Pharmacokinetic Interaction

7/28/2019 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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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 METABOLISM

ENZYME INDUCTION

OR

ENZYME INHIBITION

ENZYME INDUCTION

BY INCREASING DRUG INACTIVATIONMAY PRODUCE TOLERANCE OR

COMPLETELY NULLIFY DRUG ACTION.


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ENZYME INDUCTIONEXAMPLES INCLUDE:

PRIMARY DRUG INDUCING DRUG EFFECT OF INTERACTION

ORAL

ANTICOAGULANTS

e.g. WARFARIN

BARBITURATES

RIFAMPICIN

DECREASED

ANTI-COAGULATION

TOLBUTAMIDE PHENYTOIN

CHLORPROMAZINE

DECREASED

HYPOGLYCAEMIA

ORAL CONTRA-

CEPTIVES

PHENOBARBITONE FAILURE OF

CONTRCEPTION

PREDNISONE

DEXAMETHASONE

BARBITURATES REDUCED STEROID

LEVELS

DOXYCYCLINE BARBITURATES REDUCED DOXYCYCLINE

LEVELS

QUINIDINE PHENYTOIN

BARBITURATES

REDUCED

QUINIDINE LEVELS


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ALTERNATIVELY:

SOME DRUGS MAY ACT AS ENZYME

INHIBITORS AND RAISE THE

CONCENTRATION OF SIMULTANEOUSLY

ADMINISTERED DRUGS.


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INTERACTIONS OF LIVER ENZYME INHIBITORS

PRIMARY DRUG INHIBITING DRUG INTERACTION

PHENYTOIN ISONIZID

AZAPROPAZONE

CHLORAMPHENICOL

PHENYTOIN

INTOXICATION

ORAL

ANTICOAGULANTS

e.g. WARFARIN

ALLOPURINOL

NORTRIPTYLINE

QUINIDINE

HAEMORRHAGE

TOLBUTAMIDE

CHLORPROPAMIDE

PHENYLBUTAZONE

CHLORAMPHENICOL

DISCOUMAROL

HYPOGLYCAEMIA

6-MERCAPTOPURINE

AZATHIOPRINE

ALLOPURINOL BONE MARROW

SUPPRESSION

ANY DRUG

CIMETIDINE

KETOCONAZOLE

FLUOXETINE

RAISED PLASMA

LEVEL OF DRUG

DRUG EXCRETION


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DRUG EXCRETION

EXAMPLES

PRIMARY DRUG COMPETING DRUG EFFECT OF INTERACTION

PENICILLIN PROBENECID INCREASED

PENCILLIN LEVELS

METHOTREXATE SALICYLATES

SULPHONAMIDES

BONE MARROW

DEPRESSIONLITHIUM THIAZIDES LITHIUM TOXICITY

HYPERNATRAEMIA

DIGOXIN SPIRONOLACTONE INCREASED PLASMA

DIGOXIN LEVELS

SALICYLATES

INDOMETHACIN

PROBENECID INDOMETHACIN OR

SALICYLATES TOXICITY.


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INTERACTIONS WITH DIAGNOSTIC LAB. TEST

TEST DRUG EFFECT ON TEST

DIGOXIN (RIA)

(FAB. VE)

SPIRONOLACTONE REDUCE (FALSE-VE)

URATE (SPECTO) PARACETAMOL RAISED RAISED (FALSE +VE)

KETONES IN URINE SALICYLATES INVALIDATE TEST

FERRIC CHLORIDE CHLORPROMAZINE

NA VALPROATE

INVALIDATE TEST


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Documents

Pharmacokinetic Interaction