PHARMACOKINETIC

MECHANISM OF
INTERACTION
 Theseinteractions are clinically significant
because:

The extent of pharmacokinetic interactions

may result in a change drug concentration
at the site of action with subsequent toxicity
or decreased efficacy.
1.0. ABOSRPTION
 The oral route  most common and preferable
route of administration.
 Majority of the drugs are given by this route
 It renders the drugs to be absorbed through the
mucous membranes of the gastrointestinal tract.
 Most of the interactions which occur in the gut result
in the reduced rather than increased absorption.
 For drugs that are given chronically on a multiple
dose regimen the rate of absorption is usually
unimportant provided the total amount of drug
absorbed is not markedly altered e.g. oral
anticoagulants
1.1. Delayed absorption is clinically significant where
affected drug has short half-life or where it is
intended to achieve high plasma levels e.g.
analgesics or hypnotics.
Management Altered absorption interactions can be
avoided if an interval of 2—3hrs is allowed between
the administrations of the interacting drugs.
 There are many mechanisms by which drugs
theoretically alter the absorption of another drug,
these include altered splanchnic blood flow, gut
motility, gut pH, drug solubility, gut metabolism, gut
flora or gut mucosa.
1.1.1. Role of P-glycoprotein
 The drugs may be excreted back into the GIT lumen
by P-glycoprotein,
 Multi-drug resistant gene that lowers intracellular
drug concentration by acting as an energy
dependent drug efflux pump (ATP)
 Numerous drugs are potential substrate for P-
glycoprotein transporter.
 P-glycoprotein is found in normal tissues, including small
and large intestine, kidneys, liver (billiary, hepatocytes
and endothelial cells at the blood-brain barrier)

 Herbal products or drugs that may inhibit or induce P-gp

may increase or decrease the plasma concentration of
P-gp substrate (i.e. drugs)

 P-gp may be involved in many drug interactions

occurring in the GIT, liver and kidney.
 Orally administered drug that is substrate for P-gp
may be secreted back into the GIT lumen by P-gp
 If a drug is a substrate of a P-glycoprotein in the
GIT, uptake from the intestine will be incomplete 
Decreasing drug levels
 For example: co-administration of Digoxin and
Rifampicin  rifampicin result in decreased digoxin
level
Mechanism = unknown
Management = an increase in the digoxin dosage may be required
1.2. Changes in GI pH
 The absorption of drug across mucous
membranes depends on
 extent to which it exists in the non-ionized
 lipid-soluble form
 The ionization depends on the
 pH, pKa of drug and the
 formulation factors.
 Weakly acidic drugs  best absorbed at low pH
(salicylates) as non-ionized form predominates.
 Alteration of pH by antacids, proton pump inhibitors
or H2 antagonists potentially affect the absorption of
other drugs.
For Example: Antacids, H2 antagonists (cimetidine)
and proton pump inhibitors (omeprazole) can
significantly decrease the bioavailability of
ketoconazole and Itraconazole (both requiring
gastric acidity for optimal absorption)
 The alkanizing effects of antacids are
transient and potential for drug interaction
 Can be minimized by leaving an interval of 2
—3hrs between the antacid and potentially
interacting drugs
For Example: Quinolones / Tetracycline &
Antacids (containing Di- & Tri-valent ions)
1.2.1. Absorption, Chelation & other Complexation
Mechanisms
 It’s a physical phenomenon
 Susceptible drugs directly interact with other drugs /
foods to form insoluble complexes or chelates 
impaired abs. or complete inhibition (predominant)
 Drugs most commonly involved:
 Tetracyclines
 Quinolones—complex with iron and antacids
containing Calcium, Magnesium and Aluminum
 Dietary constituents of food containing (Di- or Tri-
valent minerals)
 Formation of insoluble complexes  Reducing the serum
concentration of either object or precipitant drug
 Adsorbents like activated charcoal may also reduce the
absorption of concomitantly administered drugs
 For Example: Colestyramine—reduces the absorption of
Digoxin, Propranolol, Warfarin, TCAs, Cyclosporine and
Thyroxin.
 Management: separating doses of the interacting drugs by a
period of several hours.
1.3. Drug-effects on GI Flora
 Bacterial flora predominates  large intestine and is
present in much smaller number in small intestine
and stomach
 drugs absorbed from the small intestine, intestinal
bacteria inactivate the drug

