Cardiovascular drugs
Digitalis
Cardiac glycosides include digoxin, digitoxin and ouabin. These are
derived from plant Foxglove (Digitalis purpurea). Cardiac glycosides
composed of steroid nucleus linked to a lactone ring and a series of
sugars.
Clinical uses: treatment of congestive heart failure and management of
supraventricular rhythm disturbances.
Pharmacokinetics: digoxin is taken orally, well absorbed but in some
patients (10%) the presence of some enteric bacteria may cause
degradation of the drug and the use of broad spectrum antibiotics may
cause sudden increase in serum digoxin level causing toxicity. Cardiac
glycosides are widely distributed to tissues including CNS. Digoxin is
excreted unchanged by the kidney; the dose should be adjusted in patients
with renal impairment. Digitoxin is metabolized in the liver and excreted
in bile.
Digoxin has narrow therapeutic index; the toxic dose is 2 ngm/ml which
is near to the therapeutic dose which is 1.1 ngm/ml.
Cardiac effect
1- Mechanical effect
Through inhibition of Na+/K+ ATPase enzyme (membrane bound
enzyme). This enzyme keep K+ inside the cell and Na+ outside the
cell; so when this enzyme is inhibited K+ transport back into the
cell is blocked and its concentration in the extracellular fluid
increases, at the same time Na ions will enter the cell and this will
promote or facilitate the entry of Ca +2 which are essential for the
contraction of actin and myosine.
2- Electrical effect ( direct effect and autonomic effect)
a- Direct effect
It causes brief prolongation of the action potential followed by a
period of shortening especially the plateau phase. The decrease
in the action potential duration is probably the result of increase
potassium conductance that is caused by increase intracellular
ca ions. All these effects can be observed at therapeutic
concentration in the absence of over toxicity.
Shortening of the action potential contributes to the shortening
of atrial and ventricular refractoriness.
At higher concentration resting membrane potential is redused
(made less negative) as aresult of inhibition of sodium pump
and reduced intracellular K+, this lead to appearance of
ascillatory depolarizing afterpotential which followed normally
evoked action potentials. The afterpotentials also known as
delayed afterdepolarizations are associated with overloading of
the intracellular Ca+2 store.
 When below threshold, these afterpotentials may interfere
with normal conduction.
 When afterpotential reach threshold it elicits an action
potential (premature depolarization or ectopic beat).
 If afterpotentials in the purkinje conducting system
regularly reach threshold bigeminy will be recorded on
the electrocardiogram (ECG).
NSR: an inverted T wave and depressed ST segment are present.
PVB: is a manifestations of depolarization evoked by delayed oscillatory
afterpotential.
With further intoxication, each afterpotential evoked action potential will
itself elicit a suprathreshold afterpotential, lead to tachycardia and
fibrillation.
b- Autonomic action (indirect)
Indirect action include sympathetic and parasympathetic.
At low dose parasympathomimetic effects predominate, lead to
decrease heart rate, decrease conduction velocity, prolongation
of refractory period so digoxin used in the treatment of
supraventricular arrhythmia.
At toxic level sympathetic out flow is increased lead to increase
heart rate and contraction.
Manifestation of digitalis toxicity
1- Gastrointestinal effect: anorexia, nausea and vomiting.
They are the earliest signs of toxicity.
2- Visual effect: blurred vision, loss of visual acuity and
yellow-green halos.
3- CNS effect: headache, fatigue and confusion.
4- Cardiac effect: sever dysrhythmia moving from decreased
or blocked atrioventricular nodal conduction, paroxysmal
supraventricular tachycardia to the conversion of atrial
flutter to atrial fibrillation, premature ventricular
depolarization, ventricular fibrillation and finally complete
heart block.
5- Endocrinological
effect:
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antiandrogenic effect of the drug.
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Factors predisposing to digitalis toxicity
1- Electrolyte disturbances: hypokalemia, hypomagnesemia and
hypercalcemia predispose digitalis toxicity.
2- Hypothyroidism, hypoxia, renal failure and myocarditis are
predisposing factors to digitalis toxicity.
3- Drugs: quinidine can cause digitalis intixicationboth by displacing
digitalis from plasma protein binding sites and by competing with
digitalis for renal excretion.
Verapamil also diplace digitalis from plasma protein binding site
and can increase digoxin levels by 50-75%, this may require a
reduction in the dose of digoxin.
Potassium depleting diuretics, corticosterois and a variety of drugs
can also increase toxicity.
4- Use of antibiotic lead to kill microorganisms like Eubacterium
lentum so lead to toxicity.
Treatment of digitalis toxicity
1- Removing of ingested drug by vomiting, gastric lavage, use of
adsorbant agents eg. Activated charcoal, cholestyramine and
colestepol.
2- Maintenance of a normal potassium concentration: hypokalemia is
more common after chronic digitalis toxicity, while massive acute
overdoses often causes hyperkalemia. Potassium compete with
digoxin on Na+/K+-ATPase pump so decrease K+ level and increase
digoxin activity and toxicity.
Hyperkalemia may require treatment with insulin, dextrose,
bicarbonate and sodium polystyrene sulfonate. In case of
hypokalemia continuous potassium replacement may be sufficient.
Potassium administration may correct arrhythmias restoring
intracellular concentration.
3- Reversal of arrhythmias: for atrial and ventricular arrhythmias that
do not respond to potassium therapy the treatment of choice
includes phenytoin and lidocaine. Phenytoin increase AV nodal
conduction and directly reverse the toxic action of digitalis at AV
node without interfering with its inotropic action. While quinidine
and procainamide are not used because they slow AV nodal
conduction.
If digitalis has produced AV block, the vagolytic action of atropine
may increase heart rate and AV conduction. Catecholamines are
contraindicated for the treatment of bradyarrhythmias because they
increase the risk of precipitating more serious ectopic arrhythmias.
Β-blockers such as propranolol are useful to suppress
supraventricular and ventricular arrhythmias induced by digitalis
toxicity.
4- Increase removal of unabsorbed drug: the use of dieresis or
hemodialysis have not been successful because of the large volume
of distribution for digitalis. Hemodialysis may be equired to
control hyperkalemia.
5- Use of specific antidote digoxin immune Fab: these are antibody
fragments prepared by conjugation of digoxin to human or bovine
serum albumin. This is then used to immunize sheep, which
produce antibodies. Their sera are obtained and purified yielding
the drug.
The fragments are less immunogenic and can be eliminated by
glomerular filtration.
Adverse effects to digoxin immune Fab are minimal including