Presentation will cover different mechanisms of drug interaction and there management.

1. Drug Interactions
Dr. Seema Bansal
Professor, Department of Pharmacology,
MM College of Pharmacy Mullana

2. Drug Interactions
• Occurs when the effects of one drug are
changed by the presence of another
drug, herbal medicine or some
environmental chemical agent
• Outcome  Good or bad or fatal

3. Drug interactions include:
 Drug-drug interactions
 Drug-herbal interactions
 Food-drug interact ions
 Pharmacogenetic interactions
 Chemical -drug interactions

4. Who are susceptible?
 Polypharmacy
 Hepatic or renal disease
 Long-term therapy for chronic illness
 Critically ill
 ICU patients

5. Drugs with high risk of interaction
Concentration dependent toxicity
1. Digoxin
2. Lithium
3. Aminoglycosides
4. Cytotoxic agents
5. Warfarin

6. Drugs with high risk of interaction
• Steep dose response curve
1. Verapamil
2. Sulfonylureas
3. Levodopa
• Saturable hepatic metabolism
1. Phenytoin
2. Theophylline

7. Mechanism of drug interactions
• Pharmacokinetic
• Pharmacodynamic
• Pharmacogenetic
• Pharmaceutical

8. Pharmacokinetic
• Absorption from Gastrointestinal tract
1. Changes in GI pH
• Proton pump inhibitors / H2 antagonist (weak acid ) reduces
ketoconazole dissolution at basic pH, results decreased drug absorption
and therapeutic failure
2. Adsorption, chelation and other complexing
mechanism
Tetracycline and aluminum/magnesium hydroxide kaolin/charcoal
Colestyramine, colestipol – digoxin, propranolol, warfarin
levothyroxine, cyclosporin

9. Pharmacokinetics
• Absorption from Gastrointestinal tract
3. Effects on GI motility
 Narcotics, atropine, antacids  motility?
 Domperidone, metoclopramide, cisapride  motility?
 Slow motility is dis/advantageous to penicllin & levodopa
 Rapid motility is dis/advantageous to enteric coated tablet &
griseofulvin
4. Induction or inhibition of drug transport proteins
Verapamil enhances digoxin bioavailability by inhibiting P-gp

10. Pharmacokinetics
• Absorption from Gastrointestinal tract
5. Alteration of intestinal flora
Antibiotics:
•Digoxin has better bioavailability taken after erythromycin.
Erythromycin administration reduces bacterial inactivation
of digoxin
•Estrogen/progestin birth control requires intestinal flora to
facilitate enterohepatic circulation. Antibiotics reduce
intestinal flora and reduce estrogen/progestin levels
resulting in failure of ovulation suppression and menstrual
changes

11. Pharmacokinetics
• Absorption from Skin
Epinephrine, a vasoconstrictor:
Decrease the percutaneous absorption of transdermal
lidocaine or transdermal fentanyl

12. Pharmacokinetics
• Distribution
Dependent on ionic composition, lipid solubility, and
protein-binding characteristics
Plasma protein binding
Albumin – acidic drugs (warfarin)
a1 acid glycoprotein – basic drugs (TCA, lidocaine,
disopyramide & propranolol)
• Valproic acid displaces phenytoin from plasma albumin
protein-binding sites and increase phenytoin levels
• Aspirin displaces warfarin from protein binding sites
hence increase its level

13. Pharmacokinetics
• Metabolism
CYP3A4 in the intestinal wall– grapefruit juice &
felodipine & cyclosporine
MAO-A in the liver & intestinal wall – tranylcypromine,
phenelzine & tyramine (diet)  increase norepinephrine

14. • Dexamethasone – R-warfarin
• Ciprofloxacin – Imipramine
• Disulfiram – halothane
• Verapamil – Midazolam
• Tobacco smoke – theophylline
• Cimetidine – theophylline
• Omeprazole – Diazepam
• Phenytoin - Nifedipine

15. Pharmacokinetics
• Metabolism
Enzyme induction
Carbamazepine, barbiturates – autoinduction
Short-half life drugs (rifampicin) induce metabolism than
long-half life drugs (phenytoin)
Chronic alcohol use, Cigarette smoking, St. John’s wort
(Hypericum perforatum)
Grapefruit juice- caution with simvastatin, tacrolimus,
vardenafil
Caution when given with drugs with narrow therapeutic
index – theophylline, phenytoin, warfarin

