Drug Interactions- June2012

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    Drug Interactions

    UY1/FMBS/L2S4/PHCL/Drug Interactions

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    Lecture plan Definition Types of drug interactions Mechanisms of drug interactions

    Drug interactions before administration Drug interactions at site of absorption Drug interactions at site of distribution Drug interactions at the level of metabolism Drug interactions at the level of excretion

    Consequences of drug interactions Effects on efficacy/toxicity Example of Harmful drug interactions Example of Beneficial drug interactions

    factors affecting Drug interactions drug-related factors drug-related factors

    drug interaction website

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    Drug interactions (DI): Definition

    Definition:Alteration of the effect and/or potency of one

    drug (Victim drug) by the prior or theconcurrent administration of another drug(s)

    (Perpetrator drug) If the interaction results in diminished

    efficacy or increased toxicity, then a

    therapeutic drug interactionhas occurred Multiple drug therapy can give rise to drug-DI

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    Types of Drug Interactions

    1. Drug Drug interactions2. Drug Nutrients interactions

    3. Drug Herbal interactions

    4. Drug Environment interactions5. Drug Disease interactions

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    Drug interactions before drugadministration

    Phenytoin precipitates in dextrosesolution

    Intra-vesicular amphotericin precipitates

    in saline.bladder wall necrosis Gentamicin covalently binds piperacillin,

    azlocillin, cefoxitin..loss of antibiotic

    effect

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    Drug interaction at absorptionsites

    Most absorption changes are observed inGI and may be due to changes in

    Chelation/complexation/adsorption

    Gastric pH

    Motility

    Flora/Gut metabolism

    Effect of food

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    Changes in Drug Absorption Alterations of gastric pH

    If a drug changes the gastric pH, it can affect theabsorption and thus concentration of other drugs thathave specific pH requirements for absorption

    Presence or absence of food Food can enhance or decrease the bioavailability of a

    drug--often because of gastric acidity Some drugs must be administered one hour before or

    two hours after eating

    Chelation Binding of two drugs/compounds to form insoluble

    complexes that cannot be absorbedthis changesabsorption of a drug

    i i h

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    Drug interactions at thedistribution site

    Altered plasma protein binding (PPB)A drug is displaced from its PPB, increases

    unbound concentration and effect

    Altered drug transport

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    Metabolism-based drug interactions(Liver and GI tract)

    CYP inhibition: enzyme activity and metabolism (Cl,AUC)

    drug effect (efficacy/or toxicity)

    Induction: enzyme activity, metabolism (Cl,AUC

    Drug effect (efficacy and/or toxicity)

    Note:

    For prodrugs, inhibition may result in loss ofefficacy/toxicity and induction in enhanced

    efficacy/toxicity

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    Substrate of CYPs1A2 2B6 2E1

    -theophylline-caffeine

    -clozapine

    -phenacetin

    - methadone-cyclophosphamide

    -enfluran-halothane

    -acetaminophen

    -benzene

    -ethanolinhibitor

    cimetidine

    fluoroquinolone

    inhibitor

    ticlopidineinhibitor

    disulfiram

    inducer

    broccoli

    tobaccoinducer

    phenobarbital

    rifampininducer

    ethanol

    isoniazid

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    2C19 2C9 2D6 3A4H+inibitor

    omeprazole

    lanzoprazolepantoprazole

    antiepileptics

    phenytoin

    phenobarbital

    antiepileptics

    phenytoin

    phenobarbitalNSAIDs

    diclofenacibuprofen

    piroxicam

    oral hypoglycemic

    tolbutamide

    glipizide

    ACEII inh

    losartan

    irbesartan

    Beta blockers

    carvediol

    metoprololtimolol

    propranolol

    antidepressants

    amitrityline

    clomipramine

    imipramine

    nortriptyline

    Macroline

    clarithromycin

    erythromycinroxithromycin

    Benzodiazepine

    alprazolam

    diazepam

    midazolam

    triazolam

    ImmuneModulator

    cyclosporine

    tacrolimus

    HIV antiviralindinavir

    ritonavir

    nelfinavir

    saquinavir

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    2C19 2C9 2D6 3A4Prokinetic

    cisapride

    Antihistamineastemizole

    terfenidine

    Ca++blockers

    amlodipine

    diltiazem

    felodipine

    nifedipine

    verapamil

    HMGCoAreductase

    atorvastatincerivastatin

    lovastatin

    not pravastatin

    simvastatin

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    2C19 2C9 2D6 3A4Azole drugs

