Drug Interaction is defined as the pharmacological activity of
one drug being altered by the concomitant use of another drug
or by presence of another substance or food.
The drug whose activity is altered by such interaction is known
as the object drug.
The agent which precipitates such an interaction is known as
precipitant.
Drug –drug interactions
Drug-food interactions
Drug-disease interactions
Multiple drugs
Multiple prescribers
Underlying patient diseases
Advancing patients age
pharmaceutical
pharmacokinetic
pharmacodynamic
Physiochemical interaction when drugs are mixed before
administration.
Either during mixing of IV medications or dilution of drugs in
incompatible infusion fluids
Interaction may lead to precipitation of drug leading to loss of
activity of the drug
Eg. precipitation of thiopental occurs when thiopental and
suxamethonium are mixed in the same syringe
Ceftriaxone precipitates if mixed into calcium-containing
infusion fluids like Ringer’s lactate
Prevention
Only one drug should be added to crystalloid solution
No additives in infusions of blood , blood products, lipid
emulsions, amino acid preparations or hypertonic saline
Complexation
Alteration in GI PH- antacids, PPIs
Alteration in GI motility- narcotics ,prokinetics
Alteration in gut microflora
Malabsorption disorders
Inhibition of GI enzymes
o Changing the pH of the gastrointestinal tract can alter the
absorption of some drugs. Some drugs require an acidic or
basic environment in order to dissolve.
Weak acids would more readily exist in a non-ionized state in
an acidic environment, thus being more readily absorbed,
whereas weak bases would be more absorbable in a basic
environment.
Drugs that increase gastric pH such as proton pump inhibitors
and antacids may thus affect absorption of other drugs.
Non- ionized form of a drug is more lipid soluble (lipophilic)
and more readily absorbed from the GIT than the ionized
forms, which are hydrophilic.
Example:
ANTACIDS / H2 antagonists given concomitantly with
KETOCONAZOLE (acidic), will decrease its tablet dissolution.
Therefore these drugs must be separated by at least 2hrs in
time of administration of both.
Anti-neoplastic drugs e.g cyclophosphamide, vincristine and
procarbazine may cause GI mucosal damage, inhibiting
absorption of other drugs e.g digoxin.
ALTERED GI MOTILITY
Metoclopramide increases the bioavailability of cyclosporine
by acting as a prokinetic agent, enhancing gastric emptying,
and accelerating its passage into the small intestine where
absorption occurs.
This interaction can result in increased blood concentrations
of cyclosporine, increasing the risk of toxicity (e.g.,
nephrotoxicity)
Antibiotics kill a large no. of normal flora in the intestine.
DIGOXIN- 40% of administered digoxin is metabolized by
intestinal flora
Concomitant antibiotic administration may affect the normal
flora, reducing digoxin metabolism within the gut and leading
to increased digoxin concentration & toxicity.
Antacids, foods and mineral supplements containing Al, Mg, Fe,
Zn and Ca2+ ions interact with drugs e.g Ciprofloxacin and
Penicillamine
This results in formation of poorly soluble or un-absorbable
complexes
Eg. administration of antacids decreases absorption of
ciprofloxacin by up to 85%.
Tetracycline interacts with Iron preparations
Drugs are transported via binding to plasma proteins.
The most important plasma proteins involved are
albumin, α1-acid glycoprotein, and lipoproteins.
Acidic drugs are usually bound more extensively to
albumin, while basic drugs are usually bound more
extensively to α1-acid glycoprotein, lipoproteins, or
both.
Only unbound drug is available for passive diffusion to
extravascular or tissue sites and typically determines
drug concentration at the active site and thus its efficacy
From a drug interaction standpoint, a drug with high binding
affinity can displace a drug with less affinity, thereby
increasing the free concentration of the drug with less
affinity.
Examples:
NSAIDs displace warfarin from plasma protein ,which may
may increase risk of bleeding.
Tolbutamide is displaced by sulphonamides, therefore
increased risk of hypoglycaemic effects
DRUG
(less affinity)
plasma protein
DRUG
(high affinity)
free concentration
drug(less affinity)
Warfarin vs NSAIDs
Many clinically important drug interactions involve pathways of
metabolism.
While metabolism takes place in numerous locations including
the plasma, intestines, lungs, and skin, the majority of the
metabolism occurs in the smooth endoplasmic reticulum of the
hepatocyte.
