DRUG INTERACTIONS
By-
Dr.A.Soujanya
PharmD
Assistant professor
Dept of pharmacy practice
DRUG INTERACTIONS
Drug interactions may be defined as a modification
in the intensity and extent of pharmacological
action of one drug by another drug. The interacting
drugs are termed as precipitant and object drugs.
Precipitant drug is the one which induces Drug
Interaction & an object drug is the one which is
affected by the precipitant drug.
Administration of more than two drugs can result in
either synergistic or antagonistic action. In
synergism, the drug action may be potentiated i.e.
may produce an additive or supra-additive effect.
In antagonism, the presence of one drug may
diminish or terminate the activity of another drug.
Classification
First Classification
Based on the clinical importance, drug
interactions can be classified as follows.
1.Beneficial Interactions:
Not all drug interactions are adverse in nature,
some can be beneficial as well. Some of the
interactions are intentional and they are called
"intentional drug interactions". Such interactions
result in reduced drug toxicity, improved potency,
reduced side effects and better outcome of drug
therapy. Most of the drug interactions occurring
inside the body may involve
pharmacodynamic/pharmacokinetic mechanisms
Combination of drugs that produce Resultant effect
beneficial effects
Sulphonamide+sodium bicarbonate decreased chances of crystalluria
methanamine+mandelic acid improved activity
penicillin+probenecid enhanced penicillin activity
rifampicin+isoniazid prevention of emergence of
resistance
ferrous sulphate +folic acid improved compliance
levodopa+carbidopa enhanced therapeutic activity of
levodopa
aluminium hydroxide+magnesium decreased adverse effects
trisilicate
sulfamethoxazole+trimethoprim synergistic action
triple ease of administration
vaccine(diphtheria+pertusis+tatanus)
gentamicin+carbenicillin enhanced activity against
pseudomonal infection
2.Adverse Interactions:
Adverse interactions can be defined as the drug
interactions where one drug opposes or
adversely modifies pharmacological effect of
another drug. This may result in failure of the
prescribed drugs to produce the desired
therapeutic action. This occurs when the
prescriber prescribes a drug being unaware of
other medications taken by the patient. The drug
interaction may take place either at
pharmacokinetic or pharmacodynamic level.
combination of drugs that resultant effect
interact adversely
digitalis+reserpine or cardiac arrythmias
chlorthiazide
tolbutamide+sulfisoxazole or severe hypoglycemia
phenyl butazone
folic acid+phenytoin megaloblastic anemias
warfarin+phenyl butazone or inc risk of hemorrhage
sulfinpyrazone
neomycin+succinylcholine respiratory paralysis
methotrexate+sulphonamides or inc risk of methotrexate toxicity
salicylates
levodopa+pyridoxine dec therapeutic effect of levodopa
phenytoin+isoniazid phenytoin toxicity
MAO inhibitors+tyramine hypertensive crisis
sulphonamides+methanamine precipitation of sulphonamides
causing crystalluria
Second Classification
1.Pharmacokinetic drug Interactions:
Pharmacokinetic drug interactions involve
alteration or modification of ADME of one drug
due to the presence of another drug. The extent
of such drug interactions is difficult to predict
because of inter individual variability. The
interactions may alter the drug concentration
which may either decrease its efficacy or cause
toxicity.
(a) Absorption-
In majority of cases when the drug interactions
occur in the GIT this decreases the rate of drug
absorption. If there is no significant change in
the extent (amount) of drug absorption,
then the rate of absorption is not of much
importance for those drugs that are
administered repeatedly. However, delay in
absorption may be significant when shorter
half-life drugs are used or when quick
attainment of plasma drug concentration is
required (E.gs: analgesics, hypnotics). Such
drug interactions can be overcome by
administering two drugs with a gap of at
least 2-3 hours. The drug interactions
occurring due to alteration in the absorption
of drugs may be due to the following
reasons-
(i) Changes in GI PH:
Numerous drugs are either weak acids or weak
bases and their extent of absorption is governed
by the GI pH. Non-ionized(lipophilic) drug is
absorbed to a greater extent than the
ionized(hydrophilic) form. Example: Absorption
of neostigmine(an ionized drug) is very poor
upon oral administration therefore higher doses
are required for obtaining therapeutic
concentration. Lower pH favours the absorption
of weakly acidic drugs (E.g.: Salicylates) as these
exist in non-ionized form. Thus, if the gastric pH
is altered due to concomitant administration of
antacids or proton pump inhibitors, then this
adversely affects the absorption of other drugs.
