1

DRUG INTERACTIONS
Vivian Soetikno
Department of Pharmacology & Therapeutics,
FMUI
 2

Definition
• Modification of the
effect of one drug
(the object drug: the
drug is affected by
the interaction) by the
prior or concomitant
administration of
another (precipitant
drug: the drug that
causes the
interaction)
 3

Contributing factor
• Multiple drug therapy
• Multiple prescribers
• Multiple diseases
• Individual variation
• Advancing age of patient
• Critically- & chronically-ill patients
• Over-the-counter nonprescription
medications
 4

Net effect of combination

• Synergism
• Multiple agents in post-transplantation
immunosuppression
• Combination chemotherapy for malignancy
• Combination antimicrobial agents of certain
infections
• Treatment of hypertension and asthma

• Antagonism
• Opioid antagonist for opioid overdose
• Anticholinergic agents for the treatment of
extrapyramidal syndromes
 5

Consequences of drug interactions

• Loss of therapeutic effect
• Diminish safety

• Drugs require careful attention:

1. Anticoagulants (warfarin)
2. Antidiabetic agents (glyburide)
3. Antineoplastic agents (5-fluorouracil)
4. Digitalis glycosides (digoxin)
5. Immunosuppressive drugs (cyclosporine)
6. Antidysrhythmic drugs (quinidine)
7. Anticonvulsants (phenytoin)
8. Lithium carbonate
9. Theophylline
 6

Mechanisms of drug interaction

Pharmaceutical
(incompatibility)

Pharmacodynamic

Pharmacokinetic
 7

Pharmaceutical interactions
• Drugs are mixed inappropriately in syringes and
infusion fluids prior to administration  precipitation
or inactivation of active principles

• Examples:
• Inactivation of gentamicin by carbenicillin
• Reaction between penicillin G and vitamin C
• Reaction between amphotericin B and NaCl or Ringer
lactate solution  amphotericin B precipitation
• Phenytoin (pKa 8.0 – 8.3) + 5% dextrose  phenytoin
precipitation
• Thiopental + suxamethonium  thiopental precipitation
 8

Sources of DDIs
 9

Pharmacodynamic interactions

• Additive, synergistic or antagonistic effects

1. Competition at receptor sites (usually

antagonism)
2. Interactions acting on the same physiological
system
3. Changes in fluid and electrolyte balance
4. Interference with intracellular transport
mechanisms

• Important in the clinical settings, can be predicted

 10

1. Interactions at receptors (a)

• Drugs acting on the
same receptor or
process  additive
• Drugs acting on
different receptors or
sequential processes
 synergistic
• Drugs with opposing
pharmacological
effects  antagonistic
 11

Types of drug-receptor interactions

• Agonist: drugs bind to & activate the receptor
• Antagonist: drugs bind to receptor, compete with &
prevent binding by other molecules
• Competitive:
• Reversible: the antagonist can be overcome by increasing the dosage
of agonist
• Irreversible: antagonist binds to the receptor sites tightly & cannot be
displaced by increasing the agonist concentration
• Non-competitive: drugs bind to the same receptor molecule but do
not prevent agonist binding, may enhance or inhibit the action of
agonist molecule (allosterically), cannot be overcome by increasing
the dosage of agonist
 12

1. Interactions at receptors (b)

• Drugs with affinity for specific receptors (agonists &
antagonists) will interact when administered concurrently:
• Atropine (cholinoceptor antagonist) competitive reversibly with
acetylcholine
• Competition for β-adrenoceptors between adrenaline and β-blockers
(propranolol)
• Drugs act on the same receptors and have potentiation
effects:
• Methyldopa combined with haloperidol  act on central dopaminergic
receptors  can cause extrapyramidal syndromes & irreversible
dementia
• Combination of antidepressant drugs  act on central serotonergic
receptors  can cause fatal serotonin syndrome
 13

1. Interactions at receptors (c)

• Drugs may alter the receptor sensitivity of another drugs
that results in synergistic or antagonistic effects:
• Opioid potentiate the sedative response to benzodiazepine in the
induction of anesthesia (benefit to the patient)
• Opioid antagonist, naloxone, diminish the sedative effects of
diazepam (benefit to the patient)
 14

