Wednesday, 5 September 2012

Chemistry and pharmacology of cardiac glycosides (drugs for congestive heart failure): Notes for GPAT


Topic of cardiac glycosides is also of prime importance for the preparation of GPAT. You will find one or two questions every in the GPAT question paper. Cardiac glycosides or cardenolides are only drugs available in the market for the treatment of congestive heart failure or CHF. Digoxin and digitoxin are two important drugs of this class of cardiac glycosides.
In this article I am discussing the complete chemistry and pharmacology of cardiac glycosides to make you understand it completely. Cardiac glycosides affect the heart in two ways-
  • Directly by increasing the positive ionotropic effect on the heart muscles.
  • Indirectly by increasing sympathetic nervous system activity (decrease vagal nerve activity).

a) Chemistry of Cardiac glycosides:

To study the cardiac glycosides, it has become indispensable to study the chemistry of these compounds. Chemistry of cardenolides mainly can be studied in two parts first, chemistry of aglycone part and second, chemistry of sugar moiety or glycone part. Here is the detail description of each part separately-

Chemistry of aglycone part of cardiac glycosides- 

Aglycone part of the cardenolides is made up of 4 rings fused to form a ring skeleton of 17 carbon atoms.
A-B & C-D rings are cis-fused whereas, B-C rings are Trans fused.
There present an angular CH3 group at C-10 and C-13 position of the primary skeleton of the ring system.
OH groups at C-12 & C-16 position are the distinguishing property between digoxgenin, digitoxgenin and gitoxigenin.
There presents a five α-β unsaturated membered lactone ring at C-17 position of the basic ring.

Structure of cardenolides/cardiac glycosides.

Chemistry of sugar moieties or glycone part of cardiac glycosides-

The OH group at C-3 of the aglycone portion usually is conjugated to a monosaccharide or a polysaccharide with β-1,4-glycosidic linkage. These sugars are present in the β-conformation in cardiac glycosides.

Structural requirement for intrinsic activity of cardiac glycosides- There are these three basic structural prerequisite for the cardiac glycosides. These are-
i) There should be β-17 lactone ring present.
ii) OH group at C-14 should also be present in β-orientation.
iii) A-B & C-D rings should be essentially fused cis.

b) Pharmacology of cardiac glycosides:

Pharmacology of the cardiac glycosides is also of prime importance as they are the only class of drugs offering successful treatment of CHF. In the pharmacology, mechanism of action and drug interaction of cardiac glycosides plays an important role so should be dealt carefully.

Mechanism of action of cardiac glycosides- 

The process of membrane depolarization/repolarisation is controlled by Na+, K+ and Ca++. At resting state, concentration of Na+ increases outside the cell and after depolarization concentration of the Na+ comes inside the cell.
This increased Na+ inside the cell activates the calcium channels and hence Ca++ concentration increases inside the cell and which is also responsible for the influx of K+ inside the cell.
At later stage, to restore the membrane potential Na+/K+ exchange occurs by Na+/K+ ATPase pump. Cardiac glycosides block this pump and this ultimately increases the con. of Ca++ inside the cell as there is no efflux of these ions.
These Ca++ ions after undergoing series of reactions enhance the contractibility of myocardial cells.

Absorption, metabolism and excretion of cardiac glycosides- 

More the lipophilicity of the cardiac glycosides more will be the absorption and t1/2 of the glycosides. As digoxin contains 1 extra Oh group than digitoxin so later is more lipophilic than digoxin.
Due to this lipophilicity profile, absorption of digoxin is 70-80% ahereas of digitoxin is 95-100% whereas, t1/2 of digoxin is 1-2 days and that of digitoxin is of 5-7 days.
Digoxin is excreted unchanged from the urine whereas; digitoxin is first metabolized to digoxin in the liver before excretion.

Drug interactions of cardiac glycosides- 

Digoxin is excreted mainly by p-gp mediated mechanism from the kidneys which plays an important role in the drug interactions of these drugs. Major drug interactions of the cardiac glycosides include-
  • In kidney, p-gp mediated renal tubular secretion of the digoxin do occurs but quinidine inhibits p-gp hence decrease the excretion of digoxin which can raise the plasma con. of the drug to toxic level.
  •  Verapamil decrease p-gp of intestine and hence decrease intestine excretion of the drug.
  •  Rifampin induces p-gp and hence enhances the excretion of cardiac glycosides.
  • Thiazine and digoxin shows additive or synergism which ultimately leads to increased hypokalemia.

This is what a student is expected to study in the chemistry and pharmacology of the cardiac glycosides. To study the chemical tests of cardenolides one can refer- Phytochemical screening of different classes of drugs in pharmacognosy.

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