introduction to CHF, classification of cardiac glycoside, MOA, pharmacological and toxic effect of cardiac glycoside

1. PRESENTED BY
MISS. ASHVINI GOVANDE
ASSISTANT PROFESSOR
KANDHAR COLLEGE OF PHARMACY,
KANDHAR
Cardiotonics

2. Content
 Introduction to CHF
 Classification of cardiac glycoside
 MOA of cardiac glycoside
 Pharmacological action of cardiac glycoside
 Toxic effect of cardiac glycoside

3. Introduction to CHF
 Heart failure or congestive heart failure are the inability of the
heart to pump sufficient blood to meet the need of body.
 Cardiotonics are the drugs which tends to increases the efficiency
of contraction of heart muscles.
 Digitalis is most commonly used drug as a cardiac glycoside. It is
obtained from the dried leaves of biennial herb Digitalis purpura.

4. Classification of cardiac glycoside
 The classification is based on source of cardiac glycoside:
 Digitalis lanta: Digoxin, Gitoxin, Gitalin
 Digitalis purpura: Digitoxin, Gitoxin, Digoxin
 Strophanthus gratus: Strophanthin K
 Strophanthus kombe: Strophanthin G, Ouabian
 Urginea: Proscillaridin
 Thevetia neriifolia(nut): Thevetin
 Covallaria majalis: Convallotoxin
 Bufo vulgaris: Bufotoxin

5. MOA of cardiac glycoside
 It inhibit membrane bound Na+/K+ ATPase pump responsible for
Na+, K+ exchange.
 The process of membrane depolarization/ repolarization is
controlled by the movement of 3 cations Na+, Ca++, K+ in and
out of the cell.
 At resting stage conc. of Na+ is high outside.
 Change in action potential causes Na+ fluxes in leading to
immediate elevation of Na+, which induce depolarization.
 Elevated intracellular Na+ triggers the influx of free of Ca++ that
enters slowly.
 The higher conc. of Ca++ results in efflux of K+.

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 The reestablishment of the action potential occurs later by the
reverse of the Na+ K+ exchange.
 The Na+/K+ exchange requires energy which is provided by an
enzyme Na+/K+ ATPase.
 Cardiac glycoside are praposed to inhibit this enzyme with a net
result of reduced sodium exchange with potassium that leaves
increased intracellular Na+. This results in increased intracellular
Ca++.
 In the heart, increased intracellular calcium causes series of
intracellular biochemical event i.e calcium are bind to troponin-C,
which increases contractility.

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8. Pharmacological action of cardiac glycoside
 Action on CVS-
 Increases the strength and speed of myocardial contraction due to
which cardiac output is increased.
 In normal individual small doses of digitalis do not produce any
significant change in CO but arterial pressure and stroke volume
may be increased.
 In CHF, the heart rate is increased. Digitalis increases oxygen
consumption of heart to normal.
 The digitalized heart can do more work with less energy.

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1) Energy production:
 Digitalis do not increase energy production by the cardiac
muscles.
 The digitalised heart can do same work with less energy
2) Blood pressure:
 The effect of digitalis depends on the initial state of blood
circulation.
 If BP is low, it is raised to the normal.
 The normal BP is not raised so hypertension effect is not shown
due to digitalis.
 In ventricular stroke, systolic BP may rise whereas diastolic BP
falls.

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3) Cardiac size:
 In normal heart, digitalis decreases, the size of the heart due to
which cardiac output decreases.
 In heart failure it returns the size of heart to normal.
4) Venous pressure:
 Digitalis causes decrease in venous pressure which has been
raised in case of CHF.
5) Diuresis:
 The major effect of digitalis, is diuresis due to decrease in venous
pressure which passes fluid into blood circulation causes diuresis.
It also inhibit reabsorption of sodium.

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6)Coronary circulation: Digitalis causes no direct effect on
coronary blood flow, but the improved CO can improve coronary
flow.
7) Effect on blood clotting: Do not affect on clotting time of blood
at therapeutic dose.
8) Vagal and extravagal effect: Digitalis in small doses causes
cardiac slowing due to vagal stimulation in large doses.
9) Effect on conduction system: Digitalis depresses conduction
system that’s why conduction rate is slowed. This effect is
produced as an increases in PR interval in ECG.
10) Effect on vomiting center: digitalis is administered orally,
intramuscular, intravenous, in many individual it produces nausea
and vomiting as vomiting center in the brain is stimulated by
digitalis.