1. Enzyme Induction- A drug can induce the
enzyme responsible for metabolism of another
drug, leading to decreased drug levels and
reduced efficacy
2. Enzyme Inhibition- An enzyme inhibiting drug
may decrease of the rate of metabolism of a
second drug, increasing its drug levels and
leading to toxicity
Examples of drug interactions at the level of metabolism
Instances of failure of antimicrobial therapy with
metronidazole, doxycycline or chloramphenicol have
occurred in patients who are on long-term medication with
an enzyme-inducing drug.
Contraceptive failure and loss of therapeutic effect of
many other drugs have occurred due to enzyme induction
in patients taking rifampicin
Induction involves gene mediated increased synthesis
of certain CYP450 isoenzymes.
It takes 1-2 weeks of medication with the inducer to
produce maximal effect.
Effects regresses gradually over 1-3 weeks after
discontinuation of the inducer
Occurs through change in renal tubular secretion of drugs,
change in urine pH or changes in renal blood flow.
Example:
Lithium given with NSAIDs reduces renal clearance of lithium
as the NSAIDs may decrease renal blood flow, leading to
lithium toxicity.
Probenecid inhibits tubular secretion of penicillins and
cephalosporins .
Aspirin decreases tubular secretion of methotrexate.
Active transport systems (anion/cation transporters) in the
proximal tubule can be inhibited by some drugs, reducing
excretion of others
Examples:
NSAIDs reducing methotrexate excretion
Probenecid inhibits active renal tubular secretion of
penicillin
Drugs like NSAIDs, ACE inhibitors, and diuretics
can decrease renal blood flow or GFR, reducing
the clearance of drugs such as digoxin, lithium,
and aminoglycosides
Increases their risk of toxicity
Most drugs are filtered at the glomerulus
Those in lipid-soluble form are reabsorbed back into the
bloodstream via passive diffusion
To increase renal excretion: Change the urinary pH to
favour the charged/ionized form of the drug
Weak acids thus excreted faster in alkaline pH
Weak bases are excreted faster in acidic pH
Weak Acids: Alkalinizing urine to a pH of 7.5 to 8.5
(e.g., with sodium bicarbonate) increases the
ionization of acidic drugs like salicylate (aspirin),
reducing their reabsorption and enhancing
excretion.
Important in management of aspirin toxicity
Weak Bases: Acidifying urine increases the
ionization of basic drugs, accelerating their
excretion.
.
o Interactions derived from modification of the action of one
drug at the target site by another drug, independent of a
change in its concentration.
o This may result in an enhanced response (synergism), an
attenuated response (antagonism) or an abnormal response.
o The drugs interaction does not result in a change in drug`s
plasma concentration or drug`s pharmacokinetics.
Drug
A
Drug
B
opposite
or similar
effects
A+B
Hi
Response
A B
Lo
Time
The effect of two chemicals taken together is greater than the sum of
their separate effect at the same doses, e.g., alcohol and other drugs
alcoh opioi
ol ds
sedativ
es
synergistic
Hi
A+B
Response
A B
Lo
Time
The effect of two chemicals is equal to the sum of the effect of the two
chemicals taken separately, eg., aspirin and ibuprofen.
NSAIDs given with glucocorticoids resulting in increased risk of GI bleeding.
Hi
A+B
Response
A B
Lo
Time
The effect of two chemicals taken together is less than the sum of their separate
effect at the same doses.
ACEi with NSAIDs reduces blood pressure lowering effect of the ACEi
May result from one drug changing the
environment necessary for the safe and
effective use of a second drug
loop diuretic digoxin
• produces • increased
potassium cardiotoxic
wasting effects
Identify risk factors
Monitor therapy
Use alternative drugs
Take a thorough drug history
Educate patients
Always consult the DRUG INTERACTION CHECKER!!!
These interactions occur when drugs react with foods, dietary
supplements or beverages including alcohol.
Examples:
Alcohol enhances the hypoglycemic effect of anti-diabetic
medication, and the hypotensive effect of many blood pressure
drugs.
Grapefruit juice enhances the effect of drugs like simvastatin,
nifedipine and cyclosporine.
Dairy products which contain calcium reduce the absorption
of bisphosphonates, oral iron, levothyroxine and certain
antibiotics e.g. ciprofloxacin and tetracycline.
Vitamin K-People on warfarin have to avoid eating large
amounts of green leafy vegetables like broccoli, spinach and
watercress because the high vitamin K content of these foods
counters the effect of warfarin.
Drug-disease interactions occur when a drug worsens or
exacerbates an existing medical condition.
NSAIDs like ibuprofen may cause airway constriction in
Asthma.
Nasal decongestants containing pseudoephedrine increase
blood pressure and thus has to be avoided by patients who are
hypertensive.
.