycerin is denitrated by glutathione S-transferase. Free nitrite ion is released which is then converted to NO NO activates guanylyl cyclase and increases cGMP A sulfhydryl (SH) group is required for both formation of NO and stimulation of guanylate cyclase N-Acetylcysteine increases the availability of SH groups

15. Effects of nitrates on vascular smooth muscle Nitro relaxes all type of smooth muscle Veins respond at the lowest concentrations, arteries at slightly higher ones Arterioles and precapillary sphincters are dilated less Partly because of the reflex response (see below) Partly because of their decreased ability to release nitric oxide In the absence of heart failure cardiac output is decreased In heart failure, by reducing a preload that is abnormally high, nitrates have a beneficial effect on cardiac output Reflex response: Activation of baroreceptors and hormonal mechanisms responding to decreased arterial pressure: tachycardia and increased cardiac contractility + retention of salt and water These compensatory responses contribute to the development of tolerance

16. Pharmacokinetics of Nitrates Liver contains nitrate reductase that removes nitrate groups in a stepwise fashion and inactivate the drugs. Bioavailability is low (< 10-20%) Sublingual route: avoids liver first pass, achieves therapeutic blood levels quickly (within few minutes), but total duration of effect is brief (15-30 minutes) Once absorbed, the unchanged trinitrate compound has half life of 2-8 min. It metabolites (dinitrates and mononitrates) have much longer half-lives The 5-mononitrate metabolite is an active metabolite and is available for clinical use as isosorbide mononitrate. It has a bioavailability of 100% Excretion is primarily in the form of glucuronide derivatives of the denitrated metabolites, and is largely by way of the kidney

17. Forms of Nitrates Nitroglycerin tablets For sublingual use Avoids first-pass hepatic metabolism Transient but effective concentration rapidly appears Isosorbide dinitrate Has low bioavailability after oral administration Undergoes hepatic metabolism rapidly Tolerance develops rapidly when it is administered as 30 mg 3-4 times daily Isosorbide 5 mononitrate Completely available with oral administration because it does not undergo first-pass metabolism by the liver Tolerance has not been demonstrated with once-a-day dosing but does occur with twice-daily dosing regimen at 12-hours intervals Sustained release preparation are available which avoid tolerance by either providing a sufficiently low nitrate level or a duration of activity of 12 hours or less Topical forms Has been shown to maintain antiischemic effects for 12 hours after patch application throughout 30 days of therapy without significant evidence of tolerance provided that the patch is not applied for more than 12 out 24 hours

18. Forms of Nitrates

19. Coronary Steal and Coronary Redistribution

20. Mechanism for Redistribution of Coronary Flow with Nitrates Nitroglycerin causes redistribution of blood flow from normally perfused to ischemic areas, particularly in the subendocardium May be mediated in part by increase in collateral blood flow And in part by lowering of ventricular diastolic pressure, thereby reducing subendocardial compression Global myocardial flow in not significantly affected

21. Mechanisms of Nitrates Tolerance Demonstrated with all forms of nitrates Is rapid in onset, but renewed responsiveness is easily established after a short nitrate free interval Possible mechanisms: Depletion of sulfhydryl groups: intra-cellular SH co-factors are depleted. They are a crucial component of the metabolic conversion of nitroglycerin to NO Neurohormonal activation: in response to decrease pre-load and the hypotensive effects of nitrates. Increase in catecholamines, ADH, plasma renin activity causing Na retention and weight gain Downregulation of nitrate receptors?

22. Beneficial and Deleterious Effects of Nitrates in the Treatment of Angina

24. Mechanism of Action of Calcium Channel Blockers The L-type calcium channel is the dominant type in cardiac and smooth muscle and contains several drug receptors Dihydropyridines bind to one site while verapamil and diltiazem bind to closely related by not identical receptors in another region The drugs act from the inner side of the membrane and bind more effectively to channels in depolarized membranes Binding of the drug reduces the frequency of opening in response to depolarization. This results in a marked decrease in transmembrane calcium current: Smooth muscle with a long lasting relaxation Reduction in contractility of cardiac muscle Decrease in sinus node and atrioventricular node activity/conduction velocity The block can be partially reversed by elevating the concentration of calcium or by the use of drugs that increase the transmembrane flux of Ca, such as sympathomimetics

25. Effects of CCB on Smooth Muscle Relaxation Vascular smooth muscle appears to be the most sensitive, but also bronchiolar, gastrointestinal and uterine smooth muscle Arterioles are more sensitive than veins; orthostatic hypotension is not a common adverse effect Reduction in peripheral vascular resistance and in coronary arterial tone Vascular selectivity: in general dihydropyridines have a greater ratio of vascular smooth muscle effect/ cardiac effects (compared to bepridil, diltiazem and verapamil) Furthermore, vascular effect may differ in potency according to vascular bed: ie nimodipine and cerebral blood vessels

26. Effect of CCB on cardiac muscle Calcium dependant action potential in the sino-atrial or atrio-ventricular nodes Excitation-contraction coupling in all cardiac cells requires calcium influx CCB reduce cardiac contractility in a dose dependant fashion (reduction of O2 demand) Interaction of CCB with calcium channels varies according to class Na and K channels are blocked by bepridil Verapamil and diltiazem block calcium channels in sinoatrial and AV nodes more selectively than do the dihydropyridines. Dihydropyridines block smooth muscle calcium channels at concentration below those required for significant cardiac effects; they are less depressant to the heart than verapamil or diltiazem.

28. Toxicity of Calcium-channel blockers Short acting CCB blockers have the potential to enhance the risk of adverse cardiac events and should be avoided Bepridil prolongs the cardiac action potential and may cause torsade de pointe Cardiac depression Bradycardia, AV block, heart failure….

29. Mechanism of clinical benefit of CCB Decrease myocardial contractility (decrease o2 demand) Decrease arteriolar tone (vasodilation) Non specific anti-adrenergic effect for verapamil Decrease heart rate (verapamil, diltiazem, bepridil) Effect on sino-atrial and AV node: verapamil > dilt >> dihydropyrines Nifedipine does not affect sinus or AV node, and does not have anti-adrenergic effect. It can cause hypotension and reflex tachycardia which may precipitate angina

30. Effects of nitrates alone and with ß-blockers or CCB in angina pectoris