Anticholesterol and Antianginal Drugs

Introduction

• Presented by Peter W. Abel, PhD, Professor and Chair, Department of Pharmacology and Neuroscience, School of Medicine.

Objectives

Anticholesterol Drugs

• Understand different types of lipoproteins and their functions.

• Discuss the mechanisms of action, uses, common adverse effects (including dental implications) of:

  • HMG-CoA reductase inhibitors (Statins): atorvastatin, simvastatin.

  • Ezetimibe.

  • PCSK9 Inhibitors.

  • Bile Acid-Binding Resins: colesevelam, cholestyramine.

Antianginal Drugs

• Comprehend hemodynamic factors affected by antianginal drugs.

• Discuss the mechanisms of action, uses, and common adverse effects (including dental implications) of:

  • Nitrates.

  • β-adrenergic receptor blockers.

  • Calcium channel blockers.

• Outline drug absorption and effects of different nitrate forms.

Drugs Used to Treat Hypercholesterolemia

• Hypercholesterolemia: High levels of LDL-cholesterol associated with atherosclerosis, a modifiable risk factor for cardiovascular disease.

• Key Management Goals:

  • Lower LDL levels.

  • Increase HDL levels.

• Management Strategies:

  • Diet modification: emphasize low-fat diets before considering medications.

  • Anti-lipid drugs for lowering LDL cholesterol:

    • HMG-CoA Reductase Inhibitors (Statins)

    • Ezetimibe

    • PCSK9 Inhibitors

    • Bile Acid-Binding Resins

  • Other agents decreasing VLDL include Niacin and Fibers.

HMG-CoA Reductase Inhibitors (Statins)

• Common medications: simvastatin (Zocor), atorvastatin (Lipitor), rosuvastatin (Crestor), lovastatin (Mevacor), fluvastatin (Lescol), pravastatin (Pravachol).

• Mechanism of Action:

  • Inhibit cholesterol synthesis in the liver.

  • Increase LDL receptor levels in hepatocytes, enhancing LDL uptake from plasma, thus lowering plasma LDL levels.

• Adverse Actions:

  • Liver dysfunction (rare).

  • Myopathy: includes myalgias, muscle weakness, rhabdomyolysis.

  • Dental Implications: Certain antibiotics and antifungals can exacerbate statin levels leading to toxicity.

  • Avoid use in pregnant patients.

• Clinical Use:

  • Indicated for various hyperlipidemias and cardiovascular disease prevention; can lower LDL by up to 60%.

Cholesterol Absorption Inhibitor

• Key drug: ezetimibe (Zetia), often combined with simvastatin (Vytorin).

• Mechanism:

  • Inhibits intestinal absorption of dietary cholesterol through NPC1L1 transporter, causing decreased hepatic cholesterol and increased LDL receptors.

• Adverse Effects:

  • Mildly tolerated; avoid in hepatic dysfunction and pregnancy; can cause myopathy.

• Use:

  • Monotherapy less effective than statins, often used in combination to enhance LDL reduction.

PCSK9 Inhibitors

• Key drug: evolocumab (Repatha), monoclonal antibodies that enhance LDL receptor availability.

• Mechanism:

  • Bind to and inactivate PCSK9, which degrades LDL receptors, decreasing plasma LDL by up to 60%.

• Adverse Effects:

  • Nasopharyngitis, itching, joint pain, injection site reactions.

Bile Acid-Binding Resins

• Key drugs: cholestyramine (Questran), colesevelam (Welchol).

• Mechanism:

  • Form insoluble complexes with bile acids in the intestine, preventing reabsorption; leads to increased LDL uptake from blood.

• Adverse Effects:

  • Generally safe, but can cause gastrointestinal issues: constipation, diarrhea, bloating. Colesevelam has fewer side effects.

Angina Pectoris

Overview

• Angina pectoris is chest pain/discomfort associated with coronary atherosclerosis and ischemic heart disease.

• Results from an imbalance between myocardial oxygen demand and supply.

Antianginal Drug Actions

• Lower heart rate, oxygen demand, and myocardial workload through:

  • Coronary artery dilation.

  • Reducing preload and afterload.

• Medications used to treat angina include:

  • Organic Nitrates.

  • β-A adrenergic Blockers.

  • Calcium Channel Blockers.

Nitrates

• Action:

  • Converted to nitric oxide (NO), leading to venous and arterial dilation.

  • Reduces cardiac preload and afterload, resulting in decreased oxygen demand and increased oxygen supply.

• Pharmacokinetics:

  • Sublingual nitrates provide rapid action (2 min onset), while oral and transdermal forms have a slower onset and longer duration for prevention.

• Adverse Effects:

  • Related to excessive vasodilation: headaches, hypotension, dizziness.

β-A adrenergic Blockers

• Mechanism:

  • Antagonize epinephrine/norepinephrine during stress/exercise:

    • Decreases heart rate, contractility, blood pressure, and oxygen demand.

• Uses:

  • Primary preventive therapy for angina, hypertension, and arrhythmias.

• Adverse Effects:

  • Cardiovascular and dental implications (dry mouth, canker sores).

Calcium Channel Blockers (CCBs)

• Three classes:

  1. Phenylalkylamines (verapamil).

  2. Benzothiazepines (diltiazem).

  3. Dihydropyridines (nifedipine, amlodipine, etc.).

• Mechanism:

  • Block L-type calcium channels, reducing intracellular Ca2+, leading to peripheral vascular relaxation and decreased myocardial oxygen demand.

• Adverse Effects:

  • Similar to nitrates: excessive vasodilation; dental effects include dry mouth and gingival overgrowth.