2. • The administration of one drug can alter the
action of another drug by one of two general
mechanisms:-
• (i) Modification of the pharmacological
effect of B without altering its concentration
in the tissue fluid (Pharmacodynamic
interaction):-
• (ii) Alteration of the concentration of B that
reaches its site of action (Pharmacokinetic
interaction).
3. • For pharmacodynamic interactions to be
important clinically it is necessary that the
therapeutic range of drug B is narrow:-
• ( that a small reduction in effect will lead to loss
of efficacy and/or a small increase in effect will
lead to toxicity).
• For pharmacokinetic interactions to be clinically
important
• (it is necessary that the concentration-response
curve of drug B is steep so that a small change in
plasma concentration leads to a substantial
change in effect).
• For many drugs these conditions are not met.
4. • Drugs like penicillins are unlikely to give rise
to clinical problems because there is usually a
comfortable safety margin between plasma
concentrations produced by usual doses and
those resulting in either loss of efficacy or
toxicity.
• Several drugs do have steep concentration—
response relationships and narrow
therapeutic margins and drug interactions can
cause major problems eg antithrombotic,
antidysrhythmic and antiepileptic drugs,
lithium and several antineoplastic and
immunosupressant drugs.
5. Pharmacodynamic interactions:
• (i) β-adrenoceptor antagonists diminish the
effectiveness of β-adrenoceptor agonists
such as salbutamol or terbutaline.
• (ii) Many diuretics lower plasma potassium
concentration and thereby enhance some
actions of cardiac glycosides and predispose
to glycoside toxicity.
• (iii) Monoamine oxidase inhibitors increase
the amount of noradrenaline stored in NA
nerve terminals and thereby interact
dangerously with drugs such as ephedrine or
tyramine that work by releasing stored NA–
this can also occur with tyramine rich foods eg
camembert & marmite.
6. • Warfarin competes with vitamin K, preventing
hepatic synthesis of various coagulation factors.
• (iv) If vitamin K production in the intestine is
inhibited (eg by antibiotics),the anticoagulant
action of warfarin is increased.
• (v) Drugs that cause bleeding by distinct
mechanisms (eg aspirin which inhibits platelet
thromboxane A2 biosynthesis and can damage
the stomach) increase bleeding caused by
warfarin.
• (vi) Sulphonamides prevent the biosynthesis of
folic acid by bacteria and other microorganisms,
trimethoprim inhibits its reduction to
tetrahydrofolate.
• Given together the drugs have a synergistic
action in treating bacterial infections.
7. • Nonsteroidal antiinflammatory drugs (NSAIDs)
such as ibuprofen or indomethacin inhibit
biosynthesis of prostaglandins including renal
vasodilator/natriuretic prostaglandins (PGE2
PGI2).
• (vii) If administered to patients receiving
treatment for hypertension, NSAIDS cause a
variable but sometimes marked increase in
blood pressure.
• (viii) NSAIDs given to patients being treated with
diuretics for chronic heart failure can cause salt
and water retention and hence cardiac
decompensation.
• (in this example there is a pharmacokinetic
component of interaction NSAIDs compete with
weak acids (including diuretics) for tubular
secretion.
8. • (ix) H1-receptor antagonists (mepyramine)
cause drowsiness.
• This is more troublesome if such drugs are
taken with alcohol and may lead to
accidents at work or on the road.
Pharmacokinetic interactions:
• All of the major processes that determine
pharmacokinetic behaviour of a drug –
absorption, distribution, metabolism and
excretion can be affected by co-
administration of other drugs.
9. Absorption:
• Gastrointestinal absorption is slowed by drugs
which inhibit gastric emptying ( atropine or
opiates) or is accelerated by drugs
(metoclopramide) which hasten gastric
emptying.
• (i) Drug A may interact with drug B in the gut
to inhibit absorption of B. (a) Calcium and
iron form insoluble complexes with
tetracycline and retard their absorption.
• (b) Cholestyramine, a bile acid binding resin
used to treat hypercholesterolaemia binds
several drugs (warfarin, digoxin) preventing
their absorption if administered
simultaneously.
10. • (c) Addition of adrenaline to a local anaesthetic
injection results in vasoconstriction which slows
absorption of the anaesthetic thus prolonging its
local effect.
(ii) Distribution:
• (a) 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 that 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.
11. Consequences of potential clinical importance
when a drug is displaced from a binding site
• Toxicity from the transient increase in
concentration of free drug before the new
steady state is reached.
• If the dose is being adjusted according to
measurements of total plasma concentration,
it must be appreciated that the target
therapeutic concentration will be altered by
coadministration of a displacing drug.
• When the displacing drug additionally reduces
elimination of the first, so that not only is the
free drug concentration increased acutely but
also chronically at the new steady state,
severe toxicity may ensue.
