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Cardiac electrophysiology and pharmacology - drdhriti


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A PowerPoint Presentation on Basic Electrophysiology of Heart and Angiotensin Converting Enzymes and their Inhibitors suitable for Undergraduate MBBS level Students

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Cardiac electrophysiology and pharmacology - drdhriti

  1. 1. CARDIAC ELECTROPHYSIOLOGY AND DRUGS AFFECTING RENIN- ANGIOTENSIN SYSTEM Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong
  2. 2. Drugs of Cardiovascular System • Drugs having major action on Heart and Blood vessels and used in various important cardiac disease conditons. • They act directly on heart structures or via Autonomic Nervous system (ANS), Central Nervous System (CNS), Kidney, Autacoids or Hormones: 1. Cardiac Glycosides 2. Sympathomimetics 3. Anticholinergic Drugs 4. Antiarrhythmics 5. Electrolytes 6. Thrombolytic 7. Anticoagulants 8. Antihypertensive 9. Analgesics
  3. 3. Recall Heart Anatomy ! 1. Right Coronary 2. Left Anterior Descending 3. Left Circumflex 4. Superior Vena Cava 5. Inferior Vena Cava 6. Aorta 7. Pulmonary Artery 8. Pulmonary Vein 9. Right Atrium 10. Right Ventricle 11. Left Atrium 12. Left Ventricle 13. Papillary Muscles 14. Chordae Tendineae 15. Tricuspid Valve 16. Mitral Valve 17. Pulmonary Valve 18. Aortic Valve (Not pictured)
  4. 4. Recall Heart Physiology ! • SA node • AV Junction • Bundle of His • His-Purkinje • Myocardial cells • Electrical potential • Autonomic Nervous system
  5. 5. Major Heart Receptors - Autonomic
  6. 6. Major Ion Channels
  7. 7. Myocardial Cells Action potential  Depolarization  Repolarization  Critical electrolytes  Sodium, potassium, calcium  Excitability
  8. 8. Cardiac Electrophysiology • Recall: to function efficiently, heart needs to contract sequentially (atria, then ventricles) and in synchronicity • Relaxation must occur between contractions (not true for other types of muscle [exhibit tetany  contract and hold contraction for certain length of time] • Coordination of heartbeat is a result of a complex, coordinated sequence of changes in membrane potentials and electrical discharges in various heart tissues
  9. 9. Myocardial Cells • 2 types – Pacemaker and non pacemaker – Pacemaker and conducting cells – SAN, AVN, Bundle of His and Purkinje`s fibres – Non pacemaker – Working Myocardial Cell (WMC) or CMC • Sinus rhythm means rhythm originates in SAN • Sinus tachycardia means tachycardia but rhythm originates in SAN – fever, exercise etc. • Tachycardia = heart rate > 100 per minute • Sinus Bradycardia = heart rate < 60 per min. • Escape rhythm: Rhythm which is not generated by SAN, but other, e.g. AVN or bundle of His etc.
  10. 10. Cardiac Action Potential - Five phases (0,1,2,3,4) • Phase 0 – opening of fast Na channels and rapid depolarization • Drives Na+ into cell (inward current), changing membrane potential • Transient outward current due to movement of Cl- and K+ • Phase 1 – initial rapid repolarization • Closure of the fast Na+ channels • Phase 0 and 1 together correspond to the R and S waves of the ECG • Phase 2 - plateau phase • sustained by the balance between the inward movement of Ca+ and outward movement of K+ • Has a long duration compared to other nerve and muscle tissue • Normally blocks any premature stimulator signals (other muscle tissue can accept additional stimulation and increase contractility in a summation effect) • Corresponds to ST segment of the ECG.
