Cardiovascular Pharmacology PDF: Antihypertensive Drugs & Heart Failure - Taibah University

uk week u bel listen- Cardiovascular Pharmacology (Antihypertensive drugs and drugs used in heart failure, Antihyperlipidemic Agents) Dr. Amani Alharbi PharmD, MSc,...

uk week u bel listen- Cardiovascular Pharmacology (Antihypertensive drugs and drugs used in heart failure, Antihyperlipidemic Agents) Dr. Amani Alharbi PharmD, MSc, PhD PHT 379 0 ‫كليــة الصيدلة‬ Cardiovascular diseases Cardiovascular system (CVS) diseases are a major cause of death - Major CVS pathologies include: Hypertension Heart failure Angina Loading… Hyperlipidemia and blood disorders (Anti-coagulant, antiplatelet and thrombolytic drugs). 2/1/25 2 Physiological and Pathological Mechanisms of Cardiovascular Function Physiological Mechanisms Cardiac Cycle: Regulated by the SA & AV nodes, alternating systole - (contraction) and diastole (relaxation). ① & ⑤ Blood Pressure Control: Managed by baroreceptors, heart RAAS, and autonomic receptor sensation the nervous system (ANS). hypertension regulate on & Cardiac Output (CO): CO = Heart Rate (HR) × Stroke Volume (SV), influenced by preload, afterload, and contractility. Smoth muscle before go & Jesstak to boxy of Vascular Function: Maintains blood flow via vasodilation (nitric oxide) & vasoconstriction (endothelin). ANS Regulation: Sympathetic → ↑ HR & BP; Parasympathetic → ↓ HR & BP. 2/1/25 3  Physiological and Pathological Mechanisms of Cardiovascular Function Pathological Mechanisms Hypertension & Atherosclerosis: Lead to heart disease, stroke, and vessel damage. heartcan't pump property when the Heart Failure (HF): Systolic (weak contraction) vs. Diastolic (impaired Loading… one relaxation). After the floo steptbefor Give -. Ischemic Heart Disease (IHD): Coronary blockage → Angina, Myocardial Infarction (MI). Arrhythmias: Electrical dysfunctions (e.g., atrial fibrillation) increase stroke risk. Cardiomyopathies & Valvular Diseases: Affect heart muscle & valve function. Shock: Circulatory failure due to heart dysfunction, blood loss, or infection. 2/1/25 4  Antihypertensive drugs Many drugs with different mechanisms of action are used for hypertension management; soit Vasodilators (why?) pump easly it cause Heart rate reduction epertensi cause - on Decrease sympathetic outflow from CNS Decrease - sodium- and water retention (Diuretics) * & Inhibiting renin-angiotensin-aldosterone system (RAAS) most important one Some antihypertensive drugs are also used for other CVS disorders. 2/1/25 5 Classification of Hypertension (Based on Etiology) 1. Primary (Essential) Hypertension - No specific cause (90-95% of cases). - Linked to genetics, age, obesity, salt intake, and lifestyle factors. 2. Secondary Hypertension (Identifiable Cause, 5-10%) - Renal: Chronic kidney disease, renal artery stenosis. - Endocrine: Hyperaldosteronism, pheochromocytoma, Cushing’s syndrome, thyroid disorders. - Cardiovascular: Coarctation of the aorta, vasculitis. - Neurological: Increased intracranial pressure, autonomic dysfunction. -Drug-Induced: NSAIDs, corticosteroids, contraceptives, stimulants. -Pregnancy-Related: Gestational hypertension, preeclampsia/eclampsia. 2/1/25 6 Hypertension Risk Factors 1. Non-Modifiable Risk Factors can't change Age: Risk increases with age. Genetics: Family history of hypertension. Race/Ethnicity: More common in African, South Asian, and Middle Eastern populations. 2. Modifiable Risk Factors Obesity: Increased body weight raises blood pressure. Diet: High salt, low potassium, and processed food intake. Physical Inactivity: Sedentary lifestyle contributes to high BP. Smoking & Alcohol: Nicotine and excessive alcohol elevate BP. Stress: Chronic stress leads to sustained hypertension. 3. Medical Conditions Diabetes & Insulin Resistance: Strongly linked to hypertension. Kidney Disease: impaired kidney function increases BP. Sleep Apnea: Causes repeated blood pressure spikes. 