Drug Interactions
Definition of drug interactions:
An interaction occurs when effects of one drug
are changed by the presence of another drug,
herbal medicine, food, drink or by some
environmental chemical agent.
Object drug: drug whose action is changed
Precipitant drug: drug that cause altered effect
Types of DI according to precipitant agent:
• Drug-drug interaction
• Drug –food interaction (tetracycline-milk)
• Drug-disease interaction (renal, hepatic,
malabsorption syndrome, hyper\hypothyroidism
• Drug-pollutant interaction (nicotine, PCAH)
• Drug-packaging interaction (sorption
,permeation)
• Drug-lab test interaction(theophylline interferes
with uric acid analysis)
• Physical incompatibilities
Outcome of DI:
1- harmful effect either:
• Reduced effect
• increased effect with risk of toxicity
2- beneficial effect either:
• Enhancement of effect (β-blocker+diuretic)
• Elimination of toxicity
(sodium bicarbonate +aspirin, ascorbic acid+
amphetamine)
• Risk categories of drug interactions:
• Risk category A and B are of academic, but not of
clinical concern.
• Risk category “A” corresponds to no evidence of
drug interaction while category “B” denotes the
presence of evidence for potential interactions but
with little evidence for clinical concern.
• Risk category “C” where there is evidence of
potential interaction which is clinically significant.
However, the benefits usually outweigh the risks.
• Risk category “D” Therapy modification is to
be considered for category “D,” which may
involve dose adjustment, considering
alternative therapy, aggressive monitoring to
minimize toxicity.
• Risk category “X”: Drug combinations in the
risk category “X” are to be avoided since the
risks usually outweigh the benefits. Such drug
combinations are considered contraindicated
Factors affecting DI:
• Sequence of administration
• Dosage form
• Dose
• Disease
• Age
• Genetic factors
Mechanisms of drug interactions
• Pharmacodynamic interaction (additive\antagonism
• Pharmacokinetic interactions
Pharmacokinetic interactions
affect the processes by which drugs are absorbed,
distributed, metabolized and excreted (ADME)
1- Drug absorption interactions
Drug absorption may be affected by:
drugs- disease-fluid intake- food
• Grisofulvin+fatty meal : increase bile acid secretion,
improve grisofulvin (lipophilic) dissolution absorption
• Macrolides+food: 50% decrease absorption
So macrolides should be taken on empty stomach
But erythromycin causes nausea, vomiting
Solution: enteric coating
1- Effects of changes in gastric pH
Antacids affect drugs by different mechanisms:
• Increase gastric PH (weakly acidic drugs salicylic
acid) increase its ionization, decrease nonionized
form, absorption
• Urine alkalinization (weakly acidic drugs salicylic
acid) increase its ionization, decrease nonionized
form, increase excretion
• Adsorption
• chelation (tetracycline)
• Slowing gut motility (aluminum containing
antacids
• H2 blockers (cimetidine,rantidine,famotidine)
• Proton pump inhibitors (omeprazole,
pentaprazole, esmoprazole, lanzoprazole)
• Anticholinergics as pirenzepine decrease gastric
secretion
Also affect gastric PH and affect absorption of weak
acids as salicylates
• Ketoconazole (require acidic medium
dissolution and absorption)
Antacids, H2-receptor antagonists, proton pump
inhibitors + Ketoconazole
• Outcome: Reduced Ketoconazole absorption
• Pravastatin (require basic medium dissolution
and absorption)
Antacids, H2-receptor antagonists, proton pump
inhibitors + Ketoconazole
• Outcome: increase pravastatin absorption
2-Changes in gastrointestinal motility(gastric emptying)
• delays gastric emptying:
✓ anticholinergic: Propantheline
✓ Antipsychotics: chloropromazine, haloperidol
✓ TCA: imipramine,amitryptiline
✓ narcotic analgesics :pethidine, dimorphine
✓ ganglionic blockers :mecamylamine
• increases gastric emptying
✓ Antiemetics, prokinetic drugs:Metoclopramide, cisapride,
mosapride
✓ cholinergic drugs
✓ large volume of fluid
1- Affect rate not extent of absorption
• single dose drug
• Rapidly soluble drugs (paracetamol)
• Potent single oral dose where rapid effect is
requires as hypnotic or paracetamol
• Propantheline + paracetamol
Outcome: decrease rate of absorption, delay
analgesia
• Metoclopramide+ paracetamol
Outcome: increase rate of absorption
2- poorly soluble drugs: digoxin, dicumarol, warfarin
Propantheline + Digoxin
• Digoxin levels increased (slow-dissolving) digoxin
tablets.
