DIGITALIS

  • Need to know PK, PD, adverse effects and interactions of digoxin well.
Structure/class
  1. Cardiac glycoside
Pharmacodynamics
  1. It is an inhibitor of Na+/K+ ATP-ase.
    • Therefore – this increases intracellular Na+ and decreased intracellular K+.
    • Because of increased intracellular Na+, there is reduced Na/Ca exchanger activity and therefore, there is an increase in intracellular calcium.
    • This increase in intracellular Ca2+ causes an increase in contractility.
  2. Electrical effects
    • At higher concentrations of digitalis, a relative extracellular hyperkalemia and intracellular hypercalcaemia occurs.
    • This leads to increased automaticity of the heart muscle (easier for the myocyte to reach threshold potential). Therefore, there are patterns of bigeminy, followed by VT and then VF.
  3. Parasympathetic and sympathetic effects
    • At lower doses, digoxin has parasympathetic effects: early signs of toxicity are bradycardia and AV block. At higher doses of toxicity, there is an increased sympathetic effect which may further sensitize the myocardium to automaticity.
  4. Other system effects
    • GIT: it excites the GIT tissues, so patients develop anorexia/nausea/vomiting/diarrhea.
    • CNS: disorientation and visual hallucinations may be present.
Absorption/Administration
Distribution
  1. It has a large Vd à 6.3L/kg. This allows it to enter the CNS. It accumulates in the heart, kidney and liver.
Metabolism
  1. Less than 20% is metabolized.
Excretion
  1. Mostly excreted unchanged in kidneys (And therefore, needs dose adjustment in renal failure). Its T ½ is 40 hours.
Indications
  1. AF, especially in the setting of heart failure.

 
Contraindications
Special precautions
  1. Renal failure
  2. Hyperkalemia
  3. Hypothyroidism
Interactions
  1. Electrolytes
    • Hyperkalemia – hyperkalemia inhibits digoxin binding to the Na/K ATP-ase. Hyperkalemia itself also reduces cardiac automaticity. Therefore, moderate hyperkalemia will reduce the toxicity of digoxin.
    • Hypercalcaemia – potentiates digoxin toxicity by increasing the intracellular Ca2+ stores, producing automaticity.
    • Hypermagnesemia – opposite effect to hypercalcaemia.
  2. Drugs that increase digoxin effect
    • Amiodarone (by increasing plasma digoxin concentrate), diltiazem, verapamil, quinidine, macrolide antibiotics (azithromycin, erythromycin and clarithromycin), K+ depleting drugs (including diuretics), spironolactone and propafenone.
  3. Drugs that decrease digoxin effect
    • Kaolin pectin, rifampicin (by increasing metabolism) and sulfasalazine (by decreasing GI absorption)

 
Adverse events
  1. As mentioned above
Dosing/administration
Toxicology
  1. Symptoms as mentioned above.
    • Specific antidote is DigiFab antibody, where 1 vial (40mg) binds to ~0.5mg digoxin.
Withdrawal syndrome
Special notes