1. Antianginal Drugs Dr. Dennis Wolff Dept. Pharmacology, ext. 3477

2. Angina pectoris pain angina pectoris is the principle symptom of ischemic heart disease it is a pain felt right in the middle of the chest, behind the sternum (not generally on the side) sensation of tightness (the feeling as though you are being gripped in a vice), yet some people describe it as only mildly painful discomfort –can spread towards the neck or the jaw, the arm and the wrist (and feel like handcuffs), most often on the left side –sometimes situated lower down, towards the pit of the stomach http://www.europa-trial.org/public/cad_symptoms.asp

3. The ischemic condition results from an imbalance between myocardial oxygen demand and myocardial oxygen supply This imbalance may be due to a decrease in myocardial oxygen supply, an increase in myocardial oxygen demand or both Unlike skeletal muscle, the heart cannot stop and take a rest when it is tired...

4. oxygen demand vs. oxygen supply

5. Hemodynamic factors modified by antianginal drugs Factors that affect myocardial oxygen demand: –contractility –heart rate –ventricular wall tension preload: –the pressure that distends the ventricular wall during diastole (ventricular end-diastolic pressure) –some antianginal drugs increase venous capacitance  which causes venous pooling  decreases venous return  decreases ventricular end-diastolic pressure  reduces cardiac work  thus decreases oxygen demand.

6. Hemodynamic factors modified by antianginal drugs cont. afterload: –the force distributed in the ventricular wall during ejection of blood (ventricular systolic wall tension) –some antianginal drugs decrease afterload by decreasing peripheral arteriolar resistance  reduced oxygen demand  results in reduced myocardial work

7. Preload: how high you raise the handle (venous return) Afterload: how hard you have to push to get air into the tire (function of tire pressure, or in case of heart, arterial pressure)

8. LaPlace's Law The larger the vessel radius, the larger the wall tension required to withstand a given internal fluid pressure For a given vessel radius and internal pressure, a spherical vessel will have half the wall tension of a cylindrical vessel.

9. R Nave at http://hyperphysics.phy-astr.gsu.edu/hbase/ptens.html

10. Work (tension) required to generate the same pressure as radius increases... For a sphere, (P X R)/2 = T, where P = pressure, R = radius and T = tension PRT 100.251.25easy work, but small radius = minimal output 100.52.5 1015 If extremes, somewhere in here lies an optimal relationship between tension development required and output 102 420 10840 101680 1032160 1064320very hard work to generate same pressure

11. Antianginal drugs Organic nitrates β-blockers Calcium channel blockers

12. Vascular steal Reason we cannot use potent vasodilators (e.g., minoxidil) to treat myocardial ischemia Blood flow follows the pathway of least resistance….

13. Hemodynamic factors modified by antianginal drugs –Factors that affect myocardial oxygen supply: coronary blood flow, which is a function of aortic diastolic blood pressure and coronary vascular resistance regional blood flow distribution –subendocardial regions of the heart are more poorly perfused than the subepicardial regions –decreasing preload decreases intraventricular pressure which allows for greater subendocardial perfusion the heart muscle is perfused primarily between beats... the faster the heart rate, the less time for perfusion

14. Organic Nitrates: organic nitrates have been used for over 100 years, and are still primary drugs for the treatment of angina pectoris all of the compounds contain one or more nitrate functional groups, -O-NO2, in their chemical structure another series of agents, the organic nitrites (e.g., amyl nitrite and isobutyl nitrite) contain the nitrite functional group, O-N-O, but are typically classified as organic nitrates.

15. Cellular mechanism of action of organic nitrates: –converted to nitric oxide (NO) which stimulates guanylate cycle –guanylate cycle increases cyclic GMP (cGMP) –cGMP dephosphorylates myosin light chains and causes vascular relaxation –cGMP is degraded by phosphodiesterase type V (PDE V) »nerves to penis release NO during sexual arousal, PDE V is blocked by drugs like sildenafil (Viagra) »this explains why sildenafil should NOT be taken if using organic nitrates (i.e., get too much systemic vasodilatation)

