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Cardiac Glycosides - drdhriti
This document discusses cardiac glycosides, which are drugs that increase the force of contraction of the heart without increasing oxygen consumption. It specifically focuses on digitalis, which is derived from foxglove. Digitalis increases myocardial contractility in a failing heart, improving cardiac output. It acts by increasing the intracellular calcium levels in cardiac muscle cells. The document covers the chemistry, pharmacology, mechanisms of action, effects on cardiac electrophysiology, pharmacokinetics, uses, and adverse effects of digitalis and other cardiac glycosides in detail over several pages.
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Cardiac Glycosides - drdhriti
- 1. D R .D . K . B R A H M A D E P A R T M E N T O F P H A R M A C O L O G Y N E I G R I H M S , S H I L L O N G , I N D I A Cardiac Glycosides
- 2. Introduction • Drugs havingthe cardiac Inotropic property – increase in force of contraction and cardiac output in a failing (hypodynamic) heart – They increase the myocardial contractility and improves cardiac output without proportionate increase in Oxygen consumption - Cardiac Tonic – Do not increase the heart rate • In contrast, Sympathomimetics or the cardiac stimulants increase Heart Rate and Oxygen consumption without increase in cardiac output MYOCARDIAL EFFICIENCY !
- 3. Cardiac Glycosides • Foxglove– William Withering (1785) • Naturally in Plants and animals – Poisons 1. Cardenolides (Cardanolides): 1. Digitalis purpurea – Digitoxin, Gitoxin and Gitalin 2. Digitalis lanata - Digitoxin, Gitoxin and Digoxin 3. Strophanthus gratus – Ouabin 4. Thevetia nerifolia – Thevetin 5. Convallaria majalis – Convallotoxin 2. Bufadienolides: • Bufo vulgris - Bufotoxin
- 4. Chemistry What isa glycoside ???? All Cardiac glycosides aglycone (genin) part (active pharmacologically) sugar (glucose or digitoxose) attached at Carbon 3 of nucleus Aglycone – Steroid ring (cyclopentanoperhydroph enanthrene ring) and lactone ring attached at 17th position
- 5. Cardiac Glycosides –act on a failing Heart What is a failing Heart ??? • Inability of the heart to pump sufficient blood to meet the metabolic demands of the body Systolic - In IHD, Valvular incompetence, cardiomyopathy and myocarditis etc. Diastolic - In Hypertension, aortic stenosis, congenital heart disease and hypertrophic cardiomyopathy Reduced efficiency of the heart as a pump – reduced Cardiac Output BY SCOTT R. SNYDER, BS, NREMT-P, SEAN M. KIVLEHAN, MD, MPH, NREMT- P, KEVIN T. COLLOPY, BA, FP-C, CCEMT-P, NREMT-P, WEMT ON MAR 29, 2015 - HTTP://WWW.EMSWORLD.COM/ARTICLE/12053437/DIAGNOSIS-AND- TREATMENT-OF-THE-PATIENT-WITH-HEART-FAILURE
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- 7. Pharmacological actions ofDigitalis - HEART Overall actions: 1. Direct Effects - Myocardial contractility and electrophysiology 2. Vagomimetic effect 3. Reflex action – alteration of hemodynamic 4. CNS effects – altering sympathetic activity Force of Contraction: Dose dependent increase in force of contraction in failing heart – positive inotropic effect Increased velocity of tension development and higher peak tension Systole is shortened and prolonged diastole In Normal Heart – what happens ??