1. Interactions at receptors (d)

Neostigmin

Tubocurarine

Drug interactions act by combining reversibly with

receptors & prevent access to the normal physiological
transmitter
 15

2. Interaction acting on same

physiological
• Combinations of drugs acting at the same site or
influencing the same physiological system may
cause reduced or exaggerated responses
• Examples:
• Antihypertensive drugs + NSAIDs  NSAIDs can 
antihypertensive effect
• Combination antihypertensive agents  synergistic
• Antidiabetic agents + corticosteroids  corticosteroids 
antidiabetic effect
• Aminoglycoside + furosemide  both  ototoxicity &
nephrotoxicity
• Thrombolytic + anticoagulant + antiplatelet  bleeding
tendency
 16

3. Changes in fluid and electrolyte

balance
• Changes in electrolyte balance may alter the effects of
drugs, mainly acting at myocardium, neuromuscular
transmission, & kidney

• Antiarrhythmic agents + diuretics  proarrhythmic potentiate

due to hypokalemia
• Cardiac glycoside + diuretics  induce hypokalemia  
toxicity of cardiac glycoside
• Pancuronium + diuretics  prolong paralysis due to
hypokalemia
• Potassium-sparing diuretics + ACEIs  hyperkalemia
• Lithium + thiazide diuretics  intoxication of lithium
• ACEI may induce hypoglycemia in diabetic patients taking
antidiabetic medication
 17

4. Interference with intracellular transport

mechanisms (a)
• Drug may interfere with the uptake and transport of
another drug to intracellular sites of action

• Adrenergic nerve blocking agents e.g., guanetidin,

debrisokuin, guanadrel can be competitively inhibited by
sympathomimetic amine e.g., fenilpropanolamin,
fenilefrin, efedrin, pseudoefedrin, amfetamin or tricyclic
antidepressants
 18

4. Interference with intracellular transport

mechanisms (b)
 19

Pharmacokinetic interactions
1. Drug absorption interactions
a) Change in pH of gastrointestinal fluids
b) Effects on gastric emptying and gastrointestinal motility
c) Binding or chelation of drugs
d) Competition for active absorption mechanisms
2. Drug distribution interactions
a) Plasma protein binding displacement
b) Tissue binding displacement
3. Induction of drug metabolism
4. Inhibition of drug metabolism
5. Interactions associated with modified drug excretion
Varies between patients  difficult to predict
 20

Drug-drug interactions mechanisms

 21

I. Interactions at absorption phase

1. Decreased absorption of one drug due to chelation
with a cation, such as calcium or iron
2. Decreased absorption due to disruption of dissolution of
highly dependent drug on gastric pH
3. Decreased absorption due to change in gastric
emptying time and gastrointestinal motility
4. Intestinal absorption disruption due to inhibition of
induction of CYP450 enzymes or the P-glycoprotein
efflux transporter in the intestinal epithelium
 22

I.1. Binding or chelation of drugs

• Drugs with chelating activity, able to form insoluble
complexes:
a. Iron supplement
b. Aluminum- and magnesium-containing antacids
c. Adsorbents, eg., kaolin, charcoal
d. Anion exchange resins, eg., cholestyramine, colestipol
e. Sucralfate
f. Bisphosphonate and calcium supplements
g. E.g, ↓ of AUC & Cmax of ciprofloxacin by 57 & 54% due
to ferrous sulfate co-administration

• Can be avoided by separating the time of

administration by ≥ 2 hours
 23

I. 2. Change in pH GI fluids (a)

• Basic drugs are more soluble in basic GI fluids
• Acid drugs are more soluble in acid GI fluids
• Weak-acid aspirin  more soluble in the stomach (pH
2.8) than in the small intestine (pH 7.4)
• Antifungal agents (ketoconazole or itraconazole) 
absorption will decrease in the co-administration with
drugs able to increase gastric pH (antacids or PPIs);
PPI or antacids administered at least 2 h after the
administration of antifungal agents

