DRUG INTERACTIONS
Dr. Ruth Namyalo M
Objectives
To define the term drug interactions
To explain:
Outcomes of drug interactions
Underlying factors of DIs
Mechanisms of DIs
Prevention of DIs
Definition
A drug interaction(DI) is a situation in which a
substance (usually another drug or food) affects the
activity of a drug when both are administered
together.
It may be drug-drug, drug-food, drug-disease, drug-
laboratory or drug-plant interactions.
It can result into an increase or a decrease in the
magnitude of an expected response.
Burden
According to the U.S. CDC, more than 10% of people take
five or more drugs at the same time.
20% of older adults take at least 10 drugs which greatly
increases the risk of ADR.
With an increasing number of approved drugs, the possibility
for interactions between drugs increases accordingly.
Therefore, predicting DDI in advance is both urgent and
increasingly difficult in clinical practice.
Outcomes of drug interactions
1) Loss of therapeutic effect
2) Toxicity
• Over dose resulting from increased concentration of a drug
by another drug
• Increase in side effects
3) Unexpected pharmacological activity
4) Beneficial effects i.e additive & potentiation or antagonism
Underlying factors
Old age
Patients taking many drugs
Genetic factors
Hepatic and renal diseases
Drug dependent factors e.g. drugs with long
half lives(Cimetidine has a long half life, while, theophylline has
a short one. When cimetidine is administered to a patient regimen
for Theophylline, interaction takes place in one day)
Mechanisms of drug interactions
DIs may be a result of;
1.Pharmacokinetic interactions
2.Pharmacodynamic changes
3.Or a combination of both
In vitro interactions(e.g. precipitation of iv drugs with
their diluents or solutions) are classified as drug
incompatibilities not drug interactions.
Pharmacokinetic interactions
a) Interactions based on absorption
b) Interactions based on distribution and binding
c) Interaction based on metabolic clearance
d) Interactions based on renal functions
Interactions based on absorption
• These include; Altered pH, altered bacterial flora,
formation of drug chelates or complexes, drug induced
mucosal damage and altered GIT motility.
a) Altered pH;
The non-ionized form of a drug is more lipid soluble and
more readily absorbed from GIT than the ionized form
does.
Examples
Antiacids ph Decrease the tablet
dissolution
of Ketoconazole (acidic)
H2 antagonists ph
Interactions based on absorption
b) Altered intestinal bacterial flora ;
EX., In 10% 0f patients that receive digoxin…..40% or more
of the administered dose is metabolized by the intestinal
flora
Antibiotics kill a large number of the normal
flora of the intestine
Increase digoxin conc.
And increase its toxicity
c) Complexation or chelation
EX1., Tetracycline interacts with iron preparations
or
milk (Ca2+ ) Unabsorpable complex
Ex2., Antacid (aluminum or magnesium) hydroxide
Decrease absorption of
ciprofloxacin by 85%
due to chelation
d) Drug-induced mucosal damage.
Antineoplastic agents e.g., cyclophosphamide
vincristine
procarbazine
Inhibit absorption
of several drugs
e.g digoxin
e) Altered motility
Metoclopramide (antiemetic)
Decrease absorption of
cyclosporine due to increase
of stomach emptying
Increase toxicity of
cyclosporine
Interactions based on protein binding
a) Displaced protein binding
• It depends on the affinity of the drug to plasma protein.
• The most likely bound drug is capable to displace others.
• The free drug is increased by displacement by another drug with
higher affinity.
EX; Phenytoin is a highly bound to plasma protein (90%),
Tolbutamide (96%), and warfarin (99%)
Therefore drugs that displace these agents are aspirin, sulfonamides
and phenylbutazone.
Interactions due to metabolism
a) Altered metabolism
The effect of one drug on the metabolism of the
other is well documented. The liver is the major site of drug
metabolism but other organs can also do e.g., skin, lungs,
and GIT.
CYP450 family is the major metabolizing enzyme in
phase I (oxidation process).
Therefore, the effect of drugs on the rate of metabolism
of others can involve the following examples.
EX1., Enzyme induction
A drug may induce the enzyme that is responsible
for the metabolism of another drug or even itself e.g.,
Carbamazepine (antiepileptic drug ) increases its own
Metabolism
Phenytoin increases hepatic metabolism of theophylline
leading to decrease its level reduces its action and vise-
versa
N.B Enzyme induction involves protein synthesis, therefore it
needs time up to three weeks to reach a maximal effect
EX2., Enzyme inhibition;
It is the decrease of the rate of metabolism of a drug by another
one. This will lead to the increase of the concentration of the
target drug and leading to the increase of its toxicity.
