DRUG INTERACTIONS

Prof. R.K.DIXIT
Dept Of Pharmacology & Therapeutics
KGMU, Lucknow
[email protected]
“Drug interaction refers to modification of
response to one drug by another when they
are administered simultaneously or in quick
succession”

Once should be vigilant about

 Drug-Drug Interactions
 Drug – Herbs Interactions (Indigenous Medicines)
 Drug-Food Interactions (Grape Fruit Juice etc.)
 Drug-Environment Interactions
 Drug-Pollutant Interactions
 Drug-and..............................Interactions
 The modification in response may be
Quantitative (In Intensity), i.e.
 Increased or
 Decreased
 It may be qualitative
 Abnormal or a different (New) type of response is
produced.
 Possibility arises whenever a patient receives more than
one drug, and
 Chances increase with
◦ More number of drugs.
◦ Patient with multiple diseases
◦ Patient treated by multiple doctors
◦ Patients with compromised physiology
◦ Patients with extreme of age ( Elderly and Children)
 Every Drug Interaction is Harmful ????
NO
 Several drug interactions are deliberately employed in
therapeutics, e.g.
◦ ACE inhibitors + diuretics to treat hypertension or
◦ Sulfamethoxazole + Trimethoprim to treat bacterial infection or
◦ Furosemide + amiloride to prevent hypokalaemia.
Doctor should elicit a detailed drug history of the patient
and record all the medication that he/ she is currently on.
Drugs more likely to be involved in drug interactions

 With Narrow therapeutic index (Low Safety Margin)

 Aminoglycosides
 Digitalis
 Lithium
 Affecting vital physiology of the body
 Antihypertensive drugs
 Anti-diabetic drugs
 Anticoagulants
 With high plasma protein binding capacity
 NSAIDs
 Warfarin
 Sulfonylureas
 Metabolized by Zero Order Kinetics or Saturation Kinetics
 Phenytoin
 Theophyllin
 MECHANISM OF DRUG INTERACTIONS

 Drug interactions can be broadly divided into

◦ Pharmaceutical Interaction
 During dosage form preparation or at time of administrations.
 Dissolving the drug in solvent,
 Mixing drugs in powder, solution or injection forms.
◦ Pharmacokinetic (ADME)
 Absorption (Complex or Chelate formation, Altered stomach pH, Ionization,
GIT motility, First Pass Metabolism)
 Distribution (Protein binding)
 Metabolism ( Enzyme induction/inhibition)
 Excretion (Altered pH, Ionization, Entero-hepatic recirculation)
◦ Pharmacodynamic ( At receptor or tissue level)
 ABSORPTION
 Insoluble and poorly absorbed complexes in the gut
 Example:-
 Tetracyclines and calcium/iron salts, antacids or sucralfate
 Phenytoin absorption is decreased by sucralfate
 Minimized by administering the two drugs with a gap of 2-3
hours.
 Alteration in Entero-hepatic recirculation
• Antibiotics like Tetracyclines (Broad Spectrum) markedly reduce
gut flora that normally deconjugates oral contraceptive steroids
secreted in the bile as glucuronides and permits their Entero-
hepatic recirculation. Contraceptive failure when concurrent use
of antibiotics due to lowering of the contraceptive blood levels.
 DISTRIBUTION
 Primarily due to displacement of one drug from its
binding sites on plasma proteins by another drug.
 Drugs highly bound to plasma proteins that have a relatively
small volume of distribution like oral anticoagulants,
sulfonylureas, certain NSAIDs and anti-epileptics are
particularly liable to displacement interactions
 The drug which is in unbound form is active while portion
which is in bound form woks as temporary storage.
 When the drug is displaced by the other drug or chemical
the unbound form of the active drug becomes more leading
to toxic level in the blood and presenting as toxicity.
 METABOLISM

 Certain drugs reduce or enhance the rate of metabolism

of other drugs and affect the bioavailability.

