3 - Pharmacology and Pharmaceutic Principles of Drugs for Ischemic Heart Disease

Why does the heart have a high O2 demand?

The heart produces ~10 kg of ATP/day → requiring a large O2 supply.

What determines myocardial O2 supply?

Regional flow distribution → how much blood/O₂ is delivered to different regions of the heart

O2 extraction → how much O2 the heart takes out of the blood

Coronary blood flow → how much blood flows through the coronary arteries

What determines myocardial O2 demand?

Heart rate

Cardiac contractility

Myocardial wall tension

What happens when myocardial O2 demand exceeds O2 supply?

Myocardial ischemia results → often causes chest pain / angina

What is ischemic heart disease?

Heart disease caused by inadequate myocardial O2 supply relative to demand

Very broad term, could be referring to many different types of HD

What is angina pectoris?

Chest pain or discomfort due to myocardial ischemia → not even O2 supply for demand

What are common symptoms of angina pectoris?

Heavy weight or pressure on the chest

Numbness/tingling in the arms

Pain (occasionally)

Shortness of breath

How is angina classified?

Demand → also called classic or effort

Supply

Demand angina?

Chronic stable angina

Supply angina?

Unstable angina

Variant / Vasospastic angina

What causes stable angina?

Atherosclerosis

Episodes can be triggered by → exercise, cold, stress, emotion, or eating

What are the therapeutic objectives of stable angina?

Increase myocardial blood flow → dilate coronary arteries/arterioles → increasing O2 supply

Decrease cardiac load (preload + afterload) → decreasing O2 demand

Increase Heart rate → decreasing O2 demand

Decrease fatty acid metabolism → decreasing O2 demand (newer class)

What characterizes unstable angina?

Change in character, frequency, or duration of angina in patients with stable angina, or angina occurring at rest

What causes unstable angina?

Small platelet clots at a ruptured atherosclerotic plaque → may cause local vasospasm

Why is unstable angina more dangerous than stable angina?

Unstable angina → higher risk of myocardial infarction (MI) than stable angina

What are the therapeutic objectives of unstable angina?

Inhibit platelet aggregation and thrombus formation → Increase O2 supply

Decrease cardiac load (preload and afterload) → Decrease O2 demand

Vasodilate coronary arteries → Increase O2 supply

What causes variant angina?

Transient vasospasm of the coronary vessels → temporary tightening of the coronary vessels

Usually associated with underlying athermas

Chest pain may develop at rest

What are the therapeutic objectives for variant angina?

Decrease vasospasm of the coronary vessels → increasing O2 delivery

CCB → are efficacious in >70% of patients → increase O2 delivery

What is the broad therapeutic objective in treating angina?

Relieve the O₂ supply–demand mismatch in the heart

What is the effect of nitrates in stable angina?

Decrease O2 demand

What is the effect of nitrates in variant angina?

Increase O2 supply

What is the effect of β-blockers in stable angina?

Decrease O2 demand

What are the effects of calcium channel blockers in stable angina?

Decrease O2 demand

Verapamil and Diltiazem → only

What are the effects of calcium channel blockers in variant angina?

Increase O2 supply

What are the effects of pFOx inhibitors in stable angina?

Decrease O2 demand

Switches the heart from fatty acid metabolism to glucose metabolism → glucose requires less O2 to make energy → less O2 needed by the heart

What are the effects Ivabradine in stable angina?

Decrease O2 demand → lowers heart rate

What drugs are not used in variant angina?

B-Blockers

pFOx

Ivabradine

need vasodilators → (CCBs + nitrates)

MOA of Nitrates?

Increase NO, which → increases cGMP. This lowers intracellular Ca²⁺, causing smooth muscle to relax and blood vessels to dilate.

Decrease both preload and afterload

What is the prototype nitrate drug?

Nitroglycerin (NTG)

What happens when nitrites and nitrates are broken down?

They are “denitrated”

They release a free nitrite ion and NO

NO is the bioactive compound that causes → vasodilation

Which drug is the only nitrite in the nitrite/nitrate group?

Amyl nitrite

It is the only nitrite → the rest are nitrates

It is a volatile liquid that can be inhaled

Which drugs are nitrates in the nitrite/nitrate group?

NTG
Isosorbide Dinitrate

Isosorbide Mononitrate

Nitrate compounds → administered via oral, sublingual, topical, transfermal and IV

What is the primary effect of nitrites/nitrates?

