SHAZIA ADNAN ASSISTANT PROFESSOR DR ZIA-U-DDIN COLLEGE OF PHARMACY

Drug Drug Interaction

phenomena that occurs when the effects (pharmacodynamics) or pharmacokinetics of a drug are altered by prior administration or coadministration of a second drug
Hartshorn, EA, Tatro, DS: Drug Interactions, 2003, Facts and Comparisons, St. Louis, MO

Pharmacodynamic Drug Interaction

Extension of underlying pharmacology / toxicology
Potentiation CNS sedation antihistamines / EtOH MAOIs and SSRIs, Phenylephrine, etc Digoxin toxicity with diuretic induced potassium wasting QTc prolongation w/ Amiodarone and clarithromycin

Antagonism Beta blockers used with NSAIDS

Pharmacokinetic Drug Interactions Absorption

Distribution

Metabolism
Elimination

Absorption

Inhibition of first pass metabolism

CYP 3A4 by erythromycin or grapefruit juice Inc. concentration of atrovostatin myopathy

P-Glycoprotein inhibition by clarithromycin Inc concentration of may drugs IV Vs ORAL

Binding in gut delayed absorption

Antacids oral contraceptives

Distribution

Protein binding alterations

Displacement from albumin binding sites by

acidic drugs
valproic acid displaces phenytoin increases

free fraction of phenytoin increasing possibility of toxicity (total phenytoin concentration may appear normal only free fraction has pharmacodynamic effect) Aspirin displaces warfarin increasing warfarin effect by both increasing free fraction and anti-platelet effect of aspirin

Metabolism

Most drugs must be lipid soluble to cross cell membranes and reach their site of action The net effect of drug metabolism is to increase water solubility and facilitate renal excretion Phase I metabolism primarily involves oxidative metabolism via the Cytochrome P450 (CYP) family of enzymes Phase II metabolism conjugates the previously oxidized molecule with a water soluble weak acid (glucouronic acid, tauric acid, etc) enhancing overall water solubility

Cytochrome P450 Nomenclature, e.g. for CYP2D6

CYP = cytochrome P450 2 = genetic family D = genetic sub-family 6 = specific gene NOTE that this nomenclature is genetically based: it has NO functional implication Isoforms = variations of the enzyme

http://www.qtdrugs.org/medical-pros/education/CERT%20Educational%20Module%201.ppt

CYP Nomenclature

Substrate A drug that is normally metabolized by the isoform May be influenced by inhibitors and/or inducers Inhibitor Decreases the activity of the CYP isoform leading to reduced clearance of drugs that are metabolized by that CYP isoform Inducers Increase the activity of the enzyme systems therefore,

increases the elimination of drugs that are substrates for that CYP isoform

CYP Substrates
Examples
2C 2D6 3A4/5

Citalopram
Nelfinavir Ibuprofen / Naproxen Warfarin Fluoxetine Phenytoin and 4-OH met Phenobarbital Omeprazole, PPIs

Dextromethorphan
Fluoxitene, SSRIs Metoclopramide Oxycodone

Clarithromycin (not Azithromycin)

Erythromycin Midazolam Cyclosporine Tacrolimus Indinavir, HIV Antivirals Atorvastatin Lovastin, HMG Coa Inh Methadone Fentanyl Ondansetron Vincristine

CYP Inhibitors
Examples
2C Amiodarone Fluconazole 2D6 3A4,5 Clarithromyicn Ketoconazole Itraconazole Indinavir (Anti-retrovirals)

Strong Inhibitors
Buproprion Fluoxetine

Moderate Inhibitors
Trimethoprim Omeprazole (PPIs) Sertaline Erythromycin Fluconazole Grapefruit Juice Diltiazem Cimetidine

Weak Inhibitors
Cimetidine

CYP Inducers
2C8,9,19 Phenobarbital Phenytoin Rifampin Rifampin Dexamethasone 2D6 3A4,5 Phenobarbital Phenytoin Rifampin Dexamethasone St. Johns Wort

Over the counter drugs:

Just to relieve the pain Read information leaflet Check expiry Check allergies : aspirin, sulfa, penicillin Pregnancy and lactation Aspirin, ibuprofen and paracetamol

Drug and food interaction

Classification Brands Anti hitamine brochodilator Telfast, fexet, soften theophyllin interventions Avoid juice( orange, apple, grapefruit) High fat = inc absorption High carbs = dec absorption and avoid tea Dec intake of garlic = hypotension Avoid orange juice Inc intake of potassium Dec intake of potassium

Beta blocker Diuretics

Tenormin, merol, concor Loop Pot. sparing

ACEI

Capotene, zestril

Avoid high fat meal = dec absorption Limit potassium intake

Drug food interaction:

Classification Statin Brands Lipiget, rovista, zocor interventions Avoid citrus fruit Take at night time = inc absorption Limit Vit K rich food and green vegetables Avoid Vit E ( > 400mg) = inc bleeding time

Anti coagulants

Warfarin

MAOI ( ANT DEPRESSENTS)

Phenelsine/NARDIL Avoid tyramine food( Tranycypromine/PARN cheese, aged meat, ATE soy sauce, raisin, banana)

Drug food interaction

Classificati on Quinolones macrolides tetracyclin Brands Ciproxin, noroxin, avelox, tarivid Erytrocin, klaricid, azithrocin Vibramycin , terramycin interventions Before meal Avoid dairy products Avoid citrus fruits Avoid soft drinks Before meal + 2 glass of water Avoid dairy products, antacids Avoid high fiber food Avoid grape fruit juice= inc p.conc= inc toxicity Avoid high fiber food Before meal

digoxin

lanoxin

thyroxin

thyroxin

Drug drug intercation

Drugs Ciprofloxacin + hydrocortisone Interventions Risk of tendinitis and tendon rupture Can occur during of several months after therapy Avoid in patients > 60 years Cause fatal reaction, ppt in kidney , lungs Difference b/w administration for 48 hours or use (oral or IM ) products of calcium

Ceftrioxane ( IV) + Ca gluconate ( IV only)

Omeprazole (PPI) + Clopidogrel ( lowplat)

PPI dec the cardio-protective effects of low plat by 47%. MI recurrence can occur Alternate : H2 antagonist ( ZANTAC)

Aspirin + ketorolac ( toradol) Inc risk of serious NSAIDs side effects Renal failure, GI ulceration and perforation
Digoxin + ca gluconate ( inc risk of arrhythmia

Drug drug interaction

Drugs Captopril + allopurinol Interventions Inc risk of Agranulocytosis and neutropenia = serious infection Watch for= fever rashes , body ache, sore throat = monitor WBC s Both inc risk of oto -toxicity and nephro toxicity NSAIDS antagonize the antihypertensive effect of B.Blockers Cause fluid retention Dose related QT interval prolongation Monitor : s.electrolytes, symptoms of dizziness, palpitation , syncope ( V. Arrhythmia)

Furosemide + amikacin NSAIDS + Beta blockers

Amiodarone + quinolone + hydrocortisone

Drug drug interaction

Iron and calcium: (ca) dec (fe) absorption Avoid in asthma: beta blocker, NSAIDS, aspirin, ACEI NSAIDS: C/I with diuretics = cause fluid retention Beta blocker = antagonize anti-hypertensive effect Promethazine (phenergen) = C/I in children under 2 years because risk of fatal respiratory depression, agitation, hallucination, seizures