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Cardiovascular Anatomy, Physiology and Pharmacology BS913 Lecture 9: Drugs used in the treatment of cardiac diseases, effects, adverse reactions, … Revision Physiology … Martini, Figure 20.12 The Conducting System Martini; Figure 20–12 Action Potentials in Skeletal and Cardiac Muscle Martini; Figure 20–15 Cardiodynamics - Cardiac output End-diastolic volume End-systolic volume Stroke volume Heart rate SUMMARY: Factors Affecting Heart Rate and Stroke Volume Martini; Figure 20–24 Dynamics of Blood Circulation Interrelationships between - Flow - Pressure - Resistance - Control mechanisms that regulate blood pressure and blood flow ANS effects on heart and vessels Heart • inotropy • chronotropy SNS PSNS + + - Vessels • Pulm./coronary • most others constrict dilate constrict no effect How is Heart Rate Regulated? • Intrinsic pacemaker rate = 100 bpm • Autonomic Influences – SNS------> B1 receptor-------> Increased HR – PSNS-> Muscarinic (Ach)--> Decreased HR • Stretch Reflex (Bainbridge): Increased filling------> Increased HR • Drugs What Factors Affect Contractility? - Anything that increases Ca++ availability in the heart muscle cell will increase Contractility. - Anything that decreases Ca++ availability in the heart muscle cell will decrease Contractility. Cardiac conditions - Hypertension - Ischemic heart disease, Angina - Heart failure; poor left ventricular function - Arrhythmias - Hyperlipidaemia Common drugs administered to cardiac patients - Nitrates - Ca-ch. blockers - ß-blockers - Aspirin - ACE inhibitors - Warfarin - Digoxin - Statins - Diuretics - others - Anti-arrhythmics Cardiac medication: ß-blockers - Body releases noradrenaline (sympathetic nervous system) - Response to increased activity, danger, positive and negative stress: increases HR and BP bronchodilation - ß-Blockers block effect of released noradrenaline Cardiac medication: ß-blockers - used for: - hypertension angina post MI heart failure arrhythmias migraine Cardiac medication: ß-blockers - Effects and side effects: bradycardia hypotension dizziness tiredness, fatigue cold fingers / toes sleep disturbances airway constriction impotence Cardiac medication: ß-blockers - Should not be stopped suddenly - can cause rapid rise in BP and HR Cardiac medication: alpha-blockers - Alpha receptors in blood vessels respond to release of noradrenaline vasoconstriction - Alpha blockers block this effect - Used for hypertension (usually combined with thiazid diuretics or ß-blockers) Cardiac medication: alpha-blockers - Effects / side effects: - - rapid drop in BP after initial dose postural hypotension headache palpitations Cardiac medication: nitrates - Act as vasodilator - Coronary arteries: blood flow to heart muscle increased - Great veins: reduces preload - Great arteries: reduces afterload Cardiac medication: nitrates - Used for: - Angina - Heart failure Cardiac medication: nitrates - Effects and side effects: - Facial flushing - Headache - dizziness - Nausea - Postural hypotension particularly after exercise Cardiac medication: potassium channel activators - Dilate the large coronary arteries and smaller resistance vessels - Increase coronary blood flow - Additional vasodilatory effect on systemic blood vessels Reduces pre- and afterload Cardiac medication: potassium channel activators - Used for: - Effects and side effects: - Dizziness Headache Hypotension Vasodilation vomiting angina Cardiac medication: Ca channel blockers - Intracellular Ca is essential for contraction - Ca channel blockers prevent influx of Ca into specific cells leading to inhibition of contraction Cardiac medication: Ca channel blockers - Effects of Ca channel blockers - Dilate arteries in systemic circulation: reduced afterload - Dilate great veins: reduced preload - Relax coronary arteries - Diltiazem / Verapamil: reduce contractility reduce oxygen demand of heart Cardiac medication: Ca channel blockers - Used for: - Type 1:verapamil - Acts mainly on conducting pathway; slows heart - angina, hypertension, and arrhythmias Cardiac medication: Ca channel blockers - Used for: - Type 2: Nifedipin etc. - Acts mainly on smooth muscle fibres in arterial walls - Angina and