CV Pharmacology hypertension & HF - 2024.pdf

BMS2047 - PHARMACOLOGY: INTRODUCTION TO DRUG ACTION CV PHARMACOLOGY DR PENNY LYMPANY [email protected] 28AY04 OUTLINE Hypertension Diuretics Angiotensin converting enzyme inhibitors (ACEI) Β-adrenoceptor antagonists (β-blockers) Vasodilators Heart failure Similar drugs for differing reasons! HY...

BMS2047 - PHARMACOLOGY: INTRODUCTION TO DRUG ACTION CV PHARMACOLOGY DR PENNY LYMPANY [email protected] 28AY04 OUTLINE Hypertension Diuretics Angiotensin converting enzyme inhibitors (ACEI) Β-adrenoceptor antagonists (β-blockers) Vasodilators Heart failure Similar drugs for differing reasons! HYPERTENSION PUBLIC HEALTH ENGLAND – HIGH BLOOD PRESSURE COST OF HIGH BLOOD PRESSURE RELATED CONDITIONS HYPERTENSION Clinically defined – 80yrs: 150/90 mmHg If salt intake is ↓ to 0.4g/100g food Predicted BP ↓ is 5mmHg Equivalent of 1 pharmacotherapy KEY CONTRIBUTORS TO MAINTENANCE OF BLOOD PRESSURE Heart rate Vascular tone Blood pressure Blood volume Cardiac output Blood pressure is the pressure of blood in the arterial side of the circulation. It is defined as the product of cardiac output and systemic total peripheral vascular resistance (BP = CO x TPR). CO = SV x HR Stroke volume NERVOUS CONTROL Factor influencing BP Hormone Effects on BP Noradrenaline (NA) Adrenaline (A) Acetylcholine (ACh) Increase Increase Decrease CARDIAC OUTPUT ↑ HR & contractility SYSTEMIC VASCULAR RESISTANCE Vasoconstriction Angiotensin II (AngII), antidiuretic hormone (ADH), NA, A (mindful of receptors) Increase Vasodilation ACh, nitric oxide (NO) Decrease ↑ blood volume Aldosterone, Antidiuretic hormone (ADH) Increase ↓ blood volume Atrial natriuretic peptide (ANP) Decrease BLOOD VOLUME KEY RECEPTORS α1 β1 β2 mAChR2 mAChR3 G-protein Gq Gs Gs Gi/o Gq Tissue distribution Blood vessels Heart Blood vessels Heart Heart Endothelium blood vessels Effect Constrict ↑ HR ↑ contractility Dilate BV (↑ HR) (↑ heart contractility) ↓ HR ↓ contractility Dilate as a result of nitric oxide Agonist potency order NA > A >> ISO ISO > NA > A ISO > A > NA ACh ACh Agonist Phenylephrine Dobutamine Salbutamol ACh ACh Antagonist Prazosin Atenolol Butoxamine Atropine Atropine AUTONOMIC CONTROL OF BLOOD PRESSURE ANTI-HYPERTENSIVE DRUG CLASSES Diuretics Angiotensin converting enzyme inhibitors (ACEI) Β-adrenoceptor antagonists (β-blockers) Vasodilators ANTI-HYPERTENSIVE DRUGS Vasodilators Ca2+ channel blockers K+ channel openers Β-blockers Ca2+ channel blockers Heart rate Vascular tone ACE inhibitors Blood pressure Blood volume Diuretics Cardiac output Β-blockers Stroke volume ACE – angiotensin converting enzyme ARB: angiotensin receptor blocker TARGETS FOR RENIN-ANGIOTENSIN SYSTEM Β-blockers Inhibit renin release from kidney Inhibit angiotensinogen → AngI ACE inhibitors Inhibit AngI → AngII binds AT1 Vasoconstrictor Na+ retention → ↑ blood volume Inhibit metabolism of bradykinin Vasodilator Captopril, enalopril Side effects - dry cough Decrease blood pressure Atenolol, propranolol Side effects – numerous see Βblockers section AT1 receptor antagonists Inhibits actions of AngII Losartan, eprosartan Side effects – hypotension, dizziness BETA BLOCKERS - ACTIONS TARGETS FOR Β-BLOCKERS Β-blockers Inhibit β1 receptors on heart ↓ heart contractility ↓ heart rate Decrease blood pressure Inhibit renin release from kidney Inhibit angiotensinogen → AngI Atenolol, propranolol Side effects – dizziness, weakness, fatigue, cold extremities, dry mouth, headache, diarrhoea or constipation DIURETICS Thiazide diuretics K+ sparing diuretics Loop diuretics DIURETICS Thiazide diuretics