CV Pharmacology Lecture Notes PDF

Learning Objectives An appreciation of the pathophysiology of hypertension An understanding of the mechanism of action Classification Drug drug interactions For the class of beta blocking agents  Physiological Compensatory Mechanisms that Counteract Decreased Blood Pressure...

Learning Objectives An appreciation of the pathophysiology of hypertension An understanding of the mechanism of action Classification Drug drug interactions For the class of beta blocking agents  Physiological Compensatory Mechanisms that Counteract Decreased Blood Pressure Brody’s Human Pharmacology 2025 Hypertension and its Complications Laffan & Bakris in Opie’s Cardiovascular Drugs 9th Edition Elsevier 2021  Hypertension The level of blood pressure above which the benefits of treatment (either with lifestyle interventions or drugs) unequivocally outweigh the risks of treatment, as documented by clinical trials Present in 60% of patients over 60 years of age ESC Guidelines for Hypertension Williams et al, EHJ 2018; 39: 3021-204 Hypertension Netter’s Illustrated Pharmacology  Hypertension Understand the mechanism of action of drugs used to treat hypertension Know the side effects of those medications Know which patients should be treated, and when treatment should be initiated Know which drugs are most effective in treating individual patients with specific comorbidities Know which drugs can be used in combination Know how to set, and measure, treatment goals in hypertension Rollins and Blumenthal. Workbook and casebook for Goodman and Gilman 2016  TREATMENT OF ESSENTIAL HYPERTENSION: 1930 Drug or Method Used Animasa Mistletoe Benzyl Benzoate “Natheim” Bath Benzyl Succinate Nitroscleran Calcium Diuretin Potassium Sulphocyanate Calcium Salts and low Protein Diet Radiation to the Skull Corpus Luteum Radium Water Desecin Subtonin Diathermy Sodium Sulphocyanate Irradiation of the Suprarenal Region Theominal Liver Extract Thyroid and Potassium Lumbar Sympathectomy Permanganate Luminal Ayman, JAMA 1930; 95:246. Watermelon Extract  Development of Antihypertensive Therapies Effective but poorly As effective and As effective and even better tolerated better tolerated tolerated 1940’s 1950 1957 1960’s 1970’s 1980’s 1990’s 2001 2007 2024 Direct ACE ARBs DRIs ? vasodilators inhibitors Others Ganglion Thiazides a-blockers blockers diuretics Central a2 agonists Peripheral Calcium antagonists sympatholytics Calcium antagonists (DHPs) Veratrum (Verapamil) alkaloids b-blockers  Classes of Antihypertensive Agents Volume reduction (various diuretics) Renin-angiotensin-aldosterone system inhibition (angiotensin-converting enzyme [ACE] inhibitors, angiotensin-receptor blockers [ARBs] mineralocorticoid receptor antagonists [MRA]) Sympathetic nervous system (SNS) inhibition (α-blockers, β-blockers, sympatholytics) Vasodilation (calcium channel blockers [CCBs], direct arterial vasodilators) Sites and Mechanisms of action of antihypertensive drugs Brody’s Human Pharmacology 2025  Drugs to be preferred in specific conditions Condition Drug Condition Drug Asymptomatic organ damage Clinical CV event (continued) LVH ACE-I, CCB, ARB Aortic aneurysm BB Asymptomatic CCB, ACE-I Atrial fib, prevention Consider ARB, ACE-I, BB, MRA CAD Atrial fib, rate control BB, non-dihydro CCB Microalbuminuria ACE-I, ARB ESRD/proteinuria ACE-I, ARB Renal ACE-I, ARB dysfunction Peripheral art disease ACE-I, CCB Clinical CV event Other Previous stroke Any agent effectively lowering BP ISH (elderly) Diuretic, CCB Previous MI BB, ACE-I, ARB Metabolic syndrome ACE-I, ARB, CCB Angina pectoris BB, CCB Diabetes ACE-I, ARB Heart failure Diuretic, BB, ACE-I, MRA Pregnancy Methyldopa, BB, CCB Eur Heart J. 2013;34(28):2159-2219. Compelling and possible contra-indications to the use of antihypertensive drugs Drug Contraindications Compelling Possible Diuretics Gout Metabolic syndrome, Glucose intolerance, Pregnancy, ↑ Ca++ ↓ K+ Beta blockers Asthma, High degree SA or AV block, Metabolic synd, Glucose intol, Bradycardia athletes & physically active pts CCB Dihydroperidines Tachyarrhythmia, HFrEF, oedema