Drugs for Angina Pectoris

• the principle symptom of ischemic heart disease
• it is a pain felt right int he middle of the chest, behind the sternum (not generally on the side)
• sensation of tightness, yet some people describe it as only midly painful discomfort
• can spread toward the neck or the jaw, the arm and the wrist, most often on the left side
• sometimes situated lower down, towards the pit of the stomach

predictable in response to exertion, stress, etc; there is a fixed block that permits adequate flow under basal conditions but impedes higher levels of flow

• manifests as symptoms of angina at rest or worsening of exeritonal angina due to vasospasm, platelet aggregation, thrombus formation, and/or emboli transiently blocking downstream vessels
• has increased risk of myocardial infarction and/or death in comparison to stable angina pectoris
• need to use therapy in addition to that discussed below such as antiplatlet therapy (e.g. aspirin), oxygen, morphine for pain

• aka Printzmetal's angina
• angina caused by coronary artery spasm
• in contrast to stable angina, can produce pain at anytime including while asleep
• between attacks, there may be little to no evidence of coronary flow impairment

• 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

• contractility
• heart rate
• ventricular wall tension

• Preload:
• the pressure that distends the ventricular wall during diastole
• some antianginal drugs increase venous capacitance which causes venous pooling, decreases venous return, decreases ventricular end-diastolic pressure, reduces cardiac work and thus decreases oxygen demand
• Afterload:
• the force distributed in the ventricular wall during ejection of blood (ventricular systolic wall tension) (it has to be greater than diastolic blood pressure to open the valves)

a function of aortic diastolic blood pressure and coronary vascular resistance

• subendocardial regions of the heart are more poorly perfushed than the subepicaridal regions
• decreasing preload decreases intraventricular pressure which allows for greater subendocaridal perfusion

• –organic nitrates have been used for over 100 years, and are still primary drugs for the treatment of angina pectoris
• –cellular mechanism of action :
• organic nitrates are converted to nitric oxide (NO)
• -->stimulates guanylate cyclase to cause an increase in the formation of cyclic GMP
• -->dephosphorylates myosin light chains and causes vascular relaxation

• –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

• –cause a marked reduction in myocardial work and concomitant reduction in oxygen demand
• –there may be some improvement in perfusion of the heart

• –differences exist in the pharmacokinetics of the various organic nitrates
• –have low oral bioavailability 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 sublingual route of administration of organic nitrates 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

–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

–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

•sublingual and other rapid acting nitrates are used to treat acute attacks of angina

–will help for both stable and vasospastic forms of angina

• –if 2-3 sublingual pills taken at 5 min intervals fail to alleviate symptoms, head to ER for thrombolytic therapy (i.e., it’s a myocardial infarction)
• long acting oral and transdermal nitrates are used prophylactically to prevent angina

• •b1-adrenergic receptors act:
• –on the heart muscle to increase contractility
• –on the cardiac conduction system to increase heart ratein the kidney to increase renin secretion

• –the b blockers antagonize the actions of epinephrine and norepinephrine released by sympathetic stimulation during stress or exercise, reducing both heart rate and contractility
• –arterial blood pressure is also reduced by b blockers
• –the three major determinants of myocardial oxygen demand—heart rate, contractility and systolic wall tension—are reduced.

• •respiratory - wheezing, bronchoconstriction in patients with airway disease, b2 > b1
• •cardiovascular – bradycardia, AV block in patients with conduction disturbances; abrupt withdrawal of b blockers can worsen angina

• • decrease nitroglycerin consumption
• • increase exercise tolerance
• •b blockers are used prophylactically to prevent exertional angina.
• –are NOT useful for vasospastic angina
• –most useful in patients whose attacks of angina are frequent and unpredictable

• •phenylalkylamines: verapamil
• •benzothiazepines: diltiazem (effects lie between extremes of other 2 classes, we will not discuss further)
• •dihydropyridines: nifedipine, amlodipine, nicardipine, nimodipine, felodipine, isradipine

• •angina pectoris
• •essential hypertension
• •cardiac arrhythmias

• •Ca2+ channel blockers bind to and inhibit L-type voltage-dependent Ca2+ channels in arterial smooth muscle.
• •CCB have little or no effect on the entry of calcium into the cell via other mechanisms
• •decreased intracellular Ca2+ in arterial smooth muscle results in coronary and peripheral vascular relaxation and a decrease in blood pressure (afterload)CCB have little or no effect on the veins and no effect on cardiac preload

• –affects the SA node and AV conduction system, exerting effects that slow the heart rate
• –also causes a greater decrease in myocardial contractility (inotropy) than the dihydropyridines; can worsen heart function in a failing heart

• –do NOT have significant direct effects on the atrioventricular conduction system or the sinoatrial node that would slow heart rate
• –moreover, these drugs are better vasodilators than verapamil… this peripheral vasodilatation leads to a reflex increase in sympathetic tone, which increases heart rate à i.e., causes a reflex tachycardia

• •New class, definitely does exert beneficial antianginal effects –
• –~No effect on HR, BP or rate-pressure product… ?
• –Initially thought to work by modifying fatty acid metabolism
• –Now thought to work primarily by blocking a Na+ channel responsible for a late phase of influx (less Nai = greater driving force for Ca2+ extrusion via Na/Ca exchanger)
• –Prolongs QT interval, so fear was that it could trigger torsades de pointes
• •MERLIN-TIMI36 trial failed to demonstrate added benefit in non-ST elevated MI patients, its initial main target
• –Oops… fire 1/4 of employees
• –Oops again… noted that patients receiving ranolazine had significantly lower incidence of arrhythmias and no torsades
• •Recently approved as initial therapy for chronic angina
• •Testimonials suggest it is a miracle drug for some patients…