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- 9. Contd. ---- • Tone:is Maximum length of fibre in a given filling pressure (Resting tension) • Not affected by digitalis • Decreasing end diastolic size of failing ventricle Rate: Rate decreased because of improved circulation - restored by vagal tone and abolished sympathetic over activity • Additionally decreases heart rate by vagal and extravagal action – Vagal tone is increased by: 1) through reflex sensitization of baroreceptor; 2) direct stimulation of vagal centre and; 3) sensitization of SA node to ACh – Extravagal action: Direct depressant action on SA and AV nodes (extravagal)
- 10. Electrophysiological actions - AP •Qualitative and quantitative difference on different fibers • Action Potential: – WMC: Excitability enhanced - RMP progressively decreased, shifted towards isoelectric • Due to reduction in gap between RMP and threshold potential • But decreased at toxic doses – below critical level – AV and BoH: Rate of “0 - phase” depolarization is reduced – PF : Phase 4 slope is increased - latent pacemaking activity (extrasystoles) – SAN AND AVN AUTOMATICITY - REDUCED – Higher doses: Oscillation at phase 4 – coupled beats: delayed afterdepolarization (DAD) – APD is reduced – at phase 2 – Amplitude of AP is diminished
- 11. Afterderpolarization Essentials of Medicalpharmacology by KD Tripathi – 7th Edition, JAYPEE, 2013
- 12. Afterpolarization actions -ouabin Basic &Clinical Pharmacology, Bertram G. Katzung (9th Edition)
- 13. Electrophysiological actions – contd. ERP: (Minimum interval between 2 propagated action potentials) Atrium: decreased by vagal action and increased by direct action – overall decreased - inhomogenicity AVN and BoH: Increased by direct, vagomimetic and antiadrenergic action Ventricles: abbreviated Conductivity: Slowed in AVN and BoH fibres ECG: Increased PR interval Decreased QT (shortening of systole) Decreased/inversion of - T wave
- 14. Digitalis action –Blood vessels Mild vasoconstrictor and increased PR in Normal individuals In CHF – compensated by improvement of increased in cardiac output-decrease in sympathetic overactivity – decrease in Peripheral resistance occurs Improved venous tone in CHF BP: No prominent action in Systolic and diastolic BP – no contraindication in hypertensive (rise in systolic and decreased in diastolic in CHF) Coronary vessels: No significant action on coronary vessels – not contraindicated in patient with coronary artery disease
- 15. Digitalis action –other tissues Kidney: Diuresis due to the improvement of circulation No diuresis in Normal persons Other smooth muscles: Inhibition of Na+/K+ ATPase – increased spontaneous activity – anorexia, nausea, vomiting and diarrhoea CNS: No major visible action in therapeutic doses High doses – stimulation of CTZ - nausea and vomiting Toxic doses – central sympathetic stimulation, mental confusion, disorientation and visual disturbance
- 16. Digitalis MOA –contd. 1. Depolarization 2. Release Ca++ 3. Contraction 4. NCX 5. Blocked 6. Na+ more X Ca++ Ca++<< Depleted K+ Essentials of Medical pharmacology by KD Tripathi – 7th Edition, JAYPEE, 2013
- 17. Cardiac glycosides -Pharmacokinetics Absorption and Distribution: Vary in their ADME Presence of food in stomach delays absorption of Digoxin and Digitoxin Digitoxin is the most lipid soluble Vd of Cardiac glycosides are high (heart, skeletal muscle, kidney - concentrated) – 6-8 L/Kg (Digoxin). Metabolism: Digitoxin is metabolized in liver partly to Digoxin and excreted in bile Reabsorbed in gut wall - enterohepatic circulation – long half life No relation with renal impairment Digoxin is primarily excreted unchanged in urine and rate of excretion parallels creatinine clearance So, renal impairment and elderly – long half life (dose adjustment) All CGs are cumulative – steady state is attain after 4 half lives (1 wk for Digoxin and 4 weeks for digitoxin) * Ouabain is administered parenterally and is excreted unchanged in urine
- 18. Digitalis – Adverseeffects • Cardiac and Extracardiac: • Extracardiac: 1. GIT: nausea, vomiting and anorexia etc. 2. CNS: CTZ stimulation, headache, blurring of vision (flashing light, altered color vision), mental confusion etc. 3. Fatigue, malaise, no desire to walk 4. Serum Electrolyte K+ : Digitalis competes for K+ binding at Na/K ATPase • Hypokalemia: increase toxicity • Hyperkalemia: decrease toxicity – Mg2+: Hypomagnesaemia: increases toxicity – Ca2+: Hypercalcaemia: increases toxicity
- 19. Digitalis – Adverseeffects Cardiac: All Arrhythmias Tachyarrythmias: Heart rate abnormally increased due to prolong diuretic and digitalis therapy (K depletion) – Potassium chloride 20 m.mol IV/hr or orally Digitalis toxicity – don’t give K+ Serum K+ estimation Ventricular arrhythmia: Excessive ventricular automaticity: Lidocaine IV (or Phenyton) PSVT: Propranolol IV or Adenosine AV block: Atropine - 0.6 to 1.2 mg IM
- 20. Digitalis - contraindications Hypokalemia: Toxicity Myocardial Infarction WPW syndrome: VF may occur (due to reduced ERP of bypass) Elderly, renal or severe hepatic disease: more sensitive to digitalis Ventricular tachyarrhythmias Partial AV block: Complete block Thyrotoxicosis
- 21. Digitalis – CommonDrug interactions Diuretics: Hypokalaemia (K+ supplementation required) Calcium: synergizes with digitalis Adrenergic drugs: arrhythmia Propranolol and Ca++ channel blockers: depress AV conduction and oppose positive ionotropic effects Metoclopramide, sucralfate and antacids – reduced absorption
- 22. Digitalis – therapeuticUses 1. Congestive Heart Failure & 2. Cardiac Arrhythmias
- 23. Congestive Heart Failure •Systolic dysfunction: dilated ventricles and unable to develop sufficient wall tension – IHD, Valvular disease, Myocarditis etc. • Diastolic dysfunction: Thickened wall, filling is impaired and low output – prolonged hypertension, CHD, hypertrophic myopathy • Long standing CHF patients have both the types of dysfunctions • Acts primarily on systolic dysfunction – Failing heart is unable to pump sufficient blood at normal filling pressure – More blood remains in ventricles – Frank-Starling compensation applied - But, Congestion starts – Digitalis therapy improves the conditions in CHF: Na+ and water retaining stops – however, neither arrest progression nor reverse pathological change – Reduction in Oxygen consumption (Laplace`s law , WT = VR X IVP) – Current status !
