DRUG INTERACTION

Trilaksana Nugroho
Dept. Of Pharmacology & Therapeutic
Faculty of Medicine, Diponegoro University
Incidence of significant drug
interaction

 Drug interactions (DI):

 Occur when effects of the drug are altered
(increased / decreased)
 Usually result an ADR, some cases is beneficial (ex:
diuretics + ACE inhibitors)
 Number of drugs in admission in USA 2x > UK
 greater chance of interaction
 Incidence of clinically important DI  0% – 22%
 Drug interactions

 Effects of one drug are changed

 by another drug, food or drink
 Outcome
 harmful, beneficial or clinically insignificant
 Pharmacokinetic
 affecting absorption, distribution, metabolism or
excretion
 Pharmacodynamic
 effect of one drug at its site of action modified by
another
 Location of drug
interactions
 Intestine
 iron prevents the absorption of tetracycline
 Site of action
 salbutamol blocked at receptors by propranolol
 Liver
 enzymes made more active (induced) by phenytoin
 enzymes made less active (inhibited) by cimetidine
 Kidney
 probenecide blocks excretion of pencillin (beneficial)
 thiazides block excretion of lithium (harmful)
Important interactions
 Drugs with a narrow  Drugs with susceptible
therapeutic index pharmacokinetics
 warfarin, digoxin,  oral contraceptive
lithium, phenytoin,  oral hypoglycaemics
theophylline,
gentamicin  Drugs with known
 Enzyme inhibitors pharmacodynamic
and inducers effects
 beta-blockers
 cimetidine,
erythromycin  alcohol
 rifampicin, phenytoin
 Incidence of Drug-Drug Interactions

 True incidence difficult to determine

 Data for drug-related hospital admissions do not
separate out drug interactions, focus on ADRs
 Difficulty in assessing OTC and herbal drug
therapy use
 Difficulty in determining contribution of drug
interaction in morbidity of medically complicated
patients
Drug Interactions

 Pharmacokinetic
 Related to the body’s effects on the drug
 Absorption, distribution, metabolism, elimination,

 Pharmacodynamic
 Related to the drug’s effects in the body
 Receptor site occupancy
Drugs likely to be involved in
interaction
 Precipitate DI:
 Highly protein bound  aspirin, phenylbutazone,
sulfonamides, trichlor-acetic
 Sodium valproat  displaces phenytoin + inhibits
metabolism
 Alter (stimulate / inhibit) the metabolism:
 STIMULATE: phenytoin, carbamazepine,
phenobarbital, rifampicin, griseofulvin
 INHIBIT: allopurinol, chloramphenicol, cimetidine,
erythromycin, metronidazole, ketokonazole, etc
 Affects renal function and clearance
Drugs likely to be involved in
interaction
 Objects of DI:
  have a steep dose-response curve  DI causing
reduced efficacy of the object drugs
  have low toxic : therapeutic ratio  DI causing
toxic effects of the object drugs

Two sides of the same coin (ex: amynoglycosides,

anticoagulant, anticonvulsant, antihypertensive,
cardiac glycoside, cytotoxic/immunosuppressant,
oral contraceptive, CNS drugs
Drug Interaction

DRUG INTERACTION

PHARMACEUTICAL INTERACTION

PHARMACOKINETIC INTERACTION

PHARMACODYNAMIC INTERACTION
PHARMACEUTICAL INTERACTION

 = Physicochemical Interaction
 Can be avoided by following principles:
 Give i.v. bolus if possible
 Don’t add the drugs infusion other than dextrose or saline
 unstable, light sensitive
 Avoid mixing in the same infusion, unless known to be safe
 Read the manufacturer’s literature
 Mix the drug thoroughly in the infusion
 Prepare the solution only when needed
 Label all infusion bottles clearly
 Use two separate infusion sites
 Consult the local hospital pharmacist
PHARMACOKINETIC INTERACTION