  11. 11. Cardiac Action Potential – contd. • Phase 3 – repolarization – K+ channels remain open, – Allows K+ to build up outside the cell, causing the cell to repolarize – K + channels finally close when membrane potential reaches certain level – Corresponds to T wave on the ECG • Phase 4 - resting phase (resting membrane potential) • At (-90mv) stable • Phase cardiac cells remain in until stimulated • Associated with diastole portion of heart cycle
  12. 12. Summary of ionic basis - WMCs
  13. 13. Cardiac Action Potential – Pacemaker Cells – slow channels • Present in SAN and AVN and His –Purkinje cells • Most characteristic feature is in Phase-4, or slow diastolic depolarization • After repolarization membrane potential decays spontaneously and sudden automatic depolarization • Therefore capable of generating own impulses • Normally SAN has steepest phase-4 • Characteristics: • Initiation at higher threshold (less negative (-75mv) • Slow depolarization • Low overshoot (+10mv), low amplitude • Very slow a propagation • Phase-1 and 3 are not clearly demarcated • Can occur in fibres depolarized too much to support fast channels
  14. 14. Drugs Affecting Renin - Angiotensin System What is Renin – Angiotensin System? (Physiological Background)
  15. 15. RAS - Introduction • Renin is a proteolytic enzyme and also called angiotensinogenase (plasma ɑ2 globulin) • It is produced by juxtaglomerular cells of kidney • Renin acts on a plasma protein – Angiotensinogen (a glycoprotein synthesized and secreted into the bloodstream by the liver) and cleaves to produce a decapeptide Angiotensin-I • Angiotensin-I is rapidly converted to Angiotensin-II (octapeptide) by Angiotensin Converting Enzyme (ACE – dipeptidyl carboxypeptidase) (present in luminal surface of vascular endothelium) • Furthermore, degradation of Angiotensin-II by peptidases produce Angiotensin-III
  16. 16. Types – Circulating RAS and Tissue RAS • Circulating: Renin is the rate limiting factor of AT-II release – AT-I is less potent (1/100th) than of AT – II – Plasma t1/2 of Renin is 15 minutes – AT-I is rapidly converted to AT-II by ACE (AT-II half life 1 mim) – Degradation product is AT-III – Both AT-II and AT-III stimulates Aldosterone secretion from Adrenal Cortex (equipotent) • Tissue RAS: – Extrinsic local RAS: Blood vessels capture Renin and Angiotensinogen to produce local AT-II – Intrinsic local RAS: Many tissues Heart, brain, blood vessels, kidneys, adrenals have all components of RAS in their cells – produce locally – Important factor in these organs
  17. 17. RAS – Physiologcal Regulation Vasoconstriction Na+ & water retention (Adrenal cortex) Kidney Increased Blood Vol. Rise in BP It is secreted in response to: • Decrease in arterial blood pressure – also fall in BP and blood volume • Decrease Na+ in macula densa • Increased sympathetic nervous activity (-) (-)
  18. 18. Actions of Angiotensin-II - CVS Powerful vasoconstrictor particularly arteriolar and venular  direct action  by release of Adr/NA release (adrenal and adrenergic nerve endings)  increased Central sympathetic outflow • Promotes movement of fluid from vascular to extravascular • More potent vasopressor agent than NA –promotes Na+ and water reabsorption and no tachyphylaxis • Overall Effect – Pressor effect (Rise in Blood pressure) Cardiac action: • Increases myocardial force of contraction (Ca++ influx promotion) • Increases heart rate by sympathetic activity, but reflex bradycardia occurs • Cardiac output is reduced • Cardiac work increased (increased Peripheral resistance) • No arrhythmia - in contrast to NA
  19. 19. Chronic effects of Angiotensin-II • Ill effects on chronic basis of exposure (Mitogenic effect!) – Directly: Induces hypertrophy, hyperplesia and increased cellular matrix of myocardium and vascular smooth muscles – by direct cellular effects involving proto-oncogens and transcription of growth factors – Indirectly: Volume overload and increased t.p.r in heart and blood vessels • Hypertrophy and Remodeling (abnormal redistribution of muscle mass) – Long standing hypertension – increases vessel wall thickness and Ventricular hypertrophy – Myocardial infarction – fibrosis and dilatation in infarcted area and hypertrophy of non-infarcted area of ventricles – CHF – progressive fibrotic changes and myocyte death – Risk of increased CVS related morbidity and mortality • ACE inhibitors reverse cardiac and vascular hypertrophy and remodeling