Inhibits Na+ reabsorption in the DCT ↓ H2O reabsorption → ↓ blood volume. Loop diuretics Inhibits Na+ reabsorption in the ascending loop of henle ↓ H2O reabsorption → ↓ blood volume. Furosemide Hypotension, hypovolaemia, hypokalaemia Decrease blood pressure Bendroflumethiazide, hydrochlorothiazide As loop diuretics but less pronouced K+ sparing diuretics Inhibit Na+/K+ exchange in CD/DCT. Limited diuretic action on their own CD accounts for ≤2% of Na+ reabsorption Prevent hypokalaemia Amiloride, spironolactone Hyperkalaemia – particularly in renal impairment CA2+ CHANNEL ENTRY BLOCKERS SERCA - sarcoendoplasmic Reticulum Calcium ATPase RYR – ryanodine receptor K+ CHANNEL ACTIVATORS VASODILATORS Ca2+ channel blockers Inhibits Ca2+ influx → ↓SMC contraction Vasodilatation Decrease blood pressure Nifedipine, amlodipine Flushing, headache, Reflex tachycardia – β blocker can counteract K+ channel activators Open K+ATP channels → hyperpolarises cell, inhibiting voltage-gated Ca2+ channels. Minoxidil, diazoxide Hirsutism Na+/H2O retention, often given with a loop diuretic Reflex tachycardia Learning outcomes - Hypertension ▪ Describe the mechanism of action in hypertension for: ▪ ACEi, ARBs and aldosterone antagonists ▪ Diuretics ▪ Vasodilators ▪ Beta-blockers HEART FAILURE HEART FAILURE Cardiac output is inadequate to meet the metabolic demands, in exercise and eventually at rest. Due to Coronary artery disease Volume overload – leaky valves Pressure overload – stenosed valves, systemic or pulmonary hypertension Hyperthyroidism HEART FAILURE Pre-load variables ↑ venous pressure Systemic and pulmonary hypertension ↑ ventricular diastolic pressure/volume Valve defects Cardiac shunt (congenital) Post-load variables ↑ peripheral resistance Cardiac variables Coronary artery disease Cardiotoxicity Congenital defects HEART FAILURE 50% of worst cases die within 6 months of diagnosis 50% of mild/moderate cases die within 5 years of diagnosis Symptoms Oedema Breathlessness ↓ perfusion Fatigue Cardiac hypertrophy Physiological compensation ↑ sympathetic activity Activation of renin-angiotensin system health.harvard.edu TREATMENT OF HEART FAILURE Diuretics ↓ blood volume Relieve peripheral oedema Vasorelaxation ↓ BP Decrease pre- & post-load Vasodilators ↑ volume of circulatory system ↓ BP Decrease pre- & post-load Treat heart failure β blockers Low dose improves prognosis ↓ sympathetic activity & cardiac hypertrophy Negative inotropic effects - worsen Decrease cardiac variables Renin-angiotensin system ↓ vascular tone & blood volume Decrease BP Decrease pre- & post-load Positive inotropes Increase force of contractions ↓ venous pressure ↓cardiac hypertrophy ↑renal blood flow - ↓ blood volume Decrease pre- & post-load Decrease cardiac variables FEEDBACK LOOPS Rang & Dale’s Pharmacology, 8th Ed VASODILATORS VASODILATORS Nitrates Release nitric oxide (NO) NO binds sGC produces cGMP which activates PKG PKG – inhibits myosin light chain kinase (MLCK) contraction +++ Vasodilatation Glyceryl trinitrate, nitroprusside Hypotension, headaches, dizziness More commonly used for angina & heart failure Decrease blood pressure BETA BLOCKERS TARGETS FOR BETA BLOCKERS HEART FAILURE – POSITIVE INOTROPES Cardiac glycosides – digoxin Inhibits Na+/K+-ATPase Effects enhanced by hypokalaemia Side effects – arrhythmia, disturbed vision, GI disturbances LEARNING OUTCOMES – HEART FAILURE Describe the mechanism of action in heart failure for: ACEi, ARBs and aldosterone antagonists Diuretics Vasodilators Beta-blockers Positive inotropes ? 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