Rug Therapy For Heart Failure: Dr. Santhosh Ramakrishna

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The document discusses drug therapy for heart failure, including classifications of drugs like cardiac glycosides, beta blockers, diuretics, ACE inhibitors, and vasodilators. It also discusses compensatory responses during heart failure and the phenomenon of decompensated heart failure.

The main classifications of drugs discussed for heart failure treatment are cardiac glycosides, beta agonists, diuretics, ACE inhibitors, vasodilators. Specific drugs mentioned include digoxin, milrinone, dopamine, furosemide, enalapril, hydralazine.

Cardiac glycosides are compounds derived mainly from plants that have a positive inotropic effect on the heart. Sources mentioned include Digitalis purpurea/foxglove and Strophanthus plants. Specific cardiac glycosides discussed are digoxin, digitoxin, ouabain, and strophanthin.

DRUG THERAPY FOR

HEART FAILURE

Dr. Santhosh Ramakrishna


INTRODUCTION
Heart failure

Heart is unable to pump sufficient amount of

blood to meet the metabolic demands of the

body.

Low Output Vs High Output Heart Failure

Left Side Vs Right Sided Heart Failure


COMPENSATORY RESPONSES
DURING HEART FAILURE
Heart failure
Dec FC, Dec CO
Inc Dec
Sympathetic Renal
discharge Perfusion

Inc Renin
Dec GFR
release

Vasoconstriction and Beta Cardiac


activation Remodeling
Inc
AT II,
Aldosterone

Inc in Preload, Afterload,


FC & HR

Inc Sodium & Water


Edema
Retention
Congestive Symptoms-
Pulmonary, Hepatic &/
Peripheral
PHENOMENON OF DECOMPENSATED HEART
FAILURE

 Pulmonary and peripheral edema


 Dyspnoea with cyanosis
 Hepatomegaly

 Cardiomegaly

 Reflex tachycardia
 Decreased urine formation
 Decrease exercise tolerance and muscle
fatique
DRUG THERAPY OF HEART
FAILURE
CLASSIFICATION
Drugs with +ve Drugs without +ve
ionotropic effects ionotropic effects
 Cardiac Glycosides-  Diuretics-
Digoxin, Digitoxin, Furosamide,
Oubain Hydrochlorothiazide,
 Bypiridines- Spironolactone
Milrinone, Inamrinone,  ACE Inhibitors-
Levosimendan Enalapril, Losartan
 Beta Agonists- (AT1 Blocker)
Dopamine,  Vasodilators-
Dobutamine, Hydralazine, Sod.
Dopexamine Nitroprusside,
Isosorbide Di Nitrate
 Vasopresssin
Receptor
CARDIAC GLYCOSIDES

Non Glycoside
Sugar sugar

Digitoxose Steroidal Cardiac


lactone Glycoside
SOURCES OF CARDIAC GLYCOSIDES

Plants-

 Digitalis purpurea /Foxglove

 Digitalis lanata,

 Strophanthus kombe,

 Strophanthus gratus,

 Thevetia nerifolia ,

 Bufo vulgaris (toad skin),


CARDIAC GLYCOSIDES

Digitalis lanata- Digitoxin, Digoxin

Digitalis purpurea- Digitoxin

Strophantus gratus- Ouabain, Strophanthin-G

Strophantus kombe- Strophanthin-K


EFFECT OF DIGITALIS

(1) CARDIOVASCULAR

&

(2) EXTRA CARDIAC ACTIONS


CARDIAC EFFECTS

a) Force of contraction : +ve inotropic and inc. in

Stroke Volume

Heart rate  - ve chronotropic

 Restores the diminished vagal tone and abolishes


sympathetic overactivity.

 Digitalis slows the heart by vagal and extravagal


actions.

 Vagal tone is increased reflexly by sensitization of


baroreceptors, as well as by stimulation of vagal
b) Refractory period :

Atrial- dec. by vagal action and inc. by direct

action (vagal action normally predominates)

AV Node & Bundle of His- decreased CV and inc.

ERP, Protects ventricles from atrial flutter

and fibrillation
Conduction velocity:

Small doses  slightly increased in conduction

velocity of the atria & ventricles

Larger doses  depress CV.

Conduction through AV node – > depressed by both

vagal & direct action.


ECG CHANGES

 Decreased amplitude or inversion of T wave.

 Increased P-R interval (due to slowing of A-V


conduction), A-V block at toxic doses.

