Antianginal Drugs

Angina Pectoralis

periodic episodes of chest discomfort or pain that can radiate from the navel to the jaw and may also radiate down the flexor surface of the arms

caused when the oxygen supply does not equal the demand; the subendocardium is most vulnerable to ischemia and manifestation of ischemia occur earlier and more severely in the inner layers of the ventricle

Oxygen Demand Depends on:

(1) Contractility

(2) Heart rate (HR)

(3) Myocardial wall tension – more oxygen is required as wall tension Ý which occurs when the heart dilates and as intraventricular pressure Ý

Limitation of Oxygen Supply – Ý coronary vascular resistance; attacks often precipitated by Ý demand and ß supply

Vessel narrowing due to atherosclerosis or other disease causing fixed impairment Þ typical angina pectoralis

characterized by pain during exertion and forms because the coronary arteries are unable to meet Ý oxygen demand during exercise

ß ST segment on ECG

Transient coronary vasospasm Þ Prinzmetal’s variant angina

pain typically occurs during rest but about 1/3 of patients have pain both at rest and during exertion

may occur in the vicinity of severe artery stenosis, but spasm can also occur without artery obstruction

Ý ST segment on ECG

Treatment of Angina – aimed at either Ý oxygen supply or ß demand

Surgery – Ý oxygen supply

Medial management – drug therapy, treatment of underlying conditions and lifestyle changes

reduce physical and/or emotional stress; caffeinated beverages; over-the-counter preparations containing sympathomimetics; smoking; heavy freeway traffic; obesity; HTN; hyperthyroidism; anemia, arrhythmia, heavy meals

Drug Therapy

(1) Nitrates

Short Acting Nitrates – Nitroglycerin (NTG) – prototype drug in class that is taken sublingually (under the tongue and directly enters blood stream) at first sign of an anginal episode or prior to activity which is likely to precipitate angina

Effect: significant improvement in exercise tolerance and delay in ECG signs of ischemia

Other Sublingual Nitrates: isosorbide dinitrate, erythrityl tetranitrate

Side Effects: headache, flushing, postural hypotension

Use: initiated at low doses and dose is Ý if necessary; 2 or 3 tablets may be necessary to relieve an attack but if the episode does not reside the patient may be having an MI – therefore patients should be advised not to take more than 2-3 tablets for a single attack

Vasospasm and nitrates: nitrates inhibit vasospasms and are very useful for vasospasm attacks

Pharmokinetics: acts very rapidly and has a brief duration of action (30-45 minutes); huge first pass effect in the liver when absorbed from the gut Þ therefore only given sublingually

Drug Stability: unstable and should be stored in a dark glass bottle; should cause burning or stinging sensation in the tongue and sense of fullness in the head (indicates it is still potent); drug should be replaced every 6 months

Mechanism of Action: NTG causes dilation of both the arterioles and veins;

venous dilation causes pooling in the venous bed which ß venous return and ß preload Þ causing ß heart size and ß cardiac output (CO) Þ ß oxygen demand

arterial dilation and ß CO Þ ß BP and ß intraventricular pressure Þ ß wall tension and ß oxygen demand

ß BP causes some reflex Ý HR and Ý contractility; this does not overcome the inhibitory effects, however

NTG does not work by directly Ý blood flow to the coronary arteries (the coronary arteries are already maximally dilated); NTG may redistribute flow to ischemic subendocardial areas because the ß intraventricular pressure results in less mechanical interference in subendocardial blood flow

Details of Mechanism: Glutathione converts NTG to nitric oxide (NO) which activates guanylate cyclase (GC); GC then converts GTP to cGMP which activates protein kinase (PK); PK now phosphorylates myosin light chain kinase (MLCK) which prevents smooth muscle contraction

Tolerance: glutathione gets used up; drug holiday during the night allows body to Ý glutathione levels

Contraindication: Sildenefil (Viagra) inhibits breakdown of cGMP and is useful in erectile dysfunction; use sildenefil and NTG together can cause severe ß ß in BP

"Long-Acting" Nitrates

many oral nitrates are available for chronic treatment of angina pectoris (no 1^st-pass effect), but there is no evidence that they are effective

the "long-acting" drugs are still metabolized by the liver, which greatly reduces their half life

NTG ointment (applied topically) and topical patches provide long lasting effect and Ý exercise capacity

(2) b-Blockers

Prototype drug: Propranolol – acts on both b₁ and b₂ receptors

Actions: blocks sympathetic activation of the heart by blocking the b ₁ receptor Þ the drug is therefore more effective in situations when there is a higher sympathetic activity; by blocking the sympathetic actions on the heart, propranolol ß HR, contractility, and BP Þ ß oxygen demand

propranolol also causes the heart to dilate which Ý wall tension and Ý oxygen demand

propranolol is not effective in managing anginal attacks caused by vasospasm; may actually exacerbate vasospasm by blocking b ₂ receptors which cause vasodilation in the coronary arteries