For Example: 10% of Digoxin is inactivated by the gut

bacteria, and introduction of broad spectrum
antibiotics result in substantial increase in the levels
of Digoxin.
 Gut bacteria also prevent the bacterial
hydrolysis of drug conjugates secreted into
bile thus reduce the re-absorption of the
active parent drug.
 Antibiotics reduce the enterohepatic
circulation of ethinylestradiol (oral
contraceptive)  Reduced circulating
estrogen levels  Therapeutic failure.
1.4. Effects on Gastric Motility
 Drugs that alter the rate at which the stomach
empties its contents can affect the absorption
For Example .
 Anticholinergic, TCAs, Phenothiazines,
Antihistamines, Opiates (morphine, pathidine &
codeine) etc.
 Metocloperamide increases the gastric emptying and
increases the absorption of Paracetamol (therapeutic
advantage in migraine).
2.0. DISTRIBUTION
 The main mechanism  Displacement of one drug
from the protein binding sites
 Drug displacement interaction may be defined as
a reduction in the extent of plasma protein binding of
one drug caused by the presence of another drug 
Increased free or unbound fraction of the displaced
drug
 Albumen is the main protein to which the acidic
drugs are bound e.g. warfarin.
 Basic drugs bind to α1 –acid glycoprotein e.g. TCAs,
Lidocaine, Disopyramide, propranolol.
 If displacement occurs, then the concentration of free drug
rises temporarily, but metabolism & distribution returns free
concentration to its previous level  time taken in this depends
on the half life of the displaced drug.
 This short-term rise in free concentration is generally of minor
importance in therapeutic drug monitoring
 For example:
Patient taking Phenytoin, is given another drug that displaces it
from its binding sites  Total plasma Phenytoin concentration
will fall even though the free (active) concentration remains the
same
Receptor Binding:
 Binding sites are also significant in drug interaction
e.g. Quinidine displaces Digoxin from binding sites
in skeletal muscle; increasing the serum
concentration of Digoxin (Quinidine also alters the
renal excretion of Digoxin).
“This is a pharmacological type of interaction than
typical drug interaction”
 A beta blocker as Propranolol may displace beta
agonist such as Terbutaline  Increasing the
likelihood of precipitating an asthmatic attack.
3.0. ALTERED METABOLISM
 Metabolism is to convert lipid-soluble active
compounds to water-soluble inactive substances
that can be efficiently excreted
 Hepatic microsomal enzymes cause the metabolism
of many drugs (Phase-I & Phase-II)
 Mixed Function Oxidases, Characterized by the
Cytochrome P-450 isozymes  responsible for the
oxidation of many drugs.
 Derived from the expression of an individual gene
3.1. Effects:
 The effects of CYP isoenzyme on a particular substrate can be
altered by interaction with other drugs.
 Drugs may be substrate for a isoenzyme and/or may inhibit or
induce
 Induction or inhibition of a single isoenzyme would have little
effects on plasma levels of the drug.
 If a drug is metabolized by a single isoenzyme, induction or
inhibition of this enzyme would have a major effect on the
plasma concentration of a drug.
For example:
Erythromycin (inhibitor of CYP3A4) is taken by
patient given carbamazipine (extensively
metabolized by CYP3A4), this may lead to
toxicity due to higher concentrations of
carbamazipine.
3.2. Enzyme Induction
 Stimulated increase in enzyme activity.
 Caused by an increase in the amount of enzyme present.
 Enzyme induction is a delayed process because it requires the
synthesis of enzyme (requiring some time).
 Approximately 400 drugs and chemicals (e.g. insecticides,
chemicals in cigarette smoke or certain vegetables) are enzyme
inducers in animals.
 Phenobarbital, Phenytoin, Carbamazepine and Rifampicin are
enzyme inducers of clinical significance.
 Drug actions altered by inducers warfarin,
oral contraceptives, chloramphenicol,
cyclosporine, disopyramide, doxycycline,
griseofulvin, metronidazole, mexiletine,
quinidine, theophylline, and varapamil.
3.3. Enzyme Inhibition
 Enzyme inhibition of drug-metabolizing enzymes generally
decreases the rate of metabolism of the object drug.
 This is likely to result in increased serum concentrations of the
object drug and if the drug has narrow therapeutic index,
potential drug toxicity.
 Drug metabolizing enzymes may become saturated when at
least 2 drugs using the same metabolic pathway are
administered, resulting in a decrease in the rate of metabolism of
1 or both drugs (e.g. fluoxetine-imipramine).
 Certain drugs may bind to an enzyme system
and inhibit enzyme function (e.g. cimetidine &
erythromycin).
 Other enzyme inhibitors include: isoniazid,
varapamil, chloramphenicol, ketoconazole,
amiodarone, disulfiram & monoamine
oxidase inhibitors.
4.0. ELIMINATION
INTERACTIONS
 Some drugs are excreted either in the bile or in the
urine. (Small molecules can easily pass across the membranes of the
glomerulus while macromolecules as plasma proteins and blood cells are
retained).
 Blood flow  removes drugs and their metabolites
 Interactions can occur when drugs interfere with the
kidney tubule pH, active transport systems, or blood
flow to the kidney thereby altering the excretion of
other drugs.
4.1. Changes in Urinary pH
 Passive reabsorption of drugs depends on the
extent to which the drug exists in the non-ionized or
lipid soluble form.
 At alkaline pH weakly acidic drugs (pKa 3.0—7.5)
largely exists as unionized lipid insoluble molecules,
which are unable to diffuse into the tubule cells and
will therefore be lost in the urine.
 The renal clearance of such drugs can be increased
if the urine is made more alkaline.
 The clearance of weak bases (pKa 7.5—10) is higher in acidic urine
 Strong acids and bases are virtually completely ionized over
physiological range of urine pH and their clearance is unaffected by the
pH changes
 These interactions are of minor clinical significance as most of the drugs
(weak acids & weak bases) are metabolized by hepatic metabolism
rather than renal excretion.
 Drugs producing large changes in the pH are rarely used clinically.
 Urine alkalinization* or acidification has been used as a means of
increasing the elimination of drug in the poisoning with salicylates* and
amphetamines* respectively.
4.2. Changes in Active Renal Tubule Excretion
 Drugs which use the same active transport system in the kidney
tubules can compete with one another for excretion. Such
competition between the drugs can be used to therapeutic
advantage e.g. Probenecid & penicillin.
 Methotrexate toxicity (life threatening) is seen in some patients
concurrently treated with salicylates and other NSAIDs. The
development of toxicity is believed to be due to increased dose
of methotrexate (competitive inhibition of renal tubular secretion)
or impaired renal function
 4.3. Changes in renal blood flow
 The blood flow through the kidneys is partially
controlled by the production of renal
vasodilatory prostaglandins.
 If the production of these prostaglandins is
inhibited (e.g. indomethacin) the renal
excretion of lithium is reduced with a
subsequent rise in serum levels
II-PHARMACODYNAMIC
MECHANISM
 Generally involve the effects of drugs acting
on the same receptors or physiological
system as
 Additive
 Synergistic
 Antagonistic

