TDM of drugs used in cardiovascular diseases
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This document discusses therapeutic drug monitoring (TDM) of drugs used to treat cardiovascular diseases, with a focus on digoxin. It provides details on the indications, pharmacokinetics, and appropriate use of TDM for digoxin including confirming toxicity, assessing factors that alter pharmacokinetics, addressing therapeutic failure, and ensuring medication compliance. The document also discusses dose adjustment and interpreting digoxin concentrations in the context of the clinical situation.
TDM of drugs used in cardiovascular diseases
- 1. TDM OF DRUGS USED IN CARDIOVASCULAR DISEASE DR. RAMESH BHANDARI ASST. PROFESSOR DEPARTMENT OF PHARMACY PRACTICE KLE COLLEGE OF PHARMACY, BELAGAVI
- 2. Dr. Ramesh Bhandari INTRODUCTION Cardiovascular drugs are primarily used for the treatment of cardiovascular diseases like angina, arrhythmias and heart failure. Digoxin used in congestive cardiac failure is therapeutically monitored. Following drugs also can be therapeutically monitored: Disopyramide Lidocaine Flecainide
- 3. Dr. Ramesh Bhandari TDM OF DIGOXIN In 1785, Sir William withering published the first account of digitalis in cardiovascular medicine. Since that time, digoxin has been used in systolic heart failure or Heart Failure and controlling ventricular response in atrial fibrillation and flutter. Digoxin’s positive inotropic effects were thought to result primarily from inhibition of the sodium potassium ATPase Pump and use in atrial fibrillation is due to enhancement of afferent inhibitory activity and diminishes sympathetic nervous system.
- 4. Dr. Ramesh Bhandari TDM OF DIGOXIN It’s been more than 30 years since TDM was introduced for digoxin and resulted in a marked reduction in the digoxin toxicity. Despite a long experience of TDM with this drug, the way in which TDM is performed is often inappropriate. Hence these problems most likely relate to a lack of knowledge about the practice of digoxin TDM.
- 5. Dr. Ramesh Bhandari General pharmacokinetics of DIGOXIN Distribution: Highly distributed to lean organ tissues (Heart, muscle, Kidney and liver) Elimination: Renal- 50-70% Non –renal 30-50% (Mainly through biliary and Intestinal tracts) Protein binding: 20-30% (Reduced during hypoalbuminemia but not clinically significant) Volume of distribution: Adults 6.7±1.4L/kg (varies according to age) Half life: Adults – 36±8 hours
- 6. Dr. Ramesh Bhandari INDICATIONS FOR TDM OF DIGOXIN Confirmation of toxicity Assessing the effect of factors altering pharmacokinetic Therapeutic Failure Medication Compliance
- 7. Dr. Ramesh Bhandari CONFIRMATION OF TOXICITY Need to measure digoxin concentration for confirmation of toxicity is related to low therapeutic index of digoxin. Recommended therapeutic range is 0.5-2.0 ng/l. Toxicity occurs with serum concentration over 2.0 ng/l and is invariable once the concentration exceeds 3.0 ng/l. Symptoms include: Nausea, vomiting, abdominal pain, diarrhoea, confusion, dizziness, agitation, arrhythmias, heat block and various visual symptoms. Toxicity is a clinical diagnosis supported by an increase digoxin concentration but clinical suspicion of toxicity correlates poorly with high concentration.
- 8. Dr. Ramesh Bhandari ASSESSING THE EFFECT OF FACTORS ALTERING PHARMACOKINETICS Various factors influence the pharmacokinetics of digoxin in an individual, but renal function is the major contributor. Maintenance dose estimation based on calculation of the patient’s creatinine clearance using the Cockcroft and Gault equation will usually result in appropriate dose in most patients. However, renal function alone does not explain all the variances in serum digoxin concentration. Some of the unpredictable relationship between dose and serum concentration of digoxin may be explained by genetic polymorphism of the p-glycoprotein gene.
- 9. Dr. Ramesh Bhandari ASSESSING THE EFFECT OF FACTORS ALTERING PHARMACOKINETICS P-glycoprotein is involved in the transport of digoxin into the body in the GIT and out of the body in the renal tubules. Mutation within these genes have been shown to alter the bioavailability and renal clearance of digoxin. Drug Interaction also affect serum concentrations of digoxin, usually through competitive inhibition of p-glycoprotein activity. Sources of variability other than renal function are less predictable or measurable, adjusting an individual maintenance dose on the basis of their creatinine clearance remains the best starting point for dose individualization.
