Coronary Heart Disease Lectures
Introduction
Lectures by Michelle Hansen from the University of Melbourne
Focus on drugs treating coronary heart disease (CHD)
Continuation of discussions from lipid regulation drug series
Coronary Heart Disease (CHD)
Caused by elevated LDL cholesterol
Leads to plaque formation in coronary arteries
Results in myocardial ischaemia, restricting oxygen supply
Understanding Angina
Angina is a key symptom of CHD, characterized by severe chest pain
Caused by reduced blood flow and oxygen to the myocardium due to arterial occlusion
Terms of Angina:
History of the term "angina": Latin for "to strangle the breast"
Symptoms of angina arise when there's an imbalance between oxygen supply and demand in the heart
Types of Angina
Stable/Classic Angina:
Occurs during exertion or stress; not at rest
Symptoms due to increased oxygen demand not met by supply
Variant Angina:
Vasospastic; unpredictable and not permanent occlusion
Caused by transient constriction of coronary arteries
Unstable Angina:
Symptoms can occur at rest; increasing intensity of pain
Risk of thrombus formation, potentially leading to myocardial infarction
Understanding Myocardial Oxygen Demand
Cardiac muscle requires oxygen supplied by coronary arteries
Perfusion varies during the cardiac cycle:
Blood flow mainly occurs during diastole when the heart muscle relaxes
Factors affecting demand: heart rate, stroke volume, preload, and afterload
Coronary Artery Functioning
Healthy coronary arteries dilate to meet increased oxygen demand (e.g. during exercise)
Angina results from partial occlusion (atherosclerosis) leading to diminished dilation response
Local dilation occurs due to mediators rather than neural control
Drug Mechanisms in Treating Angina
Aim: Prevent attacks, relieve symptoms, and stop progression to more severe heart disease
Increase Oxygen Supply:
Achieved by dilating coronary arteries (challenging in atherosclerosis)
Alternatively, decreasing heart rate to increase diastole duration
Decrease Oxygen Demand:
Target cardiac output, preload, and afterload
Techniques include venodilation (reducing preload) and arteriolar dilation (reducing afterload)
Classes of Drugs for Treatment
Nitrates: Commonly used for acute angina relief by targeting preload
Beta Blockers: Act on heart, reducing cardiac output and thus oxygen demand
Calcium Channel Blockers: Affect cardiac output and afterload depending on type
Ivabradine: Targets heart rate specifically via action on sinus atrial node
Some drugs for prophylaxis to prevent attacks; others for symptomatic relief
Conclusion
Understanding angina and its management is critical in coronary heart disease treatment.
Overview of Nitrate Class of Drugs
Nitrates are used primarily to treat acute angina attacks.
Long-acting forms can be used prophylactically to prevent angina.
Key objectives by the end of the video:
Understand the rationale for using nitrates to treat angina.
Explain the mechanism of action of nitrates.
Discuss adverse effects and limitations of nitrate use.
Mechanism of Action
Nitrates are prodrugs that release nitric oxide (NO) following biotransformation in the body.
NO mimics the action of endogenous NO produced by vascular endothelial cells to regulate vascular tone.
Once liberated, NO diffuses into vascular smooth muscle cells and stimulates guanylate cyclase (GC).
GC converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP).
Importance of cGMP:
cGMP causes dephosphorylation of myosin light chain, inhibiting contraction and promoting relaxation of vascular smooth muscle.
This leads to dilation of blood vessels, primarily affecting the veins at therapeutic doses.
Effects on the Cardiovascular System
Venous Effects:
Dilation leads to venous pooling, reducing venous return (preload).
As a result, cardiac workload and oxygen demand decrease, alleviating angina symptoms.
Arterial Effects:
At therapeutic doses, the effect on arteries (afterload) is minimal, but high doses can cause dilation of arterioles.
Coronary Effects:
Limited effect on atheromatous (stiff) coronary arteries.
Positive effect noted in dilating collateral vessels, enhancing blood flow to ischemic myocardium during angina.
Administration of Nitrates
Glycerin Trinitrate (GTN):
Effective in relieving angina but suffers from significant first-pass metabolism when taken orally.
Administered sublingually (bypassing the liver) for rapid effect.
Can also be used transdermally, releasing medication via skin absorption, avoiding first-pass metabolism.
Intravenous administration available for acute angina attacks.
Other Nitrate (Sorbitrate):
Oral formulation that undergoes hepatic metabolism to release the active metabolite, sorbate 5 mononitrate, effective for prophylaxis.
