This document discusses drug interactions and fixed dose combinations. It classifies drug interactions as additive, synergistic, antagonistic, or functional. Pharmacokinetic interactions can occur during absorption, distribution, metabolism, or excretion. Pharmacodynamic interactions act on receptors or body systems. Fixed dose combinations provide convenience but the component drugs must have matching pharmacokinetic profiles and doses should be based on their volumes of distribution and concentrations. Overall benefits include improved compliance but individual dose titration is not possible.

1. DRUG INTERACTION &
FIXED DOSE COMBINATION
MODERATOR: Dr. Ali Ahmad
RESIDENT : Fariha Fatima
JR-II

2. DEFINITION:

5. CLASSIFICATION OF DRUG INTERACTION:
additive
synergistic
potentiation
antagonism
functional
chemical

6. MECHANISMS OF INTERACTION:
Pharmacokinetic Pharmacodynamic
biotransformation
distribution
absorption
excretion
Non-receptor
receptor

7. 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)

8. 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 motility
Eg.Slowing of gastric emptying,
e.g. opioid analgesics, tricyclic
antidepressants , may delay and
reduce the absorption of other
drugs.

9. 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.

10. 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

11. 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.

12. 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

13. 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.

14. 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.

15. 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

16. Pharmacodynamic interactions:
Action on
receptors
Action on body
systems

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. advantages
 Convenience in dose schedule and better compliance
 Enhanced effect of combination
 Minimization of side effects

23. 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

32. 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.