PHARMACOLOGYCAL APPROACHES OF HEART FAILURE

Dr. Jannatul FerdoushAssistant ProfessorDepartment Of Pharmacology

• Pathophysiology of Heart Failure & site of drug action Heart Failure

↓ ↓ Myocardial contractility ↓ ↓Renal perfusion ↓ Cardiac Output ↑ sympathetic outflow ↓ ↓ ↓ ↓ ↓ ↑Renin release ↑ Aldosterone ↑Residual volume Vasoconstriction ↓ ↓ Ang I Na- H2O retension ↓ ↓ ↓ ↓ ↑Length of the muscle fibre ↑ Afterload to follow Frank Starling Law Ang II ↑ Plasma volume ↓ ↓ ↓ ↑Residual Volume Vasoconstriction ↑PreLoad ↓ ↓ ↓ ↑↑Length of the muscle fibre ↑After load Oedema ↓ Cardiac Remodelling Occur Heart dilated ↓ ↑Peripheral venous Conjestion, Pulmonary odema (shortness of breath) ↓ Detoriation of Heart Failure

(- ) POSITIVE INOTROPES

(- ) VASODILATOR(- ) DIURETICS

(- ) ACEi

Treatment of Heart Failure

To Improve contractility: Positive inotropes

i) Cardiac Glycosides

ii) β1 agonists→ Dobutamine, Dopamine

iii) PDE inhibitors→ Amrinone, Milrinone

To reduce odema:

Diuretics – Thiazide & Frusemide

To reduce preload & after load:

ACE inhibitors

Cardiac glycoside

• These are the agents which have cardiotonic property or action. Cardiotonic drugs increase myocardial contractility without a corresponding increase in O2 consumption.

Source Glycosides

Digitalis purpurea (leaf) DigitoxinGitoxinGitalin

Digitalis Lanata DigitoxinDigoxinGitoxin

Strophanthus Gratus (seed) Strophanthin G (Ouabain)

Clinically used – Digoxin (most commonly used) Digitoxin Ouabain.

• Chemistry of cardiac glycosides –• All of the glycosides - of which digoxin is the

prototype – combine a steroid nucleus linked to an unsaturated 5 membered lactone ring at the 17 position and a series of sugars at carbon 3 of the nucleus. Because they lack an easily ionizable group, their solubility is not pH dependent.

• It has both lipophilic (steroid nucleus) and hydrophilic (lactone ring, hydroxyl group, sugar) groups. The balance of these two has an important effect on pharmacokinetics.

• Steroid nucleus with lactone ring is essential for myocardial action. A sugar molecule present which is important for pharmacokinetic property.

CVS effect of Cardiac Glycosides in Heart Failure

• (+ve) inotropic.

• (-ve) chronotropic→Binding to Na pumps in the plasma membrane of central & peripheral nervous system → (-) of symp. Nervous outflow → Stimulate Baroreceptor → ↑ Vagal tone of heart ( by acting on central vagal nucleus) →↓ Firing of SA node → ↓ A-V Conduction → ↓ Heart rate.

• ↓Automaticity & Conduction Velocity at the AV nodal tissue → Use in Heart failure with arrythmia. Chance of Heart block.

• ↑ Automaticity- at high dose-cause Arrythmia.

Electrical activity of Cardiac Glycosides

No direct effect on SA node

↑ Refractory period of the AV node

↓Condution Velocity at the AV nodal Tissue

Stimulate vagal Nerve

Pharmacokinetics of different preparation of cardiac Glycosides

Factor Digoxin Digitoxin OuabainLipid solubility Less than digoxin

OH group- 2More Lipid solubleOH group- 1

H2O soluble OH group- 5

Oral bioavailability 75% 80-90% Poor

Route Oral Oral Perenteral

Distribution Less More Poor

PPB Less More Negligible

Metabolism Partly in the liver Mainly LIver Not metabolized

Excretion Mainly by kidney By bile & stool Unchanged by kidney

Half life 36 hours 7 days 24 hours

Onset 15- 20 min 25- 120min Immediate

• Indication:

• Heart failure• Atrial arrythmia- Atrial flatter

Atrial fibrilation• Paroxysmal supraventricular tachycardia

• Contraindication:

– Ventricular Tachycardia- because digitalis increase autamaticity.

– Heart block.

Adverse effect1.Extracardiac On GIT→ Anorexia, nausea,vomiting Fatigue ,weakness, diarrhoea Neurological problems-Blarring of vision, confusion Due to steroid nucleus- gynaecomastia in male

2.Cardiac effect:

i)All type of arrythmia (↑ Automaticity in high dose)

ii) Slowing A-V nodal Conduction-

Bradycardia

Heart block

Toxicity

• Anorexia is earliest symptom

bradycardia is earliest sign

( if <60 b/min, digitalis not given)

Low TI- 1-2.6nmol/L

Treatment: Rx is different in 2 different condition

i) Stop the drug

ii) Monitor K+ level( if hypokalemia administer K+ IV)

iii) If atrial arrythmia- digoxin not given because it slows AV nodal conduction—use phenytoin which decrease arrythmia but not slow AV nodal contraction.

iv) If ventricular arrythmia- lignocaine given,

it does not slows AV nodal conduction

If heart block – give atropine to increase HR.

