02 - Anti-Anginal Drugs

angina pectoris

chest pain caused by imbalance between oxygen demand and oxygen supply in the heart

• if oxygen demand becomes greater than oxygen supply, the heart muscle becomes ischemic

• ischemia → tissue not getting enough oxygen-rich blood

  • causes chest pain, pressure/tightness, shortness of breath, worsening with activity, progression towards myocardial infarction if severe/prolonged

oxygen supply vs demand

heart gets angina when oxygen demand > oxygen supply

1. demand goes up too much

   • increased heart rate

   • increased contractility

   • increased wall tension

2. supply goes down too much

   • decreased coronary blood flow

   • narrow coronary arteries

   • coronary artery spasm

   • obstruction by atherosclerotic plaque

types of anginal pectoris

• classical effort-induced agina → exertional angina due to increased myocardial oxygen demand

  • coronary arteries cannot provide enough oxygen when heart works faster

  • treatment — nitrates, beta blockers, calcium channel blockers

• variant angina → angina at rest due to decreased myocardial oxygen supply

  • treatment — nitrates, calcium channel blockers

    • beta blockers are contraindicated due to worsening of vasospasm through unopposed alpha effects

• unstable angina → effort-induced angina with plaque disruption

  • atherosclerotic plaque has fibrous cap that tears or separates and activates platelets and coagulation, worsening obstruction

  • treatment — nitrates, beta blockers, calcium channel blockers, aspirin, clopidogrel, heparin

organic nitrates

used to treat angina by generating nitric oxide, increasing cGMP, relaxing vascular smooth muscle, and increasing venous capacitance

• mechanism —

  1. organic nitrate enters vascular smooth muscle

  2. enzymes convert nitrate into nitric oxide

  3. NO binds the heme group of guanylyl cyclase

  4. guanylyl cyclase converts GTP into cGMP

  5. cGMP causes smooth muscle relaxation

     • cGMP can be converted to inactive GMP by PDE-5

     • PDE-5 can be inhibited by sidenafil (will increase cGMP)

  6. blood vessels dilate

• pharmacokinetics —

  • organic nitrate work mainly on the venous side of circulation to increase venous capacitance

  • decreases venous return, LV end-diastolic pressure, LV end-diastolic volume, wall tension, and myocardial oxygen demand

  • venous dilation decreases blood returning to the heart, so there is less oxygen demand

  • tolerance can develop to organic nitrates (>16 hr) and may be caused by decrease in tissue sulfhydryl groups

• nitrates are a dual threat

  • decrease oxygen demand → venodilation and preload reduction

  • increase oxygen supply → increase coronary blood flow and dilating large coronary vessels

• first choice for vasospastic angina (along with CCB); second choice for prevention of exertional angina

  • short-acting formulations are standby drugs for coronary artery disease (CAD)

• adverse effects — headache, dizziness, postural hypotension, syncope

  • tolerance after >16 hr; need nitrate-free interval >8 hr

  • not to be used concurrently with PDE-5 inhibitors (sidenafil) because it can cause dangerous hypotension

• NO-mediated vasodilation of large > small vessels

  • preferential preload reduction without coronary steal

  • increases collateral blood flow to ischemic myocardium

nitroglycerin and first-pass metabolism

nitroglycerin contains a glycerol backbone with three nitrate groups with the potential to generate NO

• extensively destroyed by the liver, so alternative routes of administration are commonly used to aviod first-pass metabolism

  • IV → standard of care for post-MI

  • sublingual → fast relief

  • buccal → absorbed through oral mucosa

  • transdermal → longer prevention

  • oral isosorbide dinitrate/mononitrate → longer oral formulation

• sublingual is used for fast relief of acute angina, good for 10-30 min

  • tongue is highly vascular, so drug enters blood quickly and bypasses first-pass metabolism

• transdermal patch is used for prevention, but p

beta blockers in angina

beta blockers are first choice for prevention of exertional angina and unstable angina

• only anti-anginal drug class with proven prognostic benefits in CAD

• not useful for vasospastic angina → may worsen condition

• mechanism — decrease heart rate, contractility, cardiac output, myocardial oxygen consumption

  • improves oxygen supply by increasing diastolic perfusion time to allow more time for coronary blood flow

• adverse effects — bradycardia, AV block, bronchospasm, peripheral constriction, worsening of acute heart failure, depression

  • polymorphic CYP2D6 metabolism can delay metabolism (metoprolol)

  • additional vasodilation (carvedilol, nebivolol)

• more lipid-soluble beta blockers may enter the brain more easily and can cause more CNS effects

  • propranolol → highly lipid-soluble; can cause CNS effects

  • atenolol → hydrophilic; less likely to cause CNS effects

stable ischemic heart disease treatment flow

for stable ischemic heart disease / effort-induced angina:

1. nitroglycerin for immediate relief

2. beta blocker to prevent further episode

3. if not enough → add long-acting nitrate or calcium channel blocker

4. if still not enough → consider ranolazine

   • blocks late sodium current and indirectly decreases intracellular calcium

ranolazine

add-on anti-anginal drug that blocks late sodium current and indirectly decreases intracellular calcium

1. ranolazine blocks late Na⁺ current in cardiac sodium channels

2. less Na⁺ accumulates inside cardiac myocytes

3. Na⁺/Ca²⁺ exchange is affected

4. intracellular Ca²⁺ decreases

5. wall tension / contractile stress decreases

6. oxygen demand decreases

calcium channel blockers (CCB)

treat angina by blocking L-type calcium channels

• dihydropyrimidines → mainly dilate blood vessels; have little direct cardiac depressant effect

  • prototype — nifedipine

• non-dihydropyridines → more cardiac effects

  • decrease contractility, SA node automaticity, AV node conduction velocity

  • prototypes — verapamil, diltiazem

• mechanism —

  • decrease afterload through arterial vasodilation

  • decrease contractility (mainly verapamil/diltiazem)

  • decrease heart rate / conduction (mainly verapamil/diltiazem)

  • dilate coronary arteries, especially in vasoplastic angina

L-type calcium channels

L-type calcium channels allow large, long-lasting calcium entry into excitable cells; blocked by calcium-channel blockers

• calcium-induced calcium release → calcium entering through L-type channels triggers more calcium release from intracellular stores

  • SA node → decrease automaticity and heart rate

  • AV node → decrease AV nodal conduction

  • cardiac myocytes → decrease contractility

  • coronary arteries → vasodilation

  • peripheral arteries → vasodilation / decrease afterload

summary of drug effect on oxygen demand and supply

• organic nitrates —

  • decrease oxygen demand:

    • decrease LVEDV, LVEDP, wall tension

  • increase oxygen supply:

    • dilate large coronary vessels, increase collateral blood flow

  • may cause reflex sympathetic effects and decrease diastolic perfusion time

• beta blockers —

  • decrease oxygen demand:

    • decrease heart rate and contractility

  • increase oxygen supply:

    • increase diastolic perfusion time

  • may increase LVEDV/LVEDP, decrease epicardial vessel size, worsen vasospastic angina

• calcium channel blockers —

  • dihydropyrimidines → strong vasodilation, decrease afterload

  • non-dihydropyrimidines → decrease heart rate, contractility, and AV conduction

  • both dilate coronary arteries, making them useful in vasospastic angina