drug combination

8/10/2019 Drug Combination

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Drug Combination

Two or more drugs are taken at the same time (Drug-druginteraction).

Drug Interactions:

The pharmacologic or clinical response to theadministration of a drug combination different from thatanticipated from the known effects of the two agents whengiven alone

Tatro DS (Ed.) Drug Interaction Facts. J.B. Lippincott Co. St. Louis 1992


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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 inadverse drug reactions

Drug interactions for good therapeutic effects are usually usedintentionally.


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Additive or Synergistic effect


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Antagonistic effect


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Drug interaction

Where

1. Outside the body : Pharmaceutical

2. Inside the body : Pharmacokinetic & Pharmacodynamic


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Drug interaction outside the body

Soluble insulin and protamine zinc delayed absorption

IncompatibilityDiazepam or phenytoin + Infusion fluid (saline) Precipitation .Carbenicillin + Gentamycin Inactive gentamycin

Thiopental + Suxamethonium Precipitation


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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 bodyOne drug modulates the pharmacologic effect of another:

Synergism : Potentiation & Addition

Antagonism


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I. Interactions During Absorption

A. Direct chemical interaction

Iron and tetracyclines form complex.

Antacids: Aluminium or magnesium chelate withtetracyclines bioavailability of tetracycline (2 hr apart).

Cholestyramine interfere with absorption of:

Digoxin Warfarin.

Thyroxine


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(B) Alteration of GIT Motility

Purgatives absorption

magnesium sulfate (laxative) oral decreases levels of

minocycline oral by reducing drug absorption from thestomach and intestine into the body.

Antidepressants & anticholinergic drugs e.g. Atropine

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

absorption.



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(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



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II. Distribution

A) Displacement from plasma protein binding sites.

Sulphonamide + BilirubinKernicterus

B) Displacement from other tissue binding sites. Quinidine + digoxinmore digoxin toxicity


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III. Biotransformation

A) Enzyme Induction

Rifampin + Contraceptives reduced efficacy of

the birth control Barbiturates + WarfarinAnticoagulant effect

B) Enzyme Inhibition

Cimetidine potentiates effects of Warfarin,

theophylline


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IV. Interaction During Excretion

Interference with active transport


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Pharmacodynamic Interactions

DRUG SYNERGISM

DRUG ANTAGONISM


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Synergism

When the therapeutic effect of one drug is enhanced by anotherdrug.

Types:

AdditionWhen the effect of two drugs having similar action are additives

the net effect of two drugs used together is equal to the sum ofthe individual drug effect.

1 + 1 = 2 Thiazide diuretics + Beta blocker have an additive

antihypertensive action.

S


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Potentiation

When the net effect of two drugs used together is greater than the sum of theindividual drug effects.

1 + 1 > 2

when one drug increases the action of other drug e.g. sulphamethoxazole +

trimethoprim cotrimoxazole (bactericidal)1 + 1 > 2

Synergism


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or when drug has no effect as own but increases the effect

other drugs

1 + 0 > 2

L-dopa and carbidopa

Synergism


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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


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Chemical antagonism

Drug-albumin complex in plasma: Inactive

Oxim-dialkylphosphorylated cholinesterase complex: reactivation of theenzyme

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


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Physiological antagonism

Occur no on the same receptor

Mediated by differing receptors causing opposing effects

Noradrenaline (vasoconstriction) x Histamine (vasodilation)

Noradrenaline x ACh, nitratesBarbiturates (-)Respiratory(+) Doxapram

Oral anticoagulants (-)Liver (+) Estrogens

Protrombin Oral contraceptivesClotting F

Anticoagulant synthesis Effects Coagulant effect


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Competitive antagonism:

Interaction on the same receptor

Interaction is reversible

Effect of antagonist is fully recovered by increasing agonist concentration inthe 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

Pharmacological antagonism


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Beberapa contoh tujuan kombinasi

Kombinasi antara dua jenis obat atau lebih yang mempunyaiefek 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.


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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

drug combination

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