Drugs For Heart Failure
Drugs For Heart Failure
Drugs For Heart Failure
Heart Failure
Medical students (Sem 3)
inadequate cardiac
output to meet the
metabolic need of the
body
Heart
Failure Cardiac output (CO): volume of
blood pumped by the heart
during systole
Factors affecting CO
pulmonary pressure
forces fluid out of
Clinical symptoms pulmonary capillaries
of LHF : dyspnea & pulmonary congestion
pulmonary odema
RIGHT VENTRICULAR DYSFUNCTION/FAILURE
Commonest cause: LV
failure, others:
cardiomyopathy
in amount of blood in
ventricle R atrial
RV dysfunction pressure
sympathetic activity
Renin release
angiotensin II
Heart rate & Vasoconstriction: formation
myocardial enhances venous
contractility return & cardiac
preload
Na & H20 Stimulate Vaso
retention by aldosterone constriction
Heart size kidneys release by in blood
ventricles Also afterload adrenals vessels
dilate -->
elongated
heart fibres afterload
weaker blood vol - if heart ( due to
contractions ejection peripheral
unable to pump extra vol
fraction & peripheral & pulmonary resistance)
CO odema occur
Cardiac remodeling
Objectives of Treatment
Tx Objective
preload /
Inotropic Volume overload Prevent
(oedema,SOB)
afterload(or
state both) remodeling
-Diuretics
Vasodilators
(arterial dilators) & Diuretics Beta Blockers
venodilators
A) Inhibitors of RAAS
1) Angiotensin-converting enzyme(ACE) inhibitors , ACE-I
MOA:
1) Inhibits the angiotensin-converting enzyme (ACE) which cleaves angiotensin I to form
angiotensin II
2) Inhibit degradation of bradykinin (a potent vasodilator) vasodilate reduced
peripheral vascular resistance
3) Reduce long term remodeling of the heart
Reduced preload and
Angiotensinogen afterload of the heart
(in liver) CO
Renin (from
kidney)
Angiotensin I
cardiac
ACE- Angiotensin afterload work
Inhibitors converting enzyme vasoconstriction CO
Angiotensin II Stimulate Stimulate plasma
aldosterone release kidneys to retain vol
Na+ & H20 preload
Stimulate release of
ADH hormone from H20 cardiac
pituitary retention workload
Examples:
Captopril, Perindopril, Enalapril, Ramipril, fosinopril, lisinopril
quinapril , moexipril (all are prodrugs except captopril & lisinopril)
Pharmacokinetics:
Oral mostly/IV administration (only enalapril)
food may absorption of captopril
Most ACE-I eliminated by kidneys (except fosinopril & moexipril)
Adverse effects:
Persistent dry cough (commonest) bradykinin
hypotension Important drug
interactions:
Hyperkalaemia K+ sparing
Acute renal failure/renal insufficiency diuretics,
aldosterone
Angiodema (rare) antagonists or K+
Teratogenic contraindicated in pregnancy supplements
2) Angiotensin receptor blocker (ARB)
MOA:
Block the angiotensin II (Type 1) receptors on blood vessels
No effect on bradykinin metabolism
More selective blocker of angiotensin pathway
Produce similar effects as ACE-I
preload & afterload hence CO.
