Drug Combination

Drug Combination
Two or more drugs are taken at the same time (Drug-drug
interaction).
Drug Interactions:

The pharmacologic or clinical response to the

administration of a drug combination different from that
anticipated from the known effects of the two agents when
given alone
Tatro DS (Ed.) Drug Interaction Facts. J.B. Lippincott Co. St. Louis 1992

Effects of drug interaction

Drug interaction can result in
Increased effect Additive or Synergistic effect
Increased therapeutic effect : good
Increased toxic or adverse effect : bad

Decreased effect Antagonistic effect

Decreased therapeutic effect : bad
Decreased toxic effect : good

Drug interactions usually happen unexpectedly and result in

adverse drug reactions
Drug interactions for good therapeutic effects are usually used
intentionally.

Additive or Synergistic effect

Antagonistic effect

Drug interaction
Where
1. Outside the body : Pharmaceutical
2. Inside the body : Pharmacokinetic & Pharmacodynamic

Drug interaction outside the body

Soluble insulin and protamine zinc delayed absorption
Incompatibility
Diazepam or phenytoin + Infusion fluid (saline) Precipitation .
Carbenicillin + Gentamycin Inactive gentamycin
Thiopental + Suxamethonium Precipitation

Drug interaction inside the body

Mechanisms
Pharmacokinetic interactions : What the body does with the drug.
One drug alters the concentration of another
Absorption
Distribution
Metabolism
Elimination

Pharmacodynamics Interactions : Related to the drugs effects in

the body
One drug modulates the pharmacologic effect of another:
Synergism : Potentiation & Addition
Antagonism

I. Interactions During Absorption

A. Direct chemical interaction
Iron and tetracyclines form complex.
Antacids: Aluminium or magnesium chelate with
tetracyclines bioavailability of tetracycline (2 hr apart).
Cholestyramine interfere with absorption of:
Digoxin
Warfarin.
Thyroxine

I. Interactions During Absorption

(B) Alteration of GIT Motility
Purgatives absorption
magnesium sulfate (laxative) oral decreases levels of
minocycline oral by reducing drug absorption from the
stomach and intestine into the body.

Antidepressants & anticholinergic drugs e.g. Atropine

gastric emptying & delay absorption.
Prokinetics e.g. Metoclopramide gastric emptying and
absorption.

I. Interactions During Absorption

(C) Alteration in GIT Flora
broad spectrum antibiotics potentiates
anticoagulants bacterial synthesis of Vit K.
(D) Absorption from other sites
Local anesthetic (lidocaine) + Adrenaline delay in
absorption duration of action

II. Distribution
A) Displacement from plasma protein binding sites.
Sulphonamide + BilirubinKernicterus
B) Displacement from other tissue binding sites.
Quinidine + digoxin more digoxin toxicity

III. Biotransformation
A) Enzyme Induction
Rifampin + Contraceptives reduced efficacy of
the birth control
Barbiturates + Warfarin Anticoagulant effect
B) Enzyme Inhibition
Cimetidine potentiates effects of Warfarin,
theophylline

IV. Interaction During Excretion

Interference with active transport

Pharmacodynamic Interactions
DRUG SYNERGISM
DRUG ANTAGONISM

Synergism
When the therapeutic effect of one drug is enhanced by another
drug.
Types:
Addition
When the effect of two drugs having similar action are additives
the net effect of two drugs used together is equal to the sum of
the individual drug effect.
1+1=2
Thiazide diuretics + Beta blocker have an additive
antihypertensive action.

Synergism
Potentiation
When the net effect of two drugs used together is greater than the sum of the
individual drug effects.
1+1>2
when one drug increases the action of other drug e.g. sulphamethoxazole +
trimethoprim cotrimoxazole (bactericidal)
1+1>2

Synergism
or when drug has no effect as own but increases the effect
other drugs
1+0>2
L-dopa and carbidopa

Antagonism
The effect of one drug is decreased or abolished by the administration of
another one .
- Chemical
- Physiological (on different receptors)
- Pharmacologic (on same receptor)
Pharmacologic effect < than the summation of the 2 drugs
Good : naloxone in opiate overdose
Bad: zidovudine + stavudine

Chemical antagonism
Drug-albumin complex in plasma: Inactive
Oxim-dialkylphosphorylated cholinesterase complex: reactivation of the
enzyme
Heparine(-) + Protamine sulfate(+) -> Complex formation
(acidic)
(basic)
(antagonism)
Digoxin + digoxin antibody (digibin): antagonism of digoxin
Antidote- heavy metal ring formation by chelation: Antagonism!!
Heavy metals
Antidotes
Mg, Ca, Al,
Dimercaprol (BAL)
Cu, Hg, Pb,
Na2-EDTA
Cd, Au, Fe
Penicillamine
Desferroxamine

Physiological antagonism
Occur no on the same receptor
Mediated by differing receptors causing opposing effects
Noradrenaline (vasoconstriction) x Histamine (vasodilation)
Noradrenaline x ACh, nitrates
Barbiturates (-) Respiratory (+) Doxapram
Oral anticoagulants (-) Liver (+) Estrogens
Protrombin
Clotting F
Anticoagulant synthesis

Oral contraceptives
Effects Coagulant effect

Pharmacological antagonism
Competitive antagonism:
Interaction on the same receptor
Interaction is reversible
Effect of antagonist is fully recovered by increasing agonist concentration in
the medium
Examples : Ach & atropine, Morphine & naloxone
Noncompetitive antagonism
Irreversible (covalent)
The effect is long lasting
Effect is not dependent on clerance
Antagonism is reverted only by new receptor Synthesis
Examples: -Antagonism of -adrenoceptors by Phenoxybenzamine

Beberapa contoh tujuan kombinasi

Kombinasi antara dua jenis obat atau lebih yang mempunyai
efek yang sama atau mirip untuk mengobati satu simptom
Memberikan obat kombinasi dengan maksud mengurangi
atau menghilangkan efek samping obat utama
Memberikan obat kombinasi dengan maksud meningkatkan
absorpsi (rate of absorption and extend of absorption) obat
utama
Memberikan obat kombinasi dengan tujuan timbulnya efek
potensiasi.

Prinsip Pengobatan

Obat sesuai dengan jenis penyakit yang menyerang

Obat mampu mencapai lokasi kerja atau organ sakit
Obat tersedia dalam kadar yang cukup
Obat berada dalam waktu yang cukup