12. • (b) Protein bound drugs that are given in large
enough dosage to act as displacing agents
include aspirin and various sulphonamides as
well as chloral hydrate whose metabolite
trichloracetic acid binds very strongly to
plasma albumin.
• Displacement of bilirubin from albumin by
such drugs in jaundiced premature neonates
could have consequences.
• Bilirubin metabolism is undeveloped in the
premature liver, and unbound bilirubin can
cross the blood brain barrier (which is also
incompletely developed) can cause
kernicterus (staining of the basal ganglia by
bilirubin).
13. • This causes a distressing and permanent
disturbance of movement known as
choreoathetosis (involuntary writhing and
twisting movements in the child).
• Phenytoin dose is adjusted according to
measurement of its concentration in plasma.
• A displacing drug in an epileptic stabilised on
phenytoin reduces the total plasma
phenytoin concentration owing to increased
elimination of free drug but no loss of
efficacy because the concentration of
unbound drug in the new steady state is
unaltered
14. • There are instances where drugs that alter
protein binding additionally reduce
elimination of the displaced drug.Examples
include:-
• (a) Phenylbutazone displaces warfarin from
binding sites on albumin and at the same time
selectively inhibits the metabolism of the
pharmacologically active S-isomer.This results
in prolonging prothrombin time and
increased bleeding.
• (b) Salicylates displace methotrexate from
binding sites on albumin and reduce its
secretion into the nephron by competing with
anion secretory carrier.
15. • (c) Quinidine and several other antidysrhythmic
drugs including verapamil and amiodarone
displace digoxin from tissue binding sites while
simultaneously reducing its renal excretion and
can consequently cause severe dysrhythmias due
to digoxin toxicity.
(iii) Metabolism:
• Enzyme induction (eg by barbiturates, ethanol or
rifampicin) is an important cause of drug
interactions.
• Enzyme induction usually decreases the
pharmacological activity of a range of other drugs.
• Conversely enzyme induction can increase toxicity
of a second drug whose toxic effects are mediated
by a metabolite.
16. • Paracetamol toxicity is a case in point. It is
due to N-acetyl-p-benzoquinone imine which
is formed by cytochrome P450.
• Enzyme induction can be exploited
therapeutically by administering
phenobarbitone to premature babies to
induce glucuronyl transferase thereby
increasing bilirubin conjugation and reducing
the risk of kernicterus.
• Enzyme inhibition particularly of the P450
system is caused by many drugs. Inhibition of
CYP3A a subfamily of P450 also occurs.
• Grapefruit juice contains a psoralen that
inhibits CYP3A and reduces the metabolism of
terfenadine, cyclosporin and several calcium
channel antagonists.
17. Drugs that are enzyme inducers
Enzyme inducer Drug metab. affected.
• Phenobarbitone Warfarin
• Rifampicin Oral contraceptives
• Griseofulvin Corticosteroids
• Phenytoin Cyclosporine
• Ethanol, carbamazepine Drugs on leftside
will also be affected
19. • Some inhibitors of drug metabolism influence
the metabolism of different stereoisomers.
• Drugs that inhibit the metabolism of the
active S and less active R isomers of warfarin
are shown below.
20. Stereoselective inhibitors of clearance of S
isomer of warfarin:
• Phenobarbitone
• Metronidazole
• Sulphinpyrozone
• Co-trimoxazole
• Disulfiram
Stereoselective inhibitors of clearance of R
isomer of warfarin:
• Cimetidine
• Omeprazole
21. Non-stereoselective inhibition of clearance of R
and S isomers of warfarin:
• Amiodarone.
(vi) Haemodynamic effects:
• Variations in hepatic blood flow influence the
rate of inactivation of drugs that are subject to
presystemic hepatic metabolism eg lignocaine
or propranolol.
• Negative inotropes (eg propranolol) reduce
the rate of metabolism of lignocaine by this
mechanism.
22. (v) Excretion:
1. Inhibition of tubular secretion:
• Probenecid inhibits excretion of penicillin and
azidothymidine (AZT)
• Diuretics act from within the lumen, drugs
that inhibit their secretion into tubular fluid
such as NSAIDs can reduce their effects.
2. Alteration of urine flow and pH:
• Loop and thiazide diuretics indirectly increase
proximal tubular reabsorption of lithium
(which is handled in a similar way to sodium)
and this can cause lithium toxicity in patients
treated with lithium carbonate for mood
disorders.
23. • The effect of urinary pH on excretion of weak
acids and bases is put into use in treatment of
poisoning but is not a cause of accidental
interaction.
25. (vi)Pharmaceutical interactions:
• Examples: Formation of a complex between
thiopentone and suxamethonium which must
not be mixed in the same syringe.
• Heparin interacts in this way with many basic
drugs.
• Heparin is used to keep intravenous lines or
cannulae open and can inactivate basic drugs
if they are injected without first cleaning the
line with saline.
