2. Diuretics:
•Reduce extracellular fluid volume
•Natriuresis and decrease in intravascular volume
•Reduce preload on heart
•Dietary sodium intake restriction
•Loop diuretics – furosemide, bumetanide, torsemide- inhibit
Na+-K+-2Cl- symporter in the ascending loop of Henle to
increase Na+ and water delivery to distal tubule
•Also increase K+ excretion
•Thiazide Diuretics- chlorthiazide, hydrochlorthiazide- limited
value in CHF
•Act on Na+Cl- co-transporter in distal convoluted tubule
3. •K+ loss occurs more than that with loop diuretics
•Often combined with loop diuretics when patient is refractory
to loop diuretics
•K+ Sparing Diuretics- Spironolactone, triamterene, amiloride
are weak diuretics-for achieving volume reduction with
minimal K+ loss
•Usually, treatment is started with loop diuretics either orally
(compensated) or i.v. (decompensated) patients
•Diuretic resistance- due to compensatory increase in renal
tubular reabsorption of Na+
•Diuretics do not improve upon the mortality rate in patients
4. Vasodilators:
•Nitrosovasodilators
•ACE inhibitors/ARBs
•Nitrosovasodilators:
NO donors which activate soluble guanylate cyclase in
vascular smooth muscle cells to relax them
Rapid acting nitroglycerine tablets or spray (sublingual)
Short acting oral agents like isosorbide dinitrate
Long acting oral agents like isosorbide mononitrate
Topical like transdermal patches, ointments of nitroglycerine
I.V. like nitroglycerine
5. How nitrates are helpful in CHF?
•Reduce preload due to peripheral pooling
•Reduction of pulmonary and systemic arterial resistance
•Epicardial coronary artery dilatation- reperfusion
•Given alone their efficacy is limited due to:
limited effect on systemic resistance
Nitrate tolerance
•Often combined with other vasodilators for better results
6. Na Nitroprusside: During biotransformation of nitroprusside,
cyanide is produced which is quickly converted to thiocynate in the
liver and excreted by the kidney
•ADR: Thiocynate or cyanide toxicity may occur following
prolonged drug administration
•Symptoms: unexplained abdominal pain, change in mental status,
convulsions, lactic acidosis
•Treatment:
Sodium nitrite: It oxidizes some iron of haemoglobin to ferric
state and converts it to methaemoglobin. Cyanide preferntially
binds to methaemoglobin to form cyanmethaemoglobin.
Administration of sodium thiosulphate converts
cyanmethaemoglobin to thiocyanate, sulfite and haemoglobin.
Thiocyanate is excreted by the kidney
7. Hydrocobalamin (B12): It binds to cyanide to form harmless
vitamin B12acyanacobalamin that is excreted by the kidney
4-Dimethylaminophenol: It forms methaemoglobin in the
body that binds to cyanide
Dicobalt adetate: It chelates cyanide
•ADR: Methaemoglobinemia: due to oxidation of haemoglobin
by NO-
•Treatment: Methylene blue: It acts as artificial electron
acceptor for NADPH-methaemoglobin reductase and allows the
enzyme to function again
8. Hydralazine:
•Direct acting vasodilator
•Mechanism of action not known
•Reduces both right and left ventricular afterload by reducing
pulmonary and systemic vascular resistance
•Results in increased cardiac output and decreased ventricular wall
stress during systole
•Also has moderate direct positive inotropic activity independent
of its afterload reducing effects
•Reduces renal vascular resistance and increases renal blood flow
•Increases renal blood flow more than any other vasodilator except
ACE inhibitors
•Preferred drug in CHF (ACE intolerant) with renal impairment
9. •Hydralazine is more often used in combination with isosorbide
dinitrate
•The combination is as effective in CHF as 1 blocker prazosin
•ACE inhibitors are superior to hydralazine in reducing mortality
in CHF
•ADRs: withdrawal effect, lupus like syndrome
•Oral/i.v. – oral is equally effective as i.v.
