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DRUG INTERACTIONS
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What is a drug interaction? An interaction is said to occur when the effects of one drug are changed by the presence of another drug, herbal medicine, food, drink or by some environmental chemical agent Smith JW, Seidl LG, Cluff LE. Studies on the epidemiology of adverse drug reactions. V. Clinical factors influencing susceptibility. Ann Intern Med (1969) 65, 629. 1. Pharmacokinetic interactions Pharmacokinetic interactions are those that can affect the processes by which drugs are absorbed, distributed, metabolised and excreted (the so called ADME interactions). 1.1. Drug absorption interactions (a) Effects of changes in gastrointestinal Ph (b) Changes in gastrointestinal motility (c) Adsorption, chelation and other complexing mechanisms (d) Induction or inhibition of drug transporter proteins (e) Malabsorption caused by drugs 1.2. Drug distribution interactions (a) Protein-binding interactions (b) Induction or inhibition of drug transport proteins 1.3. Drug metabolism (biotransformation) interactions (a) Changes in first-pass metabolism (i)Changes in blood flow through the liver (ii)Inhibition or induction of first-pass metabolism (b) Enzyme induction (c) Enzyme inhibition (d) Genetic factors in drug metabolism Cytochrome P450 isoenzymes and predicting drug Interactions 1.4. Drug excretion interactions (a) Changes in urinary pH (b) Changes in active renal tubular excretion (c) Changes in renal blood flow (d) Biliary excretion and the entero-hepatic shunt 1.5. Drug transporter proteins (a) P-glycoprotein interactions
2. Pharmacodynamic interactions Pharmacodynamic interactions are those where the effects of one drug are changed by the presence of another drug at its site of action. 1.1. Additive or synergistic interactions 1.2. Antagonistic or opposing interactions 1.3. Drug or neurotransmitter uptake interactions 1.4. Drug-herb interactions 1.5. Drug-food interactions (a) Cruciferous vegetables and charcoal-broiled meats (b) Grapefruit juice
Onset: How rapidly effects of drug interaction occur. Two types of onset are
Rapid: Within 24 hours Delayed: More than 24 hours or weeks
Drug Interactions of Antiarrhythmic agents,Beta-Blockers, Calcium Channel Blockers, Alpha-Blockers, Vasodilators, Diuretics, ACE-Inhibitors, Angiotensin Receptor Blockers, Cardiac Glycosides
1. Antiarrhythmic agents
Mechanism: An additive or synergetic increase in the QT interval may result Effects: The risk of life threatening cardiac arrhythmias including torsade de pointes may be increased. Management: Use certain Macrolide Antibiotics with caution and avoid Telithromycin in patients receiving class IA and class III antiarrhythmic agents.
with Theophyllines (Aminophyllines, Oxtriphylline, Theophylline) Significance: Onset: Severity: Documentation: Rapid Moderate Suspected
Mechanism: Theophylline have an antagonistic effect on adenosine receptors. Effects: Theophylline cause vasoconstriction whereas adenosine infusions generally cause vasodilatation.. Management: Assess the patient response. Aminophylline has been used to terminate persistent adverse effects of adenosine infusions.
Mechanism: Protease inhibitors, Zolpidem , Metronidazole and Grapefruit juice inhibit Amiodarone metabolism(CYP3A4) Effects: Increasing risk of toxicity including QT interval prolongation Management: Avoid coadministration of Amiodarone and Protease inhibitors,zolpidem, Metronidazole and Grapefruit juice .
with Rifampicin
Mechanism: Rifampicin induce Amiodarone, Qunidine metabolism(CYP3A4) Effects: Serum concentration of Qunidine, Amiodarone, and its active metabolite may be decreased Management: Closely monitor Amiodarone, Qunidine serum concentrations when starting or stopping Rifampicin.
Mechanism: Verapamil interfere with clearance of Qunidine and prolongs its half life. Effects: Bradycardia, Hypotension, Ventricular tachycardia and AV block can occur. Management: Use this combination when no other alternative exist. Closely monitor the patient and treat symptomatically.
Mechanism: Synergistic or additive effects. Verapamil may inhibit oxidative metabolism of certain Beta-blockers. Effects: Effects of both drugs are increased. Management: Use this combination when no other alternative exist. Closely monitor the patient and treat symptomatically and reduce the dose.
