PRINSIP INTERAKSI OBAT

Dini Permata Sari, S.Farm,

M.Si., Apt
 RUJUKAN
• Prof. Louis Roller; Department of Pharmacy
Practice Faculty of Pharmacy; Monash
Univesity
• New Zealand College of Pharmacists
DRUG INTERACTIONS DEFINITION
A measurable modification (in
magnitude and/or duration) of the
action of one drug by prior or
concomitant administration of another
substance, including prescription, non-
prescription (including complementary
medicines) drugs, food, alcohol,
cigarette smoking or diagnostic tests
 DRUG INTERACTIONS

Outside Body Pharmacokinetic

(Pharmaceutic)

Pharmacodynamic

phisic chemical
Drug INTERACTIONS: Outside Body

Kondisi Penyimpanan:
Penyebab Utama:
 Cahaya (sodium nitroprusside)
 Air (asprin)
 Udara (oxidation of drug)

Mixing
Reaksi Pengendapan (thiopentone dengan suxamethonium)
 Pharmaceutical
Interactions
Interaksi yang terjadi terutama
pada pemberian sistemik
 Contoh: inkompatibilitas antara dua
obat yang dicampurkan dalam cairan
intravenus. Interaksi ini bisa berupa
fisika (misalnya terjadi pengendapan
yang dapat dilihat) atau bisa juga
secara kimia yang dapat dilihat (no
viseble sign); ini menjadi masalah
 DRUG INTERACTIONS:
PHARMACODYNAMIC AND PHARMACOKINETIC

Pharmacodynamic Interaction
Drug A alters the effect of Drug B without a change in the concentration of
Drug B

Pharmacokinetic Interaction
Drug A alters the effect of Drug B by changing the plasma concentration of
Drug B
 TYPES OF INTERACTIONS

1. Pharmacodynamic Interactions:
 One drug causes a change in patient response to another
drug without altering that drug’s pharmacokinetics
• drugs acting agonistically at the same receptor sites
leading to potentiation
• drugs acting antagonistically at the same receptor
leading to antagonisim
 PHARMACODYNAMIC
INTERACTIONS
• Drug B INCREASES the effects of
drug A
• Drug B DECREASES the effects of
 drug A toxicity of digoxin caused by diuretic
Eg. increase
induced hypokalaemia
 Additive effects of alcohol and benzodiazepines
 Beta-blocker given with beta-agonist
Pharmacodynamic interactions;

IT MEANS ALTERATION OF THE DUG ACTION

WITHOUT CHANGE IN ITS SERUM
CONCENTRATION BY PHARMACOKINETIC
FACTORS.
Synergistic or additive
EX., Propranolol + verapamil
effect

Synergism means =1+1=3

On the other hand

Additive means= 1+1=2

Effect at the receptor site
•Antiadrenegic
Potentiation means= 1+0=2 •anticholinergic

Antagonism means 1+1=0 or 0.5

PHARMACOKINETIC
INTERACTION
Pharmacokinetic Interaction
Drug A alters the effect of Drug B by changing
the plasma concentration of Drug B
PHARMACOKINETIC
INTERACTION
• Absorption

• Distribution

• Metabolism

• Excretion

Piscitelli SC, Gallicano KD. N Engl J Med 2001;344:984-96

PHARMACOKINETIC INTERACTIONS
 Drugs affecting each other at sites of
absorption,distribution, metabolism and excretion
 One drug alters the rate or extent of absorption,
distribution, metabolism or excretion of another
drug.
 A change in blood concentration causes a change
in the drug’s effect.

 Drug B INCREASES the availability of drug A

 Drug B DECREASES the availability of drug A
 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.
 Decrease the pH
Ex1., antiacids Decrease the tablet
dissolution
of Ketoconazole (acidic)

pH
Ex2., H2 antagonists

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 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) hydroxid

Decrease absorption
of
ciprofloxacin by 85%
due to chelation
 DRUG INTERACTION:
DOXYCYCLINE – PEREPARAT
BESI
INTERAKSI TETRASIKLIN DENGAN
ALUMINIUM HIDROKSIDA
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 Increase absorption of

of cyclosporine cyclosporine due
to the increase of stomach
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
Phenytoin is a highly bound to plasma protein (90%
with higher affinity.
Tolbutamide (96%), and warfarin (99%)

