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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
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.

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


CCBs: Pharmacodynamics

Relaxation of vascular smooth muscle causes peripheral vasodilation

Arterioles are more sensitive than veins

Reduce afterload and decrease O2 demand

Little effect on preload

Also increase O2 supply due to dilation of coronaries


Calcium Channel Blocker Use in Angina

Preferred agents: diltiazem, verapamil, amlodopine, or felodipine

Added to or substituted for beta blockers in chronic stable angina

Also effective in vasospastic angina

Reduce O2 requirement by reducing heart rate and contractility

Increase O2 delivery by vasodilation and reversal of vasospasm


CCBs: Adverse Effects & Toxicity

* Generally very well tolerated

Excessive vasodilation – dizziness, hypotension, headache, flushing, nausea; diminished by long-acting formulations and long half-life agents

** Constipation (esp., verapamil), peripheral edema, coughing, wheezing, pulmonary edema

*** Use of verapamil/diltiazem with a b-blocker is contraindicated because of the potential for AV block

Verapamil/diltiazem should not be used in patients with ventricular dysfunction, SA or AV nodal conduction defects and systolic BP less than 90 mmHg

Short-acting dihydropyridines can cause reflex tachycardia



Relatively newer antianginal drug
MOA: late sodium channel blocker
Typically reserved for angina that is refractory to treatment with beta blockers, calcium channel blockers, and nitrates
Used either in combination with beta blocker or as a substitute in patients who cannot receive beta blockers


Preventative Therapies

Regular aerobic exercise
Stress reduction
Smoking cessation
Weight control
Blood pressure control
Diabetes management
Pharmacotherapies to prevent cardiovascular events:
Aspirin (or clopidogrel)
HMG-CoA reductase inhibitors (the –statins)
ACE inhibitors (the –prils) and ARBs (the –sartans)


Clinical Pharmacology of Angina

Three primary drug classes are utilized: beta blockers, calcium channel blockers, & nitrates
Nitrates are the mainstay of treatment for acute symptoms
Cardioselective beta blockers are often recommended as initial first-line therapy for long-term prophylaxis
Combinations may be more effective than monotherapy
CCBs or nitrates relieve vasospastic angina by preventing coronary artery spasm