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A PowerPoint presentation on Cardiac Glycosides suitable for reading by Undergraduate medical Students.

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Presentation Transcript

Cardiac Glycosides : 

Cardiac Glycosides Department of Pharmacology, NEIGRIHMS Shillong, India

Introduction: 

Introduction Drugs having the 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 !

Sources of Cardiac Glycosides : 

Sources of Cardiac Glycosides Cardenolides (Cardanolides): Digitalis purpurea – Digitoxin, Gitoxin and Gitalin Digitalis lanata - Digitoxin, Gitoxin and Digoxin Strophanthus gratus – Ouabin Thevetia nerifolia – Thevetin Convallaria majalis – Convallotoxin Bufadienolides: Bufo vulgris - Bufotoxin

Images of Cardiac Glycosides: 

Images of Cardiac Glycosides Digitalis purpurea Digitalis lanata Strophanthus gratus

Images of Cardiac Glycosides: 

Images of Cardiac Glycosides Urginea maritima Thevetia nerifolia Convallaria majalis

Chemistry: 

Chemistry All Cardiac glycosides aglycone ( genin ) part (active pharmacologically) sugar (glucose or digitoxose ) attached at Carbon 3 of nucleus Aglycone – Steroid ring ( cyclopentanoperhydrophenanthrene ring) and lactone ring attached at 17 th position

Cardiac glycosides - Pharmacokinetics: 

Cardiac glycosides - Pharmacokinetics Absorption and Distribution: Cardiac glycosides vary in their absorption, distribution, metabolism and excretion characteristics Presence of food in stomach delays absorption of Digoxin and Digitoxin Digitoxin is the most lipid soluble Vd of Cardiac glycosides are very high (heart, skeletal muscle, kidney) All are concentrated in heart, skeletal muscles, liver and kidney Metabolism: Digitoxin is partly metabolized in liver and excreted in bile Cardioactive metabolite ( digoxin ) and other metabolites are 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 So, renal impairment and elderly – long half life All CGs are cumulative – steady state is attain after 4 half lives

Cardiac glycosides - Pharmacokinetics: 

Cardiac glycosides - Pharmacokinetics * Ouabain is administered parenterally and is excreted unchanged in urine

Pharmacological Actions on Heart: 

Pharmacological Actions on Heart Acts on Failing Heart What is a failing Heart ??? Inability of the heart to pump sufficient blood to meet the metabolic demands of the body Reduced efficiency of the heart as a pump

Contd. ---: 

Contd. --- Starling`s law Laplace`s law WS = VR X IVP

Pharmacological actions on Heart: 

Pharmacological actions on Heart Direct Effect on Myocardial contractility, and electrophysiological properties and also has vagomimetic effect Force of contraction: Dose dependent increase in force of contraction in failing heart – positive ionotropic effect Systole is shortened and prolonged diastole Contracts more forcefully when subjected to increased resistance Increase in cardiac output – complete emptying of failed and dilated heart Tone: Decrease end diastolic size of failing ventricle Reduction in oxygen consumption

Contd. ---: 

Contd. --- Rate and Conduction: Rate Decreased Bradycardia : decreased vagal tone, stimulation of vagal centre Slowing of impulse generation (SAN) Delay of conductivity of AVN Direct depressant action on SA and AV nodes ( extravagal ) Increase in vagal tone: Is due to improvement in circulation Also due to direct stimulation in vagal center, sensitization of baroreceptors and sensitization of SA node to Ach Blocked by atropine – early but not later

Contd. ----: 

Contd. ----

Contd…. : 

Contd …. Normal Digitalis Heart failure Stroke volume Arterial impedance

Electrophysiological actions – contd.: 

Electrophysiological actions – contd. Mainly via 2 actions – autonomic and direct action Direct action: Excitability enhanced - RMP progressively decreased, shifted towards isoelectric Due to reduction in gap between RMP and threshold potential But decreased at toxic doses 0 phase depolarization rate is reduced Phase 4 slope is increased: latent pacemaking activity ( extrasystoles ) Oscillation at phase 4 – afterdepolarization APD is reduced and amplitude of AP is reduced

Electrophysiological actions – contd.: 

