11.14 Anticholesterol Antianginal Therapies (1)

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• Title: Anticholesterol and Antianginal Drugs

• Author: Peter W. Abel, PhD

• Affiliation: Professor and Chair, Department of Pharmacology and Neuroscience, School of Medicine

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Objectives: Anticholesterol Drugs

• Understand and Describe:

  • Differences between various types of lipoproteins and their functions.

  • Mechanism of action, uses, common and dental adverse actions of the following drugs:

    • HMG-CoA reductase inhibitors (statins)

    • Ezetimibe

    • PCSK9 Inhibitors

    • Bile acid-binding resins

• Included Drugs:

  • Statins: atorvastatin, simvastatin

  • Ezetimibe

  • Bile Acid Resins: colesevelam, cholestyramine

  • PCSK9 Inhibitor: evolocumab

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Objectives: Antianginal Drugs

• Understand and Discuss:

  • Hemodynamic factors targeted by antianginal drugs.

  • Mechanism of action, uses, common, and dental adverse actions of:

    • Nitrates

    • β-adrenergic receptor blockers

    • Calcium channel blockers

  • Drug absorption and effect issues related to nitrate forms

• Included Drugs:

  • Nitrates: Nitroglycerin

  • Calcium Channel Blockers: nifedipine, diltiazem, amlodipine

  • β-blockers: propranolol, metoprolol

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Hypercholesterolemia

• Definition: Elevated LDL-cholesterol linked with atherosclerosis.

• Importance: Modifiable risk factor for cardiovascular disease.

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Lipoproteins

• Five Main Classes differing in:

  • Density

  • Surface proteins

  • Composition of core lipids:

    • VLDL = triglycerides

    • LDL = bad cholesterol

    • HDL = good cholesterol

  • Function: Transport of lipids

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Management of High Cholesterol

• Goals:

  • Lower LDL, increase HDL

• Diet Modification:

  • Lifestyle changes, low-fat diet recommended before drug initiation

• Anti-lipid drugs for lowering LDL:

  • HMG-CoA Reductase Inhibitors (Statins)

  • Ezetimibe

  • PCSK9 Inhibitors

  • Bile Acid-Binding Resins

• For Decreasing VLDL (triglycerides):

  • Niacin, fibrates, fish oil

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HMG-CoA Reductase Inhibitors (Statins)

• Examples:

  • Simvastatin (Zocor)

  • Atorvastatin (Lipitor)

  • Rosuvastatin (Crestor)

• Key Points:

  • Most common for treating hypercholesterolemia

  • Highly effective with a good adverse effect profile

  • Mechanism: Structural analogs of hydroxy-methylglutaryl-coenzyme A (precursor of cholesterol)

  • Additional drugs: lovastatin, fluvastatin, pravastatin

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Mechanism of Action of Statins

• Function:

  • Inhibit cholesterol synthesis in the liver

  • Decrease hepatic cholesterol levels, leading to increased LDL receptor expression in the liver

  • Resulting Lower LDL plasma levels

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Adverse Actions and Use of Statins

• Adverse Actions:

  • Rare liver dysfunction

  • Myopathy: myalgias, muscle weakness, rhabdomyolysis

  • Dental concerns: Macrolide antibiotics and antifungals can increase statin levels, precipitating myopathy

  • Contraindicated in pregnancy

• Indications:

  • Effective for all hyperlipidemia types

  • Cardiovascular disease reduction

  • Can reduce LDL by up to 60%

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Cholesterol Absorption Inhibitor

• Example: Ezetimibe (Zetia)

• Mechanism:

  • Inhibits intestinal absorption of dietary cholesterol in small intestine

  • Decreases hepatic cholesterol by increasing LDL receptor numbers on hepatocytes

  • Combination with simvastatin (Vytorin) for enhanced effect

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Adverse Effects and Use of Ezetimibe

• Adverse Effects:

  • Generally well-tolerated

  • Avoid in hepatic dysfunction and pregnancy

  • Possible myopathy

• Uses:

  • Monotherapy for hypercholesterolemia, less effective than statins

  • Often used in combination with statins

  • Reduces LDL levels

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PCSK9 Inhibitors

• Examples: Evolocumab (Repatha)

• Mechanism:

  • Monoclonal antibodies that lower LDL

  • Bind and inactivate PCSK9 which breaks down LDL receptors, thus increasing LDL receptors for better LDL clearance from blood

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Adverse Effects of PCSK9 Inhibitors

• Common Adverse Effects:

  • Nasopharyngitis

  • Itching

  • Joint pain

  • Injection site reactions

• Administration:

  • Via subcutaneous injection one or two times a month

  • Can be used alone or in combination, and can lower LDL by up to 60%

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Bile Acid-Binding Resins

• Examples:

  • Cholestyramine (Questran)

  • Colesevelam (Welchol)

• Use:

  • Treatment for hypercholesterolemia by decreasing plasma LDL

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Mechanism and Adverse Effects of Bile Acid-Binding Resins