2/14/2025 7  s less than D -I for als infront Hypertensive Urgency: Is a severe form of hypertension with rapid & rise of blood pressure to > 180/120 mmHg not associated with target organ damage. Hypertensive Emergency: Is a severe form of hypertension with rapid rise of blood pressure to >180/120 mmHg associated with target organ damage as hypertensive encephalopathy, heart failure and renal failure. If associated with papilledema it is called malignant hypertension. 2/1/25 8  Classification of Antihypertensive Drugs 1) Diuretics 2). Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors = a-Angiotensin Converting Enzyme Inhibitors (ACEIs) b-Angiotensin Receptor Blockers (ARBs( c-Renin inhibitors: Drugs which inhibit renin enzyme as Aliskiren -contraction 1 so the Bloker ou the gake 3) Calcium Channel Blockers (CCBs) 2) Sympatholytic Drugs 5) Direct Vasodilators (DVD) 2/1/25 9 Classification of Antihypertensive Drugs… Antihypertensive Drugs are classified into: & A) First line or primary drugs used alone or in combination: Angiotensin Converting Enzyme Inhibitors (ACEIs) & Angiotensin Receptor Loading… Blockers (ARBs). Calcium Channel Blockers. Diuretics. & B) Second line or Alternative drugs that may be used in selected patients: Alpha blockers, Beta Blockers. Central α2 agonists. Vasodilators. 2/1/25 10 Nonpharmacological treatment of HTN Weight reduction Diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat: 8 -14 mmHg Dietary sodium restriction: reduce daily dietary sodium intake to less than or equal to 5 g sodium chloride): 2 - 8 mmHg Physical activity: regular aerobic physical activity (at least 30 minutes/day, most days of the week): 4 - 9 mmHg Stop alcohol consumption Stop smoking Avoid Stress Control diabetes mellitus and atherosclerosis. 2/1/25 11 & most of the exam about iv ACE inhibitors and angiotensin receptor them blockers (ARBs) Xanyone who had cuff give we function should check the venal ARBs but we cause its effect (Angiotensin Remptor-Bloker) Mechanism of action: activite sitzeffect - inhilebnis & i of it cuff ACEIs decrease the vasoconstrictor Ang II, increase the metabolism & inheleitor got thing/I ykininY vasodilator Bradykinin and ↑ decrease aldosterone. ACEIs decrease BP by decreasing PR, without affecting CO Blocker O or HR. & O together Angiotensin receptor blocker * AcEl Unlike direct vasodilators, they do not cause reflex tachycardia thus can be used safely in patients with of there The ischemic heart disease -Gladrantge 2/1/25 12  ACE inhibitors and angiotensin receptor blockers (ARBs)… Examples: ↑ main & ACE-inhibitors: Enalapril, Ramipril and Captopril 8 AT1 receptor antagonists (ARBs): Losartan and Valsartan - Adverse effects: First dose hypotension (use first dose at night without diuretics for 2 days) & Dry cough (5-30%) and rare angioneuretic edema due to bradykinin increase S(NOT with AT1 receptor antagonists)* Functional renal failure (if bilateral renal artery stenosis is present) cause cuff in Hyperkalemia (avoid using with potassium-sparing diuretics) - Teratogenic (not used in pregnancy) Sulfhydryl reactions of captopril (rash, proteinuria, taste disturbance) anythis eynya cori 2/1/25 13 Diuretics Mechanism of action: Thiazide diuretics block Na/Cl- * - transporter in renal distal convoluted - tubule - X & Loop diuretics block Na/K/2Cl transporter in renal loop of Henle-it not & & Potassium-sparing diuretics are back to Aldosteron antagonist The Goby & remove ix Examples: X Thiazide diuretics: Hydrochlorothiazide and Indapamide W & Loop diuretics: Bumetanide and Frusemide Potassium-sparing diuretics: Aldosterone Antagonists e.g. Spironolactone, eplerenone. Do water satium Aldo > - Non-Aldosterone Antagonists e.g. retension Triamterene & Amiloride. 2/1/25 14 Diuretics Mechanism of action: > - Prostagland in ! 1- Diuretic Action → decrease Blood Volume → decrease Cardiac output →decrease Blood pressure. 