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11) Ionic effect:
a) Sodium: The sodium ion are retained in body in heart failure. The
sodium ion are metabolized and eliminated by digitalization.
Digitalis inhibit sodium ion reabsorption in renal tubule and are
excreted in the urine.
b) Calcium: Calcium ions increases force of contraction of heart.
Digitalis increases force of contraction by increasing amount of
calcium in the cardiac tissue.
 The toxicity of digitalis is to increase in more calcium ion leads to
cardiac arrest in systole.
 So calcium preparation can not be administered in patient which
having digitalis treatment.
C) Potassium: it increases potassium uptake at therapeutic doses. Toxic
doses leads to potassium depletion from heart.
 Loss of pot. Ion by diuresis can induce digitalis toxicity

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12) Extracardiac action:
a) Action on kidney: Digitalis act on kidney by decreasing
venous pressure which shifts fluid into blood circulation and
improve renal circulation resulting in increased excretion of
sodium ion and water.
13) Action on gastro intestinal tract: Digitalis in toxic doses may
produce diarrhea, nausea and vomiting which may be due to
stimulation of chemo receptor triggers CTZ center. It is
absorbed from small intestine, eliminated through kidneys, so
produces cumulative toxicity if repeatedly administered for
prolong period.

14. Toxic effect of cardiac glycosides
1) Cardiac toxicity: Digitalis produces cardiac arrhythmias due to the
disturbance in impulse formation or in impulse conduction or both.
 Cardiac arrhythmias like atrial tachycardia, ventricular tachycardia,
ventricular flutter, ventricular fibrillation occur.
2) Hypokalemia: There is loss of K+ ion which increases digitalis
toxicity. In CHF patient, there is edema formation due to increases
Na+ ion retention.
3) ECG changes: The cardiac glycoside causes the shortening of Q-T
intervals, inversion of T waves and lengthening of P.R intervals.
4) Toxic effects on eyes: Digitalis produces visual disturbances like
blurred vision and color defects, color vision, appearance of dancing
and flickening dots.

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5) Neurological toxicity: Digitalis and cardiac glycoside produces
drowsiness, headache, fatigue and vertigo. Some patients feels
tingaling and numbness lips, tips of nose, ears and face. There
occurs confusion and psychotic behavior in patients on cardiac
glycoside therapy.
6) Blood coagulation effect: it produces thrombo embolic
complications as it increases coagubility of blood.
7) Gastrointestinal tract activity: Digitalis produces vomiting,
nausea and diarrhea (rare). GIT toxicity occurs prior to cardiac
toxicity due to which anorexia and vomiting are common
symptoms of toxicity.
8) Other toxic effect: Skin rash, eosinophilia. Digitalis crosses
placental barrier and may lead to premature delivery.
 Use of digitalis: Congestive heart failure

16. Digoxin
 Physical properies:
 Nature- Crystalline powder
 Color- white/ colorless
 Solubility: slightly soluble in water
 Mol.formula: C41H64O14
 It is obtain from leaves of plant digitalis lanata.
 MOA: Digoxin inhibits the sodium potassium ATPase and makes more
calcium available for contractile proteins, which increases cardiac
output, by increasing force of contraction.
 Indications: CHF, cardiogenic shock, arterial flutter, arterial
tachycardia, arterial fibrillation.
 Contraindication: Hypersensitivity, ventricular tachycardia, renal
diseases, AV blocks, pregnancy, lactation, hypokalemia, respiratory
distress.

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 Dosage:
 Adult: Initially 0.25 to 1.5 mg daily orally.
 Maintenance dose: 0.25 to 0.5mg daily.
 Child: Initially 10-20mg/kg body weight 6 hourly.
 Maintenance dose: 10-20mg/kg body weight in single or divided
dose.
 Side effects: Blurred vision, diplopia, color vision defect, green
yellow halos, headache, drowsiness, confusion, fatigue, depression,
disorientation, vomiting, nausea, anorexia, hypotension, diarrhea,
abdominal pain.
 Pharmacokinetic: Oral onset action 30 min to 2hrs, peak plasma
conc. 6hrs, duration of action 3-4days. Plasma half life 35-36hrs,
excreated in urine, crosses placental barrier.