  20. 20. Remodeling
  21. 21. Actions of Angiotensin-II • Adrenal cortex: Enhances the synthesis and release of Aldosterone – In distal tubule Na+ reabsorption and K+ excretion • Kidney: Enhancement of Na+/H+ exchange in proximal tubule – increased Na+, Cl- and HCO3 reabsorption – Also reduces renal blood flow and promotes Na+ and water retention • CNS: Drinking behaviour and ADH release • Peripheral sympathetic action: Stimulates adrenal medulla to secrete Adr and also releases NA from autononic ganglia
  22. 22. Angiotensin Receptors • 2 (two) subtypes: AT1 and AT2 – most of known Physiologic effects are via AT1 – Both are GPCR – A1 is important • Utilizes various pathways for different tissues – PLC-IP3/DAG – Ca++: AT1 utilizes pathway for vascular smooth muscles by MLCK – Membrane Ca++ channels: Ca release - aldosterone synthesis, cardiac inotropy, CA release - ganglia/adrenal medulla action etc. – DAG: PKc – promotion of cell growth – Adenylyl cyclase: in liver and kidney (AT1) – Intrarenal homeostatic action: Phospholipase A2, LT and PG production – Long term effects on smooth muscles and myocardium – MAP kinase, TAK2 tyrosine protein kinase and PKc
  23. 23. Angiotensin-II – Pathophysiological Roles 1. Mineraocorticoid secretion 2. Electrolyte, blood volume and pressure homeostasis: Renin is released when there is change in blood volume or pressure or decreased Na+ content – Reduction in tension in afferent gromerulus - Intrarenal Baroreceptor Pathway activation – PG production - Renin release – Low Na+ conc. in tubular fluid – macula densa pathway – COX-2 and nNOS are induced – release of PGE2 and PGI2 – more renin release – Baroreceptor stimulation increases sympathetic impulse – via beta-1 pathway – renin release • Renin release – increased Angiotensin II production – vasoconstriction and increased Na+ and water reabsorption • Rise in BP – decreased Renin release - Long term stabilization of BP is achieved – long-loop negative feedback mechanism
  24. 24. Role of Angiotensin-II – contd. • Short-loop negative feedback mechanism: – activation of AT1 receptor in JG cells – inhibition of Renin release – Long term stabilization of salt and water intake • Pharmacological importance: – Drugs Increasing Renin release: • ACE inhibitors and AT1 antagonists enhance Renin release • Vasodilators and diuretics stimulate Renin release • Loop diuretics increase renin release – Decrease in Renin release: • Beta blockers and central sympatholytics • NSAIDs and selective COX-2 inhibitors decrease Renin release
  25. 25. Role of Angiotensin-II – contd. 3. Hypertension 4. Secondary hyperaldosteronism Inhibitors of RAS: • Sympathetic blockade • ACE inhibitors • AT1 receptor antagonists • Aldosterone antagonists • Renin inhibitory peptides and Renin specific antibodies
  26. 26. ACE inhibitors • Captopril, lisinopril, enalapril, ramipril and fosinopril etc.
  27. 27. Captopril • MOA: – ACEIs block action of ACE – so no AT-II – Also increases plasma kinin level (temporary) • Depends on Na+ status and level of RAS • In normotensives: – With normal Na+ level – fall in BP is minimal – But restriction in salt or diuretics - more fall in BP • Renovascular and malignant hypertension – greater fall in BP • Essential hypertension: 20% hyperactive RAS and 60% hypoactive in RAS – Contributes to 80% of maintainence of tone – lowers BP – But no long term relation of fall in BP by captopril and PRA activity
  28. 28. Captopril – contd. • Actions: – Decrease in peripheral Resistance – Arteriolar dilatation and increased compliance of larger arteries – Fall in Systolic and Diastolic BP  No effect on Cardiac output  No interference with capacitance vessels - No Postural hypotension  No reflex sympathetic stimulation  Can be used safely in IHD patients  Renal blood flow is maintained – greater dilatation of vessels  Basal level of aldosterone decreased • Pharmacokinetics: • 70% absorbed, partly metabolized and partly excreted unchanged in urine • Food interferes absorption • T1/2 = 2 Hrs (6-12 Hrs)
