Drug interactionPharmacokinetic and Pharmacodynamic drug interaction| Drug-food| Drug-alcohol | Drug-cigarette Smoking Interaction

Prof. Shaikh Abusufiyan
Part-01: Drug Interaction
Pharma Learning

At the end of this e-learning session you are able to…
A. Define drug interaction, enlist risk
factors and consequences of drug
interaction.
B. Discuss mechanism of drug interaction.
2

• Modification of the action of one drug
(the object drug)
by the prior or concomitant administration
of another (precipitant drug).
Drug interactions

Risk factor
 Genetic make up
 Poly pharmacy
 Multiple prescribers
 Specific illness Ex. Hepatic disease
 Specific population
 Narrow therapeutic index drugs
 Ex. Digoxin, Warfarin
*

Consequences of drug interactions
1) Loss of therapeutic effect
2) Toxicity
3) Unexpected increase in pharmacological
activity
4) Chemical or physical interaction
Ex. I.V incompatibility in fluid
5) Beneficial effects
Ex. additive & potentiation
or antagonism (unintended).

Mechanisms of drug interactions
Pharmacokinetics Pharmacodynamics
•Pharmacokinetics: One drug modify the pharmacokinetic of
other drug i.e ADME.

Mechanisms of drug interactions
 Pharmacodynamics: Modify
pharmacological activity of the
interacting drugs
• Ex. synergism, antagonism
- altered cellular transport
- effect on the receptor site.

1. Pharmacokinetic interactions
1) Altered GIT absorption.
•It may occur due to:
a. altered pH
b. altered bacterial flora
c. formation of drug chelates
or complexes
d. drug induced mucosal
damage
e. altered GIT motility.

Pharmacokinetic interactions
1) Altered GIT absorption.
a) Altered pH:
• The non-ionized form of a drug
More lipid soluble and more readily absorbed
from GIT than the ionized form.

Ex1.antacids Decrease the tablet
dissolution
of Ketoconazole
(acidic)
Ex2.H2 antagonists
• Therefore, these drugs must be separated by at least 2h.

Q&A
Q.1 What are the risk factors for drug interaction?
Q.2 Give consequences of DI.
Q.3 Give example of drug interaction due to change in pH.
1

b) Altered intestinal bacterial flora:
EX: 40% or more of the administered digoxin 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+ ) Un-absorbable complex
Ex2. Antacid (aluminum or magnesium) hydroxide
Decrease absorption of
ciprofloxacin by 85%
due to chelation

d) Drug-induced mucosal damage.
Anti-neoplastic agents ex. cyclophosphamide
- vincristine
Inhibit absorption
of drugs
Ex. digoxin
e) Altered motility
Metoclopramide (anti-emetic)
Increase absorption of
cyclosporine due to the
increase gastric emptying time
Increase the toxicity
of cyclosporine

f) Displaced protein binding
• It depends on the affinity of the drug to plasma protein.
• The most likely bound drugs is capable to displace others.
• The free drug is increased by displacement by another
drug with higher affinity.
• Phenytoin is a highly bound to plasma protein (90%),
Tolbutamide (96%), and warfarin (99%)
• Drugs that displace these agents are Aspirin
- Sulfonamides
- Phenylbutazone

Reference:
• Dr. H. P. Tipnis and Dr. Amrita Bajaj. Clinical Pharmacy, 3rd
edition. Carrier Publication Pg. No:305-329
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Q&A
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Pharma Learning

A. Discuss impact of metabolism on
drug interaction.
B. Explain impact of excretion on
drug interaction.
0

g) Altered metabolism
• The liver is the --> major site of drug metabolism
• other organs --> WBC, skin, lung and GIT.
• CYP450 family --> is the major in phase I (oxidation process).

Ex. Enzyme induction
- A drug may induces the enzyme --> responsible
for the metabolism of another drug or even itself.
- Carbamazepine
Increases its own Metabolism.

 Phenytoin increases hepatic metabolism of theophylline
Leading to decrease its level
Reduces its action and vice versa
g.,

 Enzyme induction
involves protein synthesis.
Therefore, it needs time up to 3 weeks to reach a maximal
effect.
g.,

Ex. Enzyme inhibition:
 It is the decrease of the rate of metabolism of a drug by another drug
lead to increase in concentration of target drug
increase its toxicity.

Ex. Enzyme inhibition:
 When an enzyme inducer (e.x. carbamazepine) + administered with an
inhibitor (verapamil)
The effect of the inhibitor will be predominant

*
Ex: Erythromycin inhibit --> metabolism of
astemazole and terfenadine
Increase the serum concentration
Leading to increase in life threatening
cardiotoxicity

Q&A
Q.1 Name enzyme family which play major role in phase I
oxidative process of drug metabolism?
Q.2 Give one example of drug interaction due to enzyme
induction.
Q.3 Identify pharmacokinetic parameter responsible for
cardiotoxicity of terfenadine after co-administration with
erythromycin.
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Onset of drug interaction
• It may be from --> seconds up to weeks
• In case of enzyme induction
it needs weeks for protein synthesis.
• while enzyme inhibition --> occurs rapidly.

