Al-Azhar University ‫جامعة االزهر‬

Faculty of Pharmacy (Boys) ‫(كلية الصيدلة )بنين‬

Cairo ‫القاهرة‬

RESEARCH PROJECT
Department: Clinical Pharmacy
Academic year: 2019/2020
Course name: ‫صيدلة مستشفيات‬
Course code: PCP 322
Lecturers: Dr/Mohamed akl

Dr/Mohamed fathy
Research project title: Drug-drug interaction.

STUDENT INFORMATION
Student Name: ‫أحمد محمد ابراهيم عبد السميع‬
Student Number: 2018026
e-mail: [email protected]
Mobile number: 01120444261

STUDENT INFORMATION
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Al-Azhar University ‫جامعة االزهر‬
Faculty of Pharmacy (Boys) ‫(كلية الصيدلة )بنين‬
Cairo ‫القاهرة‬

Content

Topic Page No.

Introduction 1

Definition 2

Altered drug absorption 2-3

Altered distribution 4

Altered metabolism 5-6

First - pass metabolism 6

Altered renal excretion 6-7

Summary 8

References 9
Introduction
Two or more drugs administered simultaneously or in close sequence may operate
independently, interact to increase or decrease the intended / unintended effect of one
or both drugs, or cause a new and unexpected reaction.

The probability of interaction increases with the number of drugs used. The high
prevalence of prescription drugs in elderly patients (65-year-olds take an average of 5
drugs) increases the likelihood of drug reactions and therefore the risk of drug-induced
hospitalization. Interactions between drugs occur:

1-When two or more drugs react together. This drug interaction can cause you to
experience an unforeseen side effect. For example, mixing a drug that you are taking
to help you sleep (a sedative) and a drug that you are taking to treat allergies (an
antihistamine) can slow down your reactions and make driving a car or operating
machinery dangerous.

2 – The product of drugs that respond with food or drink. For example, mixing alcohol
with a few drugs can make you feel tired or slow down.

3-May occur when an existing medical condition can potentially cause harm to certain
drugs. For example, if you have high blood pressure, you may experience an
unexpected reaction if you take a nasal decongestant.

Over the counter (OTC) product labels contain material that is essential for reading
and understanding of ingredients, uses, warnings and instructions. The label also
contains important information on possible drug interactions. In addition, when new
information becomes known, the labels of drugs may change. That's why it's
particularly important to read the label every time you use a drug.

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Research Project
Definition: Drug interactions may be defined as: the modification of the effects of
one drug (object drug) by the prior or concomitant administration of another drug
(precipitant drug).

CoAdverse drug interactions may cause a loss of therapeutic effect, toxicity, or

unexpected increase in pharmacological activity. Knowledge of drug interactions may
allow for early prevention of adverse reactions.

This can be improved by implementing knowledge of the mechanisms of drug

interactions with the recognition of high-risk patients and the identification of drugs
with a fewer side effects. Drug interaction mechanism This may be either
pharmacokinetic or pharmacodynamics.

Pharmacokinetic interactions The effects of one drug on the drug are linked to the
pharmacological kinetics of ADME of another drug Pharmacodynamics drug
interactions The interactions are linked with Synergism, antagonism, concentration,
where changes in cellular transport and effects on changes in plasma monitoring of
serum drug levels may occur at receptor sites. Provide potential report aims to analyze
on useful Pharmacokinetic interactions These are interactions that cause changes in
the kinetics of the object drug, including absorption, distribution, metabolism, and
excretion(1).

1- Altered drug absorption:

This may be due to a variety of mechanisms: altered pH, altered bacterial flora, drug
complexation, drug-induced mucosal damage and altered gastrointestinal motility.
Drug interactions resulting from altered drug absorption usually require both drugs to
be present in the stomach; therefore, separating the dosing times of the two drugs by 2
2
hours will often prevent these interactions (dose spacing). These interactions are
significant in the case of drugs with a narrow therapeutic index and/or short half-life.

 Altered pH: Antacids that increase the pH of the stomach may delay the
absorption of certain drugs, Example: Aluminum-magnesium hydroxide
may decrease the absorption of ciprofloxacin and should be administered
6 hours before or 2 hours after the antibiotic dose to avoid this effect.
 b. Altered bacterial flora: Antibiotics may decrease the bacterial flora of
the GIT. Example: About 40% The oral dose of digoxin is metabolized
by the bacterial flora, erythromycin, by decreasing the bacterial flora,
allowing more digoxin to be absorbed, which may lead to digoxin
toxicity.
 c. Drug complexion: Some drugs may form poorly absorbed complexes
with other drugs or food Example: Tetracycline forms an insoluble,
poorly absorbed chelate containing iron and calcium salts. Sucralfate also
reduces the absorption of ciprofloxacin and norfloxacin.
 d. Drug caused mucosal damage: drugs that cause damage to the GI
mucosa can reduce the absorption of some drugs. Example:
Chemotherapeutic agents (cyclophosphamide, vincristine) reduce
Increased GI motility can result in decreased drug absorption of some
digoxin preparation.
 e. Altered gastrointestinal motility: Increasing the GI motility may result
in a decreased drug absorption by reducing the time that an orally
administered drug is in contact with the absorbing surface in the small
intestine. Example: Metcolopramide(2).