Examples: Losartan, Valsartan, Candesartan, irbesartan,
telmisartan, olmesartan
Oral administration
Indication: as an alternative in heart failure patients who is
intolerant to adverse effects of ACE-I
Adverse effects
Similar to ACE-I
However causes less cough and angioedema (as do not affect
bradykinin levels)
3) Aldosterone antagonists
MOA:
Blocks the aldosterone receptors prevents binding of
aldosterone inhibit aldosterone-mediated Na+ & water
reabsorption
Effects: promotes salt and water excretion (reduces odema)
Example: spironolactone
Also work as a potassium-sparing diuretic
Pharmacokinetic: Oral administration, renal elimination
Adverse effects:
GIT upset
hyperkalaemia
Anti-androgenic effects: gynaecomastia (males), irregular menses,
hirsutism(females)
Indication: can be combined with other diuretics (eg. Thiazide
or loop diuretics which usually causes K+ excretion) to prevent
hypokalaemia
B) VASODILATORS
2) Venodilator
Isosorbide dinitrate (ISDN)
MOA: venodilation preload by increasing venous
capacitance (pooling of blood in peripheral veins hence
ventricular volume)
Oral administration
Usually prescribed for HF patients with predominant pulmonary
edema
* Combination of both hydralazine + ISDN : effective & improve
survival in patients who are stabilised on ACE-I/B blocker)
3) Mixed arterial and venodilator
Sodium nitroprusside
Parenteral administration: usually IV
MOA: reduces both preload and afterload hence
increase CO
Nitroglycerin
Parenteral administration
Low infusion dose: selective venodilator
High infusion dose: can also act as arterial dilator
Examples:
1) Cardiac glycosides (Digitalis) : Digoxin
2) 1 agonists: Dobutamine, Dopamine
3) Phosphodiesterase inhibitors: Milrinone, Inamrinone
Mechanism of inotropic action
-Increase cAMP
-Increase Ca2+ influx into
Inhibit Na+/K+/ATPase
myocardium
enzyme
(1 Agonist &
(Digoxin)
Phosphodiesterase inhibitors)
Increase
intracellular
Ca2+
myocardial
contractility
C) Neurohormonal effects
- Exact mechanism unclear
- Proven that digoxin inhibits HR (reduce
sympathetic nervous system workload of
activation & increase vagal heart)
tone
Atrial fibrillation
Why we need to treat?
In AF : there is in atrial rate
Untreated AF -rapid ventricular rate (VR)
120-150/min
leads to reduce ventricular filling time
Reduce CO
Aim of tx is to:
reduce the high VR
Slow down AV conduction:
reducing conduction velocity
Prolongation of refractory period
DIGOXIN (cont)
Oral/IV preparation
Oral absorption good
Pharmacokinetics:
Elimination : kidney dose adjustment in renal dysfunction
Long half life : 36-40 hours (Once daily dose)
Loading dose - rapid onset (eg symptomatic atrial fibrillation)
Has low therapeutic index - toxicity
Adverse effects:
Digoxin toxicity - commonest :
Early indicators : GIT upset -
Nausea,vomiting,anorexia,diarrhea, Blurred vision,
yellowish vision (xanthopsia)
Arrythmias ca2+ overload
CNS: disorientation, hallucinations, confusion
Factors affecting digoxin toxicity
Hypokalaemia increased effect of digoxin on
Na/K+/ATPase) more binding site for digoxin on the
enzyme.
Caution if concomitant therapy with thiazide or loop
diuretics
Renal impairment
Hypercalcaemia, Hypomagnesaemia, hypothyroidism
2
4
Bradycardia, fatigue
vivid dreams
cold hands
orthostatic hypotension & dizziness (alpha 1 blockade)
Potassium-sparing diuretic
(aka aldosterone
antagonist)
-spironolactone
Indications:
Spironolactone reported to reduce morbidity & mortality
in HF via preventing Na reabsorption, and prevents
aldosterone-induced fibrotic changes in myocardium
Given together with loop/thiazide diuretics to prevent
hypokalemia
Diuretics: adverse effects
Loop diuretic Thiazide diuretics K+ sparing diuretic
(aldosterone)
Ototoxicity Hypercalcemia inhibit Hyperkalaemia (promote
reversible/permanent secretion of Ca2+ by Na+ excretion due to
kidneys inhibition of aldosterone,
retain K+)
Hypokalaemia (loss of K+) : heavy load of Na+ in Lethargy
collecting duct increased Na+ reabsorption in the
duct K+ excreted out in exchange for Na+
may need pre-tx monitoring, K+ supplementation
Acute hypovolaemia volume depletion Gastric upset - nausea