Renal excretion:
 Active tubular secretion:
 It occurs in the proximal tubules.
 The drug combines with a specific
protein
pass through the proximal tubules.

Renal excretion:
 When one drug --> has a competitive reactivity to the protein
reduce excretion of drug transported through protein
Increases its conc. and toxicity.
 Ex. Probenecid --> Decreases tubular secretion of methotrexate.
EX.,

Passive tubular reabsorption;
• Reabsorption of drugs occur in the tubules
by passive diffusion
which is regulated by concentration and lipid solubility.

 Ionized drugs are --> reabsorbed lower than non-ionized
• Ex1. Sod bicarbonate
Increases lithium clearance --> decreases its action
Increases salicylates clearance --> and decreases its action
• Ex2. Antacids

Reference:
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Q&A
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Pharma Learning

A. Define pharmacodynamic drug
interaction.
B. Explain mechanism of different types
of pharmacodynamic drug interaction.
8

• Alteration of the dug action --> without change in its serum
concentration by pharmacokinetic. F
•a
• Ex. Propranolol + Verapamil
Synergistic or additive effect
Pharmacodynamic Interaction

• Additive effect: 1 (A) + 1(B) =2
• Synergistic effect: 1 (A) + 1(B) > 2
• Potentiation effect: 1 (A) + 0(B) =2
• Antagonism: 1(A) - 1 (B)= 0
Effects of Pharmacodynamic Drug Interaction

Types of Pharmacodynamic Drug Interaction
1. Drug having exactly opposite pharmacological effect
2. Drug having similar pharmacological effect
3. Alteration of electrolyte level
4. Interaction involving adrenergic system
5. Alteration of receptor site interaction
6. Alteration of GI flora
7. Antibiotic combination

3. Alteration of electrolyte level
• Treatment with diuretics result in
depletion of electrolytes
Hypokalemia, Hyponatremia
Modify the effect of drugs

• Digitalis Glycosides diuretics:
• Thiazide diuretics like ethacrynic acid and
furosemide
Hypokalemia
Causes arrhythmia when digitalis preparations are
combined with diuretics
• The patient is advised --> to take potassium rich

• Lithium carbonate- Diuretics:
Diuretics
Deficiency of Sodium
Reduces the renal clearance &
increases the toxicity of lithium

Q&A
Q.1 What is synergistic effect?
Q.2 Enlist different types of Pharmacodynamic
drug interaction?
Q.3 Give mechanism and consequence of drug
interaction between digitalis glycoside and
diuretics.
5

4. Interaction involving adrenergic system:
a. MAO Inhibitors-Sympathomimetic agents:
• MAO --> causes breakdown of catecholamine
MAO inhibitors --> prevent breakdown
Result in increase in level of NE within adrenergic neurons.

a. MAO Inhibitors-Sympathomimetic agents:
• MAO inhibitors like pergyline, phenelzine & tranylcypromine +
sympathetic amine like amphetamine
Produces severe hypertensive crisis (Headache, hypertension & cardiac
arrhythmias)
Such combinations is contraindicated in patient with CV diseases

b. MAO Inhibitors – Tyramine- Chees Reaction
• Certain food Ex. Chocolate, yeast extract, chicken liver, cheeses & alcoholic
beverage
Contain pressor amine tyramine --> which is metabolized by MAO
MAO inhibitor --> Large amount of tyramine is accumulated
Severe Hypertensive crisis

5. Alteration of receptor site interaction:
a. Warfarin-Dextrothyroxine:
• Dextrothyroxine
Enhances the effect of warfarin
by increasing the affinity of the warfarin
for the receptor site.

5. Alteration of receptor site interaction:
• Anablic steroids Ex.
methandrostenolone
Increases affinity of
anticoagulants for the receptor
site
Increases the activity of warfarin.

6. Alteration of GI Flora
1. Anticoagulant-Antibiotics:
• Broad spectrum antibiotics like
tetracycline, chloramphenicol
Reduces/ Inhibit intestinal bacterial
flora
Reduction of vitamin K synthesis (Co-
Factor - for coagulation)
Result in increase in anticoagulant
effect

Reference:
52

Q&A
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4

Pharma Learning

A. Discuss Pharmacodynamic drug
interaction due to antibiotic
combination.
B. Explain drug-food Interaction.
6

7.Antibiotic combination:
Antagonism:
- Bacteriostatic + Bactericidal agent
- Bactericidal drugs --> inhibit cell wall synthesis and exert lethal effect ex. Penicillin
- Bacteriostatic drugs --> stop cell wall multiplication that does not lead to cell death
ex. Tetracycline
IF given concurrently --> the penicillin derivative cannot exert bactericidal effect.

b. Antibiotic combinations used to benefit:
1. Synergism:
• Treatment of enterococcal endocarditis
• Ex. use of ampicillin and penicillin along with aminoglycoside
antibiotics such as streptomycin.

b. Antibiotic combinations used to benefit:
• Prevention of resistance:
• Use of two or three antitubercular agents
prevent development of resistant strain.