• Has to be taken 3-4 times a day- patient compliance
•I.V. hydralazine is used for its immediate effect only- urgency
•10-25 mg/day orally increased gradually; maximum dose 100 mg
3-4 times a day
10. ACE Inhibitors:
•Effects of angiotensin II:
Potent vasoconstrictor
Na+ and water reabsorption from renal tubule (effect on filtration
pressure and secretion of aldosterone)
Modulation of neural and medullary catecholamine release
Arrhythmogenic
Promotes vascular and myocardial hyperplasia
Induces myocyte death
Reduction of RAS leads to beneficial effects in CHF
11. •ACE inhibitors:
Suppress angiotensin II and aldosterone production
Decrease sympathetic activity
Potentiate effects of diuretics in CHF
•Angiotensin II escape: After chronic therapy with ACE inhibitors,
angiotensin II levels return to normal but effect of ACE inhibitors
persists- the normalization of angiotensin II is called “escape”
•Suggests that other mechanisms besides ACE inhibition also play a
role in their effects
•Bradykinin and other kinins- stimulate production of NO, cyclic
GMP, vasoactive eicosanoids that dilate the blood vessels, oppose
angiotensin II effect on smooth muscle cells of blood vessels and
fibroblasts proliferation & extracellular matrix deposition in heart
12. •ACE inhibitors are preferential arterial vasodilators
• Left ventricular afterload by PVR & cardiac output
•HR remains unchanged probably due to sympathetic activity
•Acts via AT1 receptors so ARBs are more effective than ACE
inhibitors
•Both beneficial and deleterious effects are due to activation of
AT1 receptors
•AT2 receptor activation appears to counterbalance deleterious
effects of AT1 activation
•Increase in circulating levels of angiotensin II in response to
ARBs results in relative increase in AT2 receptor activation
•Combination therapy with ACE inhibitors and ARBs is under
trial
13. •ACE inhibition alone is not sufficient for optimal attenuation of
angiotensin II induced CV dysfunction in patients of CHF
•Reasons:
ACE independent pathways that convert Ang I to Ang II
Activation of ACE homologs like ACE2 occurs that are insensitive
to conventional ACE therapy
Suppression of negative feed back effect on renin secretion
•Thus, some amount of angiotensin like activity persists that is
deleterious to CV functions
•Inhibition of renin secretion prevents conversion of angiotensinogen
to angiotensin I due to which angiotensin II formation does not occur,
directly or through alternate routes
•Under trial
14. Nesiritide:
•Introduced recently for treatment of CHF
•Recombinant form of human natriuretic peptide
•Naturally secreted by the ventricles, increases cGMP in vascular
smooth muscles and reduces arteriolar and venous tone
•Causes natriuresis
•Short t½ of 18 min
•Administered as bolus dose 2 µg/kg i.v. followed by continuous
i.v.infusion of 0.01 to 0.03 µg/kg/min
•Used in acute decompensated heart failure associated with
dyspnoea at rest
•ADR: hypotension
15. Vasopressin receptor antagonists:
•Vasopressin or ADH is released in response to:
Increased plasma osmolality
Decreased arterial pressure
Reduced cardiac filling
•Two types of vasopressin receptors- V1 and V2
•V1 mediate vasoconstrictor while V2 mediate antidiuretic action
•Conivaptan is mixed V1 and V2 antagonists and Tolvaptan is V2
antagonist
•Conivaptan is given i.v. while tolvaptan is given orally
•Though beneficial, they donot reduce mortality so long term
usefullness is doubtful
16. Role of sympathetic activation in CHF
CHF
Sympathetic activation
Inotropy
( contractility)
Lusitropy
( Ventricular relaxation & filling)
Chronotropy
( Heart rate)
17. -Adrenoceptor antagonists:
• agonists dobutamine as also dopamine provide relief in CHF but
their long term use increases mortality
•Long term administration of -antagonists reduce mortality rate in
CHF
•Initially the systolic function decreases but over 2-4 months it
recovers and improvement beyond baseline occurs
•Mechanism of beneficial effects in CHF not clear
By preventing myocardial ischemia without significantly
influencing serum electrolytes, they may decrease frequency of
unstable tachyarrhythmias
Betterment of left ventricular morphology by decreasing left
ventricular size and increasing ejection fraction
18. By inhibiting sustained sympathetic discharge, they reduce
catecholamine induced cardiomyote toxicity and prevent or delay
myocardial contractile dysfunction
Decrease cardiomyocyte apoptosis
May induce positive myocardial remodeling by decreasing
oxidative stress on myocardium
•Drugs used: metoprolol, carvedilol, bisoprolol- other -blockers
are not effective
•Combined and blocker is preferred
•Carvedilol has additional advantages that it reduces free radical
induced lipid peroxidation and prevents cardiac and vascular
smooth muscle mitogenesis independent of its or receptor
blocking activity
19. • Adrenoceptor blockers have proven utility in improving
symptoms, hospitalization and mortality in patients of CHF
•They are recommended for use in patients along with ACE
inhibitors or ARBs
•Recommended only when the ejection fraction of heart is
<35% to counter the deleterious effects of circulating
catecholamines
•They are usually given in small doses initially, less than 1/10th
of the final dose and gradually titration of dose is done
•Not recommended for use in patients with severe, new onset
or acutely decompensated CHF