• No interaction with liquid or fast-dissolving tablets
Mechanism
• Propantheline reduces gut motility, allows
slow-dissolving digoxin more time to pass into
solution so that more is available for absorption.
Metoclopramide + slow-dissolving tablets Digoxin
Outcome: Reduced digoxin absorption
3- multiple dose drugs as warfarin:
Change in gut motility has no significant effect on
steady state concentration
4- acid labile drugs
• Propantheline +acid labile drugs (antibiotics):
increase destruction of drugs, decrease absorption,
decrease serum level and effect
5-drugs under intestinal metabolism
• Propantheline + drugs under intestinal metabolism
(L-dopa)
Increase exposure of L-dopa to metabolizing enzyme
reduced absorption, decrease serum level and effect
3- Binding in gut:
Adsorption: and complexing mechanisms
• Activated charcoal/kaolin , pectin in antidiarrheal
mixtures
• Antacids can also adsorb drugs
• chelation
• Divalent/trivalent metallic ions, such as Ca, Al, Fe
(dairy products , antacids) complexes with
tetracycline
• Antacids with Mg,Al and iron prepration reduce
absorption of pencillamine due to chelation
• Separation 3-4 hr can prevent this interaction
• Binding :Colestyramine binds to many drugs
(warfarin, thyroxin, digoxin, pravastatin)
Separation 3-4 hr can prevent this interaction
• Antacids with Mg,Al and iron preparation reduce
absorption of quinolone due to formation of poorly
soluble complex
• Dicoumarol form more soluble complex with
magnesium hydroxide antacids increase the
absorption of dicoumarol (beneficial interaction)
4- Malabsorption caused by drugs
Destruction of gut mucosa by neomycin,
cytotoxic drugs as MTX, 5FU impair the
absorption of drugs
5- reduction of gut flora population:
• Antibiotics + oral anticoagulant
Antibiotics decrease population of gut flora
responsible for vit k synthesis so potentiate
effect of oral anticoagulant
6- Induction/inhibition of drug transporter proteins
• Transporter proteins (P-glycoprotein) eject drugs
that have diffused across gut lining back into gut.
Digoxin + rifampicin
• Digoxin is a substrate of P-glycoprotein,
• rifampicin (induce this protein),
• Outcome: reduce the bioavailability of digoxin
2- Drug distribution interactions
Many drugs transported with some proportion of their
molecules in solution (free form) and the rest bound
to plasma proteins, particularly the albumins, both
forms are in an equilibrium.
• Free form is pharmacologically active (metabolized) ,
bound form is pharmacologically inactive reservoir
• As the free molecules become metabolized, some of
the bound molecules become unbound and pass
into solution to exert their pharmacological effect in
their turn are metabolized and excreted
• Depending on the concentrations and their relative
affinities for the binding sites, one drug may
successfully compete with another and displace it
• The displaced (free) drug molecules pass into the
plasma and their concentration rises.