• Drugs that alter pH GI fluids:

• Antacids (sodium bicarbonate, magnesium hydroxide)
• H2-receptor antagonists
• Proton pump inhibitors
 24

I. 2. Change in pH GI fluids (b)

• Sodium bicarbonate
• reduces absorption of tetracycline
• Increases absorption of levodopa & aspirin
• Antacids, cimetidine,ranitidine
• Reduces absorption of ketoconazole, itraconazole
• Omeprazole
• Inhibit cyanocobalamine absorption
• Magnesium hydroxide, H2-receptor antagonists,
omeprazole
• Increase absorption of ibuprofen, glibenclamide, glipizide
 25

I. 3. Gastric emptying and GI motility (a)

3.1. Drugs which may decrease GI motility &
gastric emptying:
• Anticholinergic agents
• Antipsychotic agents
• Certain antihistamines (eg., diphenhydramine,
promethazine)
• Opioid analgesics
Anticholinergic + levodopa   bioavailability of
levodopa by 50%
Anticholinergic + digoxin   bioavailability of digoxin
 26

I. 3. Gastric emptying and GI motility (b)

3.2. Drugs which may increase GI motility & gastric
emptying:
• Prokinetics: metoclopramide, cisapride
Metoclopramide + levodopa   bioavailability of
levodopa
Metoclopramide + digoxin   bioavailability of levodopa

• Results of interactions depend on:

• Characteristic dissolution of drug  readily or poorly
soluble drug e.g., corticosteroids, digoxin &
dicoumarol  poorly soluble drugs
• Release of the drug from its formulation  rapid or
slow
 27

I. 3. Gastric emptying and GI motility (c)

Paracetamol: its rate of absorption is directly
related to the gastric emptying time
 28

II. Drug distribution interactions

a. Plasma protein binding displacement
b. Tissue binding displacement

The clinical importance of plasma protein binding

displacement & tissue binding displacement
depend on other interactive mechanisms such as
inhibition of metabolism or excretion
 29

II. 1. Plasma protein binding displacement

(a)
• Acidic drugs bind predominantly to albumin
• Basic drugs bind to α1-acid glycoprotein
• Displacement interactions are clinically
importance for (object drug):
• Highly albumin bound acidic drugs (min. 85%)
• Have small apparent volume of distribution (≤ 0.15 L/kg)
• Narrow therapeutic index
• Warfarin + salicylate  ↑ warfarin toxicity
• Phenytoin + salicylate  ↑ phenytoin toxicity
 30

II.1. Plasma protein binding displacement

(b)
• Some acidic drugs act as displacer for albumin
binding sites:
• Clofibric acid
• Phenylbutazone
• Salicylic acid
• Sulfamethoxazole
• Valproic acid

• Erythromycin  potential as a displacer for α1-

acid glycoprotein binding
 31

II. 2. Tissue binding displacement

• Interactions can occur if one drug displaces
another from binding sites in the tissues

• Quinidine, verapamil, nifedipine, amiodarone

displace digoxin from tissue binding sites 
steady-state plasma concentration of digoxin
 32

III. Interaction at metabolism phase

1. Induction of enzyme
2. Inhibition of enzyme

The importance of the effect varies from negligible

to dramatic
 33

III. Induction of drug metabolism (a)

• Induction of enzyme requires the inducer to reach a
critical concentration at intranuclear receptor which up-
regulate mRNA & protein synthesis  time-course of
induction depends on time required for enzyme
degradation and new enzyme production
Inducers of enzyme activity
Barbiturates (2B) Rifampicin (3A4)
Carbamazepin Phenytoin (1A2)
Charcoal-broiled food (1A2)
Corticosteroids
Ethanol (chronic) (2E1)
Griseofulvin
 34

