Pharmacology lecture 22-28\12\2009
Antianginal agentsAngina Pectoris (Latin) = pain in the chest
Definition: Sudden, sever, transient, pressing retrostrenal pain. Radiating to the neck, jaw, left shoulder, and arm. Cardinal sign of coronary artery disease. A problem of O2 supply vs. O2 demand.
Pathophysiology 1- oxygen supply to the heart is insufficient to meet oxygen demand. Secondary to atherosclerosis of the coronary arteries.
2- vasoconstriction, at an atherosclerosic site of the coronary arteries.
Types of Angina Pectoris
Stable Angina ( Classic exertional Angina).
most common form (90%)
Coronary insufficiency due to vessel occlusion (atherosclerosis)
Attacks usually occur during exercise (climbing stairs, etc.) when oxygen demand exceeds supply
Variant Angina (Prinzmetals Angina)[rest angina]
Coronary insufficiency due to vasospasm (may be an effect produced by atherosclerosis on vasomotor tone)
Attacks often occur during rest (e.g., at night)
Unstable Angina ( Accelarated Angina). (acute coronary syndrome)
serious problem (impending MI)
Increased frequency & severity of attacks
Caused by atherosclerotic plaques, platelet aggregation at fractured plaques & vasospasm
Treatment Strategy
increase cardiac oxygen supply
decrease oxygen demand
Antianginal agents
Nitrites & Nitrates.
β-adrenergic blocking agents.
Calcium channel blocking agents.
Aspirin & anticoagulants.
Trimetazidine.
1- Nitrites & Nitrates
Mechanism of Action -
release NO Venodilation - primary mechanism
Venodilation results in decreased preload (decreased ventricular chamber size, end diastolic pressure, fiber tension) = decreased work
Decreased preload results in decreased O2 demand
Reduction of afterload (arterial resistance) can be produced at higher doses - can produce reflex tachycardia
Redistribution of coronary blood flow with nitrates
Subendocardial regions are most ischemic
Organic nitrates can selectively increase blood flow to ischemic areas
Total coronary flow is not increased
Nitroglycerin( Glyceryl trinitrate)
Significant first-pass metabolism of nitroglycerin occurs in the liver.
Sublingual tablet or spray acts with in (1-3min) for about 10-30 minutes.
Transdermal patches have a long duration of action(24 hours).
Therapeutic uses
It is more useful in preventing attacks than in stopping them once they have begun.
low doses (usually sublingual tablets) for acute attacks & for prophylaxis
patches used for prolonged prophylaxis
tablets oral high dose;
Nitrates are the mainstay of therapy for the immediate relief of angina
Adverse Effects
Due to vasodilation, vessels relaxed
Headache.
Facial flushing
Orthostatic Hypotension
Dizziness.
Reflex Tachycardia ((baroreceptor mediated, lowered Bp => reflex to increase Bp)
Tolerance. If tolerance develops, it can be reversed by withholding nitrates (nitrates free interval). Until the sulfhydryl content of VSM has been replenished. Can have anginal rebound during nitrate-free intervals.
lsosorbide dinitrate
lsosorbide dinitrate is an orally active nitrate.
The drug is not readily metabolized by the liver or smooth muscle
It has a lower potency than nitroglycerin in relaxing vascular smooth muscle.
Prophylactic uses.
Onset (20-40 min).
Duration ( 4-6 hr).
Amyl nitrate
Amyl nitrate is extremely volatile.
High chance of abuse.
Route is by inhalation.
Onset (0.5 min).
Duration (3-5 min).
Emergency uses.
2- β-adrenergic blocking agents:
β- blockers reduce Anginal pain by decreasing cardiac oxygen demand, due to reduced heart rate (esp. during exercise).
Reduced blood pressure (esp. systolic) during exercise.
Mechanism of action.
This is accomplished primarily through blockade of β1 receptors in the heart, which decreases heart rate and contractility.
β- blockers can reduce oxygen demand further by causing a modest reduction in arterial pressure (afterload).
Commonly Used β-adrenergic blocking agents.
Propranolol is the prototype of this class of compounds, but other β-blockers, such as metoprolol and atenolol are equally effective.
However, agents with intrinsic sympathomimetic activity (for example, pindolol and acebutolol) are less effective and should be avoided.
Therapeutic uses
Only for prophylaxis of exertional angina
Ineffective (or contraindicated) for variant angina (may make attacks worse)
Often combined with other drug types.
Adverse effects
Bronchoconstriction (nonselective).
Fatigue, insomnia
Hypoglycemia (nonselective).
Sever myocardial depression & heart failure.
Contraindication
They are contraindicated in patients with:
Diabetes,
Peripheral vascular disease,
Chronic obstructive pulmonary disease.
3- Calcium Channel Blockers (CCBs).
These agents block the channels that carry slow inward Ca++ currents in vascular smooth muscle and cardiac muscle
Resulting actions include the decrease of conduction velocity, reduction of automaticity, and coronary and peripheral arterial dilitation
These effects lead to an increase of coronary blood flow and a decrease in myocardial oxygen demand.
Examples: nifedipine, verapamil, diltiazem, amlodipine
Mechanisms of action
Block Ca entry into cell which is important for contractile action in heart. Produce decreased contractility.
Vasodilation, (Arteriolar dilation).
(O2 Demand - probably most important
Decreased HR
Decreased contractility
Decreased afterload ((TPR, BP)
little effect on venous resistance vs. arterial
Increase coronary blood flow (useful in vasospastic angina)
Nifedipine: exerts a greater effect on smooth muscle in the peripheral vasculature, functions mainly as an arteriolar vasodilator.
This drug has minimal effect on cardiac conduction or heart rate.
Nifedipine is administered orally and has a short half-life (about 4 hours) requiring multiple dosing.
Therapeutic uses
nifedipine is useful in the treatment of variant angina caused by spontaneous coronary spasm.
Side Effect
Can cause flushing, headache, hypotension, and peripheral edema as side effects of its vasodilation activity.
may cause reflex tachycardia if peripheral vasodilation is marked resulting in a substantial decrease in blood pressure.
Gingival hyperplasia, & dysgeusia
Dental Considerations: Calcium Channel Blockers
There are no significant drug interactions reported
Gingival hyperplasia can occur in patients taking calcium channel blockers; close monitoring and encouragement of optimal oral hygiene is necessary
Verapamil: mainly affects the myocardium, slows cardiac conduction directly and thus decreases heart rate and oxygen demand, but it is a weaker vasodilator.
Side Effect
Verapamil is contraindicated in patients with preexisting depressed cardiac function or AV conduction abnormalities.
It also causes constipation. Verapamil should be used with caution in digitalized patients, since it increases digoxin levels.
Diltiazem: is intermediate in its actions, it has cardiovascular effects that are similar to those of verapamil.
It reduces the heart rate, although to a lesser extent than verapamil, and also decreases blood pressure.
In addition, diltiazem can relieve coronary artery spasm and is therefore particularly useful in patients with variant angina.
The incidence of adverse side effects is low.
Note : nitroglycerin, ( blockers; CCBs in refractory pts ( combined)
Aspirin & anticoagulants.
Unstable Angina : recurrent ischemic episodes at rest
Recurrent thrombotic occlusions
Platelet aggregation.
aspirin
i.v. heparin
antiplatelet drugs (clopidogrel, others)
Trimetazidine, Ranolazine
A novel anti ischemic drug.
Mechanism of action is unclear.
Are metabolic modulators.
They are known as pFOX inhibitors because they partially inhibit the fatty acid oxidation pathway in myocardium.
Well tolerated.
Minor side effect.