Pharmacology Chapter on Cardiovascular Drugs

Drugs Related to Cardiovascular System

• Lecture outlines cover mechanism of action, indications, distribution, excretion, side effects, and drug interactions for various cardiovascular drugs.

• Included drug classes are antianginal drugs, antihypertensive drugs, lipid-lowering agents, cardiac glycosides, antiarrhythmic agents, drugs for circulatory shock, and antithrombotics/thrombolytics.

• The implications of these drugs for dentistry are also explained.

Antihypertensive Drugs

• Hypertension is defined as persistent systolic BP of 140 mmHg or higher, and/or diastolic BP of 90 mmHg or higher.

• ACE inhibitors, ARBs, α-blockers (A), Beta-blockers (B), Calcium channel blockers and centrally acting sympatholytics (C), and Diuretics (D) are types of antihypertensive drugs.

Physiologic Control of Blood Pressure and Sites of Drug Action

• Blood pressure is the product of cardiac output and peripheral vascular resistance.

• Factors influencing blood pressure include stroke volume, heart rate, filling pressure, blood volume, renal sodium excretion, renin, and the sympathetic nervous system.

• Sites of drug action are identified on a diagram, showing vasodilators, β-blockers, α-blockers, ARBs, calcium channel blockers, sympatholytics, ACE inhibitors, and diuretics.

Antihypertensive Medications: Mechanism of Action

• Diuretics reduce blood volume and sodium levels, potentially enhancing other BP medications.

• ACE inhibitors decrease angiotensin II levels and dilate blood vessels.

• ARBs block angiotensin II receptors, dilating blood vessels.

• Beta-blockers decrease heart rate and cardiac output.

• Calcium channel blockers interrupt calcium inflow into heart and vessel cells.

• Aldosterone receptor blockers decrease salt and water retention.

• Renin inhibitors block the production of angiotensin I, thus decreasing activation of the renin-angiotensin-aldosterone system.

Thiazide Diuretics

• MOA: Increased sodium and water excretion decreases blood volume and cardiac output.

• Example: Hydrochlorothiazide.

• Indication: Initial treatment for mild to moderate hypertension.

• Used in combination with other antihypertensive classes.

• Adverse effects (A/E): Hypokalemia, elevated glucose/uric acid/lipids, and potential hepatic impairment.

• Drug Interactions: ACE inhibitors, carbamazepine, and corticosteroids can have synergistic effects increasing hypokalemia risk.

Loop Diuretics

• MOA: Similar to thiazide diuretics.

• Example: Furosemide (Lasix).

• Indication: Usually reserved for hypertension patients with poor renal function or congestive heart failure.

• Do not significantly lower blood pressure in all cases.

• A/E: Electrolyte imbalance (hypokalemia), hyperuricemia, hyperglycemia, and hypovolemia.

Potassium-Sparing Diuretics

• MOA: Interfere with sodium-potassium exchange in the distal convoluted tubules of the kidneys, and act as aldosterone receptor antagonists.

• Examples: Triamterene, Amiloride and Spironolactone.

• Indication: Hypertension resistant to other medications.

• Do not cause hypokalemia and can be used with loop and thiazide diuretics.

Potassium Sparing Diuretics: Contraindications and Adverse Effects/Drug Interactions

• Contraindications: Renal dysfunction and Anuria.

• Elevated serum creatinine and elevated serum potassium levels.

• Adverse Effects (A/E): Hyperkalemia.

• Drug Interaction: Synergistic effect on potassium elevation with the use of ACE inhibitors and NSAIDS decrease diuretic effectiveness and increase potassium levels secondary to decreased synthesis of renal prostaglandins.

Adrenoceptor Antagonists (Selective a1-blockers)

• Examples: Doxazosin, Prazosin, Terazosin.

• Indication: Can be added to therapy when blood pressure is not adequately controlled.

• MOA: Inhibit sympathetic stimulation of arteriolar contraction leading to vasodilation and decreased vascular resistance.

• A/E: Activate the sympathetic nervous system increasing heart rate, contractile force, and circulating norepinephrine levels and myocardial oxygen demands. Fluid retention may occur. Orthostatic hypotension.

β-Adrenoceptor Antagonists (β-blockers)

• Examples: Atenolol, Bisoprolol, Metoprolol.

