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Drugs Used in Management of Congestive Heart Failurep

Mp    pp
›p Digoxin (Lanoxin, Lanoxicaps,) Digitoxin
›p Digitalis glycosides are composed of a steroid nucleus to which an
unsaturated lactone ring is attached at C-17. These two components, the
aglycone or genin moieties, are responsible for the inotropic activity of
glycosides.
›p Digoxin has a half-life of about 1.6 days. By contrast digitoxin's half-life
is about 5 days. Digitoxin is rarely used and may no longer be readily
available in the United States.
›p Digoxin is mainly excreted in the urine (85%). By contrast digitoxin is
mainly metabolized in the liver.
›p £uabain is very rapidly acting (5 to 10 min onset) after i.v. injection.
›p The clinical efficacy of digitalis glycosides is based on improving cardiac
contractility (positive inotropism) and on decreasing transmission through
the A-V node.
›p The most important cardiac effect is the shift of the force-velocity
relationship upward.
Mp  
pp
›p Amrinone (Inocor) and milrinone (Primacor) are bipyridine derivatives
that are relatively selective inhibitors of cGMP-inhbited, cyclic AMP
phosphodiesterase (type III).
›p These agents cause vasodilation (decreased afterload) and increase
myocardial contractility.
›p Milrinone (Primacor) is the agent of choice among the phosphodiesterase
inhibitors for short-term parenteral support in severe heart failure patients.
rp £ral formulations are not used due to intolerable side-effects
including increases in mortality.
›p Amrinone has been associated with a reversible thrombocytopenia.
Mp è
 p 
›p  p 
›p Are used for short-term inotropic support of the failing heart.
›p Dobutamine (Dobutrex) is less arrhythmogenic and produces less
tachycardia compared to endogenous catecholamines or isoproterenol
(Isuprel).
›p Dobutamine (Dobutrex) is a racemate that binds to and activates -1 and
-2 adrenoceptor subtypes.