 Broad range of activity:
• Sulfamethoxazole and trimethoprim
blocks a different step in biosynthesis of nucleic acid & protein
Essential for many bacteria.

 Types of Drug interaction
1. Drug- drug interaction
2. Drug - food interaction
3. Drug - alcohol interaction
4. Drug - smoke interaction
5. Drug - laboratory test interaction
6. Drug - environmental contaminants

1. Drug-Drug interaction:
- Prescription drug (Rx) +
- Over the counter products (OTC)

Q&A
Q.1 Give example of drug interaction with anti-
biotic combination that leads to antagonistic
effect.
Q.2 What is benefit of combination therapy of
anti-tubercular drug?
Q.3 Which antibiotic combination has synergistic
effect and use for the treatment of enterococcal
3

2. Drug food interaction:
• Presence of food in git --> modify absorption pattern of
certain drugs
• Drug transit rate --> reduced by presence of food.

Ex.
1. Tyramine containing food and
MAOI
2. Milk and tetracycline
3. Deviation from low salt diet by the
patient taking digitalis
May result in partial antagonism of
digitalis

• Many penicillin/ tetracyclin ---> given preferably 1hr before
or 2 hr after meals.
optimum absorption

• Ingestion of fatty meal
causes significant increase in the absorption of griseofulvin.
• Pyridoxine --> present in most of muti-vitamine preparation
Antagonizes the effect of levodopa.

• Diet may also influence urine pH:
• Excretion of drugs like amphetamine
less in alkalinized urine (pH 7.5) as compared to acidic pH.
• Some protein diet --> contain amino acid which may change the pH.
• Role of Pharmacist:
Patient should be notify by the community /hospital pharmacist --> foods to be avoided.

Reference:
69

Q&A
https://forms.gle/zRjbPB2mjtQEbRoBA
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1

Pharma Learning

A. Discuss drug-alcohol, drug-smoking,
drug-laboratory test, drug-
environmental contaminant interaction.
B. Explain management of drug
Interaction.
3

3. Drugs alcohol Interactions:
• Heavy drinking
Speed up metabolism of drugs ex. Warfarin, Phenytoin.
• Acute use of alcohol by non alcoholic patients
may cause inhibition of hepatic enzymes.

3. Drugs alcohol Interactions:
• Concurrent use of alcoholic beverage
with sedatives & other depressant
drugs
result in excessive depressant response.

• Very High doses --> cross tolerance occurs between alcohol and
other CNS depressants.
• Major problem arises
when psychological tolerance to alcohol develops at a faster rate than
the physiological tolerance.

4. Drug-smoke Interaction:
• Smoking increases the activity of drug
metabolizing enzymes
ex. Activity of chlordiazepoxide &
diazepam (CNS depression) was less in
heavy smokers

5. Drug laboratory test interaction:
• Drugs interfere with lab tests in a no.
of ways:
1. Colorimetric analysis
Spectrum overlapping may give more
optical density

2. Due to pharmacological action of drug
It may affect the normal physiological
level of the substances being measured.

3. Chemical reactions of drugs with
enzymes or reagents
May result in unexpected clinical test
values
Wrong diagnosis or interpretation of
result.

Q&A
Q.1 What happens to metabolism of drugs with
heavy drinking?
Q.2 What is consequence of Concurrent use of
alcoholic beverage with sedatives?
Q.3 Give one example of Drug-smoke Interaction?
1

6. Drugs Environmental Contaminants:
 Patients contact with solvent
vapors, industrial fumes or other
items that are inhaled
Altered reaction to drug therapy

6. Drugs Environmental Contaminants:
 Pesticides like DDT
increase the formation of hepatic enzymes
increase metabolism of cortisol in the human
body.
 Individuals whose jobs necessitate intensive
exposure to environmental chemicals- Should
be observe more closely.

Management of an adverse interaction
 Dose related events --> managed by changing the dose of the affected
drug.
Ex. when miconazole oral gel causes an increase in bleeding time of warfarin
reduces the dose of warfarin
Bring the bleeding time back into range
 Note: It is important to re-titrate the dose of warfarin --> when the
course of miconazole is complete.

 The potentially sever interaction
require immediate Cessation of the
combination.
Ex. The combination of erythromycin and
terfenadine
Produce high terfenadine level with the
risk of developing Torsade's de Pointes.

 Dose spacing --> appropriate for interaction involving inhibition
of absorption in the GI tract.
Ex. Avoiding the binding of ciprofloxacin by ferrous salts

Reference:
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Drug interactionPharmacokinetic and Pharmacodynamic drug interaction| Drug-food| Drug-alcohol | Drug-cigarette Smoking Interaction

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