hypertension Cardiac medication: Ca channel blockers - Used for: - Type 3: Diltiazem - Combines action of type 1 and 2 - Angina and hypertension Cardiac medication: Ca channel blockers - Side effects: - Facial flushing - palpitations - headache - Ankle swelling Constipation (verapamil) - Heart failure Cardiac medication: ACE inhibitors - Inhibits synthesis of angiotensin II, a very strong vasoconstrictor which also causes fluid retention - Main effects are: - Reduction of BP Prevention of vasoconstriction, reducing afterload and increasing cardiac output - Reduction of fluid retention Renin – Angiotensin system Renin-Angiotensin-Aldosterone Renin Angiotensinogen ACE AI AII AIII aldosterone vasoconstriction secretion Cardiac medication: ACE inhibitors - Used for: - hypertension heart failure post MI Cardiac medication: ACE inhibitors - Side effects - dry, annoying cough - Low blood pressure (start with low dose and gradually increase) - Skin rash; metallic taste - Reduced kidney function in kidney patients - Very rarely: angio-oedema Cardiac medication: Angiotensin II receptor antagonists - Block angiotensin II receptors - Used for - Used as alternative to ACE inhibitors if they are not well tolerated - hypertension Cardiac medication: Angiotensin II receptor antagonists - Side effects: - Fatigue - Hypotension and dizziness - rash - Taste disturbance Cardiac medication: Diuretics - Increase urine output by removing salt and water from circulation - Reduction in circulating fluids - Reduction in cardiac workload and BP - Three groups: - loop diuretics - thiazide diuretics - potassium-sparing Cardiac medication: Diuretics - Loop diuretics: e.g Furosemid - Used for: acute severe heart failure - Very quick acting; large volumes of urine to be passed within one h - Reduces effectively dyspnoe and ankle swelling - Also used for hypertension Cardiac medication: Diuretics - Side effects - Loss of potassium which causes tiredness muscle weakness, cramps loss of appetite ventricular arrhythmias - Can cause diabetes and gout Cardiac medication: Diuretics - Thiazide diuretics - Prevent sodium absorption in kidneys which is then lost in urine - Reduce initially by loosing volume of blood, thus reducing BP - Used for - mild heart failure - hypertension Cardiac medication: Diuretics - Side effects: - Low potassium - diabetes, gout - Can increase lipids - Impotence in high doses Cardiac medication: Diuretics - Potassium sparing: e.g. Amiloride, Triamterene - Minimise loss of potassium - Usually administered together with other more powerful diuretics - Used for: treating oedema in heart failure and cirrhosis Cardiac medication: Diuretics - Side effects: - gastro-intestinal disturbances - Dry mouth - rashes - Orthostatic hypotension - hyperkalaemia Cardiac medication: Antiarrhythmics - Affect the conduction system of the heart - ß-blockers - Ca channel blockers - Digoxin - Amiodarone Cardiac medication: Digoxin - Reduces conductivity of the heart - Increases myocardial contraction - Controls HR by preventing rapid rates - Used for: - supraventricular tachycardias - (heart failure) Cardiac medication: Digoxin - Side effects (excessive dosage): - nausea, vomiting - Loss of appetite - Fatigue - Slow pulse - Ventricular arrhythmias - Disturbance of vision Cardiac medication: Amiodarone - Increases refractory period - Used for - Atrial fibrillation - Atrial flutter - Often used with digoxin - Other (ventricular) arrhythmias Cardiac medication: Amiodarone - Side effects: - photo-sensitivity - Metallic taste - nightmares Case 1: Philip - Male, 30 yr, non-smoker, runner - builder - Nearly fell off the ladder because he felt dizzy and unwell - Was sent to a doctor - Blood pressure was taken - BP was 200 / 110 mm Hg - Hypertension Case 1: Blood pressure - Blood pressure: force of blood against walls of arteries - Measured non-invasively with sphygmomanometer - Measured by listening for Korotkoff sounds produced by turbulent flow in arteries as pressure released from blood pressure cuff Blood pressure Classification of Hypertension Recommended Followup Category SBP DBP Normal <130 <85 Recheck in 2 years 130-139 85-89 Recheck in 1 year Stage 1 (mild) 140-159 90-99 Confirm within 2 mo