Pharmacokinetic Interaction

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    032012Pharmacokinetic interaction

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    2

    All drugs known to humans are poisons, only the

    amount or dose determine the effects.Paracelsus, 1490 - 1541

    Classification of Drug Interactions

    Pharmacokinetic

    in drug absorption,

    distribution, metabolism

    or excretion

    Pharmacodynamic

    of pharmacological effect at standarddrug

    concentrations

    or

    of pharmacological effect resulting from

    alteredpharmacokinetic exposures

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    Pharmacokinetics

    Movement of drugs in the body

    Four Processes Absorption

    Distribution

    Metabolism

    Excretion

    Drug concentration at sites of action influencedby several factors, such as:

    Route of administration Dose

    Characteristics of drug molecules (e.g., lipid solubility)

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    Altered Absorption (Availability)

    Change in gastrointestinal pH

    Ketoconazole needs acidic conditions in gut

    Drug binding in GI tract

    E.g. tetracycline and calcium

    Change in gastrointestinal flora

    Antibiotics with OCs

    Change in gastrointestinal motility

    Metoclopramide and digoxin

    Malabsorption caused by other drugs

    Orlistat (Xenical) and fat soluble vitamins

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    Pharmacokinetic interactions

    1) Altered GIT absorption.

    Altered pH, Altered bacterial flora, formation of drug

    chelates or complexes, drug induced mucosal damage

    and altered GIT motility.

    a) Altered pH;The non-ionized form of a drug is more lipid

    soluble and more readily absorbed from GIT than theionized form does.

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    Ex1., antiacidsDecrease the pH Decreasethe tablet

    dissolution

    ofKetoconazole (acidic)

    Ex2., H2 antagonists pH

    Therefore, these drugs must be separated by at least 2h

    in the time of administration of both .

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    b) Altered intestinal bacterial flora ;

    EX., In 10% 0f patients receive digoxin..40% or more

    of the administered dose is metabolized by the intestinal flora

    Antibiotics kill a large number of the normal

    flora of the intestine

    Increase digoxin conc.

    and increase its toxicity

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    c) Complexation or chelation;

    EX1., Tetracycline interacts with iron preparations

    or

    Milk (Ca2+

    ) Unabsorpable complex

    Ex2., Antacid (aluminum or magnesium) hydroxide

    Decrease absorption of

    ciprofloxacin by 85%

    due to chelation

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    d) Drug-induced mucosal damage.

    Antineoplastic agents e.g., cyclophosphamide

    vincristineprocarbazine

    Inhibit absorption

    of several drugs

    eg., digoxin

    e) Altered motility

    Metoclopramide (antiemitic)

    Increase absorption of cyclosporine due

    to the increase of stomach empting time

    Increase the toxicity

    of cyclosporine

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    10

    Hepatic Drug Interactions

    OATP (azoles, echinocandins?)

    Phase I metabolism (CYP P450)(itraconazole, voriconazole)

    Phase II metabolism (glucoronidation)

    (posaconazole)

    Genetic Disease Diet Drugs Infection

    Extraction? Metabolism

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    DRUG DISTRIBUTION

    DISPLACEMENT FROM PLASMA PROTEIN

    BINDING SITES

    e.g. AZAPROPAZONE + WARFARIN

    INTERACTION(BUT INHIBITION OF WARFARIN

    METABOLISM SEEMS MORE LIKELY)

    DISPLACEMENT OF ORAL

    HYPOGLYCAEMICS BY ASPIRIN

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    Protein Binding

    Drug Displacement

    Plasma Tissue

    Drug A

    protein bound

    Drug A

    free

    Drug A

    free

    Drug B

    Drugs A and B both bind to the same plasma protein

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    f) Displaced protein binding

    It depends on the affinity of the drug to plasma protein.

    The most likely bound drugs is capable to displace others.

    The free drug is increased by displacement by another drugwith higher affinity.

