DRUG INTERACTION

Departement of Pharmacology and Therapy

Medical School Universitas Padjadjaran
SW

Drug interaction is happened when

pharmacological effect of one certain drug is
changed by an other drug or substance
Giving more than 1 drug to 1 patient are often found in
practice
More drugs are given more drug interactions will be
happened
Drug interaction can increase, decrease or change
pharmacological effect of drug

DRUG EFFECT WILL BE INCREASED CAUSED BY

SYNERGISM
1. Additive or Summation the effect will be the sum

of each drug (2 plus 2 are 4)

Ex : Betanidin and thiazide diuretic in hypertension
2. Potentiation

the effect is more then the sum of

each drug (2 plus 2 is more than 4)

Ex : Trimethoprim and sulfamethoxazole (Cotrimoxazole). Its effect is

higher than if each drug is given alone in inhibiting folic acid synthesis

The effect will be decreased caused by

ANTAGONISM
1. Competitive antagonist
Inhibition caused by the action on the same receptor
Ex : Antagonism between naloxone and morphine

2. Non competitive antagonism (physiologic)

Inhibition caused by the action on different receptor
Ex : Antagonism of adrenaline to histamine effect to the
bronchus. Can you explain this antagonism in BA?

How is the interaction ocurred ?

Interaction could occur during seconds or minutes but
the others may occur after several weeks
There are certain points that important to be attended
during interaction is occurring :
1. The first occurrence is detected/onset of reaction
2. During maximal interaction of pharmacokinetic
or pharmacodynamic effect
3. During the side effect of interaction is felt by the
patient
4. The right time to stop the interaction

Informations of points 1, point 2 and point 4 can be found in

clinic, but point 3 is difficult to be found
Even though one can be able to detect when the maximal risk
has occurred and then decides the prevention
To know when the interaction is occurring will be helpful for
the clinicians to minimize the side effects and the monitoring
budget

CLASSIFICATION OF DRUG INTERACTION

Based on the location :

1. Outside the body

Pharmaceutical interaction no more happened

Chemical interaction (incompatibility)

2. Interaction on the site of RODA (absorption process)

3. Inside the body (in distribution, metabolism and excretion
and pharmacodynamic process /receptors)

Based on the occurrence

1. Pharmacokinetics interaction
One drug changes the other drug pharmacokinetic
result in change of 1 or more drug concentration in
plasma and in receptors
2. Pharmacodynamic interaction
A certain drug does not change pharmacokinetic of the
others but changes the response to 1 drug or all drugs
or changes plasma concentration of a certain drug

Pharmacokinetic interaction
Occurred in several processes
On systemic administration
1. Drug interaction in vitro
incompatible between drug and IV fluid infusion
2. Drug interaction in absorption in vivo
Par enteral IM/SC
Per oral

How is the mechanism that caused the alteration in

Absorption ?
1. Formation of complex bound
Ex : tetracycline and cation such as Ca ion in milk or antacide
2. Alteration of intestine motility
- atropin

and opioids can inhibit gastric emptying and absorption

of some drugs such as acethaminophen (that its absorption is mainly
in intestine)
- Metoclopramide stimulates the GIT motility result in decreased
absorption of cimethidine where its absorption is in gaster

3.Inhibition of absorption
Fenitoin + Oral contraception inhibit hydrolysis of folic acid to monoglutamic
acid in intestine decreased absorption
Colchisin Vitamin B malabsorption

4. Alteration caused by diet

Food in gaster will decrease or increase some drugs absorption. Fatty food
increase the absorption of lipophilic drugs (griseovulfin), refer to dissolution and
also the rate of absorption

5. Alteration of intestinal florae

Antimicrobial drugs will cause increasing potentiality of the oral anticoagulant
effect by decreasing synthesis of vitamin K produced by intestinal florae.

6. Alteration in gastric pH
Salicylates (weak acid) is not good absorbed when gastric pH is increased
(caused by antacide)

INTERACTION IN DISTRIBUTION
1.Replacement caused by Competition in incorporation to plasma
protein . Most drugs especially the acid is bound to plasma protein replacement
often result in increased free drug that causes increased pharmacological effect
sometimes so complex and difficult to be presumed. It is important to drugs that
more than 90% bound to plasma protein such as coumarin, sulfonamid, salicylates
and other NSAIDs.
Sulfonamide will cause kern icterus in premature baby.
Fenylbutazone will increases the anticoagulant effect of warfarin and
result in heavy hemorrhage

2. Replacement caused by competition in binding to protein tissues.

Quinidine will replace digoxin in tissues and disturb digoxin excretion by kidney
result in increasing digoxin toxicity

3. Inhibition in active transport system. Tricyclic antidepressant and

fenotiazine will counter the hypotensive effects of guanidinium because both drugs
will inhibit the drug reaches its SOA

Interaction in metabolism
The change of drug concentration is very often and very
important if there is alteration in rate of drug
biotransformation.
Individual variation in certain drug concentration is very
often occurred with drugs that widely metabolized in GIT
or by FPM (propranolol). Effect of 1 drug can become long
if its metabolism is inhibited by other drug
Cytochrome P-450 will be induced or inhibited by some
drugs
Autoinducer is a drug that induces the enzyme by itself
(carbamazepin)

Microsomal enzyme inducer

Example :
Metabolism of warfarin increased by some inducers
(rifampicin, carbamazepin, fenitoin) Effect of
warfarin
Metabolism of oral contraceptive increased by
fenitoin. Effectiveness of oral contraceptive ?
Usually the maximal effect caused by inducer will
occur after 7 10 days

Microsomal Enzymes Inhibitors :

Example:
Fenitoin is inhibited by coumarin, isoniazide,
fenylbutazone, etc fenitoin intoxication .
Please look for the other examples !!!!!!
Effects that caused by metabolism inhibition is faster than
by induction

Interaction in Excretion
1.Interfere the active transport (by weak acid) decrease
the elimination of certain drugs probenezid will
inhibit excretion of penicillin, indomethazine, cefazolin
and methotrexate. And the others.
2. Interfere the passive diffussion (alternation in urine pH)
alter the elimination of weak acid or base
Alkalinization of the urine by some drugs will increase
the elimination of weak acid drugs.
3. Decrease renal toxicity by diuretics Manitol decreases
cysplatin toxicity

4. Decrease elimination of drug caused by stimulating

the bile excretion
Phenobarbital increases the elimination of drug into
bile
5. Increase elimination by binding in GIT excretion
by faeces increase
Active carbon and cholestyramin increase
elimination of the ather drug
Usually it happened to drug that goes on enterohepatic
recirculation

Pharmacodynamic Interaction
1. Interaction on the same target organ
A. On same receptor additive or comp. antagonism
B. On different receptor potentiality or antagonism
2. Interaction on different target organ
Examples : in the Buku Pedoman Farmakologi Klinik
The examples of drug-drug interactions are abundant, but the
importance for the clinician is the occurrence of interaction in
certain drugs such as :
1. Drugs with narrow therapeutic index (Glycoside)
2. Effect of drug dose interrelated with plasma concentration
3. Drug with uncertain or unpredictable effect (psychotropics)

The occurrence of side effects caused by interaction depend

on :
1. Predisposition factors (disease, organ function, dosage etc)
2. Attention of the prescriptions writer (monitoring and prevention)

How to predict the occurrence of interaction ?

1. High Predictable if occurred in almost all patient given
combination of drugs. Examples ?
2. Predictable if occurred in most of patients
3. Not predictable if only occurred in some patients
4. Not established if data of the side effects of interaction are not
enough available (observed)

SEE : Basic and Clinical Pharmacology

(B.Katzung)
APPENDIX II :
IMPORTANT DRUG INTERACTIONS AND
THEIR MECHANISM