Anti-Anginal Drugs DSA Flashcards
1) Organic Nitrates
a) Nitroglycerin
b) Isosorbide dinitrate
c) Isosorbide mononitrate
2) Calcium Channel Blockers (CCBs)
a) Dihydropyridines (DHPs)
i) Amlodipine
ii) Felodipine
iii) Nicardipine
iv) Many others…
b) Non-dihydropyridines
i) Diltiazem
ii) Verapamil
3) β-Adrenergic Antagonists (β-Blockers)
a) Atenolol
b) Metoprolol
c) Propranolol
d) Timolol
e) Many others…
Angina pectoris
chest pain that occurs during myocardial ischemia. It is primarily caused by an imbalance between the O2 requirement of the heart and O2 supplied by the coronaries. This imbalance is most often due to coronary artery disease (CAD), resulting in atheromatous obstruction of large coronary vessels. The two main treatment strategies are: (1) to decrease O2 demand, and/or (2) to increase O2 delivery. Both strategies are important components in the treatment of unstable angina. Nitrates are first-line agents for immediate relief of angina. Calcium channel blockers (especially verapamil, diltiazem, and amlodipine) and beta blockers are useful for long-term prophylaxis of chronic stable angina. The table below summarizes the hemodynamic mechanisms by which the major classes of anti-anginal agents reduce O2 demand and/or increase O2 delivery.
ORGANIC NITRATES prototype and MOA
i) Prototype: Nitroglycerin
ii) Other agents: isosorbide dinitrate, isosorbide mononitrate
iii) MOA: Release of nitric oxide via enzymatic metabolism, which binds to and activates soluble guanylyl cyclase leading to increased cGMP
ORGANIC NITRATES pharmacodynamics
(1) Nitrates dilate veins, arteries, and coronary arteries by relaxing smooth muscle (veins are more sensitive due to increased bioavailability); virtually no direct effect on cardiac or skeletal muscle
(2) Primary antiischemic effect is to decrease myocardial O2 demand by producing systemic vasodilation (more so than coronary vasodilation)
(3) Systemic vasodilation increases venous capacitance; decreases ventricular preload; reduces left ventricular wall stress; and pulmonary vascular pressures and heart size are reduced
(4) In the absence of heart failure, cardiac output is reduced
(5) Compensatory reflex mechanisms: tachycardia, increased cardiac contractility, salt and water retention
(6) Decreases platelet aggregation (due to NO stimulation of guanylate cyclase in platelets and resultant increase in platelet cGMP)
organic nitrates pharmacokinetics
(1) High first-pass effect results in low bioavailability; sublingual route of administration is typically used to avoid first-pass
(2) Therapeutic blood levels are reached within minutes and last 15-30 minutes
(3) Oral, transdermal, and buccal preparations are available when longer duration of action is needed
(4) Tolerance may occur following continuous exposure, especially with nitroglycerin; a nitrate-free period of at least 8 hours between doses is required to prevent tolerance
organic nitrates CIs
(1) Common: orthostatic hypotension, syncope, throbbing headache
(2) Mechanisms of tolerance are incompletely understood, but may include:
(a) Diminished release of NO due to reduced bioactivation
(b) Reduced availability of sulfhydryl donors
(c) Increased generation of oxygen free radicals
(d) Compensatory responses contributing to the development of tolerance: activation of the sympathetic nervous system (tachycardia & increased cardiac contractility) and activation of the renin-angiontensin-aldosterone system (retention of salt and water & vasoconstriction)
(3) Glaucoma was previously thought to be a contraindication, but it has been shown that nitrates can be used safely in the presence of intraocular pressure
(4) Contraindicated if intracranial pressure is elevated
(5) Transdermal patches should be removed before the use of external defibrillators
organic nitrates DDIs
Synergistic hypotension with phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil); severe hypotension and a few MIs have been reported in men taking both drugs; use of nitrates and PDE5 inhibitors should be separated by at least 6 hours
organic nitrates clinical uses
Hypertensive emergencies, angina, heart failure
(1) Sublingual nitroglycerin tablets or spray are the treatment of choice for acute angina episodes or for prophylaxis of activities known to exacerbate exertional angina
(2) Chronic nitrate therapy improves exercise tolerance and time to onset of angina in patients with exertional angina, but must be dosed appropriately to prevent drug tolerance
(3) Coronary vasodilation is beneficial in patients with vasospastic angina
Beta blockers: Non-ISA, ISA, selective and non-selective
Non-Selective, Non ISA:
Propanalol and Carvedilol
Non-selective, ISA:
Labetalol
B1- selective Non-ISA
Metoprolol, Atenolol
B1 selective, ISA:
Acebutolol, nebivolol (not important)
ISA means Intrinsic Sympathomimetic Activity due to partial agonist action
beta blocker pharmacodynamics
(1) With the exception of carvedilol and nebivolol, beta blockers are not vasodilators
(2) Benefit in angina is due primarily to hemodynamic effects (decreased heart rate, blood pressure, and contractility reduce O2 requirements during both rest and exercise)
(3) Unfavorable effects (increased end-diastolic volume and increased ejection time, which tend to increase O2 demand) can be offset by concomitant nitrate use
beta blocker pharmacokinetics
(1) Except esmolol, all are available as oral preparations; carvedilol, metoprolol, and propranolol are available as extended-release tablets; atenolol, esmolol, labetalol, metoprolol, and propranolol are available as parenteral preparations
(2) A wide range of half-lives contributes to differences in dosing schemes
(3) Most exhibit low-to-moderate lipid solubility; exceptions are propranolol and penbutolol, which are quite lipophilic and readily cross the blood-brain barrier (see also Katzung Table 10-2)
beta blocker adverse effects/ CIs
(1) Asthma/COPD: Blockade of β2 receptors in bronchial smooth muscle may lead to an increase in airway resistance; no currently available β1-selective agents are specific enough to completely avoid β2 blockade; these agents should be avoided in asthmatics
(2) Diabetes: glycogenolysis is partially inhibited after β2 blockade; may mask signs of hypoglycemia and delays recovery from insulin-induced hypoglycemia; use with caution in insulin-dependent diabetics (benefits may outweigh risks in diabetics after MI)
(3) Most common side effects are bradycardia and fatigue; sexual dysfunction and depression sometimes occur
(4) Chronic use has been associated with unfavorable plasma lipid profiles (increased VLDL and reduced HDL)
(5) Sudden withdrawal may cause rebound hypertension, angina, and possibly MI; mechanism may involve upregulation of receptor synthesis
beta blocker DDIs
: Can cause heart block, especially if combined with the CCBs verapamil or diltiazem, which also slow conduction