CCB Non- High degree SA or AV block, Bradycardia, Constipation dihydroperidines Severe LV dysfunction ACE-inhibitors Pregnancy, Previous Angioneurotic Oedema, Women of childbearing potential Hyperkalaemia, bilat Renal Artery stenosis without reliable contraception ARBs Pregnancy, Hyperkalaemia, bilat Renal Artery Women of childbearing potential stenosis without reliable contraception ESC Guidelines for Hypertension Williams et al, EHJ 2018; 39: 3021-204 Evolution from Hypertension to Heart Failure Gallo and Savoia Int J Molecular Sciences 2024; 25:6661 BIHS ACD Approach to hypertension β-Blockers  Sympathetic and Parasympathetic Innervation Noradrenaline Adrenergic Receptor Sympathetic Activation Rang et al. Pharmacology 2003  β1 Adrenoreceptor Increases heart rate Increases cardiac contractility Renin release  β2 Adrenoreceptor B 2 agonist Arteriole: dilatation Bronchial muscle: dilatation Gastrointestinal tract: relaxation Uterus: relaxation Pancreas: insulin release Liver: hyperglycemia  History of β-blocker Development Dr. James Black joined ICI Pharmaceuticals in 1958 to develop a drug for the treatment of angina. Foundations: Angina could be precipitated by psychic stress or injection of adrenaline. Partial thyroidectomy may improve severe angina. Myocardial oxygen demand is determined by myocardial work and is dependent on the product of heart rate and blood pressure. James Black, Drugs from emasculated hormones. Science 1989; 245:486  History of β-blocker Development The effects of adrenaline were thought to be mediated by at least two receptor types, α and β (Langley, Daley and Ahlquist). Vasoconstrictive effects could be blocked by some drugs (antagonist defined α receptor effects). Tachycardia and contractility could be stimulated by isoprenaline (agonist defined β receptor effects). Led to the search for a β receptor antagonist. Pronethanol was first compound (caused cancer in rats) Propranolol was first clinically viable drug (1965) James Black, Drugs from emasculated hormones. Science 1989; 245:486 History of β-blocker Development CONTROL PRONETHALOL extend out to 8 minutes James Black, Drugs from emasculated hormones. Science 1989; 245:486  β Blockers: resting vs activated The effects of beta blockade are mild when someone is at rest, because adrenergic tone is low. When the sympathetic nervous system is activated, e.g. with exercise, the effects of beta- blockade are much more obvious and significant.  β-Adrenergic Antagonists Maximal exercise capacity is reduced Chronotropic incompetence Reduced β-mediated skeletal muscle vasodilatation Mild reduction in coronary flow Greater reduction in myocardial oxygen utilization  Effect of β-Blockers during Exercise Heart Rate Cardiac Output Arterial Pressure No Propranolol Propranolol  β1 vs β2 Selectivity Beta 1 receptors predominate in the heart, and stimulation of these receptors leads to an increase in HR, } β1 atrioventricular (AV) conduction, and contractility; release of renin from juxtaglomerular cells in the kidneys; and lipolysis in } β2 adipocytes. Beta 2 stimulation causes bronchodilation, vasodilation, and glycogenolysis } β1 + β2 oden in Opie’s Cardiovascular Drugs 9th Edition Elsevier 2021 Morrow and De Lemos Braunwald’s Textbook of CV Disease 2019 Occupation of β1 vs β2 Receptors by Bisoprolol in the Rat Brodde Rev Contemp Pharmacotherap 1997; 8:21-33 β1:β2 Selectivity Ratios in Ligand Binding Studies Wellstein et al. J Cardiovasc Pharmacol 1986; 8(Suppl) S36-40  Nebivolol x 3.5 times more β1 selective than bisoprolol Nebivolol increases NO (probably via β3) Carvedilol is an antagonist for β1 β2 and a1 receptors Page & Clive, Integrated Pharmacology, 2006 Chapter 13, 371-434 Veira & Mehra: Opie’s Cardiovascular Drugs 9th Edition Elsevier 2021 Advantages of Cardio-selective β Blockers In airways disease In diabetes mellitus In peripheral vascular disease  Benefits of non-selective β blockers Treatment of portal hypertensive bleeding (oesophageal varices) Only non-selective β -blockers have been shown to have benefit Inhibition of β 2-induced splanchnic arterial