• MOA: Block β1-adrenoceptors in the heart, reducing sympathetic outflow from the CNS, decreasing heart rate and contractility, and reducing cardiac output.

• Indication: Hypertension with other cardiovascular diseases, including IHD (lower the risk of myocardial infarction by reducing heart rate) and heart failure (improve symptoms). Combined with other drugs to achieve greater reductions in blood pressure.

• A/E: Bronchoconstriction, bradycardia, depression, masking of hypoglycemia, decreased exercise capacity.

• Contraindication: Asthma and chronic obstructive pulmonary disease.

Centrally Acting Drugs (e.g., Methyldopa)

• Example: Methyldopa.

• MOA: Inhibit alpha-adrenergic receptors, decrease sympathetic stimulation to the blood vessels and heart, reduce heart rate and blood vessel relaxation, decreasing blood pressure.

• Indication: Hypertension in pregnant women (does not harm the fetus).

• A/E: Sedation, dry mouth, impaired mental acuity, severe rebound hypertension (if discontinued abruptly).

Angiotensin-Converting Enzyme Inhibitors (ACE Inhibitors)

• MOA: Prevent conversion of angiotensin I to angiotensin II, leading to vasodilation.

• Examples: Captopril, Enalapril, Perindopril, Ramipril

• Contraindication: Pregnancy, Bilateral renal artery stenosis.

• Adverse effects (A/E): Dry cough (possibly due to increased bradykinin levels), angioedema, rash, abnormal taste sensation.

• Drug Interactions: Diuretics and CCBs increase antihypertensive effect; potassium-sparing diuretics and potassium supplements increase serum potassium levels; lithium increase lithium levels and provoke lithium toxicity; NSAIDs reduce the effects of ACE inhibitors.

Angiotensin Receptor Blockers (ARBs)

• MOA: Selectively block AT1 receptors in various tissues, decreasing aldosterone secretion, sodium reabsorption, and norepinephrine release.

• Examples: Irbesartan, Losartan, Telmisartan.

• Indication: Combined with a diuretic or CCB when greater blood pressure reduction is needed or in high-risk patients with diabetic nephropathy.

• A/E: Rarely cause dry cough, do not increase serum glucose/uric acid/cholesterol, may cause hyperkalemia, neutropenia, and elevated serum hepatic aminotransferase enzymes, and may also be contraindicated during pregnancy.

Calcium Channel Blockers

• MOA: Block calcium ion channels in the plasma membranes of smooth muscle, relaxing vascular smooth muscle and causing vasodilation.

• Examples: Amlodipine, Felodipine, Nifedipine.

• Indication: Initial treatment of high BP, combined with diuretics or angiotensin system inhibitors, or in hypertensive patients with asthma.

• A/E: Gum hyperplasia, leg/ankle edema, lightheadedness, slower heart rate, increased appetite, and Gastroesophageal reflux disease (GERD).

Classification of Antianginal Drugs

• Vasodilators (Organic Nitrates and Nitrates) include Isosorbide dinitrate, Isosorbide mononitrate, Nitroglycerin.

• Calcium Channel Blockers include Amlodipine, Nifedipine, Diltiazem, Verapamil.

• β-Adrenoceptor Antagonists (β-blockers) include Atenolol, Metoprolol, Propranolol.

• Metabolic Modifiers include Ranolazine, Trimetazidine

Mechanism of Action

• Antianginal drugs reduce myocardial oxygen demand by decreasing heart rate, decreasing contractility, acting directly on the venous tissue.

• These drugs also increase oxygen supply by acting primarily on the arteriolar muscles(CCBs).

Preload and Afterload

• Preload: Volume of blood entering the ventricles.

• Afterload: Resistance left ventricle must overcome to circulate blood.

Isosorbide Dinitrate

• ROA: Sublingually, Orally,

• Indication: Prevention or treatment of angina attacks.

• MOA: Relaxation of vascular smooth muscle, preferentially venous muscle relaxation, reducing venous pooling of blood.

• Adverse effects (A/E): Excessive vasodilation, headache, hypotension, dizziness, and reflex tachycardia.

Nitroglycerin (GTN)

• ROA: Sublingual, transdermal, topical, oral, or IV.

• Indication: Acute angina attacks, prevent angina attacks, and in hospitalized angina/myocardial infarction (MI) patients.