Adverse Effects
Vasodilation-related effects include:
Postural Hypotension: Caused by excessive venous dilation, leading to dizziness; patients should rise slowly from sitting/lying.
Headache and Flushing: Occurs from excessive arteriolar dilation, especially in high doses.
Reflex Tachycardia: A decrease in blood pressure may lead to increased heart rate; can manage with beta-adrenoceptor antagonists.
Drug Interactions
GTN and Viagra (Sildenafil):
Both increase cGMP levels (GTN by synthesis, Viagra by inhibition of breakdown).
Using them together can cause dangerously low blood pressure due to excessive vascular relaxation.
Tolerance to Nitrates
Tolerance means increased dosage is required over time to achieve the same effect.
Mechanisms include:
Depletion of thiol compounds necessary for NO production.
Increased sensitivity/release of vasoconstrictors (angiotensin II, catecholamines).
Increased degradation of NO by free radicals.
To minimize tolerance:
Encourage taking nitrates less frequently and removing transdermal patches at night.
Conclusion
Nitrates primarily cause venous dilation, reducing cardiac preload and oxygen demand to relieve angina symptoms.
Further discussions in upcoming videos will cover drugs used for prophylaxis against angina.
Introduction to Angina Treatment
Discussion on drugs used for prophylactic treatment of angina.
Objective:
Understand rationale behind drug classes.
Explain mechanisms of action, adverse effects, and contraindications.
Beta Blockers (Beta-Adrenergic Antagonists)
Mainstay treatment for stable angina unless contraindicated.
Mechanism of Action:
Block sympathetic nervous system effects on beta adrenoreceptors.
Prevents adrenaline from increasing cardiac output and oxygen demand during stress or exercise, thus preventing angina attacks.
Effects:
Decrease heart rate.
Decrease cardiac contractility.
Reduces myocardial oxygen demand.
Increases diastolic duration, enhancing myocardial oxygen supply through prolonged perfusion.
Adverse Effects:
Cold extremities (due to impaired beta-2 mediated dilation).
Fatigue (due to decreased cardiac output).
Bradycardia (potentially life-threatening).
Bronchoconstriction in asthmatics/COPD patients.
Caution in diabetic patients (masks hyperglycemia signs).
Withdrawal Effects:
Abrupt cessation can result in increased endogenous adrenaline effects (e.g., palpitations, unstable angina).
Calcium Channel Blockers
Alternative when beta blockers are contraindicated or not tolerated.
Mechanism of Action:
Inhibit calcium entry via L-type calcium channels.
Result in vasodilation of peripheral and coronary arteries and decreased cardiac contractility, lowering oxygen demand.
Slow heart rate, increasing diastolic filling time, improving myocardial oxygen supply.
Types:
Non-selective (e.g., Verapamil, Diltiazem): act on both vascular smooth muscle and cardiac cells.
Selective (e.g., Amlodipine): primarily affect vascular smooth muscle.
Adverse Effects:
Flushing, headache, dizziness from vasodilation.
Edema resistant to diuretics due to capillary pressure.
Cautious use in patients with cardiovascular disorders.
Drug Interactions:
Non-selective calcium channel blockers should not be used with digoxin or beta blockers due to excessive cardiac suppression.
Ivabradine
Decreases heart rate without affecting cardiac contractility.
Mechanism:
Inhibits the funny current in the sinoatrial node, slowing depolarization and action potential firing rate.
Results in longer diastole period, increasing myocardial oxygen supply.
Reserved for patients intolerant to beta or calcium channel blockers.
Precautions:
Can cause bradycardia.
Eye-related symptoms due to its action.
Drug Interactions:
Metabolized by cytochrome P450, potential for interactions with other drugs.
Combination Therapy
Often necessary to effectively manage angina.
Use of different classes can control symptoms and minimize side effects.
Example: combining dihydropyridine with beta blockers.
Special Forms of Angina
Variant Angina:
Caused by vasospasm, not plaque.
Treatment: long-acting nitrate or dihydropyridine like nifedipine, avoid beta blockers.
Unstable Angina:
Similar to stable angina treatment but include low-dose aspirin to prevent thrombosis.
Summary of Pharmacological Effects
Ivabradine: decreases heart rate through funny current action.
Beta Blockers: reduce both heart rate and contractility; increase oxygen supply, decrease demand.
Calcium Channel Blockers: effects vary by selectivity.
Non-selective: reduce heart work.
Vascular selectivity: reduce myocardial work by arterial dilation.
Importance of drugs in relieving symptoms but not modifying disease progression; lifestyle modifications and further treatment necessary for underlying coronary artery issues.