vasodilation decreases portal venous flow and portal hypertension Treatment of tremor β -blockers commonly prescribed for treatment of bothersome benign essential tremor Only non-selective β -blockers have been effective for this Vascular headache prophylaxis (migraines and cluster headaches) Conventional wisdom is that propranolol more effective than more selective and less lipophilic β -blockers  β-blocker Characteristics Intrinsic Sympathomimetic Activity (ISA) Partial beta-agonists that also produce blockade by shielding beta receptors from more potent beta-agonists. Resting heart rate is not as affected (reduced). Blood pressure lowering effects are relatively preserved Drugs with ISA may not be as beneficial in treating myocardial ischaemia or in improving post-MI survival. Opie and Gersh 7th Edition, 2009 Morrow and De Lemos Braunwald’s Textbook of CV Disease 2019 Intrinsic Sympathomimetic Activity  Reduced Benefit of β- blockers with ISA post MI Yusuf et al. Prog Cardiovasc Dis 1985; 27:335-71  Route of Elimination Lipid Water Soluble Soluble Boden: Opie’s Cardiovascular Drugs 9th Edition Elsevier 2021  Lipid-soluble β-blockers Lipophilic drugs (metoprolol, propranolol, timolol) are rapidly and completely absorbed from the gastrointestinal tract but are extensively metabolised in the gut wall and in the liver (first pass effect), so that their oral bioavailability is low (10– 30%). May accumulate in patients with reduced hepatic blood flow (e.g., elderly, CHF, liver cirrhosis) Lipophilic drugs have short elimination half-lives (1-5 hours) Easily enter the central nervous system (CNS) and may lead to lethargy, depression and hallucinations across barrier blood brain Task Force on Beta-Blockers of the European Society of Cardiology Eur Heart J 2004; 25:1341–62  Water-soluble β-blockers Hydrophilic drugs (atenolol) are excreted unchanged or as active metabolites by the kidney. They have longer half-lives (6–24 h) Do not interact with liver-metabolised drugs. They barely cross the blood–brain barrier. Elimination half-life is increased when glomerular filtration rate is reduced (e.g, elderly, renal insufficiency). In patients with renal or liver disease, the simpler pharmacokinetic patterns of lipid-insoluble agents make dosage easier Task Force on Beta-Blockers of the European Society of Cardiology Eur Heart J 2004; 25:1341–62 Opie and Gersh 8th Edition, 2012  β-blocker Characteristics Half Life -> useful for titration Esmolol shortest at 9 minutes (© brevibloc) Combined Labetalol combined blockade of β1 and β2 with a1 with a ratio of 1:3 = a1: β when administered orally Anti-arrhythmic activities All β-blockers Sotalol Racemic mixture of β blocker and a class III antiarrhythmic Boden: Opie’s Cardiovascular Drugs 9th Edition Elsevier 2021  Clinical Uses of β-Blockers Cardiovascular Other Angina Hyperthyroidism Myocardial Infarction Phaeochromocytoma Arrhythmias Portal Hypertensive Bleeding Hypertrophic-Cardiomyopathy Glaucoma Hypertension Tremor Alcohol withdrawal syndrome Prophylaxis of migraine  β-Blockers in Ischaemic Heart Disease Decrease myocardial oxygen demand by reducing the double product of heart rate and blood pressure (afterload) and by limiting exercise induced increases in contractility Proven to improve survival and reduce reinfarction rate after MI (both by reducing oxygen demand, and perhaps by antiarrhythmic effects) – indicated in acute ischaemia Opie & Gersh Drugs for the Heart 8th Edition Elsevier 2013 β-Blockers in Ischaemic Heart Disease ↓ myocardial O2 consumption ↑ coronary blood flow ↑ diastolic perfusion time Improve supply/demand ratio Reduce mortality in first year post MI Improve O2 dissociation from haemoglobin Opie & Gersh Drugs for the Heart 8th Edition Elsevier 2013 in Morrow and De Lemos Braunwald’s Textbook of CV Disease 2019  Candidates for use of Beta Blocking Agents for Angina Ideal Candidates Poor Candidates Prominent relationship of physical activity to attacks Asthma or reversible airway component in patients of angina with chronic lung disease Co-existant hypertension Severe LV dysfunction with severe