2- Thiazide diuretics in addition have a direct vasodilator action by: a- Deplete Na from the arterial wall. b- Open K Channels Hyperpolarization. & c- Release of vasodilator PGs. 3- Indapamide: A thiazide analogue when used in a small dose it has a vasodilator activity, being a CCB, with some diuretic effect. 2/1/25 15  Diuretics Adverse effects: Hypokalemia and hypomagnesemia (danger with digitalis or lithium, in chronic arrhythmias or MI). Combination with potassium sparing diuretics can prevent this effect. Hyperkalemia in case of potassium sparing diuretics (avoid in renal insufficiency or with ACEIs/ ARBs) Hyponatremia and hypercalcemia (Thiazide) (not in hyperparathyroidism). While Hypocalcemia with loop diuretics Hyperuricemia (not in gout) Hyperglycemia (not in diabetes) Increase LDL (not in dyslipidemia) Reversible erectile dysfunction (spironolactone, but also with other antihypertensives) 2/1/25 16 Calcium channel blockers Mechanism of action: Block voltage-gated calcium channels In heart- decrease heart rate and contractility thus decrease CO - (decrease PR) In blood vessels: vasodilation Tit heart Examples: Non-Dihydropyridine: Diltiazem and Verapamil (more selective to the & heart). & Dihydropyridine: are more selective to blood vessels, such as Nifedipine (short acting), Amlodipine ( long acting) and nicardipine 2/1/25 17 S Calcium channel blockers Adverse effects: Short-acting preparations (e.g. Nifedipine capsules) cause flushing and headache and tachycardia (can worsen angina) thus should be avoided (even sublingual). Ankle swelling (oedema) is common Negative inotropic effect of verapamil (exacerbates cardiac failure). Constipation is common with verapamil.* Interactions: Intravenous& verapamil can cause circulatory collapse in patients treated concomitantly with β-adrenoceptor antagonists. not give together Clinical Use: & Amlodipine is used mainly as antihypertensive, while verapamil and diltiazem as antiarrhythmic and antianginal 2/1/25 18  Beta blockers Mechanism of action: β1- blocking decrease heart rate and contractility thus decrease CO Central decrease of sympathetic activity Inhibit renin secretion Examples: Non-selective β-blockers: Propranolol , Labetalol and Carvedilol (also * vasodilation by blocking α1) Selective β1-blockers: Atenolol ,Bisoprolol and Nebivolol (also vasodilator by increasing NO), and celiprolol (vasodilator as β2-agonist) & Oral (once daily), IV only in emergencies (Esmolol) * 2/1/25 19  Beta blockers Adverse effects: Bradycardia and in large doses they may cause heart block (AV block). Contraindicated in decompensated heart failure and variant angina Intolerance – fatigue, cold extremities, erectile dysfunction; nightmares (especially the non-polar such as propranolol). Hypoglycemia and lipid disturbances (with thiazides) Bronchospasm (Not in asthma or COPD) If sudden discontinuation of β-antagonists after prolonged use, upregulation of β-receptors may occur leading to tachycardia, arrhythmias and even death. Interactions: Increased toxicity with other –ve inotropic drugs such as verapamil or lidocaine Clinical Use: use only as second line β-blockers are less successful than alternative approaches based on ACE inhibitors, AT1-antagonists or calcium antagonists. > - 2/1/25 20  α adrenergic blockers Prazosin Doxazosin Terazosin Produce a competitive block of ɑ1-adrenoceptors. Tamsulosin, an ɑ1a- blocker with greater selectivity for prostate muscle, has been used in the treatment of prostate hyperplasia. α-β adrenergic blockers Labetalol and carvedilol block both ɑ1- and ß1- and ß2- receptors. Carvedilol, although an effective antihypertensive, is mainly used in the treatment of heart failure. Carvedilol has been shown to reduce mortality associated with heart failure. 2/1/25 21  Centrally acting adrenergic drugs Clonidine -Xa This ɑ2 -agonist diminishes central adrenergic outflow. ɑ-Methyldopa ɑ2 -agonist which diminishes the adrenergic outflow from the CNS. This leads to reduce total peripheral resistance and a decreased blood pressure. - ɑ-methyldopa is especially valuable in treating pregnant hypertensive patients 2/1/25 22  H. Direct vasodilators in 1) Arteriodilators: Hydralazine hair Minoxidil > - in Diazoxide 2) Venodilators: Nitroglycerine I.V. infusion in hypertensive emergencies. 