Introduction to Drug Interactions.ppt

7/27/2019 Introduction to Drug Interactions.ppt

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SHAZIA ADNAN

ASSISTANT PROFESSOR

DR ZIA-U-DDIN COLLEGE OF PHARMACY



Drug – Drug Interaction

“…phenomena that occurs when theeffects (pharmacodynamics) or

pharmacokinetics of a drug are altered

by prior administration or co-administration 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

MAOI’s and SSRI’s, 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

MetabolismElimination



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 – increasingpossibility of toxicity (total phenytoinconcentration may appear normal – only freefraction has pharmacodynamic effect)

○ Aspirin displaces warfarin – increasingwarfarin effect by both increasing free fraction

and anti-platelet effect of aspirin



Metabolism

Most drugs must be lipid soluble to cross cellmembranes and reach their site of action The net effect of drug metabolism is to

increase water solubility and facilitate renalexcretion

Phase I metabolism primarily involvesoxidative metabolism via the CytochromeP450 (CYP) family of enzymes

Phase II metabolism conjugates the previouslyoxidized molecule with a water soluble weakacid (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 functionalimplication

Isoforms = variations of the enzyme

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



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 SubstratesExamples

2C 2D6 3A4/5Citalopram Dextromethorphan Clarithromycin (not

Azithromycin)

Nelfinavir Fluoxitene, SSRI’s Erythromycin

Ibuprofen / Naproxen Metoclopramide Midazolam

Warfarin Oxycodone Cyclosporine

Fluoxetine Tacrolimus

Phenytoin and 4-OH met Indinavir, HIV Antivirals

Phenobarbital

Omeprazole, PPI’s

Atorvastatin

Lovastin, HMG Coa Inh

MethadoneFentanyl

Ondansetron

Vincristine



CYP InhibitorsExamples

2C 2D6 3A4,5Strong Inhibitors

Amiodarone

Fluconazole

Buproprion

Fluoxetine

Clarithromyicn

Ketoconazole

Itraconazole

Indinavir (Anti-retrovirals)

Moderate Inhibitors

Trimethoprim

Omeprazole (PPI’s)

Sertaline Erythromycin

Fluconazole

Grapefruit Juice

Diltiazem

Weak Inhibitors

Cimetidine Cimetidine



CYP Inducers

2C8,9,19 2D6 3A4,5Phenobarbital Rifampin Phenobarbital

Phenytoin Dexamethasone Phenytoin

Rifampin Rifampin

Dexamethasone

St. John’s 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 interventions Anti hitamine Telfast, fexet,

soften

Avoid juice( orange, apple, grapefruit)

brochodilator theophyllin High fat = inc absorption

High carbs = dec absorption and avo

teaBeta blocker Tenormin, merol,

concor

Dec intake of garlic = hypotension

Avoid orange juice

Diuretics Loop

Pot. sparing

Inc intake of potassium

Dec intake of potassium

ACEI Capotene, zestril Avoid high fat meal = dec absorption

Limit potassium intake



Drug food interaction:

Classification Brands interventionsStatin Lipiget, rovista, zocor Avoid citrus fruit

Take at night time =

inc absorption

Anti coagulants Warfarin Limit Vit K rich food

and green vegetables

Avoid Vit E ( > 400mg)

= inc bleeding time

MAOI ( ANT

DEPRESSENTS)

Phenelsine/NARDIL

Tranycypromine/PARN

ATE

Avoid tyramine food(

cheese, aged meat,

soy sauce, raisin,

banana)



Drug food interactionClassificati

on

Brands interventions

Quinolones Ciproxin, noroxin, avelox,tarivid

Before meal Avoid dairy products

macrolides Erytrocin, klaricid,

azithrocin

Avoid citrus fruits

Avoid soft drinks

tetracyclin Vibramycin , terramycin Before meal + 2 glass of

water Avoid dairy products,

antacids

digoxin lanoxin Avoid high fiber food

Avoid grape fruit juice= inc

p.conc= inc toxicity

thyroxin thyroxin Avoid high fiber food

Before meal



Drug drug intercation

Drugs Interventions

Ciprofloxacin +

hydrocortisone

Risk of tendinitis and tendon rupture

Can occur during of several months after

therapy

Avoid in patients > 60 years

Ceftrioxane ( IV) +

Ca –gluconate ( IV only)

Cause fatal reaction, ppt in kidney , lungs

Difference b/w administration for 48 hours or

use (oral or IM ) products of calcium

Omeprazole (PPI) +

Clopidogrel ( lowplat)

PPI dec the cardio-protective effects of low pl

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 InterventionsCaptopril + allopurinol Inc risk of Agranulocytosis and neutropen

serious infection

Watch for= fever rashes , body ache, sor

throat = monitor WBC s

Furosemide + amikacin Both inc risk of oto -toxicity and nephro -

toxicity

NSAIDS + Beta blockers NSAIDS antagonize the antihypertensive

effect of B.Blockers

Cause fluid retention

Amiodarone + quinolone +

hydrocortisone

Dose related QT interval prolongation

Monitor : s.electrolytes, symptoms of

dizziness, palpitation , syncope

( V. Arrhythmia)



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-hypertensiveeffect

Promethazine (phenergen) = C/I in childrenunder 2 years because risk of fatal respiratory

depression, agitation, hallucination, seizures

Documents

Introduction to Drug Interactions.ppt