 Shortening of Q-T interval (reflecting


shortening of systole).

 Depression of ST segment (at high doses— due


to interference with repolarization).
EXTRA CARDIAC ACTIONS

 KIDNEY- Mild diuresis.

 GIT- Anorexia, diarrhoea, nausea, vomiting (due


to stimulation of CTZ).

 Blood vessels- normal person- vasoconstriction,


but in CHF patients it leads to decreased in
heart rate, PVR, preload and afterload. No
effect on coronary circulation

 CNS- disorientation, hallucinations, visual


disturbance and aberration of color perception
Parameters Digitoxin Digoxin Oubain

Oral 95-100% 75-90% Nil, so given I.V


absorption
aVd (L/Kg) 0.6 6-7 18

Protein 90% 30% O


binding
Half life 6-7 days 38-40 hours 18-12 hours

Onset & 2hrs, long ½ hr, Very rapid,


duration of intermediate short
action
Metabolism 80% liver 20% liver 0

Excretion Mainly bile Urine Urine


(unchanged) (unchanged)
THERAPEUTIC USES OF DIGITALIS

1) C C F – low output type.

2) Atrial flutter.

4) Atrial fibrillation.

5) Atrial and A.V. nodal paroxysmal atrial

tachycardia.
ADVERSE EFFECTS

Cardiac
 Bradycardia,

 Partial or Complete AV Block,

 Atrial or Ventricular Extrasystoles,

 Coupled Beats,

 Ventricular Fibrillation and Fatal Cardiac


Arrhythmias
EXTRA CARDIAC

 Gastrintestinal toxicity: - Anorexia,


nausea, vomiting, diarrhea

 Neurological toxicity: - Vertigo, blurring


of vision, headache, confusion,
disorientation, delirium, stupor.

 Miscellaneous: - Skin rashes, eosinophilia


& gynecomastia.
CONTRAINDICATIONS & PRECAUTIONS

Recent M I,
Partial or complete heart block,
W P W syndrome,
Constrictive pericarditis,
Ventricular tachycardia,
Hypokalemia,
Hypothyroidism ,
Children & Elderly,
Renal & hepatic diseases
INTERACTIONS
 Diuretics
 Calcium: synergises with digitalis → precipitates
toxicity.
 Quinidine: reduces binding of digoxin to tissue
protein as well as its renal and biliary clearance by
inhibiting efflux transporter P-glycoprotein → plasma
concentration of digoxin is doubled → toxicity can
occur.
 Verapamil, diltiazem, captopril, propafenone and
amiodarone also increase plasma concentration of
digoxin to variable extents.
 Adrenergic drugs: can induce arrhythmias in
INTERACTIONS
 Digoxin absorption may be reduced by
metoclopramide, sucralfate, antacids, neomycin,
sulfasalazine.

 Absorption of digoxin is increased by atropinic


drugs, including tricyclic antidepressants.

 Propranolol, verapamil, diltiazem and


disopyramide: may additively depress A-V
conduction and oppose positive inotropic action.

 Succinylcholine: can induce arrhythmias in


digitalized patients.
TREATMENT OF DIGITALIS TOXICITY

 Stop digitalis, diuretics

 Estimate serum potassium

 Treat bradycardia with atropine

 Mild toxicity – treat with potassium.

 PSVT- treat with Propranolol.

 Ventricular tachycardia – treat with lignocaine

 Severe toxicity – treat with digitalis antibodies-


digibind.

 Potassium is C/I in presence of A.V. block,


hyperkalemia or severe renal insufficiency.
IONODILATORS- INAMRINONE,
MILRINONE

 Positive inotropic & vasodilators

 Acts by inhibiting phosphodiesterase (type 3),


enzyme responsible for intracellular degradation
of cAMP, increase myocardial contractility.