III. Induction of drug metabolism (b)

Effects depend on
the metabolite,
active or not

 Toxicity/Effect or 
effect (pharmacokinetic
tolerance)
 35

III. Induction of drug metabolism (c)

• Paracetamol-induced hepatotoxicity is increased
in alcoholic patient (induce CYP1A2)
• Acute hepatic necrosis is increased in patient
previously taking enzyme-inducing drug following
anesthesia with halothane
• Barbiturate induced warfarin metabolism
(CYP2C9/10)  effect of anticoagulant is
reduced over 1-4 weeks
• Phenobarbital and lamotrigine  induce
development of leukopenia & thrombocytopenia
 36

III. Inhibition-based DDIs (a)

Enzyme activity is reduced due to direct interactions with a
drug, usually begins with the first dose of the inhibitor, and
the extinction of inhibition is related to the drug t1/2
 37

III. Inhibition-based DDIs (b)

• Inhibition of enzyme metabolism of drugs may
result in exaggerated and prolonged responses
  risk of toxicity

• Mechanism:
• Reversible competition for enzyme binding sites
(e.g., quinidine)
• Enzyme destruction (e.g., vinyl chloride)
• Inhibition of enzyme synthesis (e.g., some metallic ions)
• Interference with drug transport (e.g., digoxin)
 38

III. Inhibition-based DDIs (c)

• Onset of inhibition can be seen within the first 24
hours of administration & dissipates rapidly after
cessation

• Inhibition of other enzymes, e.g.,  toxicity of

mercaptopurine by allopurinol due to inhibition of
enzyme xanthine oxidase
 39

III. Inhibition-based DDIs (d)

Inhibitor drug metabolism (mainly enzyme CYP3A4,
CYP2D6, CYP2C9, CYP2C19):

Amiodarone Diphenhydramine Metronidazole

Atazanavir Erythromycin Mexiletine
Chloramphenicol Fluconazole Miconazole
Cimetidine Fluoxetine Omeprazole
Ciprofloxacin Indinavir Paroxetine
Clarithromycin Isoniazid Quinidine
Cyclosporine Itraconazole Ritonavir,
Saquinavir
Diltiazem Ketoconazole Verapamil ,
voriconazole
 40

III. Inhibition-based DDIs (e)

• Non-competitive inhibition: inhibitor and substrate
do not compete for the same active site due to
presence of allosteric site  conformational
change of the active site

• Duration of this type of inhibition may be longer if

new enzymes have to be synthesized

• E.g., omeprazole, cimetidine

 41

IV. Interaction at excretion phase

1. Changes in hepatic blood flow during billiary
excretion of drug
2. Interaction at active secretion into the renal
tubule
3. Changes in ionization of drugs during renal
excretion
 42

IV. Changes in hepatic blood flow

• Drugs that can increase • Drugs that can
hepatic blood flow (high
extraction hepatic ratio): decrease hepatic
• Lidocaine blood flow:
• Glucagon
• Neuromuscular blocking
• Isopreterenol
• Phenobarbital drugs
• Verapamil • Anesthetics
• Nifedipine • Beta blockers
• Hydralazine

• Glucagon + Propranolol 
glucagon can increase the
rate of elimination of
propranolol
 43

IV. Interference with biliary excretion and

enterohepatic circulation (a)
• Enterohepatic
circulation can be
interrupted by
suppression of
intestinal bacteria with
broad-spectrum
antibiotics

• Broad-spectrum
antibiotics + estrogen in
the oral contraception
 44

IV. Interference with biliary excretion and

enterohepatic circulation (b)
• Drugs and their metabolites may compete for
biliary excretion in the transport mechanisms

• Probenecid reduce the biliary excretion of

rifampicin through competition at the MRP
(Multidrug Resistance-Associated Protein)

• Cyclosporin reduce the biliary excretion of

pravastatin, rosuvastatin through competition at
the P-glycoprotein
 45

IV. Competition for active absorption

mechanisms in renal tubule (a)

• Renal excretion of
drugs:
• Glomerular filtration
• Passive back diffusion
• Tubular secretion
• Tubular reabsorption

OAT: organic anion transporter; OCT: organic cation transporter; OATP: organic anion transporting polypeptide; URAT: uric
acid transporter; PEPT: peptide transporter; MRP: multidrug resistance-associated protein; MATE: multidrug and toxin
extrusion; MDR: multidrug resistance (= P-gp); BCRP: breast cancer resistance protein
 46

