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

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 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. 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 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. 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. Contd. ---

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. Contd.----
Normal
Digitalis
Heart failure
Strokevolume
Arterial impedance

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 Medical pharmacology 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 – 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. 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. 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 – 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. Digitalis – therapeutic Uses
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 (filling pressure)
Normal
Digitalis
CHF

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. 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
Essentials of Medical pharmacology by KD Tripathi – 7th Edition, JAYPEE, 2013

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. Vicious cycle in CHF
Essentials of Medical pharmacology by KD Tripathi – 7th Edition, JAYPEE, 2013

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. 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 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. 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. 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. 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 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. 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 of Heart failure
 Role of Diuretics/ACEIs/Beta
blockers/Spironolactone in Heart failure
 Short Note – Phosphodiesterase (PDE) Inhibitors

40. Thank You