Drug Interactions Involving Changes in GI PH
Object drug(s) Precipitant drug Resultant effect
Aspirin, Antacids Inc rate of dissolution,
sulphonamides so enhanced
absorption rate of
object drugs
Tetracyclines, Antacids Dec rate & dissolution,
ketoconazole so dec bioavailability
of object drugs
Ferrous sulphate Na2Co3 , CaCo3 Dec dissolution &
absorption of object
drugs
Bisacodyl (enteric Antacids Irritation & vomiting
coated) due to disintegration
of enteric coating in
stomach
(ii) Adsorption, chelation and complexation:
When drugs are administered along with
adsorbents like charcoal, kaolin or anion exchange
resins, then their absorption decreases as they
get adsorbed onto the surface of adsorbents.
Example: When propranolol is administered along
with cholestyramine, then its absorption is
decreased. Similarly, certain drugs may react with
other drugs and form chelates or complexes that
are not readily absorbed. Example: When
tetracycline is administered along with antacids
containing divalent or trivalent cations, they form
insoluble complexes which reduces plasma levels
of tetracyclines. These interactions can be
prevented by maintaining a sufficient time gap (2-
3 hours) between the administration of two drugs.
(iii) Alteration in GI Motility:
The main site of absorption of many drugs is
the duodenum. Thus, any modification in the
gastric emptying rate by the drugs can affect
the absorption of other drugs. Drugs having
anticholinergic action (E.g: phenothiazine)
can reduce the GI motility and prolong the
emptying of gastric contents. This may
increase or decrease the absorption of co-
administered drugs. Example: When tricyclic
antidepressants and dicoumarol are
administered concomitantly, then the
absorption of dicoumarol is increased due to
prolongation of gastric emptying.
Drug Interactions due to alteration in motility
Object drug(s) Precipitant drug Resultant effect
Aspirin, diazepam, Metoclopramide Inc absorption due to
levodopa, rapid gastric emptying
paracetamol, lithium
carbonate
Lithium carbonate, Anticholinergics(TCAs, Dec absorption rate
levodopa, mexiletine atropine) due to delayed gastric
emptying
Acetaminophen Propantheline Delayed absorption
due to delayed gastric
emptying
(iv) changes in GI flora:
Bacterial flora are present chiefly in the large
intestine. Antibiotics destroy some of the
intestinal flora which increases the levels of
certain undesirable species. Example:
Administration of antibiotics along with digoxin
increases its risk of toxicity because the gut
flora which inactivates digoxin are destroyed by
the antibiotics. Intestinal bacteria also hydrolyse
the drug conjugate that is secreted into the bile.
Certain antibiotics inhibit this process thereby
decreasing the drug reabsorption. Example:
Circulating levels of oestrogens (present in oral
contraceptives) are decreased by the antibiotics
leading to therapeutic failure.
(b)Drug Distribution-
Most of the drug molecules after absorption bind
to the plasma proteins i.e., acidic drugs bind to
albumin while basic drugs bind to alpha 1-acid
glycoproteins. If there is another drug which has
greater affinity towards plasma protein it will
compete with the former drug for the binding
site and will cause its displacement. This may
result in toxicity due to increase in the free form
of the first drug. Example: Warfarin is highly (i.e.,
98%) plasma protein bound. If phenytoin is
administered along with warfarin, then it
competes with warfarin for plasma proteins and
displaces it. Thus, there occurs an increase in the
free form of warfarin leading to its toxicity.
Drug Interactions due to Displacement of Drugs
from their Plasma Protein Binding Sites
Object drug(s) Precipitant drug Resultant effect
Tolbutamide Sulfonamides Inc hypoglycemia
Phenytoin Valproic acid Phenytoin toxicity
Warfarin, slaicylates Phenylbutazone Inc hemorrhagic tendency
Methotrexate, Salicylic acid Methotrexate toxicity
sulfonamides
Bilirubin Sulfisoxazole Precipitaion of kernectirus
leading to pseudojaundice.
(c)Drug Metabolism-
Clinically important drug interactions involve
alteration (i.e., either induction or inhibition) of
metabolism of one drug by another.
