Drug interaction & FDC
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DRUG INTERACTION & FIXED DOSE COMBINATION
MODERATOR: Dr. Ali Ahmad
RESIDENT : Fariha Fatima JR-II
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DEFINITION:
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CLASSIFICATION OF DRUG INTERACTION:
additive
synergistic
potentiation
antagonism
functional
chemical
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MECHANISMS OF INTERACTION:
Pharmacokinetic
Pharmacodynamic
biotransformation
distribution
absorption
excretion
Non-receptor
receptor
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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)
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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.
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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.
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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
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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.
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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
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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.
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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.
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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
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Pharmacodynamic interactions:
Action on receptors
Action on body systems
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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.
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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.
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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.
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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.
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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.
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advantages
Convenience in dose schedule and better compliance
Enhanced effect of combination
Minimization of side effects
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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
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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.
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Thank you