032012

Pharmacokinetic interaction
Dr.Datten Bangun MSc,SpFK & Dr.Zulkarnain Rangkuty

Dept.Farmakologi & Therapeutik Fak.Kedokteran USU MEDAN

Classification of Drug Interactions

Pharmacokinetic
Pharmacodynamic

in drug absorption, distribution, metabolism or excretion

of pharmacological effect at standard drug concentrations or of pharmacological effect resulting from altered pharmacokinetic exposures

All drugs known to humans are poisons, only the amount or dose determine the effects.
Paracelsus, 1490 - 1541
2

Pharmacokinetics
Movement of drugs in the body Four Processes
Absorption Distribution Metabolism Excretion

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

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

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

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 the ionized form does.

Ex1.,

antiacids

Decrease the pH

Decrease the tablet dissolution of Ketoconazole (acidic)

Ex2.,

H2 antagonists

pH

Therefore, these drugs must be separated by at least 2h in the time of administration of both .

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

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

d) Drug-induced mucosal damage. Antineoplastic agents e.g., cyclophosphamide vincristine procarbazine

Inhibit absorption of several drugs eg., digoxin

e) Altered motility Metoclopramide (antiemitic)

Increase the toxicity of cyclosporine

Increase absorption of cyclosporine due to the increase of stomach empting time

Hepatic Drug Interactions

Genetic Disease Diet Drugs Infection

OATP (azoles, echinocandins?) Phase I metabolism (CYP P450) (itraconazole, voriconazole) Phase II metabolism (glucoronidation) (posaconazole)

Extraction?
10

Metabolism

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

Protein Binding Drug Displacement

Drug B

Plasma
Drug A protein bound

Tissue

Drug A free

Drug A free

Drugs A and B both bind to the same plasma protein

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 drug with higher affinity.

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

Drugs that displace these agents are Aspirin Sulfonamides phenylbutazone

CYP450 Nomenclature
Family

CYP2D6
Sub-Family Individual Gene CYP = Cytochrome P450

Enzyme characteristics % drugs metabolised by enzyme

3A4 2D6 1A2 2C9 2C19 60% 25% 15%
Small no. but significant interactions Small no. but significant interactions ?

2E1

CYP 450 System Definitions

Substrate: Drug is metabolised by the enzyme system Inducer: Drug that will increase the synthesis of CYP450 enzymes Inhibitor Drug that will decrease the metabolism of a substrate

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.

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

Enzyme Inducers Examples

Rifampicin Phenobarbitone Carbamazepine Cigarette smoke

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

Enzyme Inhibition
Often rapid, reversible and relatively short acting. E.g. erythromycin and cyclosporin NB :erythromycin is a substrate and an inhibitor of CYP 3A4 May be prolonged due to long half- life of drug. E.g. amiodarone and S-Warfarin NB: amiodarone is an inhibitor of CYP2C9 but not a substrate for this CYP

Grapefruit Juice-Drug Interaction

Drug Blood Concentration (AUC)

Drug Taken with GJ

Drug Taken without GJ

Time

P. B. Watkins 2003

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.

Excretion Interactions
Mechanisms of urinary excretion: - Simple filtration - Active secretion Mechanisms for active secretion - Acids - Bases

Excretion interactions
Active secretion mechanisms have limited capacity.

e.g. One acid drug may saturate the acid drug active secretion mechanism. Another acid drug will then be secreted less efficiently

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.

Excretion Interaction Change in renal blood flow

Methotrexate and NSAIDs NSAIDS can decrease renal blood flow by inhibition of renal prostaglandins. Reduced clearance of MTX and active (toxic) metabolite

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)

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

DRUG METABOLISM
ENZYME INDUCTION

OR ENZYME INHIBITION ENZYME INDUCTION BY INCREASING DRUG INACTIVATION MAY PRODUCE TOLERANCE OR COMPLETELY NULLIFY DRUG ACTION.

ENZYME INDUCTION
EXAMPLES INCLUDE:
PRIMARY DRUG ORAL ANTICOAGULANTS e.g. WARFARIN TOLBUTAMIDE PHENYTOIN CHLORPROMAZINE ORAL CONTRACEPTIVES PREDNISONE DEXAMETHASONE DOXYCYCLINE BARBITURATES BARBITURATES PHENOBARBITONE DECREASED HYPOGLYCAEMIA FAILURE OF CONTRCEPTION REDUCED STEROID LEVELS REDUCED DOXYCYCLINE LEVELS QUINIDINE PHENYTOIN BARBITURATES REDUCED QUINIDINE LEVELS INDUCING DRUG BARBITURATES RIFAMPICIN EFFECT OF INTERACTION DECREASED ANTI-COAGULATION

ALTERNATIVELY: SOME DRUGS MAY ACT AS ENZYME INHIBITORS AND RAISE THE CONCENTRATION OF SIMULTANEOUSLY ADMINISTERED DRUGS.

INTERACTIONS OF LIVER ENZYME INHIBITORS

PRIMARY DRUG
PHENYTOIN

INHIBITING DRUG
ISONIZID AZAPROPAZONE CHLORAMPHENICOL

INTERACTION
PHENYTOIN INTOXICATION

ORAL ANTICOAGULANTS e.g. WARFARIN TOLBUTAMIDE CHLORPROPAMIDE

ALLOPURINOL NORTRIPTYLINE QUINIDINE PHENYLBUTAZONE CHLORAMPHENICOL DISCOUMAROL HYPOGLYCAEMIA HAEMORRHAGE

6-MERCAPTOPURINE AZATHIOPRINE

ALLOPURINOL

BONE MARROW SUPPRESSION

CIMETIDINE ANY DRUG KETOCONAZOLE FLUOXETINE

RAISED PLASMA LEVEL OF DRUG

DRUG EXCRETION EXAMPLES

PRIMARY DRUG PENICILLIN COMPETING DRUG PROBENECID EFFECT OF INTERACTION INCREASED PENCILLIN LEVELS METHOTREXATE SALICYLATES SULPHONAMIDES LITHIUM THIAZIDES BONE MARROW DEPRESSION LITHIUM TOXICITY HYPERNATRAEMIA DIGOXIN SPIRONOLACTONE INCREASED PLASMA DIGOXIN LEVELS SALICYLATES INDOMETHACIN PROBENECID INDOMETHACIN OR SALICYLATES TOXICITY.

INTERACTIONS WITH DIAGNOSTIC LAB. TEST

TEST DIGOXIN (RIA) (FAB. VE)

DRUG SPIRONOLACTONE

EFFECT ON TEST REDUCE (FALSE-VE)

URATE (SPECTO) KETONES IN URINE

PARACETAMOL RAISED SALICYLATES

RAISED (FALSE +VE) INVALIDATE TEST

FERRIC CHLORIDE

CHLORPROMAZINE NA VALPROATE

INVALIDATE TEST