16. Phosphodiesterase type V is blocked by sildenafil (Viagra)

18. –Pharmacological actions of organic nitrates to reduce myocardial ischemia: venous and arterial dilation, with dilation of veins predominating over that of arteries. –decreased preload and afterload results in decreased myocardial work and decreased oxygen demand. –the organic nitrates do not directly alter the inotropic (force of contraction) or chronotropic (rate) state of the heart. effects on coronary blood flow –organic nitrates dilate large epicardial coronary arteries and collateral vessels to provide some increase in oxygen delivery to the ischemic myocardium –reduced preload decreases diastolic intraventricular pressure which favors subendocardial perfusion mechanism of pain relief in angina –organic nitrate drugs cause a marked reduction in myocardial work and concomitant reduction in oxygen demand –there may be some improvement in perfusion of the heart

19. NitratesDosage FormOnset (minutes)Duration amyl nitriteinhalant0.53-5 min nitroglycerin IV1 to 23-5 min sublingual1 to 330-60 translingual spray230 to 60 transmucosal tablet1 to 23 to 5 hrs oral, sustained release20-453 to 8 hrs topical ointment30-602 to 12 hrs transdermal30-60up to 24 hrs isosorbide dinitratesublingual2 to 51 to 4 hrs isosorbide mononitrate oral20-404 to 6 hrs oral, sustained releaseup to 4 hrs6 to 8 hrs erythrityl tetranitratesublingual53 hrs oral15 to 306 hrs pentaerythritol tetranitrateoral30≈6 hrs oral, sustained release30up to 12 hrs

20. Pharmacokinetics: –differences exist in the pharmacokinetics of the various organic nitrates –the oral bioavailability of the organic nitrates is low due to extensive first-pass metabolism in the liver. »oral isosorbide dinitrate is completely absorbed, but only about 25% of the absorbed dose enters into the systemic circulation as intact drug »the biotransformation of organic nitrates is the result of reductive hydrolysis catalyzed by the hepatic enzyme glutathione-organic nitrate reductase

21. –Routes of administration for organic nitrates: the sublingual route of administration is most useful for the treatment of acute attacks of angina pectoris the oral (swallowed) and transdermal preparations have a slow onset and a long duration of action –used to provide prophylaxis against anginal attacks –must be given in sufficient dosage to saturate the liver’s capacity to degrade them

22. –Tolerance to organic nitrates: tolerance is apparent when: –repeated administration of a given dose of an organic nitrate produces a decreased effect or –when increasingly larger doses must be taken to obtain the effects observed with the original dose the magnitude of tolerance is a function of the dose and frequency of administration of the nitrate, with frequent exposure to high oral or transdermal doses of organic nitrates leading to the development of tolerance This is the reason long acting forms of nitrates should be administered on an intermittent schedule with at least 8 hrs (e.g., usually at night) without drug.

23. Adverse effects of organic nitrates: –generally, the acute adverse effects are direct extensions of the pharmacological effects of these drugs, and include: »vasodilatation – severe headache, facial flushing »hypotension – dizziness, weakness »orthostatic hypotension »reflex tachycardia

24. Use of organic nitrates in angina pectoris: –sublingual and other rapid acting nitrates are used to treat acute attacks of angina –long acting oral and transdermal nitrates are used prophylactically to prevent angina –angina or MI ?? »if 1st nitroglycerin tablet doesn't relieve angina within 5 min, take a second, »if still no help 5 min later, can take a third… »if still no relief, get to ER ASAP since likely an MI rather than angina

25. β -Adrenergic receptor antagonists These drugs: –bind to β-adrenergic receptors –reduce the response caused by the activation of β-receptors by the sympathetic nervous system  inhibiting some of the cardiovascular effects

26. CARDIAC SiteReceptorEffect of Sympathetic Stimulation Effect of β Blocker muscleβ1β1 ↑ Force ↓ Force SA nodeβ1β1 ↑ Rate ↓ Rate AV nodeβ1β1 ↑ Conduction ↓ Conduction His-Purkinjeβ1β1 ↑ Automaticity ↓ Automaticity β1β1 ↑ Cardiac Output↓ Cardiac Output

27. VASCULAR SiteReceptorEffect of Sympathetic Stimulation Effect of β Blocker Renin- angiotensin system β1β1 ↑ Angiotensin  ↑ Vasoconstriction ↓ Angiotensin β1β1 ↑ Peripheral resistance  ↑ Blood Pressure ↓ Blood Pressure

28. others will discuss the renin- angiotensin system…. blockade of β 1 receptors here is how β-blockers can decrease vascular resistance the renal afferent arterioles are a major source of renin NOTE:

30. DRUGHALF-LIFERECEPTOR SELECTIVITY Propranolol3-4 hrβ 1, β 2 Nadolol10-20 hrβ 1, β 2 Metoprolol3-5 hrβ1β1 Atenolol6-8 hrβ1β1 Acebutolol3-4 hrβ1β1 Drugs that block both β 1 and β 2 adrenergic receptors and those that block only β 1 -adrenergic receptors are both used to treat angina pectoris. The maximal effectiveness of these drugs in treating angina pectoris is similar

31. –Hemodynamic effects of β blockers in treating angina pectoris: the β blockers antagonize the actions of epinephrine and norepinephrine released by sympathetic stimulation during stress or exercise –both heart rate and contractility are reduced –there is also some reduction of resting heart rate with these drugs arterial blood pressure is also reduced by β-blockers the three major determinants of myocardial oxygen demand — heart rate, contractility and systolic wall tension — are reduced overall there is a reduced oxygen demand for a given degree of physical activity

32. Adverse effects of β-blockers: –Respiratory - wheezing, bronchoconstriction in patients with airway disease, β2 > β1 –Cardiovascular bradycardia, AV nodal block in patients with conduction disturbances abrupt withdrawal of β blockers can worsen angina

33. Use and beneficial effects of β blockers in the treatment of angina pectoris: –↓ frequency of anginal attacks –↓ nitroglycerin consumption –↑ exercise tolerance –β blockers are used prophylactically to prevent exertional angina. not useful for vasospastic angina. most useful in patients whose attacks of angina are frequent and unpredictable

34. Calcium channel blocking drugs (CCB, aka CEB [calcium entry blockers]) Drug classes used to treat angina pectoris include: –phenylalkylamines: verapamil –benzothiazepines: diltiazem –dihydropyridines: nifedipine, nicardipine, nimodipine, felodipine, isradipine… note that members of this class typically end with “dipine”

35. Channel TypeConductanceBlockersPropertiesLocation/Role L-type~ 25 pS calcium antagonists large, long-lasting current with slow inactivation cardiac and smooth muscle, neurons / excitation- contraction coupling, sinoatrial and Purkinje T-type~ 8 pS amiloride, tetramethrin, octanol tiny, transient current sinoatrial and Purkinje cells / pacemaker activity of the heart N-type~12-20 pSω-conotoxinneither L nor T Neurons / neurotrans- mitter release

36. quick FYI… there is now an official nomenclature for the Ca 2+ channels each of these channel types has subtypes based on options between the other 4 components that make it up in the this nomenclature, the traditional L-type channel is Ca v 1.2

37. L type calcium channels: –are activated when the cell is depolarized –have a large, sustained conductance and inactivate slowly –are widespread in the cardiovascular system are responsible for the plateau phase (slow inward current) of the action potential regulate arterial tone –are sensitive to Ca2+ channel blockers

39. figure from Richards, S. in Drugs 2005 - note that drugs like nifedipine and diltiazem bind on the external surface of the channel while verapamil binds on the inside… nevertheless verapamil and diltiazem are the drugs that are “frequency” or “use” depedendent

41. SA and AV Node Membrane potential (mV) 0 -50 200 msec AV node SA node Ventricular Muscle 0 -50 200 msec Slow, Ca +2 -dependent upstroke Rapid, Na+-dependent upstroke

43. blockade of L-type calcium channels has a direct negative inotropic effect on the heart –caused by a reduced inward movement of Ca2+ during the plateau phase of the action potential in the heart the decrease in intracellular Ca2+ in cardiac muscle enhances troponin inhibition of actin-myosin interactions some CCB also have direct negative chronotropic and dromotropic effects (direct effects on pacemaker activity and conduction). This depends on the class of Ca2+ channel blocker: –nifedipine and related dihydropyridines do NOT have significant direct effects on the atrioventricular conduction system or the sinoatrial node, and therefore they do NOT have direct effects on conduction or automaticity –verapamil and diltiazem decrease the rate of recovery of L- type calcium channels in the AV conduction system and in the SA node, which depresses SA node pacemaker activity and slows AV nodal conduction

44. effect on vascular smooth muscle cells –vascular smooth muscle contraction is dependent upon an increase in intracellular Ca2+ –Ca2+ channel blockers bind to and inhibit L-type voltage-dependent Ca2+ channels in arterial smooth muscle. decreased intracellular Ca2+ in arterial smooth muscle results in coronary and peripheral vascular relaxation and a decrease in blood pressure the decreased aortic pressure reduces cardiac afterload. –CCB have little or no effect on the veins and no effect on cardiac preload –CCB have little or no effect on the entry of calcium into the cell via other mechanisms