IV. Competition for active absorption

mechanisms in renal tubule (b)
Competition at transporter P-glycoprotein:
• Digoxin + quinidine, verapamil (inhibit P-gp)   digoxin
bioavailability by 60-80%
• Digoxin + clarithromycin (inhibits P-gp)  ↑ digoxin bioavailability
• Digoxin + rifampicin (inducers P-gp)   digoxin bioavailability

Competition at OAT3 transporter:

• Gemfibrozil (inhibits OAT3) + pravastatin  ↑ pravastatin exposure 2x
 ↑ creatine kinase levels

Competition at OCT3 transporter between metformin and

cimetidine (inhibits OCT3)

Competition at OAT between probenecid and cephalosporin &

penicillins
 47

IV. Interference with renal excretion due to

drug-induced renal impairment
• Some drugs can induce renal impairment by
decreasing GFR:
• Aminoglycoside
• Cyclosporin
• Amphotericin B

• Combination of aminoglycoside and other drugs

with the potential to cause renal impairment
(NSAIDs, Amphotericin B)  synergism effect to
cause renal impairment
 48

IV. Change in urine pH

• Renal clearance of weak organic bases (pKa 7.5-
10) is increased if the urine is made acid & weak
organic acid (pKa 3.0-7.5) is higher in alkaline
than acid urine
• Alkaline diuresis is commonly used in patients
with severe salicylate or phenobarbital
intoxication
• Ammonium chloride and diuretics  able to
change urine pH, may affect the excretion of
several drugs
 49

Lithium and Thiazide diuretics

• Thiazide diuretics
decrease sodium re-
absorption in the distal
tubule of renal 
creates a relative
sodium deficit
• Leads to a
compensatory increase
in proximal tubule
sodium and lithium re-
absorption  ↑ lithium
in the blood
 50

Interactions involving monoamine oxidase

inhibitors (MAOIs)
• Inhibition of MAO:
• Accumulation of large amount of noradrenaline in
sympathetic nerve endings
• Decrease in the rate of intracellular metabolism of biogenic
amines e.g., cathecholamines, dopamine and serotonin
The net effects: hypertension, severe headache, fatal
intracerebral hemorrhage or acute left ventricular failure

• “cheese reaction”  foods e.g., cheese, beer,

wine have a large amounts of tyramine + MAOI
 hypertensive crisis (AVOID)
 51

Principles of prevention of adverse drug

interactions
1. Document all drugs, incl. herbal preparations and OTC
2. Understand PD/PK of the drugs you prescribe as much as
possible
3. Minimize the number of drugs given to any patient
4. Be particularly vigilant with patients taking narrow
therapeutic index drugs
5. Be cautious in high-risk clinical settings
6. Look carefully for the possibility of an adverse drug
interaction whenever a patient’s course deteriorates
7. Use textbooks of drug interactions or modern adverse
drug interaction software programs to search for possible
drug-induced effects
8. Always be vigilant for previously undescribed interactions,
particularly when prescribing new drugs
 52

Conclusions (a)
• Not all drug interactions are predictable
• Usually only pharmacodynamic interactions that
can be predicted – same class effect
• Particular care is needed with patients receiving:
1. Anticoagulants (warfarin)
2. Antidiabetic agents (glyburide)
3. Antineoplastic agents (5-fluorouracil)
4. Digitalis glycosides (digoxin)
5. Immunosuppressive drugs (cyclosporine)
6. Antidysrhythmic drugs (quinidine)
7. Anticonvulsants (phenytoin)
8. Lithium carbonate
9. Theophylline
 53

Conclusions (b)
• The incidence of drug interactions could be
greatly reduced by a therapeutic approach 
uses the smallest number of drugs in individual
patients
• Take a medicine with water instead of juice
• Be aware if take drugs with a narrow therapeutic
ratio & potent inhibitor of CYP3A4/5
• Elderly or critically ill patients
• Patient with renal or hepatic impairment