If patient still refractory to treatment monoclonal antibody or digoxin binding specific antibody (digibind) given to remove excess digoxin from the body.

• Effect of administration of electrolyte on effect of digoxin – K+, Ca++, Mg++ toxicity

K+ and digitalis, interact in two ways-

First –Hypokalemia increases the myocardial localization of digoxin.reduction in extracellular K+, cause phosphorylation cause increased phosphorylation of Na pump. And digoxin has higher affinity for the phosphorylated form.increase K+, level can help to releive symptos of digoxin by dephosphorylation of Na pump.

. Second – abnormal cardiac automaticity is inhibited by hyperkalemia.

Ca++ facilitates the toxic actions of cardiac glycosides by accelerating the overloading of intracellular Ca++ stores that appears to be responsible for digitalis-induced abnormal automaticity. Hypercalcemia therefore increases the risk of digitalis induced arrhythmia.

Decreased Mg++ concentration enhances toxicities of cardiac glycosides.

Drug interaction

Pharmacodynamic interaction

• B –blocker + digoxin= ↓ AV Conduction –so Heart Block

• Verapamil+ digoxin= ↓ AV Conduction –so Heart Block

• Digitalis+ Diuretics(Thiazide/Frusemide)= cause K+ loss

• Pharmacokinetic interaction

• Verapamil+ digoxin→↑ plasma digitalis conc. by competing with digoxin for renal excretion →↑conc. of digoxin →toxicity

• Digitalis+Quinidine= displace digitalis from tissue binding site→↑conc. of digitalis →↑toxicity

MODULATION OF CARDIAC CONTRACTILITY DYSFUNCTION

AT CELLULAR LEVEL BY DRUG

Fig:Sites of drug action

Cardiac Glycosides• Selective inhibitor of the plasma membrane sodium pump.• Mechanism of Action:

Inhibits Na+/K+ ATPase pump

­ Intracellular Na+concentration

Inhibits Na+/Ca2+ exchangers

¯ Calcium efflux from the cell

Intracellular calcium

Cardiac Contractility

Beta-adrenergic receptor agonist

• Mechanism of action:

Acts on β1-adrenoceptor

Increase cAMP ↓ Activates protein kinase activates sarcolemmal calcium channel Increase cardiac contractility

Dopamine

acts on β1 R at moderate dose → force of contraction →CO

At low dose act on D1 R-renal vasodilatation - renal blood flow. So, it is a drug of choice.

Very short t ½ (2 – 3 minutes) due to metabolism by COMT. So, we have to give in IV infusion.

1 – 5 μgm/kg/min good β effect. > 5 μgm/kg/min α1 effect PR.

dose arrhythmia develop.

Dobutamine

• Act on β1 R

• ↑FC without increase in HR

• So, ↓ cardiac workload.

Phosphodiesterase inhibitors

• Mechanism of action

Inhibit enzymes that hydrolyzes cAMP

↑ intracellular cAMP Activates protein kinase activates sarcolemmal calcium channel Increase cardiac contractility

• In Vessels cAMP in arterial and venous smooth muscle

• vasodilatation PR Afterload

• Venodilatation ↑ venous capacitance ↑ venous return Preload

(the combination of (+Ve)chronotropic & mixed arterial &venous dilatation leads to PDEi as inodilator)

• Adverse effects –

• GIT – nausea and vomiting.

• Automaticity arrhythmia

• Amrinone – thrombocytopenia

Diuretic

• Thiazide, frusemide.

• Beneficial effect both in acute and chronic HF.• Role of diuretics in Heart Failure –

• Act on renal tubule prevent reabsorption of Na+ and H2O Na+ and H2O excretion plasma volume venous return preload relieve of edema.

ACE inhibitors circulating angiotensin II level less

vasoconstriction PR afterload.

angiotensin II aldosterone less H2O retention plasma volume venous return preload.

No direct effect on heart. As afterload so forward pressure of heart complete systolic emptying of heart so indirectly CO. So, it is a drug of choice.

• Only drug that ↓ PR ( after load) without causing a reflex activation of the sympathetic system.

• Adverse Effects:– Hypotension– Dry persistent cough

β blockers

• Most patients with CHF respond favorably to certain β blockers in spite of the fact that these drugs can precipitate acute decompensation of cardiac function.

• Trial of β blockers are based on the hypothesis that excessive tachycardia and adverse effects of high catecholamine levels on the heart contribute to the downward course of HF patients.

• Suggested mechanism of beneficial action include – attenuation of the adverse effects of high concentration of catecholamines (including apoptosis), up-regulation of β receptors, decreased Heart Rate, and reduced remodelling through inhibition of mitogenic activity of catecholamines.

• They can improve symptoms, reduce the frequency of hospitalization and reduce mortality in CHF.

Thank you