16. Phamacokinetics
• Elimination
1. Changes in urinary pH
Enhance excretion of weak acids (aspirin) at alkaline pH
Enhance excretion of weak base (paracetamol) at acidic pH
Strong acids and bases are not affected by pH changes
2. Changes in active renal tubular secretion
competition with the organic anion transporters- probenecid &
penicillin
NSAIDs, salicylates & methotrexate

17. Phamacokinetics
• Elimination
3. Changes in renal blood flow
Prostaglandins produces renal blood flow
NSAIDs & lithium
4. Influence of proximal reabsorption in relation to Na+ ions
Thiazide, loop diuretics & lithium  decrease renal clearance
of lithium
5. Changes in renal blood flow
Prostaglandins produces renal blood flow
NSAIDs & lithium

18. Phamacokinetics
• Elimination
6. Biliary excretion and enterohepatic shunt
Ethinylestradiol conjugates & antibiotics
7. Drug transporter proteins
P-glycoprotein – present in renal proximal tubule,
hepatocytes, intestinal mucosa, and blood brain barrier
Inhibitors- verapamil, atorvastatin
Inducers- rifampicin

19. Pharmacodynamic
Additive /synergistic
 Narcotics + antihistamines = Drowsiness
 Promethazine + OTC antihistamines= dryness of the mouth,
blurred vision and urinary retention
 Benzodiazepines and alcohol
 Aspirin and warfarin
 ACE inhibitor, K supplement and K sparing diuretic 
hyperkalemia
 Hydrocortisone & hydrochlorothiazide  hyperglycemia &
hypokalemia
 Increase risk of ototoxicity and nephrotoxicity from
combination of aminoglycosides and furosemide

20. Antagonistic
Flumazenil and benzodiazepines (diazepam)
Salbutamol and b-blockers (propranolol)
Vit K and anticoagulants
Levodopa and dopamine antagonist
Drug therapy can produce an adverse effect that
results in an increased sensitivity/toxicity when
another drug is given
Diuretic (thiazide derivative will deplete potassium: digoxin
toxicity
Depletion of sodium by a diuretic : lithium toxicity.
Pharmacodynamic

21. Herbal Drug Interaction
Herb
Interaction
Drug/Drug Class Effect
Black Cohosh Antihypertensives hypotension
Coenzy me Q10 Warfarin Vitamin K antagonism (increased
INR and risk of bleed)
Dong Quai Beta blockers Inhibition of CYP450
Enzymes (increased hypotension)
Dong Quai Benzodiazepines Inhibition of CYP 450 Enzymes
(increased drowsiness and CNS
depression)
Echinacea Immunosuppressants
Monoclonal antibodies
Decreased immunosuppression
(flair of autoimmune disease,
transplant graft rejection)
Ephedrine Ma
Huang
Beta blockers Sympathomimetic effect
(hypertension)
Ephedrine Ma
Huang
MAOIs Blocked Metabolism
(Hypertensive crisis)

22. Herbal Drug Interaction
Herb
Interaction
Drug/Drug
Class
Effect
Evening
Primrose Oil
Antiplatelets Decreased Platelet Aggregation (increased risk
of bleed)
Phenothiazines Additive toxicity (seizures)
Ginkgo biloba Warfarin, LMWH Increased inhibition of platelet aggregation
(increased risk of bleed)
Ginseng MAOI Increased GABA metabolism and increased
dopamine levels (mania symptoms)
Kava Kava Acetaminophen
Azole antifungals,
Statins
Increased otential for hepatic toxicity (elevated
LFT, hepatic failure)
Kava Kava Barbiturates
Benzodiazepines
Synergy (increased drowsiness, CNS
depression)
Kava Kava Levodopa Dopamine blockade (decreased effectiveness of
levodopa)

23. Herbal Drug Interaction
Herb Interaction Drug/Drug
Class
Effect
Soy Lethothyroxine Impaired Absorption (hypothyroid
symptoms)
St.John's
Wort
Irinotecan Induced CYP3A4 Metabolism
(decreased
myelosuppression)
Valerian Sedatives Increased CNS depression
(drowsiness and sedation)
Benzodiazepines Displaced benzodiazepine but
additive CNS depression (possible
increased drowsiness)
Ginger /
garlic/Wheat Grass
Warfarin Directly inhibiting platelets and
causing increased risk of bleeding

