druginteraction-120821041601-phpapp02.ppt

Defination
• It is the modification of the effect of one drug (the object
drug ) by the prior concomitant administration of
another (precipitant drug).
• Concomitant use of several drug in presence of another
drug is often necessory for achiving a set of goal or in the
case when the patient is suffering from more than one
disease.
• In these cases chance of drug interction coud increase.

content
• Defination
• Epidemiology
• Risk factor
• Out come of interaction
• Mechanism of interaction
a. pharmacokinetic
b. pharmacodynemic
• Case study
• Reference

Epidemiology
• In harvard medical practice study of adverse event 8%
were consider to be due to drug interaction.
• US community pharmacy study revealed 4.1 % incidence
of drug interaction in hospitalised patient.
• Australian study found that 4.4% of all ADR , which
resulted in hospital due to interaction.

Risk factors
• Poly pharmacy
• Multiple prescribers
• Multiple pharmacies
• Genetic make up
• Specific population like e.g,
females , elderly, obese, malnouresed , criticaly ill patient ,
trasplant recipient
• Specific illness E.g. Hepatic disease,
Renal dysfunction,
• Narrow therapeutic index drugs
Cyclosporine, Digoxin, Insulin, Lithium ,
Antidepressant, Warfarin

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

Mechanisms of drug interactions
Pharmacokinetics Pharmacodynamics
Pharmacokinetics involve the effect of a drug on another drug
kinetic that includes absorption ,distribution , metabolism
and excretion.
Pharmacodynamics are related to the pharmacological
activity of the interacting drugs
E.g., synergism , antagonism, altered cellular transport effect
on the receptor site.

Pharmacokinetic interactions
1) Altered GIT absorption.
•Altered pH
•Altered bacterial flora
• formation of drug chelates or complexes
• drug induced mucosal damage
• altered GIT motility.
a) Altered pH;
The non-ionized form of a drug is more lipid
soluble and more readily absorbed from GIT than the
ionized form does.

Ex1., antiacids Decrease the tablet
dissolution
of Ketoconazole (acidic)
Ex2., H2 antagonists
Therefore, these drugs must be separated by at least 2h
in the time of administration of both .

b) Altered intestinal bacterial flora ;
EX., 40% or more of the administered digoxin dose is
metabolised 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+
) Unabsorpable complex
Ex2., Antacid (aluminum or magnesium) hydroxide
Decrease absorption of
ciprofloxacin by 85%
due to chelation

d) Drug-induced mucosal damage.
Antineoplastic agents e.g., cyclophosphamide
vincristine
procarbazine
Inhibit absorption
of several drugs
eg., digoxin
e) Altered motility
Metoclopramide (antiemitic)
Increase absorption of cyclosporine due
to the increase of stomach empting 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

g) Altered metabolism
The effect of one drug on the metabolism of the
other is well documented. The liver is the major site of drug
metabolism but other organs can also do e.g., WBC,skin,lung,
and GIT.
CYP450 family is the major metabolizing enzyme
in phase I (oxidation process).
Therefore, the effect of drugs on the rate of metabolism
of others can involve the following examples.

E.g., Enzyme induction
A drug may induce the enzyme that is responsible
for the metabolism of another drug or even itself e.g.,
Carbamazepine (antiepileptic drug ) increases its own
Metabolism.
Phenytoin increases hepatic metabolism of theophylline
Leading to decrease its level Reduces its action
and
Vice versa
N.B enzyme induction involves protein synthesis .Therefore,
it needs time up to 3 weeks to reach a maximal effect

Eg., Enzyme inhibition;
 It is the decrease of the rate of metabolism of a drug by
another one .
 This will lead to the increase of the concentration of the
target drug and leading to the increase of its toxicity .
Inhibition of the enzyme may be due to the competition
on its binding sites , so the onset of action is short
may be within 24h.
When an enzyme inducer ( e.g. carbamazepine) is
administered with an inhibitor (verapamil)
The effect of the
inhibitor will be
predominant

Ex.,Erythromycin inhibit metabolism of astemazole and terfenadine
Increase the serum conc.
of the antihistaminic leading to
increasing the life threatening
cardiotoxicity
EX., Omeprazole
Inhibits oxidative
metabolism
of diazepam

•Onset of drug interaction
It may be seconds up to weeks for example in case
of enzyme induction, it needs weeks for protein synthesis,
while enzyme inhibition occurs rapidly.
The onset of action of a drug may be affected by the half
lives of the drugs
e.g., cimitidine inhibits metabolism of theophylline.
Cimitidine has a long half life, while, theophylline has a
short one.
When cimitidine is administered to a patient regimen for
Theophylline, interaction takes place in one day.

First-pass metabolism:
Oral administration increases the chance for liver
and GIT metabolism of drugs leading to the loss of a
part of the drug dose decreasing its action. This is
more clear when such drug is an enzyme inducer
or inhibitor.
EX., Rifampin lowers serum con. of verapamil level by
increase its first pass . Also, Rifampin induces the
hepatic metabolism of verapamil

Renal excretion:
•Active tubular secretion
 It occurs in the proximal tubules.
The drug combines with a specific protein to pass through
the proximal tubules.
When a drug has a competitive reactivity to the protein that is
responsible for active transport of another drug .This will reduce
such a drug excretion increasing its con. and hence its toxicity.
EX., Probenecid ….. Decreases tubular secretion of
methotrexate.

