1.
Dr Shivaraj D R
Assistant Professor & Clinical Pharmacist
Department of Pharmacy Practice
Sree Siddaganga College of Pharmacy and SMCRI
Tumakuru
2021-2022

2.
Unit-3
Pharmacokinetics of drug interaction

3.
DEFINITION
Drug interaction is defined as the pharmacological activity
of one drug is altered by the concomitant use of another
drug or by the presence of some other substance.
• The drug whose activity is effected by such an interaction is called as
a “Object drug.”
• The agent which precipitates such an interaction is referred to as the
“Precipitant.”

4.
Types of Drug Interactions
1. Drug-drug interactions
2. Drug-food interactions
3. Chemical-drug interactions
4. Drug-laboratory test interactions
5. Drug-disease interactions

5.
The net effect of Drug Interaction is
 Generally quantitative i.e. increased or decreased effect.
 Seldom qualitative i.e. rapid or slower effect.
 Precipitation of newer or increased adverse effects.

6.
Drug Interactions are thus-
 Mostly undesirable
 Rarely desirable (beneficial): for example,. Enhancement of
activity of penicillin's when administered with probenecid.

7.
Factors contributing to drug interactions:
1. Multiple drug therapy.
2. Multiple prescribers.
3. Multiple pharmacological effects of drug.
4. Multiple diseases/predisposing illness.
5. Poor patient compliance.
6. Advancing age of patient.
7. Drug-related factors

8.
Multiple drug therapy
• This is very common in most acute and chronic care settings.
• Example: Patient suffering from hypertension and congestive heart
failure includes antihypertensive as well as digitalis which together
may lead to abnormal heart rhythms.
• Over 50% of drug interactions occur, when a patient receiving 5
medications and probability increases 100% when 7 drugs are used.

9.
Multiple Prescribers
• Patient to be treated by one or more specialists, it is very difficult for
one prescriber to become aware of all the medications that have been
prescribed by others.
• Example: one doctor may prescribe an Anxiolytic for a patient while
another prescribes an Antihistamine having sedative properties with
the possible consequence of an excessive depressant effect.

10.
Multiple pharmacological effects of drug
• Most drugs used in current therapy exhibit more than one type of
pharmacological action and have the capacity to influence many
physiological systems.
• Therefore, 2 concomitantly administered drugs will often affect some
of the same systems.
• Example: Combining antipsychotics, antidepressants and anti-
parkinsonism drugs causing unanticipated additive anticholinergic
effect.

11.
Multiple diseases/predisposing illness
• Some patients take several drugs due to their suffering from more than
one disease.
• Example: patient with both DM & HTN; therapies like oral
hypoglycemics and beta blockers can result in decreased response to
anti-diabetic drug resulting in elevated blood sugar levels.

12.
Poor patient compliance
• Patient does not take medication in the manner intended by the doctor,
which may be due to inadequate instructions from the doctor or
pharmacist, confusion regarding taking several medicines.
• All of which may lead to either under dosing or overdosing and a
consequent drug interaction.

13.
Advancing age of patient
• Increased tendency of drug interaction episodes in elderly due to
decrease in liver function.
Drug related factors
 Clinically significant interactions are most likely to occur between
drugs that have potent effects, a narrow therapeutic index and a steep
dose-response curve.
 Example: cytotoxic, anti-hypertensive and hypoglycemic drugs,
digoxin, warfarin etc..

14.
Mechanisms of Drug Interactions:
The 3 mechanisms by which an interaction can develop are:
1. Pharmaceutical interactions.
2. Pharmacokinetic interactions.
3. Pharmacodynamic interactions.

15.
Pharmaceutical Interactions
• Also called as Incompatibility, it is a physicochemical interaction that
occurs when drugs are mixed in i.v. infusions causing precipitation or
inactivation of active principles.
• Example:
Ampicillin, chlorpromazine & barbiturates interact with dextran in
solutions and are broken down or from chemical compounds.

16.
Pharmacokinetic Interactions
“These interactions are those in which ADME properties of the object
drug is altered by the precipitant and hence such interactions are also
called as ADME interactions.”
 The resultant effect is altered plasma concentration of the object drug.
 These are classified as:
1. Absorption interactions
2. Distribution interactions
3. Metabolism interactions
4. Excretion interactions

17.
Absorption Interaction:
Are those where the absorption of the object drug is altered. The net
effect of such an interaction is:
 Faster or slower drug absorption
 More or less complete drug absorption
Major mechanisms of absorption drug interactions are:
1. complexation and adsorption.
2. Alteration in GI pH.
3. Alteration in gut motility
4. Inhibition of GI enzymes.
5. Alteration of GI micro flora
6. Malabsorption syndrome.

18.
Object drug Precipitant drug Influence on object drug
Complexation and adsorption
Tetracycline, Fluoroquinolones
like ciprofloxacin,
penicillamine
Antacids, food and mineral
supplements containing Al,
Mg, Fe, Zn, Bi, and Ca ions
Formation of poorly soluble
and unabsorbable complex
with such heavy metal ions.
Cephalexin, Sulfamethoxazole,
Trimethoprim, Warfarin and
Thyroxin
Cholestyramine Reduced absorption due to
adsorption and binding
Alteration of GI pH
Sulphonamides, aspirin Antacids Enhancement dissolution and
absorption rate.
Ferrous sulphate Sodium bicarbonate,
calcium carbonate
Decreased dissolution
Ketoconazole, tetracycline, alcohol Antacids Decreased dissolution and
bioavailability

19.
Object drug Precipitant drug Influence on object drug
Alteration of Gut Motility
Aspirin, diazepam, levodopa,
lithium carbonate,
Paracetamol, mexilitetine
Metoclopramide Rapid gastric emptying;
increased rate of absorption
levodopa, lithium carbonate,
Mexilitetine
Anticholinergic’s
(Atropine)
Delayed gastric emptying;
decreased rate of absorption
Alteration of GI Microflora
Digoxin Antibiotics
(Erythromycin, Tetracycline)
Increased bioavailability due
to destruction of bacterial
flora that inactivates digoxin
ion lower intestine.
Oral contraceptives Antibiotics
(Ampicillin
Decreased reabsorption of
drugs secreted as conjugates
via bile in the intestine.

