anti-anginal agents lecture Flashcards
primary symptom of ischemic heart disease
Angina Pectoris
Coronary artery disease is usually the underlying cause
Types of Angina
Effort angina (aka classic angina) Myocardial O2 requirement increases during exercise, but coronary blood flow does not increase proportionately Resulting ischemia usually, but not always, leads to pain
Variant angina (aka vasospastic or Prinzmetal’s angina) O2 delivery decreases as a result of reversible coronary vasospasm
Unstable angina (aka acute coronary syndrome) Angina at rest or an increase in the severity, frequency, and duration of chest pain in patients with previously stable angina
Molecular Mechanisms of Anti-Anginal Agents in the Vasculature
Increase cGMP
- Nitroglycerin (NTG), other nitrates and nitrites
- Potentiated by PDE inhibitors
Decrease intracellular Ca2+
- Calcium channel blockers
Physiologic effect: vasodilation
Molecular Mechanisms of Anti-Anginal Agents in the Heart
Decrease intracellular Ca2+
- Calcium channel blockers
- —- Verapamil > diltiazem > DHPs
- Beta blockers
Physiologic effect: decrease rate and contractility in cardiac myocytes
Organic Nitrates
Prototype: nitroglycerin (NTG) - Available in many different formulations: Sublingual tablet or spray Sustained release oral capsules Buccal tablets or gel Ointment Transdermal patch
Other agents:
Isosorbide dinitrate
Isosorbide mononitrate
Sublingual, oral, or sustained release tablets
Organic Nitrates: Pharmacodynamics
MOA: metabolism releases NO
Dilates both arterial and venous vessels—decreases TPR and venous return
Decreases both preload & afterload
Mainly relaxation of large veins ® ¯ venous return ® ¯ preload ® ¯ O2 demand (major effect), smaller ¯ in afterload
Primary antiischemic effect is to decrease myocardial O2 demand by producing systemic vasodilation (more so than coronary vasodilation)
Prevents coronary vasospasm- in this case it’s an exception to the reduction of demand MOA; instead increasing supply of O2
Nitrate Use in Angina
First-line therapy for an acute anginal attack (typically sublingual administration, spray equally effective)
Long-acting oral and transdermal formulations improve exercise tolerance and time to onset of angina
Improve antianginal and antiischemic effects of beta blockers and calcium channels blockers
Long-term utility is limited by tolerance
Nitrate Tolerance
Effectiveness diminishes significantly with continuous use
Multiple mechanisms proposed
Generally not a problem with sublingual nitroglycerin
Limits the usefulness of oral and transdermal nitroglycerin and oral isosorbide mono- and dinitrate
Prevention of Nitrate Tolerance
Intermittent therapy with a nitrate-free interval of at least 8 hours may prevent tolerance
Angina frequency and silent ischemia may increase during off-patch hours
Nitrates: Adverse Effects
Common: orthostatic hypotension, syncope, throbbing headache, flushing
Drug-drug interaction: synergistic hypotension with phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil)
Can lead to myocardial infarction and death
Beta Blockers: Pharmacodynamics
Reduce cardiac work (i.e., O2 consumption) by decreasing heart rate and contractility
Most are not vasodilators; no effect on O2 supply
Beta Blocker Use in Angina
Prototype: propranolol
First-line therapy to reduce frequency of angina (i.e., prophylaxis) and improve exercise tolerance
Reduce O2 requirement by reducing heart rate and contractility
All types are equally effective in exertional angina; cardioselective (β1-selective) often preferred
NOT effective in variant angina
Beta Blockers: Adverse Effects
Most common: bradycardia and fatigue Relative contraindications - Asthma/COPD - Diabetes - Variant angina - Acute decompensated heart failure
Can cause heart block, especially if combined with other negative inotropes (e.g., verapamil, diltiazem)
Calcium Channel Blockers (CCBs)
All CCBs bind to L-type Ca++ channels. But the two classes bind to different sites, resulting in different effects on vascular versus cardiac tissue.
Non-dihydropyridines:
Prominent cardiac effects, but also act at vascular tissues
Verapamil > Diltiazem
Dihydropyridines (DHPs):
Predominantly arteriolar vasodilation effects
Amlodipine, Clevidipine, Felodipine, Isradipine, Nicardipine, Nifedipine, Nisoldipine
Pharmacokinetic Properties of CCBs
Good oral absorption but high 1st pass effect
Amlodipine, felodipine, isradipine slowly absorbed, long t1/2 is advantage
*** DHPs with long plasma half-lives preferred to minimize reflex cardiac effects; extended release preparations available
Nifedipine, clevidipine, verapamil, and diltiazem sometimes used IV
