Antianginals

• Nitroglycerin, Isosorbide dinitrate (ISDN), Pentaerythritol tetranitrate

•Oral admin. subject to significant First Pass metabolism

 So admin sublingually

•Effective w/in 2 min for 30 min

a/ Mechanism of Action (MOA)

•denitration of drug must occur freeing nitrite ion

-nitrite ion reacts with sulfhydryl groups which comprise a “nitrite receptor”

-subsequent release of Nitric Oxide results (Endothelial Derived Relaxing Factor)

•Nitric Oxide increases cGMP leading to vascular dilation

b/

Role in relief of Effort Angina

 Dilates large veins -->  preload (little effect on arteries)

•preload leads to  cardiac work (less left ventricular wall tension)

•plus  end diastolic P may blood flow to ischemic subendocardium

•does not increase the max rate x pressure achievable before angina

•does allow for increased work before reaching the maximal rate x pressure

•ie they do not increase O₂ supply, rather they decrease O₂ demand

c/

Role in relief of Variant Angina

•remember O₂ demand is not important here

 Direct coronary vasodilation of spastic segment is the main beneficial effect

d/

Other effects

•dilates bronchial, GI, biliary, genitourinary tracts

•may be of some use in esophageal achalasia

e/

Side effects (all but one related to vasodilatory effects)

•flushed appearance (vasodilations in face)

•pulsating headache (due to meningeal a. dilation)

•hypotension, orthostatic, syncope etc…

sympathetic reflexes can’t overcome the functional antagonism on the vessels

Other side effect

-Methemoglobinemia (nitrite oxides hemoglobin, antidote for cyanide poisoing)

-halitosis due to sublingula admin.

F/ Contraindication

Elevated intra-cranial pressure

G/ Tolerance

•Subsensitivity results from depletion of sulfhydryl groups in “nitrite receptor

•Dithiothreitol reduces disulfides and restores sensitivity

•Cross tolerance between the organic nitrates occurs

•Small intermittent doses help avoid tolerance development

H/

Dependence

•can be dangerous…. slowly wean patient from use

a/ Nitroglycerin

•diluted with lactose for safe handling

•active drug produces burning sensation under tongue

Low dose

•beneficial venodilation

High dose

•arterial + venous dilation

•decreased preload + afterload => usually beneficial in reducing cardiac work (O₂ demand)

•may cause paradoxical angina due to reflex tachycardia (induced by low BP at baroreceptors)

Dermal patch

•prolonged effects + avoid sudden pressure drops

•(-) Headaches, Hypotension, tachycardia, faintness, flushing, dizziness, and skin rashes

b/

Isosorbide dinitrate (ISDN)

•slower onset than nitro. but longer effects

•converted to isosorbide mononitrate (ISMN) by the liver

•potent vasodilator with longer plasma half life than parent drug

•oral administration of large doses are effective for longer periods

•Isosorbide mononitrate (ISMO) is approved oral drug for chronic stable angina

c/

Pentaerythritol tetranitrate

•not absorbed well sublingually

•absorbed from GI tract

•converted to active form, Pentaerththritol trinitrate

Propanolol, Metoprolol, Atenolol, Pindolol, Nadolol, Labetalol

•Net effect:  myocardial O₂ consumption

•Mech:  TPR   SV

•Effort angina only ?

3/ Ca⁺⁺ Channel Blockers: (see anti-hypertensive section)

•Verapamil, Nifedipine, Diltiazem, Bepridil (last option)

•Mech: TPR ->  SV

•Net result: no change in heart size

Propanolol and Organic Nitrates

•prophylactic use of propanolol, with symptom use of nitrates

•propanolol blocks reflex tachy associated with nitro

•nitro by reducing preload tends to diminish enlarging of the heart induced by propanolol

Organic Nitrates and Calcium Channel Blockers

•very effective in relieving variant and effort angina

5/ Anti-Thrombotic (anti-coagulant) Agents

Aspirin, Ticlopidine, Clopidogrel

-Use in patient who had an acute MI

-Rationale: reduce incidence of thromboembolic and mortality from recurrent infarction

Category: Pharmacology Notes