45. Specific hemodynamic effects of individual calcium channel blockers –nifedipine and other dihydropyridines: causes vasodilatation of arterial resistance vessels, decreased afterload and a reflex increase in sympathetic stimulation of the heart reflex stimulation causes increased cardiac contractility (inotropic effect) and increased heart rate (chronotropic effect) thus the direct negative inotropic effect of calcium channel blockers is overwhelmed by sympathetic reflex stimulation, giving an overall increase in cardiac output

46. Specific hemodynamic effects of individual calcium channel blockers –verapamil: less vasodilatation than with dihydropyridines at doses that cause peripheral vasodilatation, this drug has more direct negative chronotropic, dromotropic, and inotropic effects than do dihydropyridines direct negative inotropic effect is offset by the decrease in blood pressure (afterload) and reflex increase in sympathetic tone in patients with normal cardiac function, ventricular performance is not impaired in patients with congestive heart failure, there can be a decrease in contractility and left ventricular function

47. Specific hemodynamic effects of individual calcium channel blockers –diltiazem: less potent vasodilator than verapamil or dihydropyridines at doses that cause peripheral vasodilatation, this drug also has direct negative chronotropic and dromotropic effects but less than those caused by verapamil negative inotropic effects are more modest than with verapamil

48. phenylalkylamines A (verapamil) dihydropyridines B (nifedipine) benzothiazepines C (diltiazem) vasodilatation peripheral ++++++ coronary +++++ cerebral +++ heart rate ↓↑ ** ↓ SA node ↓--↓ AV node ↓↓--↓ contractility ↓↑ ** ↓ **, reflex effect; +, mild effect; ++, moderate effect; +++, pronounced effect; --, no change Indications: Aangina; hypertension; supraventricular tachyarrhythmias Bangina; hypertension Cangina; hypertension; supraventricular tachyarrhythmias

49. approximation of differences between nifedipine with verapamil… reflex effects besides those shown (e.g., on vasculature) can further cloud the picture the key difference is that since nifedipine at therapeutic doses exerts smaller direct inotropic effects on the myocardium and no chronotropic effects, but large vasodilatory effects, HR and CO are increased by it because of the reflex SNS activation  ↑ CO

50. Major therapeutic uses of calcium channel blockers include treatment of: –angina pectoris –essential hypertension –cardiac arrhythmias

51. Use of calcium channel blockers in angina: –exertional angina: verapamil, diltiazem and dihydropyridines therapeutic effects are due to increased coronary blood flow and/or decreased myocardial oxygen consumption (secondary to decreased peripheral vascular resistance, heart rate and contractility) decreased oxygen consumption is thought to be important in some patients, calcium channel blockers (primarily the short-acting dihydropyridines such as nifedipine) may aggravate anginal symptoms –vasospastic angina: verapamil, diltiazem and dihydropyridines benefits of calcium channel blocker are primarily due to coronary artery dilation rather than alterations in peripheral hemodynamics

52. Toxicity and side effects of CCBs –most common side effects (i.e., dizziness, hypotension, headache, facial flushing, ankle edema, nausea, etc.) are due to excessive vasodilatation –aggravation of myocardial ischemia due to excessive vasodilatation has been reported primarily with dihydropyridines may be related to excessive hypotension causing decreased coronary perfusion or increased sympathetic stimulation causing increased oxygen demand –patients with ventricular dysfunction, or SA node or AV node conduction disturbances should not be treated with i.v. verapamil or diltiazem –gingival hyperplasia is a rare but known complication of this drug class… most reported cases occurred with use of nifedipine, but seen across drug class

53. Side Effect Calcium AntagonistOralIntravenous verapamil constipation (8%) facial flushing (8%) dizziness (6%) headache (8%) AV block (1%) worsening of heart failure hypotension bradycardia nifedipine ankle edema (10%) facial flushing (12%) headache (6%) nausea (4%) tachycardia (12%) dizziness (3%) N/A diltiazem headache (2%) facial flushing (1%) nausea (3%) ankle edema (2%) hypotension bradycardia

54. FYI: In the drug pipeline… “3 rd generation” dihydropyridines… manidipine, nilvadipine, benidipine, efonidine appear to block more calcium channels, including T channels… the “hype”: old CCB preferentially dilate the afferent arteriole, which damages the glomerulus while these drugs dilate both afferent and efferent arterioles and therefore do a better job of protecting the kidneys

55. MC Escher’s “Rind”, 1955