    Phenytoin is a highly bound to plasma protein (90%),Tolbutamide (96%), and warfarin (99%)

    Drugs that displace these agents are Aspirin

    Sulfonamidesphenylbutazone

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    CYP450 Nomenclature

    CYP2D6

    Family

    Sub-FamilyIndividual Gene

    CYP = Cytochrome P450

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    Enzyme characteristics

    % drugs metabolised by enzyme

    3A4 60%

    2D6 25%

    1A2 15%

    2C9 Small no. but significant interactions

    2C19 Small no. but significant interactions

    2E1 ?

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    CYP 450 System

    Definitions

    Substrate:Drug is metabolised by the enzyme system

    Inducer:Drug that will increase the synthesis of CYP450enzymes

    InhibitorDrug that will decrease the metabolism of asubstrate

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    Enzyme Induction 1

    Leads to production of more enzyme,

    usually after 3-4 days of exposure to

    inducer

    Most CYPs are inducible but not CYP2D6

    Time course of interaction depends on

    half-life of inducer.

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    Enzyme Induction 2

    Rifampicin has short half-life and induction

    apparent with 24 hours

    Phenobarbitone has longer half life so time

    to complete induction takes longer

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    Enzyme Inducers

    Examples

    Rifampicin

    Phenobarbitone

    Carbamazepine

    Cigarette smoke

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    Antibiotics and Oral Contraceptives

    Antibiotics, Phenytoin, Carbemazepine,

    Barbiturates induce hepatic Phase I enzymes

    Synthetic Estrogens & Progesterones are

    metabolised by Phase I enzymes

    Increased metabolism of Oral contraceptives

    Decreased effectiveness of Oral contraceptive

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    Enzyme Inhibition

    Often rapid, reversible and relatively shortacting.E.g. erythromycin and cyclosporinNB :erythromycin is a substrate and an inhibitorof CYP 3A4

    May be prolonged due to long half- life of drug.

    E.g. amiodarone and S-WarfarinNB: amiodarone is an inhibitor of CYP2C9 butnot a substrate for this CYP

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    Grapefruit Juice-Drug Interaction

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    Time

    DrugBlood

    Co

    ncentration(AUC

    )

    Drug Taken with GJ

    Drug Taken without GJ

    http://dev.newtontalk.net/~dpadilla/images/pill.jpghttp://dev.newtontalk.net/~dpadilla/images/pill.jpg
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    P. B. Watkins 2003

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    EXCRETION

    Drug A increases or reduces the excretion

    (usually renal) of Drug B.

    Blood levels of B fall below or rise above

    normal therapeutic range.

    Becomes either ineffective or toxic.

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    Excretion Interactions

    Mechanisms of urinary excretion:

    - Simple filtration

    - Active secretion

    Mechanisms for active secretion

    - Acids- Bases

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    Excretion interactions

    Active secretion mechanisms have limited capacity.

    e.g. One acid drug may saturate the acid drugactive secretion mechanism. Another acid drug

    will then be secreted less efficiently

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    Excretion Interaction

    Lithium + Thiazides

    Probable mechanism:

    Thiazides cause diuresis and initial sodium loss. Compensatory sodium retention in proximal

    tubules.

    Proximal tubules do not distinguish sodium

    from lithium.

    Lithium also retained and accumulates.

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    Excretion Interaction

    Change in renal blood flow

    Methotrexate and NSAIDs

    NSAIDS can decrease renal blood flow byinhibition of renal prostaglandins.

    Reduced clearance of MTX and active

    (toxic) metabolite

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    Some enzyme Inducers

    Barbiturates (3A)

    Carbamazepine

    (2C19, 3A)

    Phenytoin (3A)

    Rifampicin

    (2C19, 2C9, 3A)

    St Johns Wort (3A)

    Ethanol (2E1)

    Troglitazone (3A)

    Tobacco (1A2)

    Omeprazole (1A2)

    Nevirapine (3A)

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    Where are these enzymes ?

    Most cells

    Predominantly in endoplasmic reticulum of

    hepatocytes

    Also present in gut wall

    Kidney lungs and brain

    Liver is main site of drug metabolism

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    DRUG METABO