7. Antiarrhythmic agents
Mechanism: An additive or synergetic increase in the QT interval may result Effects: The risk of life threatening cardiac arrhythmias including torsade de pointes may be increased. Management:
Avoid Gatifloxacin, Levofloxacin, Moxifloxacin and Ofloxacin in patients receiving class IA and class III antiarrhythmic agents.
Significance: Onset: Severity: Documentation: Mechanism: Increased Potassium excretion caused by Thiazide diuretics Effects: Hypokalemia may occur. Management: Avoid this combination Delayed Major Suspected
Mechanism: Cholestyramine( anion exchange resin) binds Furosemide. Effects: Absorption of Furosemide is decreased by Cholestyramine which leads to decreased pharmacologic effects.
with Thiazide and Loop Diuretics Significance: Onset: Severity: Documentation: Delayed Major Probable
Mechanism: Increased urinary excretion of Potassium and Magnesium affecting cardiac muscle action. Effects: Digitalis induce Arrhythmiasdue to diuretic induce electrolyte disturbances. Management: Measure plasma levels of Potassium and Magnesium. Prevent further losses with dietary sodium restriction and addition of Potassium sparing diuretics
11. Digoxin
Management: Monitor Digoxin levels. If digoxin level is increased then its dose needs to be reduced.
12. Digoxin
with Macrolide and related Antibiotics(Erythromycin,Clarithromycin etc.) and Paroxetine Significance: Onset: Severity: Documentation: Delayed Major Established
Mechanism: Macrolides inhibit renal tubular P-glycoprotein excretion of Digoxin Effects: Macrolides increases Digoxin levels, toxicity may occur.
Management: Monitor Digoxin levels. If digoxin level is increased then its dose needs to be reduced.
13. Digoxin
with Quinidine
Documentation:
Established
Mechanism: Reduced renal and biliary clearance of Digoxin. Effects: Qunidine increases Digoxin concentrations resulting in Digoxin toxicity Management: Monitor Digoxin levels. If digoxin level is increased then its dose needs to be reduced to 50%.
14. Clonidine
Mechanism: Beta blocker inhibition of beta-2 receptor mediated vasodilation leaves peripheral alpha-2 receptor mediated vasoconstriction unopposed to Clonidine stimulation. Effects: Life threatening hypertension. Management: Monitor B.P. If needed discontinue Beta Blockers
15. Clonidine
Significance: Onset: Rapid Severity: Major Documentation: Probable Mechanism: Tricyclic Antidepressants inhibit central Alpha 2 receptors. Effects: Life threatening hypertension. Management: Monitor B.P. If needed discontinue Tricyclic antidepressants.
16. Prazosin
Significance: Onset: Severity: Documentation: Mechanism: Unknown Effects: Postural Hypotension may increased Management: Advice patient that postural hypotension may occur in early stages of concurrent therapy. Rapid Moderate Probable
17. Hydralazine
Significance: Onset: Delayed Severity: Moderate Documentation: Possible Mechanism: Absorption of Hydralazine altered be enteral nutrition. Effects: Hydralazine plasma concentration may be altered. Management: Carefully monitor patient and adjust the Hydralazine dose as needed.
18. ACE-Inhibitors( Captopril, Ramipril, Enalapril etc)
Mechanism: Renal clearance of Digoxin may be altered Effects: Fluctuation in Digoxin plasma levels Management: Carefully monitor Digoxin plasma levels.
with Indomethacin
Mechanism: Inhibtion of Prostaglandin synthesis. Effects: The Hypotensive effect of ACE-Inhibitors may be reduced. Management: Monitor BP . Discontinue Indomethacin or use alternative anti hypertensive.
with Phenytoin
Mechanism: Inhibtion of Losartan metabolism (CYP2C9) to its active carboxylic acid metabolite by Phenytoin. Effects: The Hypotensive effect of Losartan may be reduced. Management: Monitor BP . Discontinue Phenytoin or adjust its dose.
References: Drug Interaction Facts (David S.Tatro) British National Formulary 62nd Edition German DC, Kredich NM, Bjornsson TD. Oral dipyridamole increases plasma adenosine levels in human beings. Clin Pharmacol Ther (1989) 45, 804. Smith JW, Seidl LG, Cluff LE. Studies on the epidemiology of adverse drug reactions. V.Clinical factors influencing susceptibility. Ann Intern Med (1969) 65, 629. Stokleys Drug Interaction 8th Edition. Wanwimolruk S, Wong SM, Coville PF, Viriyayudhakorn S, Thitiarchakul S. Cigarette smoking enhances the elimination of quinine. Br J Clin Pharmacol (1993) 36, 61014.