Cardiac glycosides are positive inotropic tonic drugs prescribed for heart failure, they increase the contractile force of the myocardium by increasing the concentration of calcium in the myocardial cell, and block the Na+, K+ -ATPase, or the Na+ pump.
Sommaire
Properties
Cardiac glycosides are glucoside drugs of natural origin extracted from various species like scilla, strophanthus, and foxglove. They are used mainly in the treatment of heart failure. They have a structural analogy that makes them very similar in terms of pharmacological activity, but their pharmacokinetics are different.
Cardiotonic glycosides have a narrow therapeutic index (NTI-drugs).
CARDIAC INOTROPIC EFFECT REFERS TO MYOCARDIAL CONTRACTIBILITY, I.E. THE ABILITY OF MYOCARDIAL MUSCLE CELLS TO CONTRACT IN RESPONSE TO AN ACTION POTENTIAL. THE INOTROPIC EFFECT IS UNDER THE DIRECT INFLUENCE OF THE AUTONOMIC NERVOUS SYSTEM.
CARDIAC BATHMOTROPIC EFFECT REFERS TO CARDIAC EXCITABILITY. A DRUG IS BATHMOTROPIC POSITIVE IF IT INCREASES THIS EXCITABILITY AND BATHMOTROPIC NEGATIVE IF IT DECREASES IT.
CARDIAC DROMOTROPIC EFFECT IS THE SPEED OF CONDUCTION OF NERVE IMPULSES FROM MYOCARDIAL MUSCLE FIBRES. A DRUG IS SAID TO HAVE A NEGATIVE DROMOTROPIC EFFECT IF IT DECREASES INTRACARDIAC CONDUCTION AND A POSITIVE DROMOTROPIC EFFECT IF IT INCREASES IT.
Chemical structure and structure-activity relationship
The saturation of the lactone ring is responsible for the decrease in activity of the molecule and the shortening of its action time. However, if the ring is completely open, the molecule loses its activity completely.
The sugar bound to the genin at C3 through its β-OH can be composed of hexoses (D-glucose), or deoxy-oses (L-rhamnose). The carbohydrate residues are necessary for the solubility of the genin and its cardiotonic activity.
The presence of an OH group on C12 increases the polarity of the glycoside: digitoxin: no OH on C12 (apolar lipophilic molecule), digoxin: presence of an additional OH (more polar molecule), ouabain: presence of 3 OH (very polar molecule).
Pharmacokinetics digoxin, digitoxin
Tissue uptake is high, the tissue concentration can be 10 times the plasma concentration for digitalis and 30 times for digoxin.
Digoxin crosses the placental barrier, the fetal concentration is equal to the maternal concentration. It undergoes the enterohepatic cycle.
Metabolism of digitoxin and digoxin
Digitoxin
Digitoxin is extensively metabolised in the liver, undergoing first hydrolysis and then conjugation of the aglycones or their derivatives. 75% to 90% of the ingested dose is inactivated in the liver cell.
Elimination of the inactivated form of digitoxin is essentially via the bile, it undergoes the enterohepatic cycle. The active form is eliminated by the kidney.
Digitoxin
Digoxin is metabolised in the liver, saturation of the lactone ring and hydrolysis of the osidic molecules produce dihydrodigoxin.
Digoxin is excreted mainly in the intact (93%) active untransformed form after glomerular filtration and is very poorly secreted by the tubule.
The intensity of elimination depends on the degree of lipid solubility.
Mechanism of Action
Cardiotonic Glycosides bind to the extracellular part of the Na+, K+ -ATPase enzyme (the part that binds potassium) and cause a change in its configuration.
This change in configuration is responsible for blocking and directly inhibiting the myocardial cell membrane Na/K-ATPase pump, limiting the expulsion of sodium and increasing the slow calcium inflow.
LETHARGY: DEEP AND PATHOLOGICALLY LONG SLEEP, ACCOMPANIED BY A COMPLETE RELAXATION OF THE MUSCLES.HYPNOTIC LETHARGY. FALLING INTO LETHARGY.
Effects of digitalis
Cardiac actions
The cardiac actions of digitalis are grouped in the “3S” rule: the heart is slowed down, strengthened, and stabilized.
Positive inotropic effect: which is the increase in contractile force is based on the inhibition of membrane Na+/K+ ATPase.
Positive bathmotropic effect: which is the increase in myocardial excitability by the creation of pathological automatism foci (calcium overload in the baroreceptor cells).
Negative chronotropic effect: (bradycardia) is caused by the reduction in sympathetic activity and, to a lesser extent, by the increase in parasympathetic activity at the sinus level.
The negative dromotropic effect: which is the decrease in the conduction of electrical impulses, it results from a lengthening of the refractory periods at the level of the atrioventricular node.
The parasympathomimetic activity of digitalis is also involved.
Extracardiac actions
Actions on the central nervous system (CNS)
- Mental and visual disturbances
- CNS depression: anorexia, lethargy
- Stimulation of the vomiting centre of the medulla oblongata
Effect on the autonomic nervous system
Mainly through stimulation of the vagus directly, or indirectly through the baroreceptors.
On the digestive tract
Increase in intestinal peristalsis until the appearance of spasms leading to vomiting and diarrhea.
Other actions
On the vessels: vasoconstriction.
On the kidney: Natriuretic action in the renal tubule (inhibition of active sodium reabsorption).
Therapeutic indications
- Acute and chronic heart failure.
- Supraventricular rhythm disorders.
Intoxication
Toxic effects are often related to overdose.
| Dose | Digitoxin | Digoxin |
| Therapeutic | 15-25 ng/ml | 0.8-2.0 ng/ml |
| Toxic | > 30 ng/ml | > 2.5 ng/ml |
Symptoms
- Vomiting: earliest signs (80% of cases)
- Cardiac rhythm disorders: sinus bradycardia, tachycardia, extrasystoles, conduction disorders (auriculoventricular bradycardia).
- Disorientation, hallucinations, confusion, headache, risk of convulsions, deficient color vision (action on the retina)
- Impaired renal function, especially in elderly patients.
Treatment
Evacuation treatment: repeated gastric cleansing with activated charcoal.
Symptomatic treatment:
- Correction of dyskalaemia.
- Treatment of bradycardia by administration of atropine and of arrhythmia by administration of antiarrhythmics.
Specific treatment: Antidote: Specific anti-digoxin monoclonal antibodies (80mg Fab neutralises 1mg digoxin or digitoxin).
Analytical detection and dosage
Sampling: plasma or serum.
Characterisation Colour reaction: antimony pentachloride test: virgae from yellow to brown-black then to violet.
TLC: benzene-ethanol system (7V-3V): frontal Rf ratios of lanatoside = 0.35, Digoxin = 0.62, and Digitoxin = 0.72.
Fluorescence at 350 nm after spraying with perchloric acid: digoxin gives a Blue coloration and digitoxin gives a Red coloration.
Reaction with p-anisaldehyde and heating at 100°C: digoxin gives a Red coloration and digitoxin gives a Blue coloration.
Chromatin T test: digoxin gives a visible brown ring and a blue-green fluorescence at 366 nm.
Determination
Determination by enzyme immunoassay for digoxin.
Determination by LC/MS.