heart failure symptoms History of supraventricular tachycardia History of severe depression Previous MI Raynaud phenomenon LV Systolic dysfunction Symptomatic peripheral arterial disease Mild to moderate heart failure symptoms Severe bradycardia or heart block Prominent anxiety state Diabetes with frequent hypo-glycaemic episodes Morrow and De Lemos Braunwald’s Textbook of CV Disease 2019  Proposed MOA of β Blockers in the treatment of Hypertension 1. Reduction in cardiac output 2. Central nervous system effect 3. Inhibition of renin secretion (and possibly other steps in the renin- angiotensin-aldosterone cascade) 4. Reduction in plasma volume 5. Reduction in vasomotor tone 6. Reduction in peripheral vascular resistance 7. Improvement in vascular compliance 8. Resetting of baroreceptor levels 9. Effects on prejunctional β-receptors: reduction in norepinephrine release 10. Attenuation of pressor response to catecholamines with exercise and stress Carlberg et al Hypertension a Companion to Braunwald Elsevier 2013  Effects of reduction in systolic BP stratified by class of antihypertensive Ettehad et al. Lancet 2016; 387:957-67  β Blockers in the treatment of Hypertension No longer considered first line therapy for hypertension Other agents have better outcome data Increased development of diabetes β Blocker β Blocker  β-blockade in CHF dont give a beta blocker if they are in uncompensated Heart failure! stabilise it using it diuretics first Counterintuitive BUT they work! Mechanisms unkown but perhaps Improved β-adrenergic signaling Protection from catecholamine myocyte toxicity Avoids hyperphosphorylation of the ryanodine receptor Antiarrhythmic effects Bradycardia Anti-apoptosis Renin-angiotensin antagonism Opie Drugs for the Heart 8th Edition Elsevier 2012  β-blockade in CHF Hoste, AM, Glaucoma Volume 1: Medical Diagnosis & Therapy, 2009 525-537  its better to survive than to not Effect of beta blockade on mortality in heart failure Metoprolol Bisoprolol Carvedilol Braunwald’s Heart Disease  Adverse Reactions to β Blockers Fatigue (potentially aggravated by β2 blockade) Bradycardia Cold peripheries (vasoconstriction via β2 blockade may worsen the situation) Aggravation of heart failure Rare cases of symptomatic hypotension Bronchospasm in patients with reversible, labile, reactive airways disease Depression and sleep disturbance Cruikshank, The Modern Role of Beta-blockers in Cardiovascular Medicine 2011  Withdrawal of β Blockers Sudden withdrawal of beta-adrenoceptor antagonists may result in severe exacerbation of angina pectoris, acute myocardial infarction, sudden death, malignant tachycardia, sweating, palpitation, and tremor These are consistent with transient adrenergic hypersensitivity. Meylers Side Effects of Drugs 2016  Withdrawal of β Blockers More apparent after drug withdrawal in patients with ischaemic heart disease than hypertension Hypersensitivity from 2-6 days post withdrawal The density of beta-adrenoceptors on human lymphocyte membranes increased by 40% during treatment with propranolol for 8 days Withdrawal should be accomplished by gradual dosage reduction over 10–14 days Meylers Side Effects of Drugs 2016 Royster et al Kaplans Cardiovascular Anaesthesia 2024  Adverse Effects of β-adrenergic Antagonists Hypoglycaemia Mask response to hypoglycaemia in diabetes mellitus Adverse Lipid Profile Rang et al. Pharmacology 2003  Compensatory Mechanisms limiting the response to antihypertensive agents Class BP Compensatory mechanism Alpha1 antagonists Salt/water retention; tachycardia Alpha 2 agonists Salt/water retention CCBs (especially short acting) Tachycardia Direct vasodilators Salt/water retention; tachycardia (hydralazine, minoxidil) Diuretics Salt/water retention American Heart Association European Core Drug Treatment for Uncomplicated Hypertension ESC Guidelines for Hypertension Williams et al, EHJ 2018; 39: 3021-204  Possible combinations of classes of antihypertensive drugs Useful combinations Preferred Possible combinations Not Recommended Modified from Eur Heart J. 2013;34(28):2159-2219. doi:10.1093/eurheartj/eht151