Use: effective in Ý exercise tolerance

Dose: must be optimized for desired effect (due to a first-pass effect that varies widely from patient to patient)

Pharmokinetics: completely absorbed from the gut, but only 30-60% enters circulation due to liver metabolism; the first-pass effect varies greatly among patients and causes variations in effective doses; patients usually begin on a low dose and the dose is gradually Ý until a therapeutic level is achieved

Abrupt Cessation: may cause "rebound phenomenon" causing exacerbation of angina and may result in fatal arrhythmias or MI; the action is poorly understood but may be due to

continued Ý exercise in patients who used the drug to improve exercise Þ causing oxygen supply and demand imbalance

Ý sympathetic tone

progression in underlying coronary disease which becomes apparent when b blockers are stopped

sensitization of the heart to catecholamines during the block so that excess response to normal levels of catecholamines occurs after removal of the b blockers; may be due to Ý number of receptors

Contraindications of b-Blockers: Þ an intact sympathetic nervous system (SNS) is important in some diseases; undesirable effects usually occur at low doses

CHF: Þ SNS augmentation is necessary to maintain CO in CHF; b -blockers can worsen the congestive heart

Sinus Bradycardia or Greater than First Degree Heart Block: Þ catecholamines Ý HR and improve conduction through the A-V node

Asthma or Chronic Bronchitis: catecholamines cause bronchiole dilation; b blockers can cause bronchospasm

Hypoglycemia: propranolol may mask the sympathetic response to hypoglycemia

Other b blockers

differ in b receptor selectivity, degree to which they have agonist activity, and degree of membrane stabilizing activity

propranolol is the most effective b blocker

Metoprolol – relatively selective for b₁ receptor; may be useful in the treatment of patients with asthma

(3) Combined NTG and Propranolol Therapy – each drug complements the other by reversing negative effects

the deleterious reflex in HR and contractility following NTG is attenuated by propranolol while the Ý in heart size and wall tension associated with propranolol is attenuated by the ß preload associated with NTG

(4) Calcium Antagonists – block voltage gated L-type channels

Voltage gated L-type calcium channels – open around -40 mV; regulated by phosphorylation which is mediated by catecholamines, ACh and other agents which alter cyclic nucleotide levels; composed of 5 subunits and the calcium channel blockers bind the a1 subunit

Action: interfere with slow inward calcium current but not the fast inward sodium current

interfere with excitation-contraction coupling in the heart and ß contractility Þ ß oxygen demand

interfere with excitation-contraction in the vascular smooth muscle Þ relax systemic vessels, relax coronary vessels, prevent vasospams

alter the electophysiological properties of slow fibers where inward current is carried primarily by calcium; slow fibers are primarily located in the SA and AV nodes

fast fibers take on the characteristics of slow fibers when they are depolarized sufficiently

prevent injury due to calcium during ischemia

Nifedipine – calcium antagonist effective for treatment of angina caused by both Ý oxygen demand and by vasospasm

interferes with excitation-contraction in both the heart and systemic smooth muscle Þ ß contractility of heart and causes vasodilation which ß oxygen demand by the same mechanism as the nitrates

causes coronary vasodilation Þ Ý coronary blood flow at rest and when tachycardic

Ý coronary blood flow is only seen with calcium antagonists and not with nitrates of b blockers Þ most important reason for the efficacy of the calcium antagonists in angina attacks precipitated by Ý oxygen demand

Classes of Ca⁺⁺ channel blockers:

Diphenylalkylamines: VerapamilÞ short T½, ß ß chronotropic + ionotropic, vasodilation; slow release form available

Benzothiazepines: Diltiazem Þ short T½, pharmakodynamically similar to verapamil

Dihydropyridines: Nifedipine Þ short T½, potent vasodilation; weak chronotropic and ionotropic effects

Uses: Anti-HTN (all), Antianginal (all), Antiarrhythmic (verapamil + diltiazem for supraventricular tachycardia), Esophageal spasm (all), Raynaud’s syndrome (dihydropyridines), Migraine (verapamil), LV diastolic function (dihydropyridines and diltiazem)

(5) Combined Nifedipine and Propranolol Therapy–more effective than either alone in managing typical angina

drugs complement each other in the same way that nitrates and propranolol complement each other

Nifedipine Ý oxygen blood flow to the ß oxygen demand produced by propranolol