20.
Object drug Precipitant drug Influence on object drug
Malabsorption syndrome
Vitamin A, B12, digoxin Neomycin Inhibition of absorption due
to Malabsorption caused by
neomycin

21.
Distribution Interaction:
 Are those where the distribution pattern of the object drug is altered.
 The major mechanism for distribution interaction is “alteration in
protein-drug binding.”
Competitive Displacement Interactions
Displaced drug Displacer Influence
Anticoagulants Phenylbutazone, choral
hydrate, Salicylates,
Increased clotting time;
increased risk of
hemorrhage
Tolbutamide Sulphonamides Increased
hypoglycemic effect
Methotrexate Sulphonamides, Salicylic
acid
Increased Methotrexate
toxicity
Phenytoin Valproic acid Phenytoin toxicity

22.
Metabolism Interaction:
 Are those where the metabolism of the object drug is altered.
 The mechanism for metabolism interaction includes;
 Enzyme induction: increased rate of metabolism.
 Enzyme inhibition: decreased rate of metabolism. It is the most
significant interaction in comparison to other interactions and can be
fatal.

23.
Object drug Precipitant drug Influence on object drug
Enzyme Induction
Corticosteroids, oral
contraceptives, coumarins,
tolbutamide, tricyclic
antidepressants.
Barbiturates Decreased plasma levels;
decreased efficacy of object
drugs
Enzyme Inhibition
Tyramine rich food
(Cheese, liver, yeast products)
MAO inhibitors
(Phenelzine, paragyline)
Enhanced absorption of
unmetabolised Tyramine;
increased pressor activity;
potentially fatal risk of
hypertensive crisis

24.
Excretion Interaction:
 Are those where the excretion pattern of the object drug is altered.
 Major mechanisms of excretion interactions are;
i. Alteration in renal blood flow: example: Ex: NSAID’s with lithium.
ii. Alteration of urine pH: antacids with amphetamine.
iii. Competition for active excretion: probenecid and penicillin.
iv. Forced diuresis.

25.
Object drug Precipitant drug Influence on object drug
Changes in active tubular secretion
Procainamide, Ranitidine cimetidine Increased plasma levels of
basic drugs; risk of toxicity
Acetohexamide Phenylbutazone Increased hypoglycemic effect
Changes in urine pH
Amphetamine, tetracycline,
Quinidine
Antacids, thiazide,
acetazolamide
Increased passive reabsorption
of passive drugs; increased risk
of toxicity
Changes in Renal Blood Flow
Lithium bicarbonate NSAID’s Decreased renal clearance of
lithium; risk of toxicity

26.
Pharmacodynamic Interactions
 Are those in which the activity of the object drug at its site of action is
altered by the precipitant.
 There are 2 types
1. Direct Pharmacodynamic Interaction
2. Indirect Pharmacodynamic Interaction

27.
Direct Pharmacodynamic Interactions
In which drugs having similar or opposing pharmacological effects are
used concurrently.
The 3 consequences of direct interactions are;
1. Antagonism
2. Addition or summation
3. Synergism or potentiation

28.
Antagonism:
“The interacting drugs have opposing actions.”
Example: Ach and NA having opposite effects on heart rate.
Addition or Summation:
“The interacting drugs have similar actions and the resultant effect is the
some of individual drug responses.”
Example: CNS depressants like sedatives and hypnotics etc..
Synergism or potentiation:
“It is an enhancement of action of one drug by another.”
Example: Alcohol enhances the analgesics activity of aspirin.

29.
Indirect Pharmacodynamic Interactions
“In which both the object and the precipitant drugs have unrelated
effects but the latter in some way alerts the effects of the former.”
Example:
Salicylates decreases the ability of the platelets to aggregate thus
impairing the homeostasis if warfarin induced bleeding occurs.

30.
CONSEQUENCES OF DRUG
INTERACTIONS:
It may be;
 Major: life threatening.
 Moderate: Deterioration of patient status.
 Minor: little effect.

31.
REDUCING THE RISK OF DRUG
INTERACTIONS
1. Reducing the patient risk factors.
2. Take through drug history & maintain complete patient medication
records.
3. Keep knowledge about the actions of drugs being used.
4. Consider therapeutic alternatives.
5. Avoid complex therapeutic regimens when possible.
6. Educate the patient.
7. Monitor therapy: Any change in patient behavior should be suspected
as drug related until that possibility is excluded.

32.
INFLUENCE OF SMOKING ON DRUG
INTERACTIONS:
Smoking increases the activity of drug metabolizing enzymes in
the liver, with the result that certain therapeutic agents.
Example:
Diazepam, propoxyphene, theophylline, olanzapine, are
metabolized more rapidly and their effect is decreased.

33.
INFLUENCE OF ALCOHOL ON DRUG
INTERACTIONS:
 Chronic use of alcohol beverages may increases the rate of
metabolism of drugs such as warfarin and phenytoin, probably by
increasing the activity of hepatic enzymes.
 Acute use of alcohol by non alcoholic individuals may cause an
inhibition of hepatic enzymes.
 Use of alcohol beverages with sedatives and other depressants drugs
could result in an excessive depressant response.