Drug Interactions

(Lecture 25)

W.M. Tom

Department of Pharmacology & Pharmacy

Drug Interactions
modification of the action of one drug by another
consequence
beneficial
enhancement of therapeutic effectiveness
diminution of toxicity
e.g. combinations of different anticancer drugs

adverse

diminution of therapeutic effectiveness

enhancement of toxicity
dose alteration may be necessary
or alternative medications prescribed

Adverse Drug Interactions

represent 3-5% of preventable in-hospital ADRs
patients on six or more drugs have an 80% chance of ADRs
ADRs are most important for drugs with a low therapeutic index
the sicker the patient, the greater the risk of an ADR
drugs removed from the market because of ADRs
terfenadine (1998); mibefradil (1998); astemizole (1999); cisapride
(2000)

Classification
Site of interactions
external
physicochemical incompatibilities
e.g. drugs mixed in IV infusion vials precipitation or
inactivation

internal
can be a body site or system or the site of action

Pharmaceutical interactions
physicochemical interactions may occur prior to systematic availability

Classification
Mechanism
pharmacokinetic interactions
changes in the pharmacokinetics of one drug that are produced by the
presence of another drug
change in blood concentration occurs causing a change in effect

pharmacodynamic interactions
drug-induced changes in the effects of other drugs

Interactions based on Absorption

one drug affects the rate or extent of absorption of the other drug
changes in the rate of absorption affect the peak concentration but
not usually the extent of absorption
altered rate is of little importance unless immediate effect is required,
e.g. analgesics or sedatives-hypnotics
a change in the extent of drug absorption that exceeds 20% is
generally considered clinically significant

Interactions based on Absorption

Gastrointestinal absorption
physicochemical interactions

changes in GI pH
chelation
exchange resin binding
adsorption
dissolution

changes in GI motility
increased gastric emptying and
intestinal motility
decreased gastric emptying and
intestinal motility

Interactions based on Absorption

changes in the rate of
absorption
e.g. increasing or decreasing
gastric emptying or intestinal
motility
e.g. metoclopramide
(prokinetic agent) hastens
gastric emptying
e.g. opioid analgesics, TCAs
(antimuscarinic) delays gastric
emptying

Interactions based on Absorption

changes in the extent of
absorption
iron, calcium and other divalent or
trivalent ions may form chelate
complex with some drugs
e.g. quinolones and tetracyclines are
chelated by antacids, and by calcium
in milk
decreasing extent of absorption can
be prevented if the doses are
separated by at least 2 hrs

Mn+

Interactions based on Absorption

changes in the extent of absorption
e.g. inhibition of drug transporters in the wall of the intestine
some drugs inhibit the P-glycoprotein drug transporter and increase the net
absorption of drugs that are normally expelled by the transporter

e.g. induction of metabolism in gut lumen, gut wall or liver

agents induce CYP3A4

e.g. altered bacterial flora by antimicrobials

erythromycin reduces gut flora that degrade digoxin

Interactions based on Distribution and Binding

competition for the non-specific binding sites on plasma proteins

interactions affecting plasma protein binding are of greatest importance
when the displaced drug
is highly protein bound
has a narrow therapeutic index
has a low apparent volume of distribution
is of low potency

limited clinical relevance

Interactions based on Distribution and Binding

altered drug distribution is not

usually a major problem
because distribution is not
relevant to steady-state plasma
concentrations

Valproic acid-phenytoin interaction

control

mg valproic acid daily

plasma protein binding of

phenytoin is decreased when
valproic acid is administered
chronically to a group of
patients stabilized on
phenytoin

a resultant fall in the steadystate plasma phenytoin

concentration

no substantial change in the

unbound phenytoin
concentration

no need to alter the dosing

rate of patients receiving
valproic acid

Displacement interactions
administration of a dose of displacer

to a patient already stabilized on a drug

Interactions based on Distribution and Binding

may be altered by other drugs that compete for binding sites on

plasma proteins
e.g. antibacterial sulphonamides can displace methotrexate, phenytoin,
sulphonylureas and warfarin from binding sites on albumin

changes in drug distribution can occur if one agent alters the size of
the physical compartment in which another drug distributes
e.g. diuretics, by reducing total body water, can increase plasma levels of
aminoglycosides and of lithium, possibly enhancing drug toxicities

Interactions based on Metabolic Clearance

nearly always due to interaction at

phase I enzymes, rather than phase II
i.e. commonly due to interaction at
cytochrome P450 enzymes, some of
which are genetically absent
metabolic interactions include
enzyme induction or inhibition

Relative importance of phase I enzymes

in drug metabolism

Examples of drugs withdrawn

because of CYP-related drug interactions

Drug interactions due to enzyme induction

enzyme induction by drugs increases first-pass metabolism, increases

clearance, decreases t1/2 and lowers average steady-state
concentrations

Drug activation of nuclear receptors

PXR and CAR

Interactions due to enzyme induction

Drug interactions due to enzyme inhibition

enzyme inhibition causes less first-pass metabolism, decreased
clearance, longer t1/2 and higher average steady-state concentrations

interactions arising from

simple competition for the
same enzyme would only be
important if the concentration
resulted in saturation of the
enzyme system

examples of potent enzyme

inhibitors: erythromycin, SSRIs,
ketoconazole, cimetidine,
grapefruit juice

Drug interactions due to enzyme inhibition

Interactions Based on Absorption

changes in the extent
of absorption
e.g. inhibition of first pass
metabolism

First-Pass Metabolism after Oral Administration of Felodipine and

Its Interaction with Grapefruit Juice

grapefruit juice selectively inhibits CYP3A in the

enterocyte, with the net result being a 3-fold
increase in the oral bioavailability of felodipine

First-Pass Metabolism after Oral Administration of Felodipine and

Its Interaction with Grapefruit Juice

Wilkinson GR, N. Engl. J. Med.