Electrophysiological actions – contd. ERP: Atrium: decreased by vagal action – inhomogenicity AVN and BH: Increased Ventricles: abbreviated Excitability: Enhanced Conductivity: Slowed in AVN and BoH fibres ECG: Increased PR interval Decreased amplitude or inversion of T wave Decreased QT (shortening of systole) Depression of ST

Digitalis – Electrophysiological actions: 

Digitalis – Electrophysiological actions

Aftederpolarization: 

Aftederpolarization

Afterpolarization actions - ouabin: 

Afterpolarization actions - ouabin

Digitalis – Electrophysiological actions: 

Digitalis – Electrophysiological actions Autonomic actions: Involves both Parasympathetic and sympathetic systems At therapeutic doses – cardio selective parasympathomimetic action Sensitization of baroreceptors, central vagal stimulation and falicitation of muscarinic transmission at cardiac muscle cells More prominent action in atria and AV nodal function than purkinje fibers However sympathetic action is increased in toxic doses

Digitalis – Electrophysiological actions: 

Digitalis – Electrophysiological actions Autonomic actions: Involves both Parasympathetic and sympathetic systems At therapeutic doses – cardio selective parasympathomimetic action Sensitization of baroreceptors, central vagal stimulation and falicitation of muscarinic transmission at cardiac muscle cells More prominent action in atria and AV nodal function than purkinje fibers However sympathetic action is increased in toxic doses

Digitalis – Electrophysiological actions: 

Digitalis – Electrophysiological actions

Digitalis action – Blood vessels: 

Digitalis action – Blood vessels Mild vasoconstrictor in Normal individuals In CHF – compensated by improvement of increased in cardiac output – decrease in Peripheral resistance occurs No prominent action in Systolic and diastolic BP – no contraindication in hypertensive (rise in systolic and decreased in diastolic in CHF) No significant action on coronary vesels – not contraindicated in patient with coronary artery disease

Digitalis action – other tissues: 

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

Digitalis – mechanism of action: 

Digitalis – mechanism of action Inhibition of Na/K ATPase blunting of Ca 2+ extrusion ­ Ca 2+ ­ sarcomere shortening

Digitalis MOA – contd.: 

Digitalis MOA – contd.

Uses of Digitalis - Congestive Heart Failure : 

Uses of Digitalis - Congestive Heart Failure Systolic dysfunction: dilated ventricles and unable to develope 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 Digitalis therapy improves the conditions in CHF, but neither arrest progression nor reverse pathological change

Contd. ---: 

Contd. --- Stroke Volume Preload Normal Digitalis CHF

Digoxin Digitalization: 

Digoxin Digitalization Digoxin has 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 Slow digitalization: Administer digoxin 0.25 mg (or even 0.125mg) daily in the evening – full response in 5-7 days If no improvement administer 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

Digitalization – contd.: 

Digitalization – contd. Rapid digitalization (oral): Administer 0.5 to 1 mg stat 0.25 mg every 6 Hrly Monitor for toxicity Patient is digitalized within 24 Hrs 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

Digitalis – Adverse effects: 

Digitalis – Adverse effects Cardiac and Extracardiac : Extracardiac : GIT: nausea, vomiting and anorexia etc. CNS: CTZ stimulation, headache, blurring of vision (flashing light, altered color vision), mental confusion etc. Serum Electrolyte K + : Digitalis competes for K binding at Na/K ATPase Hypokalemia : increase toxicity Hyperkalemia : decrease toxicity Mg 2+ : Hypomagnesemia : increases toxicity Ca 2+ : Hypercalcemia : increases toxicity

Digitalis – Adverse effects: 

Digitalis – Adverse effects Cardiac: PSVT: Propranolol IV or oral AV block: Atropine - 0.6 to 1.2 mg IM Ventricular arrhythmia: Excessive ventricular automaticity: Lidocaine IV (or Phenyton ) Tachyarrythmias : Heart rate abnormally increased due to prolong diuretic and digitalis therapy – Potassium chloride 20m.mol IV/hr Toxicity due to large ingestion – no KCl

Digitalis – Common Drug interactions: 

Digitalis – Common Drug 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

Digitalis - contraindications: 

Digitalis - contraindications Hypokalemia: Toxicity WPW syndrome: VF may occur Elderly, renal or severe hepatic disease: more sensitive to digitalis Diastolic dysfunction of heart Partial AV block: Complete block

Digitalis – therapeutic Uses: 

Digitalis – therapeutic Uses Congestive Heart Failure & Cardiac Arrhythmias

Video: 

Video

Enlarged Heart - Images: 

Enlarged Heart - Images

Cardiac dysrhythmia (arrhythmia): 

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 Digitalis is mainly indicated in Atrial fibrillation Atrial flutter PSVT

Digoxin - Cardiac Arrhythmias: 

Digoxin - Cardiac Arrhythmias Atrial fibrillation: is the most common type of arrhythmias although not life threatening Often irregular and rapid atrial contractions originating in atrial muscles Atrial Fibrillation: 350-550/min, electrophysiological inhomogenicity of atrial muscles (bag of worms) Ultimately interferes with ventricular contractions (heart beat) If treated, it is not life threatening Generally occurs above 50 years of age Digitalis: reduces ventricular rate by reducing the number of impulses passing down by AVN: Increases ERP of AVN by Vagomimetic and antiadrenergic action Increases rate of Atrial fibrillation, Decreases atrial ERP and reduces ventricular rate. Better ventricular filling

Digoxin - Cardiac Arrhythmias: 

Digoxin - Cardiac Arrhythmias Atrial flutter: Regular and synchronous contractions Atrial rate is less than AF (200-350) 2: 1 rate of conduction Variable degree of AV block naturally established Digoxin enhances AV block and reduces ventricular rate Converts atrial flutter to fibrillation – reduction in atrial ERP PSVT: common arrhythmia Heart rate is 150-200/min A-V conduction is 1:1 due to reentry in SA or AV node IV injection of Digoxin prevents this by increasing vagal tone

Pharmacotherapy of CHF – Goal : 

Pharmacotherapy of CHF – Goal Improvement of cardiac function Ionotropic drugs: digoxine , dopamine, dobutamine and amrinone Diuretics: frusemide and thiazide Vasodilators: ACE inhibitors/AT1 antagonists, hydralazine or Nitroprusside Beta blockers: Metoprolol , carvedilol Arrest or reversal of Progression ACE inhibitors or AT1 antagonists - Beta-blockers Aldosterone antagonists - spironolactone

Heart failure - Classification: 

Heart failure - Classification Class I (Mild): No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath). Class II (Mild): Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnoea . Class III (Moderate): Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnoea . Class IV (Severe): Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased.

Pharmacotherapy of CHF – Diuretics: Furosemide: 

Pharmacotherapy of CHF – Diuretics: Furosemide Actions: Decrease in preload and improvement of ventricular function Removal of peripheral oedema and pulmonary congestion Increase in venous capacitance – symptomatic relief Resistance on chronic use – combined with Thiazides / spironolactone No action on disease progression RAS stimulation – remodelling and apoptosis Not preferred in mild cases Mild cases – ACEI/ARBs and beta blockers Reserved for advance ceases

CHF –Vasodilators : 

CHF –Vasodilators Nitrates: GTN and IDN reduce preload by pooling of blood in capacitance vessels – reduction in end diastolic volume Reduction in CO may be dangerous – nitrate tolerance Arteriolar dilators: Hydralazine , Minoxidil , CCBs and Pot channel openers ( Diazoxide , minoxidil , pinacidil ) etc. decrease in peripheral resistance and facilitates more blood pumping by weak heart Useful in forward failure ADR: Marked tachycardia and retention of fluid

Vasodilators - Pre and afterload reduction: 

Vasodilators - Pre and afterload reduction ACEIs/ARBs effective orally (low efficacy) and Nitroprusside IV dilator (high efficacy) Acts by reducing both preload and afterload In severe decompensated patients: IV nitroprusside (titrated) + loop diuretic + IV ionotropic drugs – to tide over crisis For maintenance, Hydralazine + ACEIs/ASRBs are used Acute Heart failure: GTN or Hydralazine or nitroprusside Long term survival: Hydralazine + IDN or ACEI/ARBs ACEIs and ARBs are recommended for all grades of failure Hydralazine : Renal insufficiency cases: as renal vasodilator

ACE inhibitors/ARBs – current status: 

ACE inhibitors/ARBs – current status Afterload reduction Preload reduction Reduction of facilitation of sympathetic nervous system Reduction of cardiac hypertrophy Drugs of choice in heart failure (with diuretics) Used in all class of CHF

CHF – Beta blockers, how?: 

CHF – Beta blockers, how? Beta Blockers: metoprolol & bisoprolol Initially reduce cardiac contraction and stroke volume and ejection fraction - but slowly Ef increases over weeks Prevention of ventricular wall stretching – prevent remodeling Prevention of Renin-angiotensin system Overall: Mortality due to worsening of cardiac failure is reduced Antagonism of ventricular wall stretching (rise in Ef ) Countering apoptosis and remodeling due to excess sympathetic activity Prevention of arrhythmias

Beta blockers – which cases?: 

Beta blockers – which cases? Used in mild and moderate cases of heart failure with dilated cardiomyopathy and systolic dysfunction (class II and Class III failures) Also in Class IV cases under constant monitoring No use in severe decompensate heart, other drugs should be continued – stop in acute episodes of HF attack Dose: start as low dose, carvedilol – 3.125 mg/day, metoprolol – 200 mg/day and titrated upoward to target level

CHF –Aldosterone antagonist (Spironolactone): 

CHF – Aldosterone antagonist (Spironolactone) Rise in plasma aldosterone level in CHF leads to Increase in preload due to ECF rise Risk of arrhythmia due to hypokalaemia – sudden death Pathological remodeling of myocardium Enhancement of sympathomimetic activity Spironolactone antagonizes all the above effects – mobilization of edema fluid, prevents hypokalaemia ACEIs lowers aldosterone level but not sufficiently So, used as add on therapy to ACEI/ARBs in moderate to severe CHF Retards the progression, reduce episodes of decompensation However only low Dose is used to avoid hyperkalaemia: low dose of 12.5 to 25 per day Prevents hypokalaemia induced by diuretics Serum K+ monitoring required – risk of hyperkalaemia

CHF – Phosphodiesterase III inhibitors: 

CHF – Phosphodiesterase III inhibitors Amrinone : (amicor/inocor/iarditone) Selective PDE III inhibitor MOA: Prevents intracellular breakdown of cAMP by PDE III – increases cAMP conc. And Ca++ influx Clinically, positive ionotropy and vasodilatation Dose: IV Bolus 0.5 mg/kg followed by 5-10 mcg/kg/min Adverse Effects: Thrombocytopenia, hepatotoxicity, arrhythmia, nausea, & vomiting Uses: Only for short term therapy of CHF and not used for maintenance although effective orally

CHF – Sympathomimetics (inotropic): 

CHF – Sympathomimetics (inotropic) Dobutamine:(2-8 mcg/kg/min) Beta-1 agonist and acts via cAMP and increase in Ca++ conc. Relatively do not increase heart rate Further Beta-2 effects – muscle vasodilatation Less change in heart rate and BP Cardiac workload decreases – low oxygen demand Uses: acute heart failure with MI, cardiac surgery and advanced decompensate CHF Adverse effects: Tachycardia (reflex action due to beta-2 action), tolerance (down regulation of beta receptors after 72 Hrs)

CHF - Dopamine: 

CHF - Dopamine 3 – 10 mcg/kg/min IV Acts on pre-junctional D2 and post-junctional D1 receptors Actions: Splanchnic and Renal vasodilatation (D1) and suppression of NA release (D2 effect) – increase renal perfusion and increase g.f.r Uses: Patient in shock, adjunct to frusemide in refractory cases (short term only) Adverse effects : tachycardia, arrhythmias and peripheral vasoconstriction

Remember: 

Remember Sources and names of Cardiac Glycosides Digoxin – Pharmacological actions in failing heart, process of digitalization Digoxin – Drug interactions Role of Diuretics, Beta-blockers, ACE inhibitors, Vasodilators, Aldosterone antagonists in Heart failure Role of Phosphodiesterase -III inhibitors in Heart failure Pharmacotherapy of Heart failure

Thank You: 

Thank You Big Hearted ?