Drugs for the treatment of Congestive Heart Failure (inotropes)

CHF is a disease state in which the heart is unable to pump enough blood to
body tissues (to meet the metabolic needs)

• The disease state is fatal if not treated

CHF

Low blood pressure = ventricular output is ____

• Blood backs up in the ventricles = congestion

• Can cause peripheral and pulmonary edema.

• Agents used to treat heart failure: increase cardiac muscle contractility (positive inotropes)

decreased

Cardiac glycosides

• Natural products: found in plants (eg. Foxglove plant)

• like any other glycosides) are composed of two parts:

  • Sugar (glycone)

  • Non-sugar (aglycone)

  • The combination of sugar and non-sugar entities through an ______ is called glycoside

ether bond

steroid nucleus

Digitoxin

digoxin

The cardiac glycosides inhibit _______ of the action potential that we covered before under calcium channel blocker.

• By inhibiting the Na-K-ATPase pump, sodium will not efflux from the cell, and the phase-2 plateau phase will be extended and more Ca will be intracellularly to induce stronger muscle contraction (+ionotropic effect).

phase 4(sodium/potassium ATPase Pump)

________ are cardiac glycosides

digoxin and digitoxin

non-glycosides positive inotropic agents includes

PDEi, B1-agonist, nesiritide, entresto

PDE is an enzyme in the biological system targets cAMP (two phosphate
esters on the same sugar) and hydrolyze one of the two cyclic esters the inactive non- cyclic AMP

• ATP in the cardiac cell is converted by adenylate cyclase enzyme into cAMP (similar to guanylate cyclase that produce cGMP we studied with the mechanism of action of NO).

• When cAMP levels ▲ it leads to ▲Ca influx which leads to cardiac muscle contraction

After cardic muscle contraction, the system has to terminate the action of cAMP, this is done by an enzyme called phosphodiesterase type 3. If we inhibit PDE-3, we ▲cAMP and ▲Ca and ▲ cardiac muscle contraction; that is the rational of using PDE-3 inhibitors are positive ionotropic agents.

• Chemistry wise cAMP has two phosphate ester function connected to the - same sugar, hence the name of the enzyme phosphodiesterase

What is the pathway of PDE3?

ATP -adeylate cyclase→ cAMP -PDE3→ AMP

list the two PDE3

inamrinone, milrinone

both PDE3i have what is called Bi-pyridine backbone, with an amide functionality. Some difference in the substitution results in differences in potency, with ____. Both drugs are used only IV, in severe cases of CHF

milrinone more potent than inamrinone

inamrinone

milrinone

dobutamine

dobutamine is classified as ____

b1- agonist

dobutamine: Phenyl ethyl amine backbone with catechol structure like dopamine but with big N- substitution to drive it to the beta receptors, the absence of the _____ group to the nitrogen atom is what make it selective to the B-1 receptors in the heart as we covered before.

beta hydroxyl

dobutamine is availiable as

IV

a polypeptide drug, synthesized by recombinant DNA technology with the same amino acid sequence of endogenous agent called natriuretic peptide. Natriuretic peptide is produced by the heart tissues and acts as diuretic to alleviate edema, and as a heart stimulant when pumping blood is slowed down.

Nesiritide

Being a polypeptide, this drug is used only by injection

Nesiritide

Entresto is a newly approved medication to treat CHF that helps the heart to pump blood into body tissues.

• consists of 2 ingredients

  • _____ used to treat HF

  • ____ inhibits enzyme system responsible for the degradation of endogenous nesiritide

valsartan/sacubitril

Valsartan

Sacubitril