- 24. Contd. --- StrokeVolume Preload (fillingpressure) Normal Digitalis CHF
- 25. Digoxin Digitalization Digoxinhas low therapeutic window and margin of safety is very low Therapeutic level of digoxin is 0.5 – 1.5 ng/ml It is administered such a way that patient gets maximum benefits with minimal adverse effects Previously rapid digitalization was done but obsolete now Rapid IV: Seldom used now: As desperate measure in CHF and atrial fibrillation - 0.25 mg slow IV stat followed by 0.1 mg every Hrly Slow digitalization: Digoxin 0.25 mg (or even 0.125mg) daily in the evening – full response in 5-7 days If no improvement administer 0.375 for 1 week If no, administer 0.5 mg in next week Monitor patient for blood levels, if no monitor in improvement of signs and symptoms If bradycardia, stop the drug Rapid digitalization (oral): 0.5 to 1 mg stat then 0.25 mg every 6 Hrly - Monitor for toxicity - Patient is digitalized within 24 Hrs
- 26. Cardiac dysrhythmia (arrhythmia) Large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart The hearts too fast or too slow, and may be regular or irregular 1. Atrial fibrillation (350-550/min): Direct, vagomimetic and antiadrenergic action Increased ERP in AVN Average ventricular rate decreases – dose dependent Therapeutic endpoint can be defined – 70- 80/min 2. Atrial flutter (200-350, 2:1): Synchronous beating – enhances AV block Digitalis converts AF to Afl Converts AFl to AF 3. PSVT (150-200, 1:1) Vagal tone increase – depresses path of re- entry IV digitalis
- 27. Pharmacotherapy of CHF Essentialsof Medical pharmacology by KD Tripathi – 7th Edition, JAYPEE, 2013
- 28. What is afailing Heart ??? Inability of the heart to pump sufficient blood to meet the metabolic demands of the body Systolic - In IHD, Valvular incompetence, cardiomyopathy and myoca rditis etc. Diastolic - In Hypertension, aortic stenosis, congenital heart disease and hypertrophic cardiomyopathy Reduced efficiency of the heart as a pump – reduced Cardiac Output BY SCOTT R. SNYDER, BS, NREMT-P, SEAN M. KIVLEHAN, MD, MPH, NREMT- P, KEVIN T. COLLOPY, BA, FP-C, CCEMT-P, NREMT-P, WEMT ON MAR 29, 2015 - HTTP://WWW.EMSWORLD.COM/ARTICLE/12053437/DIAGNOSIS-AND- TREATMENT-OF-THE-PATIENT-WITH-HEART-FAILURE
- 29. Vicious cycle inCHF Essentials of Medical pharmacology by KD Tripathi – 7th Edition, JAYPEE, 2013
- 30. Goals and Drugsof Therapy Relief of congestive/Low output symptoms and restoration of Cardiac performance: Inotropic: Digoxin, Dopamine, Dobutamine, Amrinone/Milrinone Diuretics: Furosemide, thiazides Vasodilators: ACE inhibitors/ARBs, Hydralazine, Nitroprusside and Nitrates Beta-blockers: Metoprolol, Bisoprolol, Carvedilol Arrest/Reversal of disease progression and prolongation of survival ACE inhibitors/ARBs, Beta-blockers Aldosterone antgonist: Spironolactone Non-pharmacological measures: Rest and salt restriction (for all grades of CHF)
- 31. NYHA Classification Asymptomatic :Left ventricular dysfunction Class I: no limitation of physical activity ordinary physical activity does not cause fatigue, breathlessness or palpitation Cass II: slight limitation of physical activity patients are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, breathlessness or angina pectoris (symptomatically 'mild' heart failure) Class III: marked limitation of physical activity although patients are comfortable at rest, less than ordinary activity will lead to symptoms (symptomatically 'moderate' heart failure) Class IV: inability to carry out any physical activity without discomfort symptoms of congestive cardiac failure are present even at rest. Increased discomfort with any physical activity (symptomatically 'severe' heart failure)
- 32. Diuretics Almost allcases of CHF are treated with diuretics High ceiling diuretics (furosemide, bumetanide) are preferred – IV diuretics – rapid symptomatic relief Chronic cases – resistance to furosemide - maintained by combination with thiazides/spironolactone (alone limited Role) Benefits: Decrease in preload – more ventricular efficiency Relief from Oedema and pulmonary congestion Increases venous capacitance – relief of LVF No need of digitalis therapy – diuretics + vasodilators Drawbacks: No influence in disease process and no Role in asymptomatic heart failure Activation of RAS Chronic therapy: hypokalaemia, alkalosis, carbohydrate intolerance Current opinion: Mild cases – ACEIs/ARBs + Beta-blockers No prognostic benefits
