Drugs Used in Cardiac Failure (CCF)

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Pharmacology (Personal Note) - by Dr. Mohammad Shariful Alam (Shohan)



Mohammad Shariful Alam (Shohan)


CCF: It is a condition of the heart when heart fails to provide sufficient cardiac output so that there will be inadequate blood supply & O2 supply throughout the body. In CCF cardiac muscle fails to contract sufficiently and about 95% cases are of right heart failure. Causes of CCF: i. Chronic hypertension ii. Vulvular heart disease iii. Myocardial infarction iv. Severe anaemia. Path physiology of CCF: i. Decrease pumping action of heart ii. Increase cardiac after load iii. Increase cardiac preload.
[Preload: The end diastolic stretch of a heart muscle fiber. In the intact ventricle, this is approx. equal to the end-diastolic volume or pressure. Afterload: The forces that impede the flow of blood out of the heart. The heart contracts against a resistance primarily composed of the pressure in the peripheral vasculature, the compliance of aorta, and the mass and viscosity of blood. / Preload is directly related to venous return / Afterload is directly related to peripheral vascular resistance]

Heart failure ↓ Decrease cardiac output ↓ Decrease blood pressure ↓ Decrease glomerular filtration rate ↓ Decrease renal blood flow ↓ Renal hypoxia ↓ Increase renin secretion ↓ Increase synthesis of Angiotensin II ↓ Causes vasoconstriction (↑ PVR) ↓ Increase afterload

Mohammad Shariful Alam (Shohan)


Heart failure ↓ Decrease cardiac output ↓ Decrease blood pressure

Sympathetic loop

Endothelial loop ↓ Increase aldosterone secretion ↓ Increase salt (Na+) and water retention ↓ Increase blood volume ↓ Increase venous return ↓ Increase preload.

Feature (S/S) of CCF:  Tachycardia  Exercise intolerance  Shortness of breath → Dyspnoea  Oedema → may be pulmonary oedema  Cardiomegaly → due to ↑ preload it stretches myocardium & cause muscular hypertrophy. Drugs used in CCF: a. Drugs that decrease afterload: Vasodilator Hydralazine  Na-nitroprusside  Minoxidil  Diazoxide.



b. Drugs that decrease preload: Diuretic Frusemide ii. Nitrate Glycerol tri nitrate (GTN)  Isosorbide mono nitrate. c. Drugs that decrease both preload and afterload: ACE inhibitor Captopril  Enalapril  Lisinopril  Ramipril. 2


Mohammad Shariful Alam (Shohan)

i. ii.


d. Drugs that increase contractility (cardiotonics): Cardiac glycoside (cardenolides) Natural: Digoxin  Synthetic: Digitoxin. ß-adrenoceptor agonist Isoprenaline {ß1 agonist- Dobutamine  Dopamine Nonselective adrenergic drug- Dopamine}  Dobutamine  Xamoterol. Phosphodiesterase (PDE) inhibitor Amrinone  Milrinone  Bipyridine.
[Glycosides: Glycosides are compounds formed from a condensation between a monosaccharide or monosaccharide residue and the –OH group of a second compound that may or may not be another monosaccharide. Criteria: i. Plant origin ii. Non nitrogenous substance iii. Consists of sugar (glycone) and non sugar (aglycone) portion connected by gycosidic linkage. iv. Soluble in organic solvent and it depends on the sugar part. Example: Cardiac glycosides.]

Digital is
Structure: It bears a steroid nucleus with an unsaturated 5-membered lactone ring at 17th position and a series of sugars linked to the carbon 3 of the nucleus. Lactone ring is related with pharmacodynamic action of the digitalis. Sugar moiety is related to the pharmacokinetic property. Source: 1) Natural Animal source → comes from skin of toads.  Plant source → (white and purple foxglove family) a. From leaves of foxglove: i. Digitalis purpurea:  Digoxin (Prototype of cardiac glycosides)  Digitoxin ii. Digitalis lanata:  Digoxin  Lanatoside-C b. From seeds of foxglove:  Ouabain



Synthetic sourceDigitoxigenin Digoxigenin.

Mohammad Shariful Alam (Shohan)

Cardiac glycosides: Cardiac glycosides are active principle of leaves of plants of the Foxglove family (digitalis) which causes increased force of contraction and cardiac slowing (partial A-V block).
[Classification of cardiac glycosides plant source]

Function of different parts: i. Sugar radical (C3 position of the steroid nucleus): Responsible for potency and duration of action Helps in easy absorption and neutralization of digitalis Facilitates attachment of drug to heart muscle. ii. Non sugar part (it contains a steroid nucleus, a lactone ring, a OH group): Responsible for pharmacological action of the drug e.g., cardiac muscle contraction (ß lactone ring & steroid nucleus) Properties of three typical cardiac glycosides: Lipid solubility (oil/water coefficient) Oral availability (percentage absorbed) Half-life in body (hours) Plasma protein binding (percentage bound) Percentage metabolized Volume of distribution (L/kg) Onset of action Duration of action Excretion Ouabain Low 0 21 Nil Nil 18 Immediate Short Renal (80%) Digoxin Medium 75 40 Medium (20-40) Medium (<40) 6.3 15-30 min. 6 days Renal (80%) Digitoxin High >90 168 High (>90) High (>80) 0.6 Within 25-120 min. 3 weeks Undergoes enterohepatic recycling

Mechanism of action of digitalis: Digitalis binds with Na+-K+ ATP-ase pump. There will be some direct effect and some indirect effect. Direct effect: Blockade of Na+-K+ exchange through the Na+-K+ ATP-ase pump leading to increase intracellular Na+ concentration and decrease intracellular K+ concentration. Increase intracellular Na+ concentration will increase the Na+-Ca++ exchange activity through the Na+-Ca++ pump.