 Occurs when A, D, M, E of object drug is

altered
 Absorption interaction
 Protein binding displacement interaction
 Cellular distribution interaction
 Metabolism interaction
 Excretion interaction
Absorption interaction
The absorption can be reduced by:
 Reduced GI motility (ex: morphine-like drug,
anticholinergic, tricyclic antidepressant)
 Reduced GI pH (ex: omeprazole/cimetidine – ketoconazole)
 Chelation of calcium, aluminium, & iron salts by tetracyclin
 Binding warfarin & digitoxin by cholestyramine

Beneficial Absorption interaction:

 Metoclopramide – paracetamol  increase gastric
emptying, hasten absorption Pct
 Charcoal binds  prevent absorption / reabsorption 
treatment of self poisoning (ex: Cbz, Phenobarbital,
Theophylline)
 Ketoconazole Interactions
pH-dependent absorption
Ketoconazole Cp (mcg/ml)

8
7
6
5 Keto
4 K + Sucral
3 K + Ranit
2
1
0
0 0.5 1.5 2.5 4 6 12
Hours

Piscitelli S et al. Antimicrob Agents Chemother 1991;35:1765-1771

 Protein Binding Interactions

“…the overall clinical importance of plasma protein binding

displacement interactions continues to be overstated…”

“Despite the theoretical and experimental data to the

contrary, the concept that plasma protein binding
displacement is a common cause of clinically significant
interactions may still be widely taught in some medical
schools, often appears in textbooks and is accepted by
many in the medical community and by drug regulators.”

Sansom LN & Evans AM. Drug Safety 1995;12:227-233.

Rolan PE. Br J Clin Pharmacol 1994;37:125-128.
Protein Binding displacement
interaction
 Displacement of drug (by another drug) 
increase unbound drug concentration in
plasma  increase the effect.
should be:
Highly protein bound

Low volume distribution

Significant impact
Cellular distribution
interaction
Rifampicin

inhibiting uptake by hepatocytes

Induce warfarin metabolism

Reduced effect of warfarin

Metabolism interaction

 Mostly in liver
 Term of “Oxydation”  several different
metabolic transformation:
 Hydroxylation, deamination, dealkylation,
sulfoxidation, desulfuration, dehalogenation
 Dependence on precence of NADPH &
Cytochrome P450
 Can be :
 Induction of drug metabolism
 Inhibition of drug metabolism
Excretion interaction

 Mostly in kidney
 Important mechanism  competition for
tubular secretion
 Probenecid  inhibits tubular secretion of:
 Penicillin  beneficial effect
 Chloroquin  toxicity on retina
 Quinidine, verapamil  inhibits tubular
secretion of digoxin by inhibiting P-
glycoprotein
PHARMACODYNAMIC INTERACTION

 Occur when precipitant drug alters the effect

of object drug at its site of action
 Can be direct or indirect
Direct PD interaction

 Occur when both two drugs act on the similar

site OR different sites with the similar end result
 Antagonism at the same site  opiates –
naloxone, warfarin – Vitamin K
 Synergism at the same site  depolarizing
muscle relaxant – aminoglycosides, verapamil –
b-adrenergic
 Summation or synergism of similar effects at
different sites  alcohol – depressants,
cytotoxic - antibiotics
Indirect PD interaction
  pharmacological therapeutic or toxic effect of the
precipitant drug alter the therapeutic or toxic effect
of the object drug, BUT these two effect do not
related and do not themselves interact
 Coagulation  warfarin + other anticoagulants
 Platelet aggregation
 GI ulceration
 Fibrinolysis
 Fluid electrolyte balance:
 Depletion of potassium (diuretics)  enhance digitalis
toxicity, arrhythmia in patient that taking antiarrhythmia
 Thiazides  potassium depletion  impairment secretion
of insulin  attenuate hypoglycaemic effect of
sulfonylureas
 Carbamazepine, NSAID  fluid retaining  attenuate
diuretic effects