  29. 29. Captopril – Adverse effects • Cough – persistent brassy cough in 20% cases – inhibition of bradykinin and substanceP breakdown in lungs • Hyperkalemia in renal failure patients with K+ sparing diuretics, NSAID and beta blockers (routine check of K+ level) • Hypertension: CHF and diuretic patients • Hypotension – sharp fall may occur – 1st dose • Acute renal failure: CHF and bilateral renal artery stenosis • Angioedema: swelling of lips, mouth, nose etc. • Rashes, urticaria etc • Dysgeusia: loss or alteration of taste • Foetopathic: hypoplasia of organs, growth retardation etc • Neutropenia • Contraindications: Pregnancy, bilateral renal artery stenosis, hypersensitivity and hyperkalaemia
  30. 30. ACE inhibitors - Enalapril • It’s a prodrug – converted to enalaprilate • Advantages over captopril: – Longer half life – OD (5-20 mg OD) – Absorption not affected by food – Rash and loss of taste are less frequent – Longer onset of action – Less side effects
  31. 31. ACE inhibitors – Ramipril (Cardace) • It’s a popular ACEI now • It is also a prodrug with long half life • Tissue specific – Protective of heart and kidney • Uses: Diabetes with hypertension, CHF, AMI and cardio protective in angina pectoris • Blacks in USA are resistant to Ramipril – addition of diuretics help • Dose: Start with low dose; 2.5 to 10 mg daily • EBM Reports: 1) improves mortality rate in early AMI cases 2) reduces the chance of development of AMI 3) reduces the chances of development of nephropathy etc. (1.25, 2.55 … 10 mg caps)
  32. 32. ACE inhibitors – Lisinopril (Lipril/Listril) • It’s a lysine derivative • Not a prodrug • Slow oral absorption – less chance of 1st dose phenomenon • Absorption not affected by food and not metabolized – excrete unchanged in urine • Long duration of action – single daily dose • Doses: available as 1.25, 2.5, 5, 10 1nd 20 mg tab – start with low dose
  33. 33. ACE inhibitors and hypertension • 1st line of Drug: – No postural hypotension or electrolyte imbalance (no fatigue or weakness) – Safe in asthmatics and diabetics – Prevention of secondary hyperaldosteronism and K+ loss – Renal perfusion well maintained – Reverse the ventricular hypertrophy and increase in lumen size of vessel – No hyperuraecemia or deleterious effect on plasma lipid profile – No rebound hypertension – Minimal worsening of quality of life – general wellbeing, sleep and work performance etc.
  34. 34. ACE inhibitors – uses • Hypertension • Congestive Heart Failure • Myocardial Infarction • Prophylaxis of high CVS risk subjects • Diabetic Nephropathy • Schleroderma crisis
  35. 35. Angiotensin Receptor Blockers (ARBs) • Losartan • Candesartan • Valsartan • Irbesartan • Eprosartan
  36. 36. Losartan • Competitive antagonist and inverse agonist of AT1 receptor • Does not interfere with other receptors except TXA2 • Blocks all the actions of A-II - vasoconstriction, sympathetic stimulation, aldosterone release and renal actions of salt and water reabsorption • No inhibition of ACE
  37. 37. Losartan • Theoretical superiority over ACEIs: – Cough is rare – no interference with bradykinin and other ACE substrates – Complete inhibition of AT1 – alternative pathway remains for ACEIs – Result in indirect activation of AT2 – vasodilatation (additional benefit) – Clinical benefit of ARBs over ACEIs – not known • However, losartan decreases BP in hypertensive which is for long period (24 Hrs) – heart rate remains unchanged and cvs reflxes are not interfered – no significant effect in plasma lipid profile, insulin sensitivity and carbohydrate tolerance etc – Mild uricosuric effect
  38. 38. Losartan – contd. • Pharmacokinetic: – Absorption not affected by food but unlike ACEIs its bioavailability is low – High first pass metabolism – Carboxylated to active metabolite E3174 – Highly bound to plasma protein – Do not enter brain • Adverse effects: – Foetopathic like ACEIs – not to be administered in pregnancy – Rare 1st dose effect hypotension – Low dysgeusia and dry cough – Lower incidence of angioedema • Available as 25 and 50 mg tablets
  39. 39. Losartan/ARBs - uses • Hypertension • CHF • MI • Diabetic Nephropathy • Combination with ACEIs
  40. 40. Important • ACEIs – Pharmacological actions and ADRs • Therapeutic uses of ACEIs • Role of ACEIs/ARBs in management of Hypertension • Losartan
  41. 41. Thank you Next Class – Cardiac Glycosides