- 10. Dr. Ramesh Bhandari DRUG INTERACTIONS FOR DIGOXIN Drugs that increase digoxin concentration: •Diuretics: Spironolactone, Amiloride, Triamterene •Antiarrhythmics: Quinidine, Amiodarone •Calcium Antagonist: verapamil •Statins: Atorvastatin Drugs that decreases digoxin concentration: •Rifampicin: Induces P-glycoprotein mediated tubular secretion. •Liquid Antacids: Reduce digoxin absorption
- 11. Dr. Ramesh Bhandari THERAPEUTIC FAILURE oWith respect to improving rate control in chronic atrial fibrillation, few studies suggested weak correlation between digoxin concentration and ventricular rate. oThis is may be due to number of other influences on the atrio- ventricular node such as altered sympathetic drive with other comorbidities like sepsis, hypoxia etc. oThus, TDM for individual patients may be useful to detect patients with a low digoxin concentration and who may benefit from an increase in digoxin dose.
- 12. Dr. Ramesh Bhandari THERAPEUTIC FAILURE oIn Heart failure there is increasing evidence that concentration lower than the currently recommended limit of the therapeutic range may be as efficacious as higher concentrations. oResults from many trials suggests that digoxin concentration between 0.5 – 1 ng/L is more efficacious than higher concentrations in patient with heart failure.
- 13. Dr. Ramesh Bhandari APPROPRIATE SAMPLING TIME Digoxin concentrations should be measured at least eight hours following an oral dose of digoxin and ideally when concentration have reached steady state. Digoxin is well absorbed with peak serum concentrations occurring within one hour. A large volume of distribution reflects that digoxin concentrates in the tissues with the active site being within the myocardium. Redistribution from serum to tissue takes at least 6 – 8 hours. Steady state of digoxin had to have been reached after 5 half lives after digoxin was initiated or after digoxin dose adjustment. (with normal renal function)
- 14. Digoxin Concentration (ng/L) Time in Hours 0 4 8 12 16 20 24 1 2 3 4 Distribution phase Sampling Time Elimination Phase PLASMA DIGOXIN CONCENTRATION PROFILE AFTER AN ORAL DOSE
- 15. Dr. Ramesh Bhandari DOSE ADJUSTMENT Digoxin serum concentrations should be interpreted with respect to the clinical context. Generally, concentration is above the therapeutic range, the dose should be reduced even in the absence of obvious toxicity because the patient is at risk of arrhythmia and there is no any efficacy associated with high concentration. Toxicity can occur with concentrations within the therapeutic range due to several known factors that change tissue sensitivity to digoxin and alter the therapeutic index.
- 16. Dr. Ramesh Bhandari DOSE ADJUSTMENT The period of time that digoxin should be withheld following an episode of toxicity depends on concentration and half life of digoxin in that patient. In normal renal function patient, if concentration is 3.0 ng/L, the digoxin should be withheld for 1-2 days before restarting at the appropriately altered dose, as this will allow the concentration to drop to within the therapeutic range. In renal impairment with a prolonged digoxin half life doses may need to be withheld for several days.
- 17. Dr. Ramesh Bhandari DOSE ADJUSTMENT When the measured digoxin concentration is low, either stopping treatment or increasing the dose or making no change. In atrial fibrillation, if current heart rate is appropriate in the presence of low digoxin concentrations a trial without digoxin may be appropriate. If ventricular rate is not controlled a dose increase is usually indicated. Dose adjustment for therapeutic failure should ideally only be performed following a digoxin concentration measured at steady state.
- 18. Dr. Ramesh Bhandari DOSE ADJUSTMENT A change in dose will normally result in a proportional change in digoxin concentration. i.e. doubling the dose will double the digoxin concentration and half the dose will half the concentration. (Assuming normal Renal function and no drug interaction) If change in renal function, the adjustment can be estimated by calculating the change in creatinine clearance using the Cockcroft Gault equation.
- 19. Dr. Ramesh Bhandari DOSE ADJUSTMENT CrCl Percentage of normal recommended dose Interval >50 ml/min 100 24 hour 10-50 ml/min 25-75 24-36 hour <10 ml/min 10-25 48 hour
- 20. THANK YOU