 Used in refractory cases of C C F

 The common A/E  thrombocytopenia and pro-


arrhythmic, hence not preferred routinely.
BETA AGONISTS- DOBUTMAINE

 Mainly +ve ionotropic than chronotropic agent

 No significant change in TPR and BP

 Half life is 2minutes so given by I.V infusions

 Mainly used for short periods in acute HF and HF


patients associated with MI or cardiac surgery

 It increases O2 demand so may ppt angina

 Also increases atrial conduction so use with


caution in atrial fibrillation
BETA AGONISTS- DOPAMINE

 2-5mcg/kg/min- acts on D1 receptors

 5-10mcg/kg/min- also acts on Beta 1 receptors

 > 10mcg/kg/min- acts only on alpha 1 receptors

 Used mainly in low CO HF with compromised

renal functions
DIURETICS
 Loop diuretics
 Decreases edema and improves cardiac performance
 Loss of electrolytes mainly potassium, calcium and
magnesium is a major problem, also hypokalemia,
alkalosis and Carbohydrate intolerance
 Resistance develops on prolonged use
 Potassium sparing diuretics
 No digitalis toxicity, prevents remodelling
 Can be used in loop diuretic resistance cases
 Main ADR are hyperkalemia and gynecomastia
ACE INHIBITORS
(ENALAPRIL,RAMIPRIL)
 First choice of drugs in HF

 Not only prevents generation of AT2 but also


prevents bradykinin metabolism

 Prevents pathological remodelling

 Also reduce deaths due to arrhythmias, MI and


stroke

 Combination of spironolactone and ACE inhibitor


more beneficial effects and less mortality

 “Aldosterone escape” phenomenon


VASODILATORS

 Arteriolar Dilator- Hydralazine

 Venular Dilator- Nitroglycerine

 Arteriolar And Venular- Sodium Nitroprusside

 Reduce after load/ pre load or both

 Severe Hf- combination of both


VASOPRESSIN RECEPTOR ANTAGONISTS

 Conivaptan- mixed V1 and V2 antagonist

 Tolvaptan- V2 antagonist

 V1 vasoconstriction action

 V2 antidiuretic action

 Indicated in patients having acute heart failure


with hyponatremia

 Although helpful it doesn’t seem to reduce


mortality
Β-ADRENERGIC BLOCKERS

 β1 blockers (mainly metoprolol, bisoprolol,


nebivolol) and the nonselective β + selective α1
blocker carvedilol are used in mild to moderate
CHF treated with ACE inhibitor ± diuretic,
digitalis.
 Though the immediate hemodynamic action of β
blockers is to depress cardiac contractility and
ejection fraction, these parameters gradually
improve over weeks.
 Morbidity & mortality is improved, However, β
BETA BLOCKERS
 The benefits appear to be due to

 Antagonism of ventricular wall stress enhancing,


apoptosis promoting

 Pathological remodeling effects of excess


sympathetic activity (occurring reflexly) in CHF,

 Prevention of sinister arrhythmias.

 β blockers lower plasma markers of activation of


sympathetic, renin-angiotensin systems and
endothelin-1.
GUIDELINES OF USE OF BETA BLOCKERS

 Greatest utility of β blockers has been shown in mild


to moderate (NYHA class II, III)
 There is no place for β blockers in decompensated
patients
 Starting dose should be very low—then titrated
upward as tolerated to the target level
 A long-acting preparation (e.g. sustained release
metoprolol) or 2–3 times daily dosing to produce
round-the-clock β blockade should be selected.
 There is no evidence of benefit in asymptomatic left
ventricular dysfunction
ALDOSTERONE ANTAGONIST
(SPIRONOLACTONE, EPLERENONE)
 Disease progression in CHF is by direct and indirect
effects:

 (a) Expansion of e.c.f. volume → increased cardiac


preload

 (b) Fibroblast proliferation and fibrotic change in


myocardium → worsening systolic dysfunction and
pathological remodeling.

 (c) Hypokalemia and hypomagnesemia → increased


risk of ventricular arrhythmias and sudden cardiac
death.
GUIDELINES FOR USE OF ALDOSTERONE
 It is indicated as add-on therapy to ACE inhibitors +
other drugs in moderate-to-severe CHF.
 It can retard disease progression, reduce episodes
of decompensation and sudden cardiac deaths, over
and above the protection afforded by ACE
inhibitors/ARBs ± β blockers.
 Only low doses (12.5–25 mg/day) of spironolactone
should be used to avoid hyperkalaemia; particularly
because of concurrent ACE inhibitor/ARB therapy.
 It may help restoration of diuretic response to
furosemide when refractoriness has developed.
 It is contraindicated in renal insufficiency
NESIRITIDE
 This recombinant brain natriuretic peptide (BNP)
has been approved for i.v. use to relieve
dyspnoea and other symptoms in refractory CHF.
 It enhances salt and water excretion and is a
potent vasodilator with profile of action similar
to i.v. glyceryl trinitrate; reduces ventricular
filling pressure.
 Additional haemodynamic and symptomatic
improvement can be obtained for short-periods,
but no longterm benefits are evident in CHF.

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