Drugs that displace these agents are:

Aspirin

Sulfonamides

Phenylbutazone
Drug Metabolism
Drug Metabolism
DMEs broadly classified into two types of reactions
(see Biotransformation lectures):

• PHASE I: typically a functional group (e.g.

hydroxyl) is created or exposed in a drug molecule

• PHASE II: conjugation of either the parent

compound and/or its metabolite(s) involving a polar
endogenous substrate that is able to react with the
functional groups formed via Phase I reactions
 Human Phase I Enzymes of Drug Metabolism

CYP2D6
CYP2E1 CYP3A4/5/7
CYP2E1
CYP2C19
CYP2D6
CYP2C9 CYP2C19
CYP2C9
CYP2C8 CYP2C8
CYP2B6 CYP2B6
CYP2A6 CYP2A6
CYP1B1 CYP1B1
CYP3A4/5/7 CYP1A1/2 CYP1A1/2
others
others epoxide hydrolase
esterases
epoxide hydrolase NQ01
Esterases/amidases DPD
ALDH NQ01 ADH
ADH
DPD ALDH

CYP: cytochrome P450, NQ01: NADPH:quinone oxidoreductase (DT diaphorase);

DPD: dihydropyrimidine dehydrogenase; ADH: alcohol dehydrogenase; ALDH:
aldehyde dehydrogenase Evans and Relling, Science (1999)
 Human Phase II Enzymes of Drug
Metabolism
COMT HMT STs
TPMT UGTs
TPMT
COMT
HMT
GST-A
STs
GST-P GST-A
UGTs GST-P
GST-T
GST-M GST-T
GST-M
NAT2 NAT2
NAT1
NAT1 others
others
: histamine methyltransferase; TPMT: thiopurine methyltransferase;
MT: catechol O-methyltransferase; UGT: Uridine Glucuronosyl-S-Transferases;
Sulfotransferase; GST: Glutathione-S-Transferases
Evans and Relling, Science (1999)
Relative Amounts of Individual
Human Hepatic CYPs
Other
26% CYP1A2
13%

CYP2A6
4%
CYP2B6
CYP3A
<1%
30%

CYP2E1 CYP2C
7% CYP2D6 18% CYP2C8
2% 1.7%

CYP2C19
Shimada et al., JPET: 1994 CYP2C9 2.7%
13.6%

Lasker et al., Arch. Bioch. Biophys:1998

 Human Cytochromes P450 and their
Relative Contribution to Hepatic Drug
Metabolism
Shimada et al., JPET: 1994

CYP3A CYP2C19
40-50% 4%
CYP2A6
2%

CYP2C9
10% CYP2D6
CYP1A2 30%
6% CYP2E1
5%

60% of drugs are metabolized primarily by CYPs

(Bertz & Granneman, Clin. PK: 1997)
 PENGARUH TERHADAP
METABOLISME OBAT

Terkait dengan
enzim CYP-
450:
 CYP-450 di
usus
 CYP-450 di
hati:
• Induser
• Inhibitor
 Cytochrome P450
• Cytochrome P450: is a family of isozymes responsible for
the biotransformation of several drugs.
• Drug metabolism via the cytochrome P450 system has
emerged as an important determinant in the occurrence
of several drug interactions that can result in drug
toxicities, reduced pharmacological effect, and adverse
drug reactions.
• Recognizing whether the drugs involved act as enzyme
substrates, inducers, or inhibitors can prevent clinically
significant interactions from occurring.
• Avoiding coadministration or anticipating potential
problems and adjusting a patient's drug regimen early in
the course of therapy can provide optimal response with
minimal adverse effects.
 Cytochrome P450
• A greater degree of interaction predictability has been
achieved through the identification of P450 isozymes and
some of the drugs that share them.
• Six different P450 isozymes—CYP1A2, CYP2C19, CYP2C9,
CYP2D6, CYP2E1, and CYP3A4—that play important roles
in drug metabolism have been identified
• Of these 6 isozymes, shared metabolism by the CYP3A4
isozyme has resulted in several clinically significant drug-
drug interactions.
• More information about the effects of certain drugs on
enzyme-mediated biotransformation has led to
identification of enzyme inducers and inhibitors, providing
even greater insight into the nature of the interactions.