• Mechanism:

  • Bind bile acids in the intestine, preventing bile acid and cholesterol reabsorption

  • Increased LDL uptake from blood due to increased LDL receptor expression in the liver

• Safety and Adverse Effects:

  • Generally safe with GI-related side effects: constipation, diarrhea, bloating

  • Colesevelam has fewer adverse effects

  • Considered less effective and inconvenient

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Angina Pectoris

• Definition:

  • Chest pain or discomfort, a primary symptom of ischemic heart disease

• Associated Condition:

  • Generally linked with coronary atherosclerosis

• Mechanism:

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

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Mechanisms of Antianginal Drugs

• Primary Actions:

  • Decrease heart rate, contractility, preload, and afterload to reduce O2 demand

• Coronary Artery Dilation:

  • Critical for angina treatment

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Drugs Used to Treat Angina

• Classes:

  • Organic Nitrates

  • β-Adrenergic Receptor Blockers

  • Calcium Channel Blockers

• Underlying Condition:

  • Coronary artery disease due to atherosclerosis

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Nitrates

• Form:

  • Isobutyl Nitrite, Nitroglycerin

• Mechanism:

  • Converted into the vasodilator nitric oxide (NO)

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Actions of Organic Nitrates for Angina

• Effects:

  • Major:

    • Venous and arterial dilation leading to decreased preload, reducing cardiac work and O2 demand

  • Minor:

    • Decreased afterload by relaxing arteries, lessening force against heart contraction

  • Also:

    • Increased coronary blood flow due to large artery dilation

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Nitrate Pharmacokinetics

• Effectiveness:

  • Rapid-acting nitrates have low oral effectiveness due to first-pass metabolism

• Administration:

  • Sublingual nitroglycerin acts rapidly (effects within 2 min) for acute angina

  • High-dose oral and transdermal forms are slower to act for prevention

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Organic Nitrate Drugs

• Dosage Forms and Effects:

  • IV: 1-2 min onset, duration 3-5 min

  • Sublingual: 1-3 min, duration 30-60 min

  • Translingual Spray: 2 min onset, duration 30-60 min

  • Oral Sustained Release: 20-45 min onset, duration 3-8 hrs

  • Topical Ointment: 30-60 min onset, duration 2-12 hrs

  • Transdermal: 30-60 min onset, duration up to 24 hrs

  • Isosorbide dinitrate: sublingual onset 2-5 min, oral 20-40 min

  • Isosorbide mononitrate: sustained release up to 4 hrs, oral duration 6-8 hrs

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Adverse Effects of Nitrates

• Generalized Effects:

  • Excessive vasodilation can lead to:

    • Severe headache, facial flushing

    • Hypotension, dizziness, and weakness

    • Orthostatic hypotension

    • Reflex tachycardia

• Management of Angina:

  • If severe pain occurs, stop activity, reassure patient, administer sublingual nitroglycerin, repeat as necessary, and seek emergency help if unresolved

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Actions of β-blockers for Angina Pectoris

• Mechanism:

  • Antagonize epinephrine and norepinephrine effects during stress, decreasing heart rate and contractility

  • Decrease renin release, lowering blood pressure and afterload

• Overall Result:

  • Reduced cardiac work and O2 demand

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β-Adrenergic Receptor Blockers

• Types:

  • Nonselective (1st Generation)

  • Cardioselective (2nd Generation)

• Use:

  • Most common preventive drugs for angina; also for hypertension and arrhythmias

• Adverse Actions:

  • Cardiovascular effects: bradycardia, tiredness, dizziness, cold extremities

  • Dental concerns: Limit epinephrine in local anesthetics for nonselective blockers, risk of dry mouth and canker sores

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Calcium Channel Blockers (CCBs)

• Classes:

  • Phenylalkylamines: verapamil

  • Benzothiazepines: diltiazem

  • Dihydropyridines: nifedipine, amlodipine, etc.

• Mechanism:

  • Block L-type Ca2+ channels in the heart and blood vessels

• Uses:

  • Prevent angina, treat hypertension, and some arrhythmias

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CCB Effects on Blood Vessels

• Blood Vessel Action:

  • Inhibit L-type Ca2+ channels in arterial smooth muscle

  • Result in peripheral relaxation, decreased blood pressure, afterload, and O2 demand

  • Modest vasodilation and increased O2 supply in coronary arterial smooth muscle

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CCB Effects on the Heart

• Heart Action:

  • Some CCBs (verapamil, diltiazem) block channels in SA and AV nodes, slowing heart rate and conduction

  • Reduction of myocardial contractility lowers cardiac work and O2 demand

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Adverse Effects of CCBs

• Common Adverse Effects:

  • Most associated with excessive vasodilation:

    • Dry mouth

    • Taste disturbances

    • Gingival overgrowth

• Interference:

  • Macrolide antibiotics (clarithromycin, erythromycin) can increase CCB effects