• However, this rise is transient due to metabolism
and excretion
Clinically significant displacement reaction occur if:
1- Displacing drug inhibit metabolism or excretion
displaced drug
2- Displaced drug has narrow therapeutic index
• Phenyl butazone + warfarin:
Phenyl butazone displaces warfarin from plasma
protein binding sited and inhibit its metabolism,
increases warfarin conc and effect
• Aspirin+ warfarin:
PD: additive effect, PK: displacement
• Kernicterus :physiological displacement reaction
between sulfonamide and bilirubin (neurotoxic
substance) leading to brain damage
• Highly bounded to PP: salicylate, sulfonamide,
phenyl butazone, warfarin ,phenytoin,
chloropromamide glibenclamide
3- Drug metabolism interactions
• Drug metabolism goes on in the serum, the kidneys,
the skin and the intestines, but the greatest
proportion is carried out by enzymes of liver cells
‘liver microsomal enzymes, cytochrome P450’. MFO
mixed function oxidases
• Cytochrome P450 is not a single entity, but is in fact
a very large family isoenzymes
• The most important isoenzymes are CYP1A2,
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6,
CYP2E1 and CYP3A4.
(A) Enzyme induction
• increase the activity of the microsomal enzymes and
metabolism, decrease serum conc and effect
• It may take 7-10 days to develop and may persist for
a similar length of time when the enzyme inducer is
stopped. Enzyme induction interactions are delayed
in onset and slow to resolve.
• Management: simply by raising the dose of
the drug affected, this requires good monitoring
• Enzyme inducers: barbiturates (tolerance),
phenytoin,primidone, Carbamezipine,refampicin,
smoking, chronic alcoholism, DDT insecticide
(B) Enzyme inhibition
• Reduced metabolism of an affected drug leads to
its accumulate within the body, increase serum
level, effect, toxicity
• enzyme inhibition can occur rapidly, resulting in
the rapid development of toxicity and persist
after withdrawal depending on its t1\2 (usually
persist 4t1\2)
• Enzyme inhibitors: choramphenicol,erythromycin
ciprofloxacin,isonaizide,ketoconazole,allopurinol,
fleuxetine,verapamil,amiodarone,cimetidine,
omeprazole, phenyl butazone, valproate, MAO
inhibitors, acute alcholism, disulfuram
4- Drug excretion interactions
(a)Changes in renal blood flow
• Renal blood flow(RBF)is partially controlled by the
production of renal vasodilator prostaglandins
• NSAIDs inhibit synthesis of renal vasodilator
prostaglandins, decrease RBF, reduce renal
excretion of drugs
• NSAIDs + lithium
NSAIDs reduce renal excretion of lithium, increase its
serum level with expected toxicity (tremors,
leukocytosis, dyskinesia)
(b)Changes in urinary pH
• Passive reabsorption of drugs in non-ionized lipidsoluble form, depends on its pKa and urine pH
• Urine acidification(ammonium chloride,ascorbic acid
➢Weakly basic drug (amphetamine):
Increase its ionization, decrease non-ionized portion,
reabsorption and increases its excretion
➢Weakly acidic drug (aspirin, barbiturate)
decrease its ionization, increase non-ionized portion,
reabsorption and decreases its excretion
• Urine alkalinization (sodium bicarbonate,antacids)
• Weakly acidic drug (aspirin, barbiturate)
Increase its ionization, decrease non-ionized portion,
reabsorption and increases its excretion
Weakly basic drug (amphetamine,quinidine,
mecamylamine):
decrease its ionization, increase non-ionized portion,
reabsorption and decreases its excretion
(c) Changes in active tubular secretion excretion
• Drugs that use the same active transport systems
in the renal tubules can compete for excretion
• Penicillins, Cephalosporins + Probenecid
Outcome: probenecid reduces the excretion of
penicillin, increase t1\2 (beneficial interaction)
• Quinidine + digoxin: decrease digoxin excretion,
cause digoxin toxicity (dose dependent DI>1200mg
• Aspirin+ MTX: displacement, decrease RBF,
competition for active tubular secretion
High risk of MTX toxicity (myelosupression, mucositis
Pharmacodynamic interactions
Effects of one drug are changed by the presence of
another drug at its site of action either by competing
for particular receptors or indirect by interference
with physiological mechanisms.
