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Bioavailabilitas dan Interaksi

Obat
Nurina Hasanatuludhhiyah dr., M.Si
Refferences
• Zaman N. 2009. Ars Prescibendi Resep yang
Rasional. Airlangga University Press. Surabaya
• Katzung, B.G., 2012. Basic and Clinical
Pharmacology. 12th Ed. USA: McGraw-Hill
• Shargel L & Yu ABC. 2016. Applied
Biopharmaceutics and Pharmacokinetics 7th
ed.Singapore : McGraw-Hill
• Basori A. 2014. Interaksi Antar Obat. Dep
Farmakologi FK UNAIR. Surabaya
Bioavailability
the rate and extent to which the active
ingredient or active moiety is absorbed from a
drug product and becomes available at the
site of action (US-FDA, DCER 2014a)
Time course of drug concentration
Determination of bioavailability

• = The fraction of
unchanged drug reaching
systemic circulation
following administration
by any route

• A drug given by the


intravenous route :
absolute bioavailability of 1
(F=1 or 100%
bioavavailable)

• Drugs given by other


routes usually have an
.

absolute bioavailability of
less than one

• ~Area under the curve (AUC)


Absolute Bioavailability
• Compares the
bioavailability of the
active drug in systemic
circulation following
extravascular
administration with the
bioavailability of the
same drug following
intravenous
administration
• Fabs = AUCpo . Div
AUCiv . Dpo
Relative bioavailability
• the bioavailability of a given drug from a ‘test’
dosage form is compared to that of the same
drug administered in a ‘standard’ dosage
form, which is either an orally administered
solution (from which the drug is known to be
well absorbed) or an established commercial
preparation of proven clinical effectiveness
• Frel = 100. AUCB / DB
AUCA /DA
Bioequivalence
• The absence of a significant differences in the
rate and extent to which the active ingredient
or active moiety becomes available at the site
of drug action when administered at the same
molar dose under similar conditions in an
appropriately designed study
Factors affecting bioavailability-drug
• The Dose
• Physicochemical properties of the drug
• Dosage form
• Formulation
• Route of administration
• Excipient
Physicochemical properties of the drug
• Lipid & water solubility
• Stability
• pKa & pH profile
• Particle size
• Polymorphism
• Partition coefficient
• Chirality
Dosage form (pulveres)
Drug Formulation
Routes of administration
Factors affecting bioavailability-px
• Age, weight, body surface area
• Physiologic factors
• Occurence of certain hepatic or renal disease
• Drug interaction
• First pass effect
Physiologic factors
- pH of Stomach and intestine
- Surface area of the of the intestine – microvilli
- Presence of carrier proteins for absorption &
efflux (Pgp)
- Enzymes
- GI blood flow
- Gastric Emptying & intestinal transit
When to concern bioequivalence?
• Antimicrobials
• Anticonvulsants
• Oral antidiabetic medication
• Anticancer
• Anticoagulant
• Cardiovascular drugs
Drug product Dose (mg) AUC
(μg.h/mL)
Oral tablet 200 89,5
Oral solution 200 86,1
IV bolus 50 37,8
injection

Fabs ? Frel?
Drug interaction
• The alteration of patient’s responses to drugs
by concurrent administration of other drugs,
herbals, supplements, food or beverage
Cases
Drug Interaction
• Pharmaceutical
• Pharmacokinetic
• Pharmacodynamic

