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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 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 !
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
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 ??
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
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
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 !
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
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
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