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 Drug interation: Increased bradycardia with beta adrenergic blockers,
antidysrythmics.
 Brand name- Digoxin: Tablet, Injection, Cardioxin, Sangoxine, Lanoxine,
Dixin, Digox 0.25mg tablet, injection 0.25mg/ml.
 Precautions for patient:
 Patient should not to discontinue drug suddenly.
 Patient should not take any other medicine, with treatment.
 Patient should take salt restricted.
 Patient to inform difficulty in breathing, edema, weight gain, loss of appetite,
headache, yellow vision, skin rash to treating doctor.
 To store drug in cool place, airtight container, protect from heat and light,
away from children.
 Treatment overdose: Discontinue digoxin, give potassium administer antidote
of digoxin ‘digoxin immune FAB’.

19. Digitoxin
 It is digitalis preparation.
 It is white powder insoluble in water
 Mol. Formula: C14H64O13
 Used as cardiac glycoside
 It is obtain from leaves of digitalis purpura, digitalis lanata.
 MOA: Same as that of Digoxin.
 Indication: CHF, arterial flutter, arterial tachycardia, arterial fibrillation.
 Dosage:
 Adult and child age 12 years and above: Orally 1.2-1.6mg/day in divided
doses.
 Maintenance dose: 0.05-0.3mg/daily.
 Child 1-2 yrs age-0.04mg/kg body weight daily
 Above age 2 year- 0.03mg/kg

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 Contraindication: Hypersensitivity, hypokalemia, prgnanacy,
lactation, hepatic disease, AV blocks, ventricular tachycardia, elderly.
 Side effects: Blurred vision, diplopia, green yellow halos, headche, loss
of appetite, confusion, fatigue, depression, disorietation, vomiting,
nausea, anorexia, hypotension, bradycardia, muscular weakness.
 Pharmacokinetics: Oral onset of action 1hr, peak plasma conc. 4-
12hrs, serum half life 4-9days, absorbed in stomach, duodenum and in
jejunum, metabolized in liver, excreated in urine.
 Drug interaction: Decreases the level of digitoxin with thyroid drugs.
toxicity occurs with diuretics, quinidine and thioamines.
 Treatment overdose: Discontinue drug, to administer digoxine
immune FAB, potassium, monitor ECG.

21. Digoxin immune FAB
 It is used as antidote in digoxin, digitoxin over dose toxicity.
 MOA: Digoxine immune FAB do not allow digoxin, digitoxin to
bind to the sites of action and reverse their toxicity.
 Indication: Digoxin or digitoxin toxicity
 Dosage:
 Dose ingested (mg) serum digoxin conc. 5.6 wt of the patient in
kg divided by 1000.
 Contraindications: Hypersensitivity, mild digoxine toxicity,
children, pregnancy, lactation.
 Side effects: Facial swelling, redness, rapid respiration rate, low
cardiac output, arterial fibrillation.

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 Pharmacokinetics:
 Excreted in urine
1) To administer after diluting 40mg in 4ml water for injection
may further dilute with normal saline. Use a clear solution.
2) To advice patient to report, chills, fever, itching, dyspnea,
urticaria, skin rash to treating doctor.
3) To evaluate therapeutic response, correction of digitoxin
toxicity, investigate digoxine level 0.5-2mg/ml, digitoxin level
9-25mg/ml.

23. Strophanthus
 The important glycoside of strophanthus is g strophanthin called
as quabain.
 Obtain from plant Strophanthus gratus.
 It is administered through IV route because it is poorly absorbed
from GIT tract.
 The action of quabain is similar to digitalis the action is quick but
of a short duration, can be used in emergency.
 MOA: Same as that of digitalis.
 Indication: Arterial fibrillation and flutter, heart failure.

24. Squill
 It contain cardiac glycoside.
 Drimia indica plant contains cardioglycoside.
 The action of squill is quick than digitalis and can be given to
patient who can not tolerate digitalis.
 It produces gastric irritation so it is rarely used at present.

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