 Inhibition of drug metabolism may be due to competition

for the same CYP450 iso-enzyme or cofactor, and attains
clinical significance mostly for drugs that are metabolized
by saturation kinetics.
 SOME IMPORTANT INHIBITORS OF
METABOLISM OF MULTIPLE DRUGS (MAO-QC)
 Macrolide antibiotics,
 Azole antifungals,
 Chloramphenicol,
 Omeprazole, SSRIs,
 HIV -protease inhibitors,
 Cimetidine,
 Quinolones (Ciprofloxacin)
 Metronidazole.
Risk of statin induced myopathy is increased by fibrates,
niacin, erythromycin, azole anti-fungals and HIV -protease
inhibitors, due to inhibition of statin metabolism.
 Induction involves gene mediated increased
synthesis of certain CYP450 isoenzymes.
 It takes 1-2 weeks of medication with the inducer to
produce maximal effect.
 Effects regresses gradually over 1-3 weeks after
discontinuation of the inducer
 IMPORTANT MICROSOMAL ENZYME
INDUCERS (RBC)

 Barbiturates,
 Phenytoin
 Carbamazepine
 Rifampin
 Cigarette smoking
 Chronic alcoholism
 Pollutants
 Instances of failure of antimicrobial therapy with
metronidazole, doxycycline or chloramphenicol have
occurred in patients who are on long-term medication
with an inducing drug.
 Contraceptive failure and loss of therapeutic effect of
many other drugs have occurred due to enzyme induction
(Patient taking Rifampicin)
 Toxic dose of paracetamol is lower in chronic
alcoholics and in those on enzyme inducing medication,
because one of the metabolites of paracetamol is
responsible for its overdose hepatotoxicity
 EXCRETION
 Interaction involving excretion are important mostly in
case of drugs actively secreted by tubular transport
mechanisms. The alteration of urinary pH alters the
process of reabsorption of the drug leading to increase
or decrease excretion.
 Probenecid inhibits tubular secretion of penicillins and
cephalosporins .
 Aspirin blocks the uricosuric action of probenecid and
decreases tubular secretion of methotrexate.
 Alkalization of urine increases the excretion of
barbiturates
 PHARMACODYNAMIC INTERACTIONS

 These interactions derive from modification of the

action of one drug at the target site by another drug,
independent of a change in its concentration.

 This may result in an enhanced response

(synergism), an attenuated response (antagonism)
or an abnormal response.
Examples:-

 Excessive sedation, respiratory depression, motor

incoordination due to concurrent administration of a
benzodiazepine (diazepam), a sedating antihistaminic
(promethazine), a neuroleptic (chlorpromazine),
an opioid (morphine).
 Excessive fall in BP and fainting due to concurrent
administration of α1 adrenergic blockers, vasodilators,
ACE inhibitors, high ceiling diuretics and cardiac
depressants.

 Excessive platelet inhibition resulting in bleeding due to

simultaneous use of aspirin/ ticlopidine / clopidogrel and
carbenicillin.

 Increased risk of bleeding due to concurrent

use of antiplatelet drugs (aspirin, clopidogrel) with
anticoagulants (warfarin).
 Abnormal responses sometimes result from
pharmacodynamic interaction between certain drugs.
(Mechanism may be explainable or unexplainable)
 e.g. Metronidazole and Cefoperazone inhibit the enzyme
aldehyde dehydrogenase resulting in bizarre distressing
symptoms if the patient drinks alcohol. (Disulfiram Like
reaction)
 The basis of certain interactions is not explained, e.g.
ampicillin has produced high incidence of skin rashes in
patients treated with allopurinol.
 DRUG INTERACTIONS BEFORE
ADMINISTRATION

 Certain drugs react with each other and get inactivated

if their solutions are mixed before administration.

 In practice situations, these in vitro interactions occur

when injectable drugs are mixed in the same syringe or
infusion bottle.
Some examples are:

• Penicillin G or ampicillin mixed with gentamicin or

another aminoglycoside antibiotic.

• Thiopentone sodium when mixed with succinylcholine or

morphine.

• Heparin when mixed with penicillin

gentamicin/hydrocortisone.
 Not all patients taking interacting drugs experience
adverse consequences, but it is advisable to take due
precautions to avoid mishaps in all cases where
interactions are possible.

 Two drugs have the potential to interact does not

necessarily contraindicate their concurrent use.

 In many cases, knowledge of the nature and

mechanism of the possible interaction may permit
their concurrent use provided appropriate dose
adjustments are made or other corrective measures are
taken
“ It is prudent to consider the possibility of drug
interaction whenever two or more drugs are
prescribed to a patient, or any drug is added to what
the patient is already taking”
Thanks