Stage 2 (mod) 160-179 100-109 Eval or refer 1 mo Stage 3 (severe) 180-209 110-119 Eval or refer 1 week High Normal Hypertension Stage 4 (very sev) >210 >120 Eval or refer immediately Case 1: Hypertension … - Serious condition - - Increases risk of heart diseases - - causes the heart to work harder contributes to atherosclerosis congestive heart failure kidney disease blindness stroke “silent killer” because it has no warning symptoms Differential Diagnosis of Hypertension • Primary Hypertension (95%) • Secondary Hypertension, e.g. caused by – – – – – Contraceptive use Renal disease Renal artery stenosis Cushing’s syndrome Pregnancy induced hypertension Risk factors for Hypertension - Increases risk of (primary) hypertension - smoking age (women > 65 yr, men > 55 yr) obesity diabetes lack of physical activity chronic alcohol consumption family history sex (men and postmenopausal women) Treatment of hypertension - Lifestyle changes quitting smoking weight loss reduction of stress dietary changes (less salt) regular aerobic exercise - Case “Phil”: normal weight, nonsmoker, regular exercise training - If not sufficient drug therapy required Treatment of hypertension - What kind of drugs would you choose? - Consider age and “lifestyle” Revision Alastair’s lecture Blood pressure regulation Case 1: Phil‘s treatment - Diuretic - - Diuretic + ß-blocker - - BP decrease not sufficient BP decrease still not sufficient Diuretic + ß-blocker + ACE inhibitor - BP decrease sufficient Struggling with adverse effects Treatment of hypertension Treatment of hypertension - Diuretics and ß-blockers are first-line drugs - Mode of action in both cases unclear - Several groups of drugs reduce BP by decreasing vasoconstrictor tone and hence peripheral resistance, e.g. ACE inhibitors Ca antagonists Thiazid diuretics - initially: BP falls because of a decrease in blood volume venous return cardiac output - gradually: cardiac output returns to normal - however, hypotensive effect remains because peripheral resistance has decreased Thiazid diuretics - No direct effect on blood vessels - Vasodilation seems to be associated with small but persistent reduction in body Na+ - Act on kidney inhibit NaCl reabsorption - Excretion of Na+, Cl- and accompanying H2O is increased Thiazid diuretics - however, also K+ excretion increased - Safe drug, orally active - Act within 1-2 hours Duration of 12 hours - Adverse effects are important because drug may be taken for life Thiazid diuretics: adverse effects - Weakness - Loss of libido, impotence - Diarrhoea - Tinnitus - Metabolic side-effects: Thiazid diuretics: adverse effects - Metabolic side-effects: - hypokalaemia: can cause arrythmias - hyperuricaemia: May precipitate gout - lipids: Increase cholesterol levels, at least during the first 6 months of administration ß-adrenoreceptor antagonists - initially: Produce a fall in BP by decrease in cardiac output - gradually: Cardiac output returns to normal, but BP remains low - Unknown mechanism “resets” peripheral vascular resistance at a lower level ß-blockers: adverse effects - Cold hands - Loss of libido, impotence - Fatigue - Serious side effects: provocation of asthma heart failure conductance block - Tend to raise trigycerides and decrease HDL-cholosterol ß-blockers: - Vary in lipid solubility and cardioselectivity - All block ß1-receptors and are equally effective in reducing BP - More lipid-soluble drugs: more rapidly absorbed, more first-pass hepatic metabolism, more rapidly eliminated - Cardioselective ß-blockers may have sufficient ß2-activity to cause bronchospasm in patients with asthma Vasodilator drugs: - ACE-inhibitors: Inhibit synthesis of angiotensin II which is powerful vasoconstrictor - Ca antagonists: tone of vascular smooth muscle is determined by cytosolic Ca2+ concentration prevent influx of Ca and as result inhibit contraction dilate arteries reduce BP Case: Gerry - 55 yr, sees his GP because of nose bleeding - BP 180 / 100 mm Hg - newly diagnosed with primary hypertension - Lifestyle changes recommended and ß-blocker prescribed - Second morning, very early he fell in the bathroom Case: Gerry - Massive problems with orthostatic hypotension - What would you recommend? Case: Paul - healthy, successful modern pentathlete Took ß-blockers shortly before pistol shooting event - Great results - Change in follow-up of events: Now running event immediately after shooting and not the next day - Great results in shooting but catastrophy in running Case: Paul - Can you explain this? - What does it tell you about pharmacokinetic and –dynamic of ß-blockers? Antihypertensive Therapy Ischemic Heart Disease • Etiology: – Coronary Atherosclerosis • Risks: • Clinical Syndromes: – – – – angina pectoris myocardial infarction chronic ischemic heart disease sudden cardiac death Angina pectoris Pathogenesis of Atherosclerosis Lipid accumulates in vascular wall Macrophages infiltrate the wall and oxidize the lipids Cell injury and release of local growth factors (Angiotensin II) Plaque formation on intimal wall Pathogenesis of Ischemia Plaque Disruption or Breakdown Tissue Thromboplastin Exposed Platelet Aggregation and Clotting Cascade Activated Thrombus Formation Acute Ischemia Demand > Supply: Angina Perfusion pressure fixed stenosis oxygen content SUPPLY afterload contractility preload heart rate DEMAND How to increase supply? How to decrease demand? Ischemic Syndromes Stable Angina Unstable Angina Patho: Fixed stenosis Thrombus >75% + lysis Pain: predictable relieved by rest (3-5 min) Serum Enz: not elevated MI Thrombus with occlusion unpredictable unpredictable not relieved not relieved rest rest (>15-30) not elevated elevated ECG Changes with Ischemia • Indicative Leads show: • Ischemia: ST elevation or depression T-wave peaking, flattening, inversion Bigger than normal Q-waves ST elevation Q Sequela of Myocardial Infarction Decreased Myocardial Perfusion Partially ischemic cells Anaerobic metabolism and lack of ATP Totally ischemic cells No ATP Cell rupture and death Ion leak across cell membrane ST changes Dysrhythmias Q-waves Elevated Enzymes Compensatory Response to Decreased Stroke Volume Decreased Stroke Volume IMMEDIATE baroreceptor activation HOURS RAS activity WEEKS Increased LV wall tension fluid retained SNS SV, CO preload SV, ventricular hypertrophy CO Copyright © 2000 by W. B. Saunders Company. All rights reserved. SV, CO Differential Diagnosis of Chest Pain - Cardiac ischemia Chest wall trauma, costochondritis Pleural pain - pneumonias Pneumothorax Gastrointestinal (GERD) Treatment of Cardiac Ischemia • Stable angina – – – – SL nitroglycerin Platelet inhibitor (e.g. Aspirin) beta blocker add long acting nitrate (remove at night) – add calcium channel blocker (not verapamil) Relief of Angina Treatment of Cardiac Ischemia - Medication to increase myocardial blood supply reduce the amount of work the myocardium performs Treatment of Cardiac Ischemia - Dilate coronary arteries Slow heart rate Reduce force of each contraction Lower systolic BP Treatment of Cardiac Ischemia - Increase supply (coronary flow): Ca antagonists nitrates revascularization procedures (bypass surgery, angioplasty ..) ß-blockers (extend diastole) Treatment of Cardiac Ischemia Reduce demand: - decreased HR (ß-blockers) reduced wall tension (nitrates, Ca anatagonists, ß- blockers) reduced contractility (ßblockers, Ca antagonists) Case: Michael - Male - 36 yr - 65 stone - Heart failure Case: Michael - Symptoms - fatigue - oedema - breathlessness Heart Failure • Def: Inability to effectively PUMP the amount of blood delivered to the heart • Etiologies: Many – – – – – MI hypertension Valve Disease Congenital Defects Cardiomyopathy Heart as a Two Pump System right heart lungs Left heart arteries veins Tissues Left Heart Failure Backward Effects Increased pressure behind the pump Pulmonary congestion Forward Effects Low Cardiac Output Right Heart Failure Backward Effects Systemic Venous Congestion Forward Effects Low Cardiac Output Principles of Heart Failure Treatment GOAL: Optimize Cardiac Output and Minimize Cardiac Workload - Management of Preload - Management of Afterload - Management of Contractility Heart failure Heart Failure Treatment Diuretics: reduce circulatory volume decreases preload and oedema Vasodilators: e.g. ACE inhibitors decrease pre- and afterload Digoxin: increase cytosolic Ca increase force of contraction Drugs used to treat cardiac conditions:
