Cardiac Glycosides - drdhriti

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A Power point presentation on "Cardiac glycosides" suitable for UG MBBS level students

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  • Ether like combination of a sugar and an organic structure. Acid hydrolysis - sugar and non-sugar compounds
  • Preload – initial stretching of the cardiac myocytes prior to contraction - sarcomere length. Frank Starling law – increased preload increase stroke volume
    WT = VR X IVP
  • Cardiac Glycosides - drdhriti

    1. 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. 2. 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 !
    3. 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. 4. Chemistry  What is a 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. 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
    6. 6. Contd. ---
    7. 7. Pharmacological actions of Digitalis - 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 ??
    8. 8. Contd.---- Normal Digitalis Heart failure Strokevolume Arterial impedance
    9. 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. 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. 11. Afterderpolarization Essentials of Medical pharmacology by KD Tripathi – 7th Edition, JAYPEE, 2013
    12. 12. Afterpolarization actions - ouabin Basic &Clinical Pharmacology, Bertram G. Katzung (9th Edition)
    13. 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. 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. 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. 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. 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. 18. Digitalis – Adverse effects • 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. 19. Digitalis – Adverse effects 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. 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. 21. 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  Metoclopramide, sucralfate and antacids – reduced absorption
    22. 22. Digitalis – therapeutic Uses 1. Congestive Heart Failure & 2. Cardiac Arrhythmias
    23. 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. 24. Contd. --- StrokeVolume Preload (filling pressure) Normal Digitalis CHF
    25. 25. 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  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. 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. 27. Pharmacotherapy of CHF Essentials of Medical pharmacology by KD Tripathi – 7th Edition, JAYPEE, 2013
    28. 28. 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 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. 29. Vicious cycle in CHF Essentials of Medical pharmacology by KD Tripathi – 7th Edition, JAYPEE, 2013
    30. 30. Goals and Drugs of 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. 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. 32. Diuretics  Almost all cases 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. 33. RAS Inhibitors  ACE Inhibitors 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. 34. Vasodilators  Used IV to 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. 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. 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. 37. Inotropic drugs and PDE 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. 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. 39. Remember  Pharmacotherapy of Heart failure  Role of Diuretics/ACEIs/Beta blockers/Spironolactone in Heart failure  Short Note – Phosphodiesterase (PDE) Inhibitors
    40. 40. Thank You

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