DRUG INTERACTION & FIXED DOSE COMBINATION

MODERATOR: Dr. Ali Ahmad

RESIDENT : Fariha Fatima JR-II

DEFINITION:

CLASSIFICATION OF DRUG INTERACTION:

additive

synergistic

potentiation

antagonism

functional

chemical

MECHANISMS OF INTERACTION:

Pharmacokinetic

Pharmacodynamic

biotransformation

distribution

absorption

excretion

Non-receptor

receptor

Pharmacokinetic interactions:

ABSORPTION :

Gastrointestinal absorption is slowed by drugs that inhibit

gastric emptying, such as atropine or opiates, or

accelerated by drugs that hasten gastric emptying (e.g.

metoclopramide)

At the site of absorption:

By direct chemical interaction in the gut

Eg.Antacids that contain aluminium and magnesium form insoluble complexes with tetracyclines, iron and prednisolone.

By altering gut motilityEg.Slowing of gastric emptying, e.g. opioid analgesics, tricyclic antidepressants , may delay andreduce the absorption of other drugs.

By altering gut flora Eg.Antimicrobials potentiate oral anticoagulants by reducing bacterial synthesis of vitamin K

Interactions other than in the gut

Eg.Hyaluronidase promotes dissipation of a subcutaneous injection, and vasoconstrictors, e.g. adrenaline,delay absorption of local anaesthetics, usefully to prolong local anaesthesia.

DURING DISTRIBUTION: Displacement from plasma protein binding sites:

One drug may alter the distribution of another, by competing

for a common binding site on plasma albumen or tissue

protein.

Displacement of a drug from binding sites in plasma or

tissues transiently increases the concentration of free

(unbound) drug, but this is followed by increased elimination

So, a new steady state results in which total drug

concentration in plasma is reduced but the free drug

concentration is similar to that before introduction of the

second 'displacing' drug.

Eg, sodium valproate can cause phenytoin toxicity as it

displaces phenytoin from its binding site and also inhibits

its metabolism.

DURING METABOLISM:

Enzyme induction

Enzyme inhibition

Other substances accelerates metabolism and is a cause of therapeutic failure

Potentiates other drugs that are inactivated by metabolism causing adverse reactions

Eg. Unwanted pregnancy

can result in the users of OCPs if potent enzyme inducer like phenytoin or rifampicin are used concomitantly.

Eg. Cimetidine with

theophylline,warfarin,phenytoin.

DURING EXCRETION:

Inhibition of tubular

secretion

Alteration of urine flow and

pH

Reabsorption of a drug by the renal tubule can be reduced and its excretion increased by altering urine pH

Organic acids are passed from the blood into urine by active transport across the renal tubular epithelium.

Eg, Probenecid was developed

to inhibit penicillin secretion and thus prolong its action.

It also inhibits the excretion of other drugs, including zidovudine

Eg, loop and thiazide diuretics

indirectly increase the proximal tubular reabsorption of lithium (which is handled in a similar way as Na+), and this can cause lithium toxicity in patients treated with lithium carbonate for mood disorders

Pharmacodynamic interactions:

Action on receptors

Action on body systems

Action on receptors:

Beneficial interactions

Harmful interactions

In overdose, as with use of naloxone for morphine overdose.

Atropine for anticholinesterase i.e.,insecticide poisoning

Loss of antihypertensive effect of β-blockers when cold remedies containing ephedrine or phenylephrine are taken.

Action on body systems: provide scope for a variety of interactions.

β- adrenoceptor blockers lose antihypertensive efficacy

when NSAIDS are co-administered.

Diuretics lose efficacy if administered with NSAIDS.

Fixed dose combinations:

It means the combination of 2 different drugs in a single

pharmaceutical formulation.

Rational fixed dose formulation can be advantageous but

inappropriate combination could be dangerous.

If 2 drugs are combined in a single pharmaceutical

formulation , these should have equal half lives.

Eg, cotrimoxazole is a combination of sulfamethoxazole

(t1/2 =11hrs) and trimethoprim (t1/2 = 10hrs);

Clavulanic acid (t1/2=1-1.5hrs)is combined with ampicillin

(t1/2=1-1.5hrs) for treatment of various infections.

The ratio of doses of each component in such a formulation

depends on their apparent volume of distribution and peak

plasma concentration of individual drug.

advantages

Convenience in dose schedule and better compliance

Enhanced effect of combination

Minimization of side effects

The dose of any component cannot be adjusted

independently if desired.

If the pharmacokinetic characteristics of 2 drugs do not

match, there would be unacceptable range of fluctuations in

the plasma concentration of the component drugs at steady

state.

It becomes difficult to identify one particular drug causing

harmful/beneficial effects.

disadvantages

Thus , the fixed dose combination should not be used

unless:

There is a good reason to believe that the patient needs all

the drugs in the formulation.

The pharmacokinetic parameters of the component drugs

match with each other.

Thank you