Drugs used in angina pectoris Antianginal drugs

Learning Objectives By the end of this class, you can… Describe the antianginal mechanism of Nitrites, β-blockers and CCBs Clarify the vasodilatory mechanism of NO Select antianginal agents for the treatment of different types of angina pectoris

Methods for treatment To improve perfusion: To reduce metabolic demand

Factors affecting myocardial oxygen demand and oxygen supply Regional myocardial distribution Contractile state Heart rate Oxygen demand Oxygen supply Coronary vascular resistance = Ventricular volume > Wall tension Coronary blood flow LV pressure Aortic pressure

Drugs classifications Organic nitrates: Nitroglycerin Calcium antagonists β-Receptor blockers

Chemical structures of two nitrates Nitroglycerin Isosorbide dinitrate (IDSN) Rapid onset effect Longer lasting effect -O-NO2

Mechanism of action in VSM NO(EDRF) activate GC increase c-GMP activate cGMP- dependent kinase decrease Ca induce de-phosphorylation of the myosin light chain relaxation

Concentration of Ca2+ in VSMC↓ Nitroglycerin ↓ SH NO/SNO ↓+ guanylate cyclase cGMP ↑ 5’GMP Concentration of Ca2+ in VSMC↓ PDE Activation of protein kinase Inhibition platelet Ca2+ influx↓ Ca2+ efflux↑ VASODILATION

Organic nitrates Pharmacological effects and mechanism: dilate peripheral vein preload dilate peripheral artery afterload Dilate coronary artery perfusion of ischemic myocardium Oxygen consumption

Pharmacokinetics: very low bioavailability per os Sublingual Rapid onset(2~5min) Acute adverse effects: postural hypotension, throbbing headache Tolerance : depletion of free –SH (hydrosulfuryl ) groups

NITRATES TOLERANCE " Decrease in the effect of a drug when administered in a long-acting form" Develops with all nitrates Is dose-dependent Disappears in 24 h. after stopping the drug Tolerance can be avoided - Using the least effective dose - Creating discontinuous plasma levels Treatment of Heart Failure. Nitrates: Tolerance Repetitive administration of nitrates over days is accompanied by a reduction in intensity and duration of its effects (tolerance), that obligates sequential increases in dose to obtain the desired effect. Nitrate tolerance appears with all nitrates, crosses over from one nitrate preparation to another (explaining the poor effect that IV NTG can have in patients on oral nitrate therapy), and is not dose dependent. Additionally, tolerance appears within 8-24 hours of administration of preparations that allow for maintenance of stable plasma nitrate levels (i.v., patch), but disappears rapidly (<48hrs) after stopping treatment. Increasing dosage does not overcome the tolerance effect. Tolerance can be avoided, however, by using the lowest effective dose, and by avoiding continuous plasma levels (drug-free periods).

NITRATES CONTRAINDICATIONS Previous hypersensitivity Hypotension ( < 80 mmHg) 1st trimester of pregnancy

β-Receptor blockers Pharmacological effects: Myocardial contractility Heart rate Clinic use : stable and unstable angina Propranolol not for variant angina because of coronary artery contraction due to its β-receptor blocked and α -receptor relatively activated. Oxygen consumption

ß-ADRENERGIC BLOCKERS CONTRAINDICATIONS Hypotension: BP < 100 mmHg Bradycardia: HR < 50 bpm Chronic bronchitis, ASTHMA Severe chronic renal insufficiency Treatment of Heart Failure. Beta-Blockers: Contraindications Contraindications to beta-blocker therapy in heart failure patients are the same as those for the general population.

Effects of nitrates alone and with β-blockers in angina pectoris   Nitrates alone β-blockers Combined nitrates with β-blockers Heart rate Reflex increase Decrease Arterial pressure Decrease* End-diastolic volume Increase None or decrease Contractility None Coronary vasospasm

Pharmacological effects of CCB Cardiac contractility, heart rate Peripheral vessels dilation , afterload dilate coronary artery, release its spasm Ca2+ overload apoptosis,necrosis Myocardial oxygen consumption

Calcium channel blockers Clinic use : variant angina Nifedipine not for unstable angina? Reflex increase in heart rate and cardiac contractility How to control ? β-Receptor blockers

Other drugs for angina Anti-platelet drugs: aspirin, persantin Chinese medicine: salvia miltiorrhiza, panax notoginseng -promoting blood circulation to remove blood stasis

Non-Pharmacologic Management Limit alcohol No high saturated fat/high cholesterol foods Maintain normal blood lipid levels Maintain blood pressure within normal range Regular exercise Optimal weight Maintain blood glucose within normal range No tobacco 21

The Original Question from Step1-USMLE A 60 y-o woman with a history of smoking presents with the chief complaint of chest pain that occurs at night while at rest. A treadmill test is negative. A 24 hr holter recording reveals transient ST elevation and AV block (suggestive of occlusion of her right coronary artery) that are temporally associated with anginal attacks. A coronary angiography with provocative testing with acetylcholine injection reproduces her chest pain & ECG changes. Which drug will be contraindicated in her treatment? A. diltiazem  B.  isosorbide dinitrate  C.  metoprolol  D. nitroglycerin sublingually  E.  verapamil

Features & diagnosis of Variant angina Symptoms typically occur at rest, rather than on exertion (thus attacks usually occur at night). The treadmill stress test is always negative. It is associated with specific ECG changes (elevation rather than depression of the ST segment). The gold standard is coronary angiography with injection of provocative agents into the coronary artery. Depending on the local protocol, provocation testing may involve substances such as ergonovine, methylergonovine or acetylcholine.

Beta blockers (both beta-1 selective and nonselective types) are contraindicated in vasospastic angina because of the concern about blocking beta-2 receptors in coronary arteries, and leaving "alpha receptors unopposed"...resulting in enhanced likelihood of vasospasm.