352:2211-21 (2005)

First-Pass Metabolism after Oral Administration of Felodipine and

Its Interaction with Grapefruit Juice

Wilkinson GR, N. Engl. J. Med.

352:2211-21 (2005)

Drug interactions due to grapefruit juice

component(s) in grapefruit inhibits the CYP3A4 enzymes responsible for

metabolizing many drugs as they pass through the gut wall, leading to
large increases in serum concentrations of susceptible drugs
increases in the AUC of up to 16-fold have been reported,
e.g. lovastatin

drugs affected have the following characteristics

metabolized largely by CYP3A4
subject to marked first-pass metabolism

Some Common Drugs with Low Oral Bioavailability and

Susceptibility to First-Pass Drug Interactions

Theoretical plasma concentrationtime profiles of drug

in the presence of a CYP enzyme inducer and inhibitor

Interactions based on Metabolic Clearance

metabolic clearance can be increased by other agents that cause the
induction of hepatic drug metabolizing enzymes
induction of drug metabolizing enzymes occurs predictably with the
chronic administration of barbiturates, carbamazepine, ethanol,
phenytoin, or rifampin
the metabolism of some drugs may be decreased by other drugs that
inhibit drug metabolizing enzymes
such inhibitors of drug metabolizing enzymes include cimetidine,
disulfiram, erythromycin, ketoconazole, propoxyphene, quinidine and
sulphonamides
the CYP3A4 isozyme of cytochrome P450, the dominant form in the
human liver, is particularly sensitive to such inhibitory actions

Some other interactions

based on metabolic clearance
drugs that reduce hepatic blood flow, e.g. propranolol, may also reduce
the clearance of other drugs metabolized in the liver, especially those
subject to flow-limited hepatic clearance such as morphine and
verapamil
ability of some drugs to increase the stores of endogenous substances
by blocking their metabolism
sensitization of patients taking MAO inhibitors to indirectly acting
sympathomimetics (amphetamine, phenylpropanolamine, etc.); such
patients may suffer a severe hypertensive reaction in response to
ordinary doses of cold remedies, decongestants and appetite
suppressants

Interactions based on Renal Function

Glomerular filtration

drugs affecting renal perfusion or plasma protein

binding could give rise to interactions

pH-dependent reabsorption

altered by drugs affecting urine pH (directly or

indirectly)

Renal tubular secretion

competition for the transporter

e.g. aspirin interferes with the transport of both
endogenous compounds (uric acid) and drugs
(methotrexate)

Competitive interactions for renal tubular transport

Pharmacodynamic interactions

usually predictable
may relate to the principal site of action of the drug or secondary sites
of action that are responsible for the unwanted effects of the drug
drugs that are highly selective for a single site of action are less likely to
produce pharmacodynamic interactions than are drugs that show low
selectivity
e.g. ACEI and spironolactone combination life-threatening hyperkalemia

Interactions based on Additive Effects

algebraic summing of the effects of 2 drugs
the two drugs may or may not act on the same receptor to produce
such effects
the combined use of tricyclic depressants with diphenhydramine or
promethazine predictably causes excessive atropine-like effects since all
of these drugs have significant muscarinic receptor- blocking actions
TCA may increase the pressor responses to sympathomimetics by
interference with amine transporter systems
additive depression of CNS function cause by concomitant administration
of sedatives, hypnotics, and opioids with each other or associated with
the consumption of ethanol

Interactions based on Additive Effects

patient with moderate to severe hypertension maintained on one

drug is at risk of excessive lowering of blood pressure if another drug
with a different site of action is added at high dosage
additive effects of anticoagulant drugs can lead to bleeding
complications
e.g. in the case of warfarin, the potential for such adverse effects is
enhanced by aspirin (via an antiplatelet action), quinidine (additive
hypoprothrombinemia), thrombolytics (via plasminogen activation) and
the thyroid hormones (via enhanced clotting factor catabolism)

Interactions based on Supra-Additive Effects

synergistic interaction occurs if the result of interaction is greater

than the sum of the drugs used alone
e.g. antibiotic combinations such as sulphonamides and dihydrofolic
acid reductase inhibitors such as trimethoprim

potentiation occurs when a drugs effect is increased by another

agent that has no such effect
e.g. therapeutic interaction of -lactamase inhibitors such as clavulanic
acid with lactamase-susceptible penicillins

Interactions based on Drug Antagonism

antagonism is often predictable
e.g. antagonism of bronchodilating effects of 2 -adrenoceptor
activators used in asthma is to be anticipated if a -blocker is given for
another condition
e.g. action of a catecholamine on heart rate (via -adrenoceptor
activation) is antagonized by an inhibitor of acetylcholinesterase that
acts through ACh (via muscarinic receptors)

some antagonisms do not appear to be based on receptor

interactions
e.g. NSAIDs may decrease the antihypertensive action of ACE inhibitors
by reducing elimination of sodium

Pharmacodynamic interactions

The End

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