Proc (Bayl Univ Med Cent). 2000 October; 13(4):

421–423.
 Substrates, Inducers & Inhibitors of Human CYPs

CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP2E1 CYP3A4

Bupropion
Caffeine Diclofenac Omeprazole
Midazolam Bufuralol Acetaminophen Nifedipine
Imipramine Losarten Phenytoin
Tamoxifen Codeine Ethanol Erythromycin
Substrates Tacrine Phenytoin Indomethacin
Verapamil Desipramine Chlorzoxazone Midazolam
Theophylline Tolbutamide R-warfarin
Testosterone Lidocaine Sevoflurane Testosterone
R-warfarin S-warfarin

Cimetidine Ketoconazole
Ciprofloxacin Ketoconazole Fluconazole Quinidine
Ketoconazole Erthyromycin
Furafylline Tranylcypromine Isoniazid Methadone
Inhibitors Paroxetine Disulfiram Grapefruit juice
Mibefradil Troglitazone Sulfaphenazole Cimetidine
Ticlopidine Ritonavir
Ticlopidine Orphenadrine Paroxetine Fluoxetine

Insulin
Omeprazole Dexamethasone Carbamazepine
(Cruciferous Phenobarbital Ethanol Phenobarbital
Rifampin Prednisone
Inducers vegetables) Rifampin None identified Isoniazid Phenytoin
Secobarbital Rifampin
(Char-grilled Sodium (Starvation) Rifampin
meat) valproate
(Tobacco)

omprehensive list can be found at: http://medicine.iupui.edu/flockhart/table.htm

 MECHANISM OF PHARMACOKINETIC DRUG-DRUG
INTERACTION BASED ON METABOLISM
 Inhibition (is reduced enzyme activity due to direct interaction with a
drug).
• This process usually begins with the first dose of the inhibitor, and
the start and finish of inhibition correlate with the half-lives of the
drugs involved
• There are three basic types of enzyme inhibition (competitive,
non-competitive and uncompetitive), and clinical effects are
influenced by these basic mechanisms
• The first type is competitive inhibition between inhibitor and
substrate for the same binding site on an enzyme.
• For example, when single oral doses of metoprolol (50 mg), a beta-
adrenoceptor blocking agent and/or propafenone (150 mg) were administered,
or when the two drugs were given in combination to healthy subjects, an
approximately two-fold reduction in the oral clearance of metoprolol was
observed when propafenone was included.
• The dose of metoprolol should be reduced when propafenone is also given
• Similar drug-drug interactions : the combined administration of thioridazine
and propranolol (CYP2D6), fluoxetine and desipramine (CYP2D6) , omeprazole
and diazepam (CYP2C19), tolbutamide and phenytoin (CYP2C9) and diltiazem
and cyclosporin (CYP3A)
• The most typical example of the second type DDI:
terfenadine and erythromycin. The combined use of
these drug, terfenadine, and macrolides (antibiotics) or
ketoconazole prolongs electrocardiographic QT
intervals, thereby triggering a specific cardiac
dysrhythmia known as torsades de pointes‘.
• The mechanism of this interaction is considered to
occur when a nitro compound, namely a metabolite
demethylated by P450, forms a complex with P450.
• Since macrolides are catalysed by CYP3A, metabolites
selectively form CYP3A and a stable enzyme-substrate
complex
• Another type is non-competitive inhibition:
– where the inhibitor binds at a site on the
enzyme distinct from the substrate
– Such examples include interactions between
cimetidine and a number of drugs.
– The duration of this type of inhibition may be
longer if new enzymes are synthesized after the
inhibitor drug is discontinued
– Cimetidine is bound to P450 and produces a
stable cytochrome-substrate complex. It is the
formation of this complex which prevents access
of other drugs to the P450 system
 Induction
– The effect of induction is simply to increase the amount of P450
present and speed up the oxidation and clearance of a drug
– Sukar diprediksi krn banyak faktor yang mempengaruhi:
half life obat dan sintesis enzim
– The short half-life of rifampicin results in enzyme induction
(CYP3A4, CYP2C), apparent within 24 h, whereas phenobarbital,
which has a half-life of 3–5 days, requires ≅1 week for induction
(CYP3A4, CYP1A2, CYP2C) to become apparent
– One example has been described by Lee et al. who reported that
changes in the pharmacokinetics of prednisolone were caused
by administration or discontinuation of rifampicin
– Pharmacokinetic studies of prednisolone (1 mg/kg) in patients
over a 1-month period of rifampicin co-treatment or after its
withdrawal revealed significant changes in the area under the
curve (AUC), total body clearance, non-renal clearance and half-
life
 PERKIRAAN MEKANISME INTERAKSI
CLOPIDOGREL - PPI
CLOPIDOGREL HATI METABOLIT AKTIF
thienopyridine CYP-450:2C19 gugus tiol
(2C19) &3A4
competitive inhibition
of the CYP2C19 HAMBAT
isoenzyme R-purinergik ADP- P2Y12
PLATELET
PROTON PUMP
INHIBITOR ASAM NAIK?