* Passive tubular reabsorption;
Excretion and 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 ones
Ex1., Sod.bicarb. Increases lithium clearance
and decreases its action
Ex2., Antacids Increases salicylates
clearance and decreases its
action

It means alteration of the dug action without change in its
serum concentration by pharmacokinetic factors.
EX., Propranolol + verapamil Synergistic or additive
effect
Pharmacodynemic interaction
Additive effect : 1 + 1 =2
Synergistic effect : 1 +1 > 2
Potentiation effect : 1 + 0 =2
Antagonism : 1-1 = 0

Pharmacodynamic interactions
• Receptor interaction
– Competitive
– Non-competitive
• Sensitivity of receptor
– Number of receptor
– Affinity of receptor
• Alter neurotransmitter release /drug transportation
• Alter water/electrolyte balance

Drug-Food interactions
• Grapefruit juice and Terfenadine
• Grapefruit juice and cyclosporin
• Grapefruit juice and felodipine
• Grapefruit contains : furanocoumarin compounds that
can selectively inhibit CYP3A4

Pharmacogenetics
Pharmacogenetics
Pharmacogenomics
Pharmacogenomics
Pharmacology + Genetics/Genomics
• The study of how individual’s genetic inheritance aff
ects the body’s response to drugs (efficacy & toxicity)
• The use of genetic content of humans for drug discov
ery

Variations in drug response and drug toxi
city may result from
Variation in drug transp
orters
• P-glycoprotien
Variation in disease mo
difying genes
• Apolipoprotein (APOE)
Variation in drug
metabolizing enzym
es
• Cytochromes P450
• Thiopurine S-methyltr
ansferase
Variation in drug target
s
•Beta2-adrenergic rece
ptor

 Changes in the
DNA sequence
such as
–Nucleotide
mutation
•The most
frequent
DNA
variation
found in the
human
genome is
single
nucleotide
DNA polymorphism
DNA polymorphism

Common genetic polymorphism of human
Common genetic polymorphism of human
drug metabolizing enzymes
drug metabolizing enzymes
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Management of an adverse interaction
 Dose related events may be managed by changing the
dose of the affected medicine.
• Eg.,when miconazole oral gel causes an increase in
bleeding time of warfarin then redusing the warfarin dose
will bring the bleeding time back into range and reduse the
risk of haemorrhage
• It is important to retitrate the dose of warfarin when the
course of miconazole is coumplete.

 The potential severity of some interaction require immediate
Cessation of the combination.
• Eg,.the combination of erythromycin and terfenadine can
produse high terfenadine level with the risk of developing Torsel
de Points.
 Dose spacing is appropriate for interction involving the
inhibition of absorption in the GI tract .
• Eg.,avoidig the binding of ceprofloxacin by ferous salts

Case study
• Aim : Evaluation of p’kinetic drug
interaction
 The proposal of the study was approved by the ethical
committee of the shaheed beheshti medical university.
 At first questionnaries was designed for collecting data.
 First part of the questionnaries contain demographic data
of patients including sex and age.
 In the second part there was a table for writing all drugs
prescribed including drug name, dosage form, dosage
amount, rout of administration and timing of the
administration.

Continue….
• A total number of 116 patients of ICU ward were visited
during the study and one questionnaire was filled for each
visit.
• Data for total number of 567 prescriptions were recorded.
The extent of occurrence and frequency of potential
pharmacokinetic drug interactions were investigated based
on the reference text Drug Interaction Facts published in
the year 2004.

Continue…..
• All of the potential pharmacokinetic drug interactions were
extracted and classified in terms of mechanism,
significance, onset, severity .
• Onset shows how rapidly the clinical effects of interaction
can occur. This determines the urgency with which
preventive measures should be instituted to avoid the
consequences of the interaction.

Severity of interactions is classified in 3 categories:

Result
• A total number of 116 patients were enrolled the study
with the mean age of 46(± 7) years. 65 (%56.03) patients
were male and 51 (%43.97) were female.
• From 567 prescriptions, 413 pharmacokinetic interactions
were identified. . Four of the most common types have
shown respectively in table 1.

Table 1. The most common pharmacokinetic interactions in
the studied ICU prescriptions
No. Interaction between Number in 413
cases of
interactions
Percentage in 413
cases of
interactions
1 Ciprofloxacin- Sucralfate 137 33.17
2 Ciprofloxacin-
Magnesium sulfate
22 5.32
3 Digoxin- Metoclopramide 17 4.11
4 Theophylline- Rifampin 16 3.87

• Among the mechanisms of pharmacokinetic interactions, the
most dominant type was metabolic interaction with a total
percentage of %60.05.
• Table 2. Distribution of different mechanisms of the pharma-
cokinetic interactions
Mechanism Total number percentage
Metabolism 248 60.05
Absorption 158 38.26
Elimination 4 0.97
distribution 3 0.72

Table 3. Categories of drug interactions
Interaction type Number of interaction Percentage
Onset
Delayed 251 61%
Rapid 162 39%
Severity
Major 72 17.43%
Moderate 335 73.61%
Minor 0 0%
Unknown 37 8.96%
Documentation
Establised 102 24.7%
Probable 166 39.95%
Suspected 109 26.39%
Unknown 37 8.96%
Significance
1 72 17.43%
2 335 73.61%
Unknown 37 8.96%

discussion
• Whenever a patient receives multiple drug therapy, the
possibility of a pharmacokinetic interaction exists.
• This study shows the most prevalent pharmacokinetic
interactions in ICU may be metabolic and those related to
absorption alterations (about %98.31).
• Interaction between ciprofloxacin and sucralfate, an
absorption type, was the most prevalent one .
• In the ICU, nurses usually determine timing of drug
administration.

Continue…
• Study showed the higher the number of drugs in
prescriptions, the higher the number of interactions.
Therefore, polypharmacy should be avoided as much as
possible .

Reference :
• Text book of Clinical pharmacy by Parth sarthi.
• K.D.Tripathi
• Iranian journal of p’ceutical research .page 215-218,2006
by school of pharmacy shahid baneshti university of
medical science and health services.

druginteraction-120821041601-phpapp02.ppt

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