3) Arteriovenodilators: Sodium Nitroprusside 2/1/25 23  Antihypertensive drugs Drug classes Examples Angiotensin Converting Enzymes (ACE) inhibitors Captopril, Enalapril, Lisinopril, Ramipril Angiotensin receptor antagonist (ARB) Losartan, Candesartan Calcium channel blockers (CCB) Nifedipine, Felodipine, Amlodipine, Verapamil, Diltiazem Diuretics Chlorothiazide, Frusemide, Spironolactone, Triamterene, Amiloride β-adrenergic blocker Propranolol, Metoprolol, Atenolol α- adrenergic blocker Prazosin, Terazosin Central sympatholytic Clonidine, Methyldopa Vasodilators: Arteriolar Hydralazine, Minoxidil, Diazoxide Arteriolar & venular Sodium nitroprusside, Pinacidil 2/1/25 24  jm What is congestive heart failure? Definition: Congestive heart failure (CHF) is a condition that occurs when the heart is unable to pump enough blood to meet the needs of the body's tissues. Causes includes: (1) Artery disease (2) High blood pressure (hypertension) (3) Heart defects present at birth (Congenital heart disease) (4) Past heart attacks (myocardial infarction) (5) Heart muscle disease 2/1/25 25 Heart Failure Symptoms Symptoms: Shortness of breath occurs during activity, rest, or sleeping Persistent coughing /wheezing produces white/blood mucus Edema: swelling in extremities Tiredness and fatigue Increased heart rate, Heart remodeling (enlargement) 2/1/25 26  Drugs used in heart failure X m onlyneed Digoxin an important cardiac drug which reduces the pulse and increase force of contraction. 2/1/25 27  Drugs used in heart failure 1. First-Line Therapy A. ACE Inhibitors (ACEIs) / Angiotensin II Receptor Blockers (ARBs) Examples: Enalapril, Lisinopril (ACEIs); Losartan, Valsartan (ARBs) Mechanism: Loading… Inhibit RAAS → Vasodilation, ↓ afterload & preload ↓ Aldosterone → Less sodium/water retention Uses: Chronic HF, post-MI Side Effects: Hypotension, hyperkalemia, cough (ACEIs), angioedema 2/1/25 28 Drugs used in heart failure important very B. β-Blockers (Reduce Cardiac Workload) Examples: Carvedilol, Metoprolol, Bisoprolol Mechanism: Block β1 receptors → ↓ HR & contractility → Less myocardial oxygen demand Prevents sympathetic overstimulation that worsens HF Uses: Chronic HF (Stable patients only) Side Effects: Bradycardia, hypotension, fatigue 2/1/25 29 Drugs used in heart failure C. Diuretics (Reduce Fluid Overload) -Loop Diuretics: Furosemide, Bumetanide (for acute decompensated HF) -Thiazide Diuretics: Hydrochlorothiazide (for mild HF) -Aldosterone Antagonists: Spironolactone, Eplerenone (for HF with reduced ejection fraction) Mechanism: Increase urine output → reduce pulmonary & peripheral edema Side Effects: Electrolyte imbalances, dehydration, hypotension 2/1/25 30 2. Second-Line & Adjunct Therapy A. Digoxin (Positive Inotrope) Mechanism: Inhibits Na⁺/K⁺ ATPase → ↑ intracellular calcium → ↑ contractility Slows AV node conduction → used in HF with atrial fibrillation Uses: Chronic HF (in refractory cases), Atrial fibrillation Side Effects: Arrhythmias, nausea, toxicity risk (narrow in The only therapeutic index) 2/1/25 hospfal 31  Second-Line & Adjunct Therapy von Gregl Digoxin Toxicity Therapeutic Index: Extremely low (~2), increasing the risk of toxicity. CNS Effects: Malaise, confusion, depression, vertigo. Gastrointestinal Effects: Anorexia, nausea, intestinal cramping, diarrhea. Cardiac Effects: Bradycardia, arrhythmias. Visual Disturbances: Yellow-tinted vision (xanthopsia). Contraindications: AV block. Hypokalemia - (exacerbates toxicity). 