Benefit HARM
Pharmaceutical drug-drug interaction
• Precipitation of Sodium Thiopentone with
Vecuronium within an intravenous set
• Mixture of Phenobarbital and water can not
be soluble
Pharmacokinetic- Absorption
• Directly, before absorption :
-- Adsorbant : Kaolin, Pectin, Charcoal
-- Anion exchange resins (Cholestyramine;
Colestipol)
-- Chelation : Tetracyclin, Azithromycin,
Fluoroquinolone w/ divalent or trivalent
cations (Fe2+, Ca2+, Al3+) (susu)
Pharmacokinetic- Absorption
• Alteration of pH of GI tract
-- Antacid, H2 blockers, proton pump inhibitor :
reduce absorption of Ketokonazole,
Itrakonazole, Isoniazid, Indinavir, Fe2+ ,
Cefuroxime
increase absorption of Aspirin, Glibenclamide,
Glipizid
Pharmacokinetic- Absorption
• Alteration of gastrointestinal physiology
-- Gastric transit time :
↓Metoclopramide; Domperidon; Laxatives;
MgOH2
↑Anticholinergic; Opioid
-- Intestinal motility : opioid
-- Damage of intestinal mucosa : antineoplastic;
antiretroviral; NSAIDs
Pharmacokinetic- Absorption
• Alteration of active and passive transport
Ex : grape fruti juice may reduce bioavailability
of β-blockers
• P-glyprotein efflux transporter
P-glyprotein inhibitor: Ketokonazole,
Amiodarone, Quinidine, Macrolide → ↑
Digoxin
Pharmacokinetic- Absorption
• Alteration of intestinal normal flora : Broad
spectrum AB may ↑ effect of oral anti
coagulant
• Food :
-- ↓ absorption of Penicillin; Erythromycin;
Tetracycline; Rifampicine; Captopril; Isoniazid
-- ↑ absorption of Hidrochlorotiazide; Phenytoin;
Nitrofurantoin; Albendazole
Drug-food interaction
• Pectin ↓ Paracetamol absorption
• High protein food ↓absorption of levodopa;
methyldopa; Teophyliine; Cimetidine; Sucralfate
• Fatty food ↑ absorption of Griseovulfin;
Itraconazole; Lovastatin; Spironolacton;
Teophylline
• Spinach; broccoli : ↓ effect of anti coagulant
• Vitamin C ↑ absorption of Fe
• Vitamin D ↑ absorption of Ca
Pharmacokinetic- distribution
• Higly protein bound drugs
• Low Vd
• Narrow margin of safety
Drug interaction-distribution
Drug B Drug A
Valproic acid Phenytoin
Phenylbutazone (89%; Vd 0,7 L/kg)
Sulphonamide Tolbutamide
(96%; Vd 0,11 L/kg)
Warfarin
(99%; Vd 0,14 L/kg)
Bilirubin
Salicilic acid Bezodiazepine
Ibuprofen
Ketoprofen
Naproxen
Pharmacokinetic- Metabolism
• CyP450 inducer
• CyP450 inhibitor
CyP1A2 hepatic enzyme
Substrate Inducer Inhibitor
Acetaminophen Hydrocarbon Fluvoxamine
Caffeine of cigarette
Tamoxifen Hydrocarbon
Teophylline of food
Warfarin Omeprazole
CyP2C9 hepatic enzyme
Substrate Inducer Inhibitor
Celecoxib Barbiturate Phenylbutazone
Phenytoin Rifampicin Metronidazole
Ibuprofen Phenytoin
Losartan
Tolbutamide
S-Warfarin
CyP3A4 hepatic enzyme
Substrate Inducer Inhibitor
Amiodarone Barbiturate Phenylbutazone
Acetaminophen Rifampicin Metronidazole
Dapsone Phenytoin
Diazepam Glucocorticoid
Dihydropiridine
Diltiazem
Ethinyl estradiol
Lidocaine
Macrolide
CyP2E1 hepatic enzyme
Substrate Inducer Inhibitor
Acetaminophen Ethanol Disulfiram
Enflurane Isoniazid
Ethanol
Halothane
Pharmacokinetic-excretion
• Glomerular filtration
• Secretion
• Passive reabsorption
Pharmacodynamic
• Additive
Mechanisms:
• Potentiation
• Synergistic - Receptor
• Antagonism - Non receptor
Additive
• Imipenem & Cilastatin (dehydropeptidase
inhibitor)
• Penicillin & clavulanic acid; sulbactam (β-
lactamase inhibitor)
Synergistic
Antibiotic combination :
• Trimetoprim & Sulphametoxazole
• Penicillin & Aminoglycoside
Antihypertensive combination :
• ACE inhibitor & diuretic
• ARB & CCB
Anticancer combination :
• Cyclophosphamide & Doxorubicin & 5-Fluoroacil
Triple or Quadruple Tx for eradication of H pylori
in peptic ulcer
Synergistic
• Antipsychotic drug with mood stabilizer
• Opioid analgesic with sedative hypnotic drug
• MAOI with tricyclic antidepressant
Antagonism
• Chemical : Heparin intoxication with Protamin
sulphate
• Functional : amphetamine intoxication with
anti convulsant
• Dispositional : Aspirin intoxication with
sodium bicarbonate
• Receptor : Morphin intoxication with
Naloxone
Receptor
• Intracellular receptor : Vitamin A & Vitamin D
• Transmembrane receptor :Muromonab &
Cyclosporine A
• Ion channel : Benzodiazepine & Phenobarbital
non receptor
• Interaction due to alteration of fluid &
electrolyte balance
• Interaction between drugs which work
through the same physiologic system
• Interaction due to hormonal change
• Interaction with MAO inhibitor
How to avoid drug interaction
• Thorough anamnesis & physical examination
• Avoid polypharmacy
• Special caution on : MAO inhibitor; oral
anticoagulant; oral antidiabetic drug; Digoxin;
anti cancer; anti conculsant; antihipertension;
CNS-depressant
• Give instruction to Px to not consume other
drugs or herbals without consultation
• Give instruction to Px to avoid alcohol