24. Food Drug Interaction
Effect of food on drug Bioavailability
Food Reduced bioavailability:
NSAIDs, Aspirin, Acetaaminophen, Ethanol
Food Reduced bioavailability
Griseofulvin, Metoprolol, Phenytoin, Propoxyphene, Dicumarol,
Morphine
Complexat ion and adsorption of the drug in the GI tract
Quinolone antibiotics complex with calcium ( found in milk
products)
Phenytoin and Quinolone antibiotics are adsorbed to calcium and
iron in tube feedings
Grape fruit and Valencia oranges inhibit the CYP3A4
isoenzyme system: causing increased levels of substrate drugs
Saquinavir , indinavir , midazolam, nimodipine, nifedipine,
lovastatin, cyclosporin, carbamazepine, and verapamil .

25. Chemical Drug Interaction
Smoking induce the CYP1A2 isoenzyme metabolism and
decrease levels of substrate drugs such as theophylline,
diazepam, tricyclic antidepressants, duloxetine, and
ramelteon
Chronic alcoholism can increase the rate of metabolism of
tolbutamide, warfarin and phenytoin
 Acute alcohol intoxication can inhibit hepatic enzymes in
nonalcoholic individuals
Disulfiram inhibits alcohol dehydrogenase, resulting in
limited metabolism of ethanol and causing severe ethanol
intolerance

26. Pharmacogenetics and Drug Interaction
Reason: Genetically based variations in alleles for genes that
code for enzymes responsible for the metabolism of drugs.
1. In normal enzyme function, the gene encoding for the enzyme
is composed of two normal alleles.
2. In Polymorphisms, the genes contain abnormal pairs or
multiples of abnormal alleles leading to altered enzyme
function.
3. Polymorphisms can occur in any enzyme system including the
CYP450 hepatic enzymes, the mixed oxidase and n-acetyl
transferase systems.
4. Differences in enzyme activity occur at different rates
according to racial group

27. Polymorphisms affect drug interactions by altering the
effect of inhibitors and inducers on the enzymes. The
result is an exaggerated effect or minimal effect on the
substrate.
1. EM (Extensive metaboliser): The level of substrate drug is
normally low because of the rapid metabolism by the
enzyme
2. PM (Poor metaboliser), the level of substrate drug remains
high because the metabolism of the substrate is much less
than normal
3. Intermediate metaboliser

28. Specific Pharmacogenomic Drug
Interactions from the literature
Enzyme Inhibitor Substrate Effect of
EM/UM on
substrate
Effect of PM
on substrate
CYP2D6 Diphenhydramine Metoprolol Increased
61%
Little change
CYP2D6 Quinidine Svenlafaxine Increased 4x Little Change
CYP2D6 Diphenhydramine Venlafaxine Increased 2x Little Change
CYP2D6 Fluoxetine Risperidone Increased 4x Increase 1.3x
CYP2C19 omeprazole moclobemide Increased 2x Little Change
CYP2C19 Fluvoxamine diphenydramine Moderate
Change
Little Change

29. Imatinib Atomosetine Dapsone
Fluoxetine Tamoifen Venlafaxine
Capecitabine Celecoxib Omeprazole
Rifampin Beta-blockers Tramadol
Rasburicase Valproic acid 5FU
Irinotecan Primaquine Voriconazole
FDA Encourages Genetic Testing for
Patients Who Will Take Specific Drugs

30. Clinical Significance
Combination drug therapy can have beneficial effects
Trimethoprim and sulfamethoxazole
 Amoxici ll in and clavulanate potassium
Hydrochlorothiazide and triamterene
 Ritonavir is given as a “booster ” with tipranavir
Probenecid inhibits renal tubular secretion of penicillin
Drug Food Interactions: Phenytoin is given with dietary fats to
increase its bioavailability through enhanced absorption

31. Management of drug interactions
Review the patient profile, including drug history and patient risk
factors.
Avoid complex therapeutic drug regimens.
Determine the probability of a clinically significant drug
interaction. Genetic testing may be useful
Suggest a different drug if there is a high probability for a
clinically significant drug interaction.
Carefully instruct the patient as to the timing of the medication.
Monitor the patient for adverse events
Evaluate the risks of drug therapy with respect to pharmacogenetic
polymorphic status of metabolism.

32. Thank You