(i) Enzyme Induction:
Enzyme induction is a process where the synthesis
of hepatic microsomal enzymes is increased in
the presence of certain drugs such as
barbiturates, phenytoin, rifampicin,
carbamazepine. Certain drugs like
carbamazepine and barbiturates are capable of
inducing their own metabolism, they are known
as autoinducers and the process is known as
autoinduction. Induction of enzymes enhances
the metabolism leading to decreased
pharmacological activity of the parent object
drug; except incase of prodrugs where the
metabolites are pharmacologically active.
Drug Interactions due to Enzyme Induction
Object drug(s) Precipitant drug
Oral hypoglycemics, oral Rifampicin
contraceptives(OCs)
Corticosteroids, phenytoin, Barbiturates
tolbutamide, OCs, coumarins
Corticosteroids, cyclosporin, OCs Phenytoin
Tolbutamide Alcohol
Warfarin, dicoumarol Chloral hydrate
In the above examples, plasma levels of object
drugs decreases leading to therapeutic failure
(ii) Enzyme Inhibition:
There are some drugs that can oppose the activity
of CYP450 which inhibit the metabolism of
concomitantly administered drug leading to its
accumulation. Enzyme inhibition is a dose related
process. The inhibition of metabolism of the
concomitantly administered drug starts as soon as
sufficient inhibitor concentration in the liver is
achieved. Thus, the inhibitory action for shorter
half-life drugs is seen within few days of
concomitant administration of enzyme inhibitor
while for longer half-life drugs it takes a long time
for the appearance of effects. Example:
Prescribing ritonavir (enzyme inhibitor) to a
patient on sildenafil increases the concentration of
sildenafil thus increasing the risk of hypotension.
Drug Interactions due to Enzyme Inhibition
Object drug(s) Precipitant Resultant effect
drug
Warfarin, dicoumarol Ciprofloxacin, Higher risk of hemorrhage
clarithromycin
Carbamazepine Cimetidine Carbamazepine toxicity
Sildenafil Ritonavir Enhanced risk of
hypotension
Azathioprine Allopurinol Inc levels of azathioprine,
may lead to toxicity
Oral hypoglycemics Phenylbutazone, Precipitation of severe
chloramphenicol hypoglycemia
(d)Drug Excretion-
The excretion of majority of drugs takes place
through urine or bile. Thus, there are chances of
drug interactions if one of the concomitantly
administered drug interferes with the urinary Ph,
glomerular rate and tubular secretion.
(i) Alteration in Blood Flow to Kidneys:
Renal blood flow is controlled to a limited extent
by the prostaglandins which are renal
vasodilators. Hence, if any drug interferes with
prostaglandin syntheis, there would be
alteration in excretion of other drugs. Eg: If
indomethacin (inhibitor of PG synthesis) is given
to a patient on lithium carbonate then there
would be inhibition of excretion of lithium
leading to toxicity.
(ii) Alteration of Urine pH:
When the urinary pH is modified, the action of the
drug excreted either in active or unchanged form is
altered. This may cause either excretion or
reabsorption of the therapeutically active drugs. The
extent to which the drug is present in non-ionized or
ionized form influences its reabsorption. Only non-
ionized molecules are reabsorbed. The effectiveness
of weakly acidic drugs is reduced in alkaline urine
(pKa 3-7.5), because being present as ionized
molecules these are not reabsorbed and are readily
excreted. However, changes in urinary pH does not
affect strong acids and bases as they are ionized to a
larger extent over the physiological range of urinary
pH. Moreover, the process of acidifying or alkalinizing
the urine is used as a means for enhancing the drug
excretion during poisoning (E.gs: Salicylate and
amphetamine poisoning).
Drug Interactions due to Alteration in Urinary pH
Object drug(s) Precipitant drug Resultant effect
Methanamine Mandelic acid Enhances the drugs’ activity by
favouring the conversion of
methanamine to active
metabolite (formaldehide)
Sulfonamides Methanamine Precipitation of sulfonamides
leading to crystallization
Salicylates Acidifying agents Higher plasma concs of
salicylates leading to toxicity
Sulfadiazine Sodium bicarbonate Enhanced solubility of
sulfadiazine thus reducing
chances of crystalluria
Streptomycin, Alkaline agents Inc effectiveness from
ranamycin, permitting use of low dosage
erythromycin hence reduces toxicity
(iii) Competition for Renal Tubular
Excretion:
When two drugs utilize the same active
transport mechanism for excretion, then the
drug with higher affinity for the excretion
mechanism gets excreted first. Such
condition can be employed for therapeutic
success. Example: Probenecid may be
administered concomitantly with penicillin
because it competes with penicillin for renal
secretion and gets excreted first due to
higher affinity. This leads to increased
systemic levels of penicillin resulting in its
enhanced therapeutic activity.
Drug Interactions due to competition for renal tubular
secretion
Object drug(s) Precipitant drug Resultant effect
Salicylates Furosemide Inc. risk of salicylate toxicity
due to its retention
Methotrexate NSAIDs Inc. risk of methotrexate
toxicity.
Digoxin Quinidine Higher serum levels of
digoxin causing toxicity.
(iv) Biliary Excretion:
Apart from urine, many drugs are excreted
through biliary excretion either in conjugated
or unchanged form. There occurs reabsorption
of certain conjugates that undergo metabolism
by gut flora (to give their corresponding parent
compounds) thus extending their stay in the
body. However, gut flora may decrease upon
concomitant use of antibacterial drugs which
inhibit the recycling of process leading to quick
loss of drug from the body
Example: When oral contraceptives are
concomitantly administered with antibiotics
their enterohepatic circulation is reduced
resulting in therapeutic failure.
Methods for Detecting Drug Interactions
Role of Pharmacist in the Detecting and
Preventing Drug Interactions-
If the pharmacist follows proper instructions and
precautions regarding the medication, then most of
the drug interactions are predictable and can be
easily prevented.
Patient counselling plays an important role in the the
prevention of drug interactions. A pharmacist
counsels the patient regarding the safe use of the
drugs. The complete patient medication profile
should be reviewed thoroughly by the pharmacist,
before dispensing the medicines to the patient. If the
pharmacist does not get the essential information
from the patient medication profile, then he should
ask the patient various questions in order to get
complete information. He has to review the drug
profile record.
Patient Counselling
The pharmacist counsels the patient regarding the following
aspects.
1. To take the medicines prescribed by the physician only and
not to go for self medication.
2. Medication should be taken as directed i.e., dose,
frequency and route of administration should be correct to
achieve the desired therapeutic effect.
3. Proper instructions to be followed while taking the
medicines i.e., time of administration.
4. To advise the patient regarding drug interactions or other
drug related problems the patient may encounter.
5. Pharmacist should counsel the patient regarding drug-food
interactions such as to avoid milk and milk products with
tetracyclines, to avoid tyramine rich foods with MAO
inhibitors and to take sugar free diet during antidiabetic
therapy.
6. To avoid consumption of alcohol during therapy.
7. To counsel the patient to take a healthy and balanced diet.
Methods:
A pharmacist can detect and manage the drug
interactions by the following methods.
1. Identification of Patient Risk Factors
During patient counselling, various factors like
age, sex, medication history, habits (smoking,
alcohol consumption) etc., should be taken into
consideration by the pharmacist.
2. Taking Consideration of Proper Drug
History and Patient Medication History
Unawareness of prescription and nonprescription
drugs causes various drug interactions. Hence, the
pharmacist can obtain the complete current
prescription and nonprescription medication
records of a patient and also his dietary habits.
3.Having Thorough Knowledge on Drug
Actions
The pharmacist must have thorough
knowledge on therapeutic effects, properties
and dosages of various drugs in order to
recognize and manage the drug interactions.
4. Considering Alternative Therapy
If the pharmacist recognizes the two drugs
interacting with each other as prescribed by
the physician, then with the help of his
Therapeutic Drug Monitoring (TDM)
knowledge, he can alter and adjust the dose
of these drugs or else he can replace these
drugs with alternative drugs possessing same
therapeutic activity.
5.Avoiding Complex Multiple Drug
Therapy
If Possible Usage of complex multiple drug
therapy can be minimized, if possible. In this
case, dosage regimen can be adjusted to
reduce the risk of drug interactions.
6.Patient Education
The pharmacist must educate the patient
about their medication like route, time of
administration, dosage, precautions etc., in
order to improve patient compliance. He
must encourage the patient to ask various
questions regarding his medication and also
to report any drug-related problems.
7.Therapeutic Drug Monitoring
The pharmacist should monitor the drug
therapy in case of risk of drug interactions,
adverse drug reactions and noncompliance.
Pharmacist should maintain a complete past
and present medication history of the patient
and should monitor the drug therapy in order
to recognize and prevent drug interactions. If
any drug interactions are noticed by the
pharmacist, then it should be recorded
immediately and reported to the PTC
(Pharmacy and Therapeutics Committee).
After case study, necessary steps and
precautions can be taken by the PTC to
prevent further drug interactions.