The primary effect is the dilation of VEINS

Veins hold more blood → so less blood returns to the heart

Dilate veins > arteries → decreases venous return → decreases preload → decreases O2 demand

What is the secondary effect of nitrites/nitrates?

Dilate large coronary arteries → increase coronary blood flow

Decreases preload → decreases wall stress → improves blood flow to the subendocardium → increases O2 supply

What are other effects of nitrites/nitrates?

NTG → via NO stimulates → guanylyl cyclase in platelets → decrease platelet aggregation

Pharmacokinetics of NTG and Isosorbides Dinitrate (ISDN)?

High first pass metabolism → due to hepatic nitrate reductase in the liver

LOW oral availability → 10-20%

Hepatic blood flow and disease → hepatitis → can affect the PK of both

What formulation of NTG and Isosorbide dinitrate bypasses the first pass metabolism?

Sublingual or Transdermal

What form of nitrites/nitrates is 100% orally available?

Isosorbide mononitrate → 5-ISMN

Is not subject to first-pass metabolism

Why can continuous/frequent nitrate exposure cause tolerance?

Can lead to the inactivation of aldehyde dehydrogenase

A mitochondrial enzyme that converts nitrate/nitrite to NO

Adverse effects of nitrites/nitrates?

Orthostatic hypotension → BP drop while standing

Reflex tachycardia → heart rates goes up while BP drops

Severe throbbing headache

Why should nitrates NOT be used with PDE5 inhibitors (e.g., Viagra)?

Nitrates → increase NO → increase cGMP

While PDE5 inhibitors → prevent cGMP breakdown → too much cGMP → excessive vasodilation →

Causes Dangerously LOW BP

What drugs are major contraindicated with nitrites/nitrates?

Sildenafil

Vardenafil

Tadalafil

ANY PDE-5 INHIBITOR used with erectile dysfunction

How long should you wait if you are taking a PDE5 inhibitor with a nitrovasodilator?

Should not be taken within 6 hours of taking the nitrovasodilator

When are nitrates contraindicated?

Elevated intracranial pressure

Examples of pFOxs?

Ranolazine → used in US, also a Class 1 anti-arrhythmic

Trimetazidine → widespread in other countries

Perhexiline → used in australia/new zealnd

What is a pFOx?

Partial Fatty-acid oxidation inhibitor

How do pFOx inhibitors work?

Switch heart fuel from fatty acids → to glucose → glucose uses less O2 to make ATP → overall decreases O2 demand

Do pFOx inhibitors cause hemodynamic changes?

No → they decrease O2 demand without changing heart rate, BP, or other hemodynamics

What is the primary MOA of Ranolazine / Ranexa ?

Inhibits late Na⁺ current → decreases Ca2+ entry during phase 2 → decreasing inotropic effect, weaker contraction → overall decreasing O2 demand

Similar to Class 1B effect

What else does ranolazine do at higher doses?

Acts as a pFOx inhibitor → shifts heart from fatty acids → glucose → decrease O2 demand

Why does ranolazine combine well with other anti-anginal drugs?

No hemodynamic changes → can be combined with other anti-anginal medications

How is ranolazine metabolized?

Hepatically → CYP3A4

What is a major contraindication with ranolazine?

Risk of long QT → avoid/caution with other QT-prolonging drugs

CYP3A4

What are the minor adverse effects of ranolazine?

Dizziness

Constipation

What drugs interact with ranolazine?

CYP3A4 inhibitors → macrolides, diltiazem, verapamil

QT-prolonging drugs → Class IA/IC, Class III, antipsychotics

What does ivabradine inhibit?

Blocks the “funny current” (If) in pacemaker cells of the SA/AV nodes and Purkinje fibers → slows their automatic firing → decreasing HR

What is the “funny current” (If)?

Na⁺/K⁺ current that helps pacemaker cells generate their next heartbeat

What is the main effect of ivabradine?

Blocks If → decrease HR without decreasing contractility

Slows the heart rate → but the heart still contracts with the same strength

Adverse effects of Ivabradine?

Visual disturbances → “halo-ing” and luminous objects

High doses → excessive decrease in HR → bradycardia + AV block (signals blocked between atria and ventricles)

Contraindications and drug interactions of Ivabradine?

Sick sinus syndrome → already abnormal HR → alternating brady/tachycardia → ivabradine can worsen bradycardia

Verapamil/diltiazem or β-blockers → additive decrease HR → excessive bradycardia