ASSIGNMENT

DRUG INTERACTIONS

SUBMITTED TO:

Asst Prof. M.YAR RIZWAN

SUBMITTED BY:

IJAZ ALI ROLL NO:

643

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

Severity: Potential of effects of drug interaction. Three degrees of severity are

Major: Life threatening Moderate: An extended hospital stay or additional treatment is required Minor:An additional treatment is not required

Documentation: There are five documentation levels

Established: Drug interaction proved to occur in well controlled studies. Probable: Very likely but not proven clinically Suspected: Need more studies Possible: Data is very limited Unlikely: No good evidence

Drug Interactions of Antiarrhythmic agents,Beta-Blockers, Calcium Channel Blockers, Alpha-Blockers, Vasodilators, Diuretics, ACE-Inhibitors, Angiotensin Receptor Blockers, Cardiac Glycosides

1. Antiarrhythmic agents

(Amiodarone,Bretylium,Disopyramide,Dofetilide,Procainamide,Sotalol) with Macrolide and related atibiotics (Erythromycin,Azithromycin,Clarithromycin,Telithromycin)

Significance: Onset: Severity: Documentation: Delayed Major Suspected

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.

2. Antiarrhythmic agents (Adenosine)

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.

3. Antiarrhythmic agents (Amiodarone)

with Protease inhibitors(Ritonavir,Nelfinavir) ,Metronidazole, Zolpidem,Grapefruit juice

Significance: Onset: Severity: Documentation: Delayed Major Possible

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 .

4. Antiarrhythmic agents (Amiodarone,Qunidine)

with Rifampicin

Significance: Onset: Severity: Documentation: Delayed Major Possible

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.

5. Antiarrhythmic agents (Qunidine)

with Verapamil Significance: Onset: Severity: Documentation: Rapid Major Possible

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.

6. Antiarrhythmic agents (Atenolol, Propanolol and other Beta Blockers)

with Verapamil Significance: Onset: Severity: Documentation: Rapid Major Probable

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

(Amiodarone,Bretylium,Disopyramide,Dofetilide,Procainamide,Sotalol) with Quinolones (Gatifloxacin, Levofloxacin, Moxifloxacin, Ofloxacin)

Significance: Onset: Severity: Documentation: Delayed Major Suspected

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.

8. Thiazide Diuretics( Chlorothiazide, chlorthalindone, Hydrochlorothiazide etc)

with Antiarrhythmic agents (Dofetilide)

Significance: Onset: Severity: Documentation: Mechanism: Increased Potassium excretion caused by Thiazide diuretics Effects: Hypokalemia may occur. Management: Avoid this combination Delayed Major Suspected

9. Loop Diuretics (Furosemide)

with Cholestyramine Significance: Onset: Severity: Documentation: Rapid Moderate Suspected

Mechanism: Cholestyramine( anion exchange resin) binds Furosemide. Effects: Absorption of Furosemide is decreased by Cholestyramine which leads to decreased pharmacologic effects.

Management: Administer two medicines with 2 hours gap.

10. Digoxin

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

with Diltiazem Significance: Onset: Severity: Documentation: Delayed Moderate Supected

Mechanism: Diltiazem decreases renal or extra renal clearance of Digoxin

Effects: Diltiazem increases Digoxin concentrations resulting in Digoxin toxicity

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

Significance: Onset: Severity: Delayed Major

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

with Beta Blockers

Significance: Onset: Severity: Documentation: Delayed Major Suspected

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

with Tricyclic anti depressant

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

with Beta Blockers

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

with Enteral nutrition( Ensure)

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)

with Digoxin Significance: Onset: Severity: Documentation: Delayed Moderate Possible

Mechanism: Renal clearance of Digoxin may be altered Effects: Fluctuation in Digoxin plasma levels Management: Carefully monitor Digoxin plasma levels.

19. ACE-Inhibitors( Captopril, Ramipril, Enalapril etc)

with Indomethacin

Significance: Onset: Severity: Documentation: Rapid Moderate Probable

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.

20. Angiotensin receptor blockers(losartan)

with Phenytoin

Significance: Onset: Severity: Documentation: Delayed Moderate Possible

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.