Membentuk ikatan:
ATORVASTATI HAMBAT DISULFIDA - SISTEIN
N
PLATELET
(Iireversibel)

• PubMed (1980-January 2009);

Abstracts : 2008 American Heart INHIBISI
Association dan 2009 Society of TROMBUS
Cardiovascular Angiography and
 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
 CONTOH
CYP Substrat Inhibitor Induser
CYP3A Felodipine Grapefruit
4 juice 
plasma
felodipine
CYP1A Imipramin Cigarette
2 e smoking :

plasma
imipramine
THEOPHYLLINE-SMOKING
CYP3A4-INHIBITOR
(Grafefruit Juice)
SAQUINAVIR –
Grapefruit Juice
 RISK FACTORS FOR DRUG
INTERACTIONS
1) High risk drugs
 These are the drugs that show a
narrow therapeutic index e.g.,
corticosteroids rifampin, oral
contraceptives, quindine, lidoquine
 Recognised enzyme inhibitors or
inducers
 RISK FACTORS FOR DRUG
INTERACTIONS
2) High risk patients: These are the groups of patients
that should be treated with caution due to a specific
heath condition e.g:
 Elderly:
• multiple chronic disease states
• multiple prescribers
• multiple medications; interactions/ADRs
• lack of education
• poor adherence with complex drug regimens
• age related physiological changes
• declining cognition/sensorium
• Non-prescription medications
 Young, pregnant women, very sick, multiple
disease, malignant cases, diabetic patients,
multiple drug therapy, patients with liver
impairment or kidney disorders, asthmatic
 Some drugs with a low therapeutic index
 

Lithium Digoxin

Carbamazepine Cyclosporin

Phenytoin Phenobarbitone

Theophylline Warfarin
(Aminophylline)
 
 OUTCOMES OF DRUG
INTERACTIONS
• Harmful
– Toxicity or increased toxicity
– decreased efficacy
– Unexpected increase in pharmacological
activity
• No clinical significance or Loss of therapeutic
effect
• Beneficial
– e.g additive & potentiation (intended) or
antagonism (unintended).
– increased activity (eg penicillins/
cephalosporins with probenecid)
• Chemical or physical interaction e.g I.V
incompatibility in fluid or syringes mixture
 ONSET OF DRUG INTERACTION
 It may be seconds up to weeks for
example in case of enzyme induction, it
needs weeks for protein synthesis while
enzyme inhibition occurs rapidly

 The onset of action of a drug may be

affected by the half lives of the drugs e.g.,
cimitidine inhibits metabolism of
theophylline.
 Cimitidine has a long half life, while,
theophylline has a short one.
 When cimitidine is administered to a
patient regimen for Theophylline,
Mix Food, Drink and Drugs Carefully
• Ask doctor questions
• Talk to pharmacist
• Read medicine labels
• Read printed
material from
pharmacy
• Read inserts
provided by
manufacturers
 The Responsibility is Yours!
• Tell your doctor and
pharmacist about
ALL your drugs
• Take all your drugs
to each doctor’s
appointment and
review
 In General
Take pills and
capsules
with a large
glass of
water
Know Whether the Drug Should Be
Taken on a Full or Empty Stomach
Don’t mix a drug directly into a food
or drink
Take NO
Medicines
with
Alcohol !
DRUG INTERACTIONS OF CLINICAL
SIGNIFICANCE
DRUG INTERACTIONS OF CLINICAL
SIGNIFICANCE
DRUG INTERACTIONS OF CLINICAL
SIGNIFICANCE