Digoxin (Does not reduce mortality but reduces morbidity and hospitalisation for heart failure)
9.1 Mechanism of action:
1. ***Potent inhibitors of the active transport of Na+/K+ across cell membranes.
-Reversible binding to subunit of Na+, K+ ATPase.
-Both sodium and calcium ions enter cardiac muscle cells during each depolarisation.
Normally, Calcium entry triggers contraction. It is then taken into the Sarcoplasmic reticulum via SERCA (S.R. calcium ATPase)
-It is also removed from the cell via Na+/Ca2+ exchanger (NCX) and sarcolemmal Ca2+ ATPase.
∴Inhibition of Na+/K+ ATPase by digoxin results in a reduction in rate of Na+ removal (dump out of cell). Na+ accumulates in cell.
-Reduces ability of NCX ability to remove Calcium ions during myocyte repolarisation.
-As Ca2+ accumulates (due to repeated entry of ions) and reduced efflux of Calcium ions, the calcium ion intake into the SR is increased.
Ultimately, the calcium present in the SR increases and more is released during the next ECC (excitation-contraction coupling). Increases myocardial contractility!!!
2. Increases force of myocardial contraction (Positive inotropic)
3. Decreases AV nodal conduction (predominantly by its vagotonic effect on the heart). Decreases automaticity.
4. Increases diastolic resting membrane potential in atrial and AV nodal tissues (Easier to reach threshold) ??? ASK JOE WOULDN’T THAT INCREASE AUTOMATICITY?
Vagontonic: hyperexcitability of the vagus nerve, producing bradycardia, decreased heart output, and faintness.
4. Modulates ANS (autonomic nervous system). This contributes to their efficacy in the management of CHF. Decreases sympathetic tone.
5. May increase excitability of cardiac muscle (particularly at higher doses)–>Atrial and Ventricular arrhythmias (AT HIGHER DOSES).
-This simultaneous non-uniform increase in automaticity and depression of conduction in Purkinje fibres and ventricular muscle fibres can cause serious ventricular arrhythmias.
9.2 Clinical Indications
(a) Atrial and AF flutter (Decrease heart rate)
(b) Heart Failure
1. Hyperthyroidism and fever. Both of these conditions increase sympathetic tone thus making digoxin relatively ineffective (Since digoxin affects ANS too)
Solution: Treat underlying cause and use larger doses or another agent.
2. Hypothyroidism. May increase sensitivity to digoxin
Solution: Require smaller doses.
3. Hypokalemia, Hypomagnesemia, Hypercalcemia (i.e. lack of electrolytes) and Hypoxia (lack of oxygen)
-Increase risk of digoxin toxicity
-Increases risk of digoxin toxicity due to electrolyte imbalance and oxygen imbalance.
Solution: Correct electrolyte imbalance.
4. Cardiac Issues
-Contraindicated in second or third degree heart block (without pace-maker)–>Arrhythymias
-Contraindicated in SVT (sino-ventricular tachycardia) involving accessory pathway–>Wolff-Parkinson-White syndrome (Bundle of Kent affected)
*Second-degree heart block may result in the heart skipping a beat or beats. This type of heart block also can make you feel dizzy or faint.
*Third-degree heart block limits the heart’s ability to pump blood to the rest of the body. This type of heart block may cause fatigue (tiredness), dizziness, and fainting. Third-degree heart block requires prompt treatment because it can be fatal.
-Contraindicated in Ventricular tacycardia and filbrillation
-Contraindicated in Hypertrophic obstructive cardiomypopathy or cor pulmonale (acute and chronic)
*Cor Pulmonle-Enlargement of the right ventricle of the heart as a response to increased pressure in lungs (Pulmonary hypertension)
-Contraindicated in constrictive pericarditis
Use cautiously in the following cardiac conditions:
–In acute MI, ischemic heart disease or myocarditis. Digoxin incresaes risk of arrhythmias.
-Sick Sinus Syndrome. Increases risk of severe bradycardia or sinoatrial block.
-Severe aortic stenosis. Digoxen may worsen cardiac function because it increases force of myocardial contraction (Positive inotropic)
5. Renal Issues (Impaired)
-Digoxin is mainly renal cleared (70%)
Solution: Reduce dose in renal impairment.
6. Elderly-Reduce dose.
7. Pregnancy-Safe to use, dose requirement is not predictable. Safe to use when breastfeeding.
Solution: Depending on circumstance, increased dose may be required. ***Used to treat fetal arrhythmias (CAT A-AUS)
9.4 Adverse effects/ Side effects
***Potential to worsen arrhythmia/Proarrhythmic effect
VERY VERY VERY VERY IMPORTANT: DIGOXIN HAS A NARROW THERAPEUTIC INDEX (Side effects may occur at <1 nanomol/L)
1. Effect on ECG. Digoxin results in prolonged PR interval, ST depression or T-wave inversion.
-Apart from the effect on PR interval, which is a sign of toxicity, these ECG changes do not necessarily mean digoxin toxicity or MI.
-In children, arrhythmias (including sinus bradycardia) are the earliest and most frequent indicator that digoxin dosage is too high.
2. Blurred vision (Xanthopsia Yellow)
3. Arrhythmias (mentioned above)
7. Psychosis (acute)
Acronym: BAN CARDIAC DIGOXIN PLANTS!!!