- 33. RAS Inhibitors ACEInhibitors and ARBs are mainstay in treatment of CHF – orally effective medium efficacy Symptomatic as well as disease modifying benefits: Vasodilatation – arterio-venous Retardation/Prevention of ventricular hypertrophy - myocardial cell apoptosis, fibrosis and intercellular matrix changes and remodeling Raises kinin level – stimulate NO and PG synthesis - cardio protective Starts with low dose and gradual increase Used in all grades of CHF unless contraindicated (Class I to Class IV) – including asymptomatic cases
- 34. Vasodilators Used IVto treat acute CHF cases Preload reduction: Nitrates – pooling of blood to Capacitance vessels – reduce ventricular end-diastolic pressure Glyceryl trinitrate (GTN) – controlled IV – rapid relief of ALVF Limitations: Marked lowering of preload with diuretics and Nitrate tolerance Afterload reduction: Hydralazine – dilate resistance vessels – reduce aortic impedance Limitations: Tachycardia and fluid retention – long use Pre-and after load reduction: ACEIs/ARBs – medium efficacy and Nitroprusside – high efficacy IV Used with loop diuretics + IV inotropics to tide over crisis in severely decompensated patients Long term benefit: hydralazine + IDN/ACE-ARBs • Hydralazine: Maked renal dilatation – preferred in renal insufficiency where ACE inhibitors are contraindicated
- 35. Βeta-adrenergic blockers Selective β1-receptor blockers – metoprolol and bisoprolol and non-selective (+selective alpha 1) carvedilol – in mild to moderate cases Decreases cardiac contractility and ejection fraction – immediate action - initially Adaptation occurs after months of therapy – EF improves Long term benefit – reduce mortality – worsening of cardiac failure – slow upward titrating dosing usually Mechanism: antagonism of sympathetic over activity – ventricular wall stretching, remodeling, apoptosis etc. prevented … also decreases RAS
- 36. Aldosterone antagonists -Spironolactone Rise in plasma aldosterone – worsens CHF By Na+ and water retention: Expansion of ECF – increased preload Fibrotic changes in myocardium - remodeling Hypokalaemia and hypomagnesia – arrhythmia Enhancement of sympathetic over activity Aldosterone antagonists help Uses: Add-on therapy to ACE inhibitors + other drugs in mild to moderate cases Retards disease progression and prevents sudden cardiac death along with ACEIs and beta- blockers Low dose – to prevent hyperkalaemia (ACEIs) – 12.5 to 25mg /day Restoration of furosemide refractoriness Contraindicated in renal insufficiency (hyperlkalaemia) – K+ monitoring ADR: Gynaecomastia
- 37. Inotropic drugs andPDE Inhibitors Dobutamine (2-8mcg/kg/min) – selective beta1 – agonist – used in acute Heart failure of MI and cardiac surgery Dopamine: (2-10mcg/kg/min): Cardiogenic shock due to MI D1 receptor – renal and mesenteric vasodilatation – increased GFR Limitation: Raises systemic vascular resistance (little higher dose) – limited utility if no shock
- 38. Phosphodiesterase (PDE III)Inhibitors Bipyridine derivative – different from digitalis and catecholamines Inamrinone, Milrinone – positive inotropy and vasodilataion PDE III is specific for degradation of intracellular cAMP and cGMP Increases the cAMP and transmembrane influx of Ca++ Most important action – positive inotropy and vasodilatation (INODILATOR) IV administration – action starts quickly and lasts for 2-5 Hours Indicated only in short-term IV therapy in severe and refractory cases and as an add-on drug Oral maintenance therapy – NOT USED ADR: Thrombocytopenia, nausea, diarrhoea, abdominal pain, liver damage and arrhythmia etc.
- 39. Remember Pharmacotherapy ofHeart failure Role of Diuretics/ACEIs/Beta blockers/Spironolactone in Heart failure Short Note – Phosphodiesterase (PDE) Inhibitors
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