rp The (-) enantiomer stimulates 1 and 2 receptors, but this effect


in humans appear negated by binding of the inactive (+)
enantiomer.
rp Therefore the positive inotropic action mediated by beta receptor
activation predominates.
›p Dobutamine (Dobutrex) does not activate dopamine receptors and
therefore does not increase renal blood flow.
›p Because of its vasodilator properties, dobutamine's positive inotropism is
accompanied by a decrease in afterload. For this reason dobutamine may
be favored over dopamine for most advanced heart failure patients who
have not improved with digoxin, diuretics, and vasodilator therapy.
›p  p   
›p Dopamine (Intropin)may produce tachycardia which may increase left
ventricular work.
›p Dopamine (Intropin)-induced vasodilation is mediated by direct
stimulation of D1 and D2 post-synaptic dopamine receptors.
›p Vasodilation of renal vasculature is noteworthy and may benefit patients
with marginal GFR due to poor renal perfusion.
Mp ÿ
 p
›p Vasodilators may be used in the management of congestive heart failure as
a means of reducing afterload.
›p Ô
 p è  p 
p  
p    are the prominent
members of the class, although minoxidil is preferred.
›p Both drugs can induce reflex-mediated cardiac stimulation and water
retention although in patients with advanced failure significant
sympathetic tone may already be present. In that situation intervention that
improve cardiac output and tissue perfusion may actually reduce overall
sympathetic activity.
›p Vasodilator therapy is typically not used initially. ACE inhibitors,
diuretics and digoxin would be likely tried first. More aggressive diuretic
treatment and/or addition of vasodilators could follow.
›p Adverse effects include those induced by vasodilation such as
hypotension, palpitation, tachycardia, angina, fluid retention and
headache.
rp A drug-induced lupus syndrome is associated with hydralazine.
rp A drug-induced hypertrichosis is associate with minoxidil
Mp p   p
›p u  
p p 
p p  
p 
p
p
  p 
p 
 are "high-ceiling" loop diuretics acting
primarily at the ascending limb of the loop of Henle.
›p The effectiveness of these agents is related to their site of action because
reabsorption of about 30 - 40% of the filtered sodium and chloride load
occurs at the ascending loop.
›p Distal sites are not able to compensate completely for this magnitude of
reduction of NaCl reabsorption.
2+
›p Loop diuretics increase urinary Ca in contrast to the action of thiazides.
›p Loop diuretics also increase renal blood flow by decreasing renal vascular
resistance.
›p These drugs are beneficial in managing systemic and pulmonary fluid
overload produced by congestive heart failure (CHF).
›p Adverse Effects:
rp £totoxicity
rp Furosemide (Lasix) and ethacrynic acid (Edecrin) block renal
excretion of uric acid by competition with renal secretory and
biliary secretory systems.Therefore these agents can precipitate
gout.
rp Potassium depletion.
Mp è    p   p  p    p
›p Angiotensin II, a potent vasoconstrictor, is produced by the action of
angiotensin converting enzyme (ACE) on the substrate angiotensin I. p
›p Angiotensin II activity produces:p
rp (a) a rapid pressor response p
rp (b) a slow pressor response p
rp (c) vascular and cardiac hypertrophy and remodeling. p
›p Benefits of ACE inhibitors in treating congestive heart failure and
antihypertension are due to the reduction in the amount of angiotensin II
produced.p
›p Reduction in angiotensin II levels results in venous and arterial
vasodilation which decreases both preload and afterload. p
›p Cardiac output improvement reduces sympathetic tone which may further
decrease peripheral resistance. p
›p Use of ACE inhibitors improves survival (40%) in patients with overt
heart failure (C£NSENSUS,1987 study). p
›p ACE inhibitors are efficacious in management of congestive heart failure
and hypertension and have a favorable side effect profile. p
›p ACE inhibitor are advantageous in management of diabetic patients by
reducing the development of diabetic neuropathy and glomerulosclerosis. p
›p ACE inhibitor are probably the antihypertensive drug of choice in
treatment of hypertensive patient who have hypertrophic left ventricles. p
›p Hypertensive patients who have ischemic heart disease with impaired left
ventricular function also benefit from ACE inhibitor treatment. p
›p ACE inhibitors reduce the normal aldosterone response to sodium loss
(normally aldosterone opposes diuretic-induced sodium loss).p
rp Therefore, the use of ACE inhibitors enhance the efficacy of
diuretic treatment, allowing the use of lower diuretic dosages and
improving control of hypertension. p
rp If diuretics are administered at higher dosages in combination with
ACE inhibitors significant and undesirable hypotensive reactions
can occur with attendant excessive sodium loss. p
›p Reduction in aldosterone production by ACE inhibitors also affects
potassium levels. The tendency is for potassium retention, which may be
serious in patients with renal disease or if the patient is also taking
potassium sparing diuretics, nonsteroidal anti-inflammatory agents or
potassium supplements. p
›p Adverse Effects: p
rp Angioedema, although rare, may be potentially fat p
rp ACE inhibitors should not be used during pregnancy. p
rp Dry cough. p
rp In renovascular hypertension, glomerular filtration pressures are
maintained by vasoconstriction of the post-glomerular arterioles,
an effect mediated by angiotensin II. Used of ACE inhibitors in
patients with renovascular hypertension due to bilateral renal artery
stenosis can therefore precipitate a significant reduction in GFR
and acute renal failure. p
rp Initial dose of an ACE inhibitor may precipitate an excessive
hypotensive response. p

›p  p pp  p



›p Angiotensin II, a potent vasoconstrictor, is produced by the action of
angiotensin converting enzyme (ACE) on the substrate angiotensin I.
›p Angiotensin II activity produces:
Mp (a) a rapid pressor response
Mp (b) a slow pressor response
Mp (c) vascular and cardiac hypertrophy and remodeling.
›p   pÿ 
›p u  p  
›p    p   
›p    p  
›p Ú  pè  
›p V  pè 
Hollenberg, S.M. and Parrillo, J.E., Shock, In Harrison's Principles of Internal
Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B.,
Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division),
1998, p. 215-222

Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and


Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial
Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W,
and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.222-224.

Stoelting, R.K., "Sympathomimetics", in Pharmacology and Physiology in Anesthetic


Practice, Lippincott-Raven Publishers, 1999, p.259.

Applied Therapeutics: The Clinical Use of Drugs", Sixth edition, edited by Lloyd
Lee-Young and Mary Ann Koda-Kimble, p 15-5, Applied Therapeutics, Inc., 1995,
Seattle, WA.

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