8. Vomitting, diarrhoea, anorexia, drowsiness, dizziness, nightmares, agitation
Infrequent side effects: Delirium, amnesia, shorterned QRS complex, atrial or ventricular extrasystoles, paroxysmal atrial tachycardia with AV block, ventricular tachycardia or filbrillation, heart block, Gynaecomastia (prolonged use)
Rare: Rash, thrombocytopenia, seizures
-t1/2 for digoxin is 36 hours in patients with normal renal function.
-Steady-state blood levels achieved in around 5 days-1 week after initiation of maintenance therapy
-Digoxin excreted via kidneys (mentioned previously) at a clearance proportional to GFR. This means that if anything that alters GFR (e.g. renal insufficiency/renal arterial stenosis will potentially affect clearance of digoxin.
-It is a CYP3A4 substrate [Note and remember all the CYP3A4 substrates]. Potential drug interactions.
9.6 Practice Points + Counselling
1. ADJUST DOSAGE ACCORDING TO PATIENTS RENAL/HEPATIC/CARDIAC CONDITION!!!
Adjust/Tailor dosage according to renal function, clinical response and therapeutic drug monitoring.
-Digitalisation with loading dose is needed only to treat arrhythmias and is usually not required for heart failure.
-IV administration is seldom required and offers little therapeutic advantage over oral dosage.
What is a loading dose?
e.g. Adult loading dose, oral/IV 250-500 mcg/ every 4-6 hours. Max 1.5 mg
Maintenance dose, oral 125250 mcg/ once daily (Rarely increased up to 500 mcg daily)
*The above dosages are from AMH 2012.
2. MONITOR DIGOXIN SERUM CONCENTRATIONS!!!
*Careful concentration monitoring is required!!!
-Take blood sample at least 6 hours after a dose to allow for redistribution.
-Steady state is reached in about 5 days if renal function is normal (half life is 36 hours). Renal impairment t1/2 increases.
-Manufacturers recommend a therapeutic range of 0.5-2 mcg/L (0.5-2 nanograms/ml). However, do note that toxic effects (e.g. anorexia, nausea, vomitting) occur at this range.
*Strike a balance between clinical benefit and the occurance of clinical side effects. Reduce dose if necessary.
-Remember that (look at precautions) that we said that the elderly, electrolyte imbalanced individual, hypoxia or hypothyroidism individuals are more susceptible to digoxin toxicity.
-Interpret the results of concentration monitoring in relation to clinical condition (DON’T JUST ASSUME ONE SIZE FITS ALL e.g. PATIENT MAY APPEAR TO have normal levels but has hepatic impairment.
3. USE IN HEART FAILURE!!!
-Consider using lower concentrations of 0.5-0.8 micrograms/L for patients with Heart Failure who are in sinus rhythm (normal beating of the heart, as measured by an electrocardiogram (ECG)).
-Higher concentrations of digoxin within the therapeutic range may be associated with increased rates of mortality and hospitalisation.
4. ADVICE/COUNSEL/INFORM PATIENTS ON ADMINISTRATION!!!
*Administration: Give IV over at least 5 mins, compatible fluids are sodium chloride 0.9%, glucose 5% and glucose/sodium chloride solution
*DO NOT GIVE INTRAMUSCULARLY (unpredictable absorption, local irritation)
*Counselling-Check if the patient is taking any OTC or herbal products.
-Always check the renal function and electrolyte concentration before starting digoxin
-OAA: 4-6 hours after initial dose
-Regularly assess patients for evidence of digoxin toxcitiy (including resting heart rate) , Routine measurement of pulse rate before giving next dose of digoxin is not needed.
-Assume that any arrhythmia that occurs in a child taking taking digoxin is due to the drug until proven otherwise. (GUILTY UNLESS PROVEN OTHERWISE)
-Stop Digoxin if patient reverts to sinus rhythm. *DOES NOT HAVE ANY PREVENTIVE ROLE IN PAROXYSMAL AF OR FLUTTER.
Paroxysmal-Sudden attack or incidence of symptoms
-If another arrhythmic agent (e.g. Verapamil, Diltiazem) is combined with digoxin, try to reduce and stop digoxin once patient is stable.
Therapeutic range of 0.5-2 mcg/L (0.5-2 nanograms/ml) [Manufacturer recommended]
Therapeutic range of 0.5-2 mcg/L (0.5-2 nanograms/ml)
Therapeutic range of 0.5-2 mcg/L (0.5-2 nanograms/ml)
9.7 Drug Interactions
1. Digoxin is a CYP3A4 substrate. SO ANYTHING THAT CAN INHIBIT OR A SUBSTRATE OF CYP3A4 WILL AFFECT METABOLISM!!!
-Remember list of CYP3A4 SUBSTRATES AND INHIBITORS.
2. Anti-arrhythmic agents used in combination (e.g. amiodarone)
3. Care with drugs that lower K+ levels (ARBs, ACE-inhibitors–>Refer to acronym…Captain Ace….)(Loop diuretics also will affect) or
4. Care with drugs that lower Mg2+ levels
*Note: There are drugs out there that can reduce digoxin toxicity (e.g. DIGIBIND-Digoxin specific antibody/Fab fragments)