2/1/25 32 Second-Line & Adjunct Therapy B. Vasodilators (Reduce Afterload) class Examples: Hydralazine + Isosorbide Dinitrate nitroglycrim Mechanism: Hydralazine → Arterial vasodilation → ↓ Afterload Isosorbide dinitrate → Venous dilation → ↓ Preload Uses: HF in African American patients, ACEI/ARB intolerance Side Effects: Hypotension, headache 2/1/25 33  Second-Line & Adjunct Therapy C. SGLT2 Inhibitors (Sodium-Glucose Cotransporter-2 Inhibitors) (Newer HF Therapy) Examples: Dapagliflozin, Empagliflozin Mechanism: Inhibit SGLT2 in the proximal renal tubules, reducing glucose reabsorption and promoting urinary glucose excretion. → diuresis, reduces cardiac workload Uses: HF with reduced ejection fraction (HFrEF), even in non- diabetics Side Effects: UTIs, dehydration 2/1/25 34  3. Emergency/Severe HF Treatment A. Inotropes (Increase Cardiac Contractility in Acute HF) the injectany Examples: Dobutamine (β1 agonist), Milrinone (PDE-3 inhibitor) Mechanism: Dobutamine → Increases contractility & CO Milrinone → Increases cAMP → vasodilation & contractility Uses: Acute decompensated HF, cardiogenic shock Side Effects: Arrhythmias, hypotension 2/1/25 35 # Lipid lowering drug (Antihyperlipidemic Agents) The clinically important lipoproteins include: - LDL (Low-Density Lipoprotein) - VLDL (Very Low-Density Lipoprotein) - HDL (High-Density Lipoprotein) Causes of Hyperlipidemia: 1. Lifestyle Factors– Lack of exercise and high consumption of fatty acids. 2. Genetic Factors – Single inherited gene defect in lipoprotein metabolism. 3. Combination of Genetics and Lifestyle– The most common cause. Elevated levels of LDL cholesterol and triglycerides, along with low levels of HDL & cholesterol, are correlated with an increased incidence of heart failure. 2/1/25 36 Lipid lowering drug (Antihyperlipidemic Agents) Antihyperlipidemic drugs must generally be taken indefinitely, as discontinuation often results in plasma lipid levels returning to pretreatment values. Strategies Targeted by Antihyperlipidemic Drugs: 1. Decrease the Production of Lipoproteins - Drugs like statins inhibit cholesterol synthesis in the liver, lowering levels of LDL and triglycerides. 2. Increase the Degradation of Lipoproteins - Some agents, such as fibrates and PCSK9 inhibitors, enhance lipoprotein degradation, promoting the clearance of LDL from the blood. 2/1/25 37 Lipid lowering drug (Antihyperlipidemic Agents) Strategies Targeted by Antihyperlipidemic Drugs(Cont..): 3. Decrease Cholesterol Absorption or Increase Cholesterol Removal - Agents like ezetimibe reduce cholesterol absorption in the & intestines, while bile acid sequestrants and niacin enhance cholesterol excretion from the body. These agents may be used alone or in combination, depending on the patient's condition and treatment goals. 2/1/25 38 Lipid lowering drug Statins: Lovastatin, Atorvastatin, Simvastatin Fibrates: Gemfibrozil, fenofibrate Niacin Inhibits lipolysis Bile acid sequestrants: Colestipol and Cholestyramine Absorption inhibitors: Ezetimibe PCSK9 Inhibitors :Alirocumab, Evolocumab 2/1/25 39 (Antihyperlipidemic Agents) 2/1/25 40  Common Side Class Examples Mechanism of Action Effects Effects * Statins (HMG-CoA Reductase Atorvastatin, Inhibit HMG-CoA Myopathy, Inhibitors) Simvastatin, reductase, reducing ↓ LDL, ↑ HDL, ↓ TG hepatotoxicity First-line therapy for Rosuvastatin cholesterol synthesis hyperlipidemia. * Fibrates Activate PPAR-α, Gemfibrozil, ↓ TG, ↑ HDL, mild ↓ Myopathy (esp. with Used for increasing lipoprotein Fenofibrate LDL statins), gallstones hypertriglyceridemia E lipase activity Cholestyramine, Bind bile acids, Bile Acid ↓ LDL, slight ↑ HDL GI upset, bloating, Colestipol, preventing their Sequestrants & TG constipation Colesevelam reabsorption Inhibits NPC1L1 Cholesterol Diarrhea, rare liver Ezetimibe transporter in the ↓ LDL Absorption Inhibitor dysfunction intestine Inhibits lipolysis, Flushing, Niacin (Nicotinic Niacin (Vitamin B3) reduces hepatic VLDL ↑ HDL, ↓ LDL, ↓ TG hyperuricemia, acid) synthesis hepatotoxicity Inhibit PCSK9, Alirocumab, increasing LDL receptor Injection site reactions, PCSK9 Inhibitors ↓ LDL Evolocumab recycling and LDL flu-like symptoms 2/1/25 clearance 41