Classification of Drugs for Hyperlipidemia

• HMG-CoA Reductase Inhibitors (Statins): Atorvastatin, Pravastatin, Simvastatin.

• Cholesterol Absorption Inhibitors: Ezetimibe.

• Fibric Acid Derivatives: Fenofibrate, Gemfibrozil.

• Bile Acid-Binding Resins: Cholestyramine, Colestipol, Colesevelam.

• Other Drugs: Niacin (Vitamin B3).

Statins (HMG-CoA Reductase Inhibitors)

• Effective for lowering blood cholesterol.

• Prevent coronary artery disease and reduce mortality.

• Examples: Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin, Simvastatin.

• Adverse effects (A/E): Myalgia, Myositis, Rhabdomyolysis.

• Indications: Hypercholesterolemia.

Bile Acid-Binding Resins

• MOA: Bind to bile acids, preventing reabsorption into the blood and promoting their excretion in the bile, which increases the liver's need for cholesterol to produce more bile.

• Effective drug class for hypercholesterolemia.

Drugs for Heart Failure

• Vasodilators: Isosorbide dinitrate, examples.

• Positive inotropes: Digitalis glycosides (Digoxin), inotropic agents (Dobutamine).

• Other classes of drug: β-Adrenoceptor Blockers (e.g., Carvedilol), Angiotensin-converting enzyme Inhibitors (ACE) Inhibitors (e.g., enalapril), Aldosterone antagonists (e.g., spironolactone), Diuretics (e.g., Furosemide).

• Phosphodiesterase Inhibitors (e.g., Inamrinone, Milrinone). .

Digitalis Glycosides (e.g., Digoxin)

• MOA: Inhibit Na+/K+-ATPase, increase intracellular calcium, leading to increased cardiac contractility and slowed heart rate, and slowed atrioventricular conduction.

• Indication: Chronic symptomatic heart failure.

• Adverse effects (A/E): Nausea, vomiting, diarrhea, cardiac arrhythmias.

Adrenergic Agonists (e.g., Dobutamine)

• Indication: Acute decompensated heart failure, intermittent therapy to reduce symptoms.

• MOA: Beta1-selective agonists, increasing cAMP synthesis, enhancing cardiac contractility and output.

• Adverse effects (A/E): Arrhythmias.

Phosphodiesterase Inhibitors (e.g., Inamrinone, Milrinone)

• Indication: Acute decompensated heart failure.

• MOA: Inhibit phosphodiesterase, increasing cAMP levels, enhancing contractility; vasodilate to lower peripheral vascular resistance.

• Adverse effects (A/E): Arrhythmias.

Classification of Antiarrhythmic Drugs

• Vaughan Williams classification categorized into classes I-IV, including sodium channel blockers, β-blockers, potassium channel blockers, and calcium channel blockers. Further classification exist within each of these categories.

• Examples: Adenosine, Amiodarone, Digoxin.

Mechanism of Action of Antiarrhythmics

• MOA: Suppress abnormal impulse formation or conduction. Block sodium or calcium channels to reduce abnormal automaticity and slow conduction. Block potassium channels to prolong repolarization and increase the refractory period.

Class I (Sodium Channel Blockers)

• drugs bind to sodium channels when open and inactivated during the cardiac action potential. They dissociate during the resting state.

• Reduce abnormal automaticity and conduction velocity of cardiac impulses.

Class II (β-Blockers)

• Inhibit sympathetic activation, slowing the heart rate, decreasing conduction velocity, and increasing the refractory period of AV node.

Class III (Potassium Channel Blockers)

• MOA: Act primarily by blocking potassium rectifier currents, that repolarize the heart during Phase 3 of the action potential. Prolong repolarization and increase the refractory period of cardiac tissue.

Class IV (Calcium Channel Blockers)

• MOA: Block calcium channels, significantly effect cardiac tissue, slow the AV node conduction velocity, increase refractory periods of AV node, and have a smaller effect on SA node and heart rate.

Test your knowledge on cardiovascular pharmacology with this quiz covering key concepts such as the mechanisms of action of various drug classes, their contraindications, and common adverse effects. Dive into how selective α1-blockers, β-blockers, and calcium channel blockers function and are utilized in treating conditions like hypertension and angina.