Mohammad Shariful Alam (Shohan)

Net effect is increase intracellular Ca++ concentration by three mechanismsi. ↑Na+-Ca++ exchange through Na+-Ca++ pump. ii. Release of Ca++ from the sarcoplasmic reticulum. iii. ↑intracellular calcium influx through voltage gated Ca++ channel. Increase intracellular Ca++ concentration leads to excitation –contraction coupling, causative ionotropic action, finally there is increased myocardial contractility, complete systolic emptying of ventricle. Net result of direct effect iso Decreased heart size o Relieve of oedema o Improved cardiac function o Reduces pulmonary congestion and decrease JVP. Indirect effect: Decrease intracellular K+ concentration leads to decrease heart rate due to increase vagal tone, depress SA node, and decrease AV conduction, prolongation of refractory period. Increase excitability leading to arrhythmia. Q. How oedema is relieved by digoxin/digitalis? Digitalis ↓ Blocks Na+-K+ ATPase pump ↓ ↑Intracellular Na+ (membrane depolarization) ↓ Release of Ca++ from sarcoplasmic reticulum (-) Na+-Ca++ exchanger Voltage sensitive Ca++ channel Entopic focus Bigeminy Trigeminy

↑ Intracellular Ca++ ↓ ↑ Cardiac contractility ↓ ↑ Cardiac output ↓ Withdrawal of sympathoadrenal activity ↓ ↓ Arterio-venous resistance (↓PVR) ↓ ↓ Afterload ↑ Renal perfusion ↓ ↑ GFR ↓ No aldosterone secretion ↓ Withdrawal of RAAS activity


↑ Diuresis ↓ Relief of oedema Indication: • • • • • • Adverse effect/digoxin toxicity: a) Cardiac toxicitiesb) Extra cardiac side effects: i. GIT : - Nausea, vomiting - Abdominal pain - Feeding intolerance Congestive cardiac failure (CCF) Left ventricular failure (LVF) Atrial fibrillation Atrial flutter Paroxysmal supraventricular tachycardia Left ventricular hypertrophy.

Mohammad Shariful Alam (Shohan)

Bradycardia (earliest adverse effect) Multiple ventricular ectopics Heart block Atrial tachycardia Ventricular fibrillation/tachycardia.


Eye : - Haziness - Disturbance of colour vision (yellow, green) - Blurring of vision


Neurological : - Fatigue, weakness, neuralgia - Paraesthesia, headache - Dizziness, confusion

c) Miscellaneous- Hypokalaemia - Gynaecomastia in male - Galactorrhoea in female i. ii. Management of toxicity: Discontinuing the drug K+ supplement to correct the hypokalaemia K+ syrup/KCl preparation K+ containing food e.g., green vegetables, coconut water, banana etc. K+ sparing diuretics e.g., spironolactone. iii. Management of arrhythmia –  To correct bradycardia : Atropine  To correct ventricular dysrrhythmia : Phenytoin


 To treat ventricular tachycardia: Lignocaine. iv. Digoxin antibody: Digoxin specific binding fragment inactivates digoxin in plasma. Contraindication: i) Renal impairment ii) Hypokalaemia iii) Hypothyroid patient iv) Heart block v) Recent myocardial infarction vi) Cardiac temponade vii) High output cardiac failure viii) Constrictive pericarditis ix) Idiopathic hypertrophic subaortic stenosis. M/A: Digitalis/Digoxin ↓ Binds with K+ binding site of Na+-K+ ATPase pump ↓ + + Blocks Na -K exchange through the Na+-K+ ATPase pump ↓ Increase Na+ & decrease K+ conc. inside the cell

Mohammad Shariful Alam (Shohan)

Direct effect ↓ ↑ intracellular Na+ concentration ↓ ↑ Na+-Ca++ exchange activity through the Na+-Ca++ pump ↓ ↑ intracellular Ca++ conc. byi. ↑ Na+-Ca++ exchange through
Na+-Ca++ pump ii. Release of Ca++ from sarcoplasmic reticulum iii. ↑ intracellular Ca++ influx through voltage gated Ca++ channel.

Indirect effect ↓ ↓ intracellular K+ concentration ↓ results a) Decrease heart rate due to - ↑ CO → causes withdrawal of sympathetic action → ↓ HR - Increase vagal tone
- Depress SA node & delay conduction velocity of A-V node. - Prolongation of refractory period of A-V node.

↓ Excitation-contraction coupling ↓ Positive ionotropic action ↓ ↑ myocardial contractility ↓ Complete systolic emptying of ventricle net result ↓ a. Decrees heart size

b) Decrease resting membrane potential (↓ RMP) ↓ Increase excitability ↓ Arrhythmia (Extra systole)


b. c. d. e.

Relieves oedema Improve cardiac function Reduces pulmonary congestion & Decrease JVP

Mohammad Shariful Alam (Shohan)

[Alkaloids: Alkaloids may be defined as the basic nitrogenous white (crystalline) compound of plant origin, soluble in alcohol and produce salt when it is combined with acid & is physiologically active both in plant and animal.] Digitialation: It means achievement and maintenance of physiological saturation of digitalis in the blood to obtain optimum therapeutic effect. Dose of digitialation: i. Digitalizing dose/initial loading dose:  Oral route : 0.75-1.25 mg  IV route: 0.5-1.0 mg ii. Maintenance dose:  Oral : 0.125-0.5 mg  IV : 0.25 mg Types of digitilation: i. Emergency digitilation ii. Rapid digitilation iii. Slow digitilation.


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