    Ketoconazole

    itraconazole

    Steroid 6-beta-OH

    estradiol

    Inhibitors

    cimetidine

    indomethacineaaInhibitors

    isoniazid

    Inhibitors

    celecloxib

    cimetidine

    Inhibitors

    cimetidine

    ciprofloxacin

    Inducer

    corbamazepine

    rifampinInducerrifampin

    Inducer

    rifampindexamethasone

    Inducerrifampin

    barbiturate

    phenytoin

    glucocorticoids

    I t ti d t lt d

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    Interaction due to alteredrenal excretion

    Tubular secretion can be affected by otherdrugs with have the same mechanism of

    secretion:

    Example: penicillin+ probenecid

    Water soluble drugs eliminated by glomerular

    filtration and largely unchanged by kidneys

    Glomerular filtration unlikely to be affected by other

    drugs

    C f D

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    Consequences of DrugInteractions

    Clinically unimportant (occasional) Many process and pathways of drug

    elimination are minor to be of concern; noneed to change dose, regimen or schedule

    Clinically important (many are avoidablewith proper knowledge of PK, PD andmechanisms of interaction)

    Mild - require dosage monitoring/adjustment(unusual)

    Severe (life threatening)contraindicated

    (rare)

    C f D

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    Consequences of DrugInteractions

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    Beneficial Drug Interactions

    The antiretroviral agent saquinavir (ProteaseInhibitors-PI) Drug interactions:

    Problems:

    Limited efficacy even when combined with NRTIs because ofvery unfavorable PK:

    low and variable oral bioavailability

    high systemic clearance (short half-life).

    Consequences: Administration of high doses of the drug to enhance antiretroviral activity:

    High pill burden Increased cost of antiretroviral therapy

    Solution:

    PK Interaction: saquinavir/ritonavir results in increasedbioavailability of saquinavir

    PK I t ti

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    PK Interaction:saquinavir/ritonavir (Kaletra)

    Mechanism:

    Ritonavir is very potentinhibitor of intestinaland hepatic CYP3A

    Enhance bioavailabilityand prolong half-life ofsaquinavir

    Improve antiretroviraleffect of saquinavir(Pharmacoenchancement)

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    PHARMACOENHANCMENT

    Principle:

    Administer a low, non-therapeutic dose of a drug toinhibit the metabolism and / or transport of a seconddrug and thereby reduce first-pass elimination andsystemic clearance.

    Result:

    Increase the bioavailability, AUC and half-life oftarget drug.

    Utility: Plasma concentrations maintained above viral IC95

    for entire dosing interval.

    Dosing interval extended to 12 hours.

    Some drug related factors

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    Some drug-related factorsaffecting Drug interactions

    Drug dosage/concentration

    Narrow therapeutic index

    Low bioavailability

    Duration of treatment

    Timing and sequence of administration

    Number of drugs prescribed*

    Route of administration

    Fraction metabolized

    Problematic PK (nonlinear)

    Compliance

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    Relationship between DrugInteraction and Number of

    drugs prescribed*

    D i t ti d d ff t

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    Drug interaction and adverse effects

    increase with the number of drugs used

    Absolute number of drugs concurrentlyreceived by a patient is the best predictorof adverse effects:

    3-5% in patients taking a few drugs may

    experience drug interaction

    Up to 20% in patients who receive 10-20drugs may experience interaction

    Patient population with poly-pharmacyinclude:

    HIV infected patients, elderly patients, patients onchemotherapy

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