cardiac glycoside

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Group of steroidal glycosides act as cardio tonic agent. They increase tone, excitability and contractility of cardiac muscles.

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NARENDRA SINHG LODHI :

NARENDRA SINHG LODHI FROM ORIENTAL COLLEGE OF PHARMACY BHOPAL [M.P] INDIA

The Cardiac Glycosides Cardio-active Glycosides:

Group of steroidal glycosides act as cardiotonic agent. They increase tone, excitability and contractility of cardiac muscles. The Cardiac Glycosides Cardio-active Glycosides

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Heart diseases can be primarily grouped into three major disorders: Cardiac failure Ischemia Cardiac arrhythmia.

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Cardiac failure can be described as the inability of the heart to pump blood effectively at a rate that meets the needs of the metabolizing tissues. This occurs when the muscles that perform contraction and force the blood out of heart are performing weakly. Thus cardiac failures primarily arise from the reduced contractility of heart muscles, especially the ventricles. Reduced contraction of heart leads to reduced heart output but new blood keeps coming in resulting in the increase in heart blood volume. The heart feels congested. Hence the term congestive heart failure . Congestive Heart Failure

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Congested heart leads to lowered blood pressure and poor renal blood flow. This results in the development of edema in the lower extremities and the lung (pulmonary edema) as well as renal failure.

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Cardiac Glycosides Increasing the force of contraction of the heart (positive inotropic activity) is very important for most heart failure patients. Structure composed of two structural features : Cardiac glycosides Aglycone Sugar (steroid nucleus) (monosaccharide or a polysaccharide with β-1,4- glucosidic linkages)

Structure features::

Structure features: Steroidal nucleus must be present. 3 b -OH group involved in glycosidic linkage. 14 b -OH group at C-14. A/B ring junction cis B/C ring junction trans C/D ring junction cis Additional oH groups at C-5, C-11 and C-16 may be present. The presence of lactone ring:

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According to the type of lactone ring Cardiac Glycosides are classified into: Cardinolides: They are C-23 containing 5-membered unsaturated lactone ring e.g. Digitalis & Strophanthus Bufadienolides: They are C-24 containing 6-membered unsaturated lactone ring e.g. Squill

The Sugar Part::

The Sugar Part: The glycosides usually contain 3 to 4 sugars attached at C-3 OH. Beside Glucose and Rhamnose they usually contain deoxysugars.

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Biochemical Mechanism of Action The mechanism whereby cardiac glycosides cause a positive inotropic effect and electrophysiologic changes is still not completely clear. Several mechanisms have been proposed, but the most widely accepted involves the ability of cardiac glycosides to inhibit the membrane bound Na + -K + -ATPase pump responsible for Na + -K + exchange. The process of muscle contraction can be pictured as shown below.

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Cardiac glycosides cause positive inotropic effect At the resting state (no conduction) (Conc. of Na + is high on the outside ) sodium fluxes-in leading to an immediate elevation of the action potential On membrane depolarization Elevated intracellular Na + triggers the influx of free of Ca ++ that occurs more slowly

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This results in the efflux of K + The reestablishment of the action potential occurs later by the reverse of the Na + -K + exchange The Na + / K + exchange requires energy which is provided by an enzyme Na + -K + - ATPase Cardiac glycosides inhibit Na + -K + - ATPase enzyme

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Reduced sodium exchange with potassium (i.e. ↑ sed intracellular Na + ) Results This results in increased intracellular [Ca ++ ] Elevated intracellular calcium concentration triggers a series of intracellular biochemical events that ultimately result in an increase in the force of the myocardial contraction or a positive inotropic effect.

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S tructure - Activity Relationships 1. The sugar moiety appears to be important only for the partitioning and kinetics of actionIt possesses no biological activity. For example, elimination of the aglycone moiety eliminates the activity of alleviating symptoms associated with cardiac failure. Pharmacokinetics of Cardiac Glycosides The commercially available cardiac steroids differ markedly in their degree of absorption, half-life, and the time to maximal effect (see table below).

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Agent GI absorption Onset (m) Peak (h) Half-life Ouabain Unreliable 5-10 0.5-2 21 h Deslanoside Unreliable 10-30 1-2 33 h Digoxin 55-75% 15-30 1.5-5 36 h Digitoxin 90-100% 25-120 4-12 4-6 days Usually this is due to the polarity differences caused by the number of sugars at C-3 and the presence of additional hydroxyls on the cardenolide.

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Two cardiac glycosides may differ by only one sugar residue their partition co-efficients may be significantly different resulting in different pharmacokinetics .

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In general, cardiac glycosides with more lipophilic character are absorbed faster and exhibit longer duration of action as a result of slower urinary exretion rate. Lipophilicity is markely influenced by the number of sugar residues and the number of hydroxyl groups on the aglycone part of the glycoside.

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2 . The "backbone" U shape of the steroid nucleus appears to be very important. Structures with C/D trans fusion are inactive.

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3. Conversion to A/B trans system leads to a marked drop in activity. Thus although not mandatory A/B cis fusion is important. 4. The 14b-OH groups is now believed to be dispensible . A skeleton without 14b-OH group but retaining the C/D cis ring fusion was found to retain activity. 5. Lactones alone, when not attached to the steroid skeleton, are not active. Thus the activity rests in the steroid skeleton.

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6. The unsaturated 17-lactone plays an important role in receptor binding. Saturation of the lactone ring dramatically reduced the biological activity. 7. The lactone ring is not absolutely required. For example, using a,b -unsaturated nitrile (C=C-CN group) the lactone could be replaced with little or no loss in biological activity.

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The End

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