Inhibition of the enzyme may be due to the competition on its
binding sites , so the onset of action is short may be within 24h.
N.B; When an enzyme inducer (e.g. carbamazepine) is
administered with an inhibitor (verapamil) , the effect of the
inhibitor will be predominant.
EX., Omeprazole inhibits oxidative metabolism of diazepam
First-pass metabolism:
Oral administration increases the chance for liver and GIT
metabolism of drugs leading to the loss of a part of the
drug dose decreasing its action.
EX., Increased dofetilide concentrations and risk of QT prolongation
with administration of verapamil, which is thought to increase
absorption through increased hepatic blood flow
Interactions based on renal function
Renal excretion
Active tubular secretion;
It occurs in the proximal tubules (a portion of renal tubules).
The drug combines with a specific protein to pass through the
proximal tubules.
When a drug has a competitive reactivity to the protein that is
responsible for active transport of another drug. This will reduce
such a drug excretion increasing its con. and hence its toxicity.
Example: probenecid decreases tubular secretion of methotrexate.
Passive tubular reabsorption
Excretion and reabsorption of drugs occur in the tubules
by passive diffusion which is regulated by concentration
and lipid solubility.
N.B., Ionized drugs are reabsorbed lower than non-
ionized ones
Sodium bicarbonate increases lithium clearance and
decreases its action
Antacids increase salicylate clearance and decreases
its action
Pharmacodynamic effects
It means alteration of the drug action without change in
its serum concentration by pharmacokinetic factors.
Synergism means =1+1=3
Additive means= 1+1=2
Potentiation means= 1+0=2
Antagonism means 1+1=0 or 0.5
Interactions based on opposing actions
or effects(antagonism)
Antagonism of broncho dilating effects of β2-agonists
used in asthma is to be anticipated if a β-blocker is given
for another condition
Action of catecholamines on heart rate is antagonized by
acetylcholinesterase inhibitor
NSAIDS may decrease antihypertensive action of ACE
inhibitors by reducing renal elimination of sodium
Interactions based on additive
effects(potentiation or synergism)
The 2 drugs may or may not act on the same receptor to
produce such effects.eg
Combined use of TCAs with diphenhydramine cause
excessive atropine like effects
Additive depression of CNS functions caused by
concomitant admnistration of sedatives, hypnotics,
opioids etc
Interaction of Herbal Medication with
other drugs
Certain herbs tend to interact with purified drugs eg;
Dong quai increases anticoagulant effects of warfarin
Garlic increases risk of bleeding (anticoagulants, antiplatelet)
St. John’s wort increases metabolism of drugs(oral
contraceptives, cyclosporine, digoxin, HIV, protease inhibitors,
warfarin)
Drug-lab interactions
• Antibacterials, such as cephalosporins, can interfere with laboratory tests, such as
coagulation tests and urine glucose tests.
• Psychotropics, such as antidepressants and antipsychotics, can cause false
positives in drug screens and in pregnancy tests.
• Contrast media, used for imaging tests, can affect the results of thyroid function
tests and serum creatinine tests.
• Proton pump inhibitors, used for acid reflux, can alter the results of urine tests for
tetrahydrocannabinol (THC) and amphetamines.
• Biotin, a vitamin supplement, can interfere with many immunoassays, such as
those for thyroid hormones, cardiac markers, and hormones.
Predictability of Drug interactions
The estimates of predictability models are intended to
indicate simply whether or not the interaction will occur,
and they do not always mean that the interaction is likely
to produce an adverse effect.
Whether or not the interaction occurs (precipitant drug
produces a measurable change in the object drug action)
and produces an adverse effect depends on both patient
and drug-specific factors.
E, Expected; HP, Highly predictable- Interaction occurs in almost all patients
receiving the interacting combination; P, Predictable- Interaction occurs in
most patients receiving the combination; NP, Not predictable- Interaction
occurs only in some patients receiving the combination; NE, Not established-
Insufficient data available on which to base estimate of predictability.
Prevention of drug interactions
Incorporating judicious prescribing concepts into patient
care,
Identifying patients at high risk
Obtaining a comprehensive medication history
Consulting relevant general and specialized resources
as necessary
Prevention of drug interactions
Monitoring therapy and making adjustments
TDM
Monitoring some parameters that may help to
characterize the early events of interaction or toxicity
e.g., with warfarin administration, it is recommended to
monitor the prothrombin time to detect any change in
the drug activity.
Increase the interest of case report studies to report
different possibilities of drug interaction
References
Katzung and Trevor’s Pharmacology and
Board review, 14th edition, ch 66