These interactions are much less easy to

classify
ANTAGONISM
 Drug with agonist actions at a particular type of receptor interacts
with antagonist at the same receptor.
 For example: Bronchodilator action of a selective β2
adrenoreceptor agonist such as salbutamol or terbutaline will be
antagonized by β adrenoreceptor antagonists.
 Many of the antagonistic interactions occurring at receptor sites
are used for therapeutic advantage  Specific antagonists
may be used to reverse the effect of another drug at the receptor
sites.
 For example: Opioid antagonist  naloxone, benzodiazepine 
flumazenil.
Additive or Synergistic Interactions
 Two drugs with similar pharmacological effects are given together the
effects can be additive.
 It is not a typical interaction but it in most cases contributes to the
adverse drug reactions
 For example: concurrent use of drugs with CNS depressant effects
such as hypnotics, antidepressants, antiepileptics and antihistamines
may lead to excessive drowsiness.
 Combinations with such as antiarrhythmics, neuroleptics, TCAs and
those producing electrolyte imbalance (diuretics) may lead to ventricular
arrhythmias and should be avoided.
 Some combinations induce ventricular tachycardia with a potential of
prolonging QT intervals in ECG.
RFERENCES
 David S. Tatro, Drug Interaction Facts 2009
 Roger Walker, Cate Whittelsea, Clinical
Pahrmacy and Therapeutics, 4th edition
 Stockley’s Drug Interaction, 6th edition