• Additive or synergistic interactions
two drugs that have the same pharmacological effect
are given together
• CNS depressants + CNS depressants
Outcome: excessive drowsiness, risk of respiratory
depression
Alcohol + Antihistamines
Benzodiazepines + General Anesthetics
Opioids + Benzodiazepines
• Antipsychotics + Anticholinergic
• TCA + Anticholinergic
Outcome: potentiate anticholinergic effects
(heat stroke in hot and humid conditions,
adynamic ileus, urine retention…)
• Nephrotoxic drugs + Nephrotoxic drugs
(Aminoglycosides, Cyclosporin, Cisplatin,
cephalosporins)
Outcome: Increased nephrotoxicity
• Potassium supplements + K-sparing drugs
(ACE inhibitors, ARBs, K-sparing diuretics)
Outcome: Hyperkalaemia
• Ototoxic drugs + ototoxic drugs
(Aminoglycosides, ethacrynic acid)
Outcome: : Increased ototoxicity
Antagonistic or opposing interactions
• Anticoagulants + Vitamin K
Outcome: antagonize anticoagulant effects
• Thaizide (hyperuricemia) +allopurinol (antigout)
• Antidiabetics + corticosteroids, thiazide
Outcome: antagonize blood glucose-lowering effects
• Caffeine+ hypnotics
Outcome: antagonize hypnotic effect
• Beta blocker + beta2 agonist bronchodilator
Outcome: antagonize bronchodilator effect
Peripheral adrenergic neurons
Propranolol + salbutamol
• Outcome: Propranolol antagonize bronchodilator
effects of salbutamol
Tricyclic antidepressants + noradrenaline
TCA block the uptake mechanism by which
noradrenaline is taken into the neuron and
removed from the receptor area. As a result the
effects of administered noradrenaline are
exaggerated (severe hypertension)
MAOIs + indirectly-acting sympathomimetics
(amphetamine)
• Indirectly-acting sympathomimetics stimulate
the release of noradrenaline
• MAOIs inactivate monoamine oxidase (MAO)
and cause the accumulation of NA at nerve
ending
• Outcome: massive stimulation of the
receptors and a grossly exaggerated pressor
response (severe hypertension)
Tricyclic antidepressants + guanethidine
• Guanethidine exert hypotensive action firstly
by entering adrenergic nerve endings in blood
vessels using monoamine reuptake pump.
• TCA prevent the uptake of guanethidine into
the neurones, thereby blocking its
antihypertensive effects
• Interactions due to electrolyte imbalance:
• Digoxin+ thaizide (digoxin toxicity)
• Lithium carbonate +sodium restricted diet
increase Li renal tubular reabsorption leading
to Li toxicity
• Reduction of hepatic blood flow:
• Propranolol+ lidocaine :
Lidocaine has narrow TI undergoes first pass
metabolism
Propranolol decrease myocardial contractility,
hepatic perfusion, lidocaine metabolism,
increase serum level and lead to toxicity
• Evaluation of DI:
1- pharmacodynamics and s\e
2- PK
3- doses: quinidine\digoxin
4- diet: milk\Tc , tea\Fe, caffiene\hypnotics, vit k
\warfarin, smoking, alchol, charcoal broiled food
5-residual effect of drugs: MAOI, amiodarone t1\2
6- narrow TI: aminoglycosides, digitalis, Li,
theophylline, phenytoin
7- age : neonates, eldrly more susciptible
8- environmental factor: smoking, DDT, PCAH,
9- disease state: renal, hepatic disease, diarrhea,
malabsorption syndrome
Hypothyroidism (low metabolism) sensitive to
digoxin, theophylline aminophylline, oxitriphylline
(xanthine except dyphylline)
But need higher doses of warfarin due to low
metabolism of clotting factors
10-pharmacological class:
H2 blockers cimetidine only affect matabolism
Ca channel blockers: verapamil only inhibitor not
Nifidipine, deltiazem
Nifidipine+propranolol (PDI)
Verapamil+propranolo (PDI+PKI)
11- prodrugs require activation as: tamoxifen, 5FU, clopidogril
Clinical application of beneficial DDI:
Migracid (paracetamol+metoclopramide): rapid
effective treatment of migraine and decrease
nausea and vomiting symptoms accompanying
migraine