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Research Project
2- Altered distribution:
A lot of drugs are reversibly bound to plasma proteins. Concurrent administration of
more than one drug bound to the plasma protein fraction may displace either agent
from its binding site, increasing the free concentration of the drug. The drug with the
highest affinity to the binding site will displace the drug with the lowest affinity.
Bound drugs are pharmacologically inactive and are also not available for metabolism
or excretion. The total plasma concentration of a drug is the sum of the bound form
and the free form (unbound).

When the drug is released from plasma proteins, the increase in the free drug
concentration is temporary as it becomes available for metabolism. The balance
between the free drug in circulation and the bound drug is maintained and, as the drug
is metabolized and excreted, the agent is transferred from its protein binding site.
Highly bound drugs have a small amount of distribution.

Clinically important contacts may result from protein displacement if they are
accompanied by inhibition of the enzyme or if the drug has a small Vd, a narrow
therapeutic index and a rapid onset of action.

Examples: Highly protein bound drugs include phenytoin (90%), tolbutamide (96%)
and warfarin (99%). The metabolite of chloral hydrate, trichloroacetic acid, displaces
warfarin from its protein binding site, thus increasing the effect of warfarin on
hypoprothrombinemia. This effect is slight and transient because the level of free
warfarin returns to the intensity that existed prior to the interaction.

4
Phenylbutazone displaces warfarin from plasma proteins and also prevents the
metabolism of more potent warfarin enantiomorph, increasing the anticoagulant
response to warfarin(3).

3- Altered metabolism:
Concurrent administration of one drug to another may result in an increase or decrease
in the metabolic rate. Modifications may affect both drugs in water-soluble
metabolites that are more easily excreted.

Drug metabolism may be categorized into two kinds, phase I, which includes
hydroxylation, oxidation and reduction, and phase II, which includes glucuronide,
glycine and sulfate conjugation.

a. Increased metabolism (enzyme induction): this mechanism is the result of increased

drug production-metabolized enzymes and involves phase I metabolism. This
interaction has a slow onset and may take up to 3 weeks before the overall limit is
observed. The precipitant drug induces enzymes that enhance the metabolism of the
drug. A few drugs like carbamazepine increase their metabolism. The induction
process of the enzyme is reversed when the precipitant drug is discontinued, but the
reversal process is slower than the onset. Examples: Phenytoin helps to increase the
hepatic metabolism of mexiletine, resulting in a decrease in steady-state plasma
mexiletine levels and a decrease in efficacy. Theophylline and phenytoin increase
each other's metabolism. Other drugs that induce hepatic enzymes include
barbiturates, carbamazepine, Griseofulvin, and rifampicin.

b. Decreased metabolism (inhibition of the enzyme): this mechanism involves direct

competition between precipitant and object drugs for binding sites to the enzyme;
therefore, the occurrence of interactions is faster than with induction of the enzyme,

5
where the overall limit is reached within 24 hours. Drug interactions involving
inhibition of the enzyme are intensified when the drug object reaches a steady-state
plasma level. When the metabolism of the drug object is inhibited, a new steady-state
serum level is associated after 5 half-lives. However, the inhibitory effect of the
precipitant drug on the metabolism of the drug object is no more than 3 half-lives.
Plasma concentrations of the object drug will decrease when the precipitant drug is
discontinued. The time of reversal of this reaction depends on the half-life of the drug
object and usually takes 24 hours. Examples: Omeprazole inhibits the oxidative
metabolism of diazepam resulting in higher serum levels. Isoniazid inhibits the
hepatic metabolism of phenytoin. Other drugs that inhibit metabolic enzymes include
allopurinol, cimetidine, erythromycin and metronidazole(4).

First - pass metabolism:

Some drugs are extensively metabolized in the wall of the GIT and the liver, thus the
drugs that increase or decrease hepatic blood flow will significantly impact the
bioavailability of the drug. Examples: Rifampicin lowers the serum verapamil levels
by increasing the first passing effect of verapamil, and rifampicin also induces the
hepatic microsomal metabolism enzymes of verapamil(5).

4- Altered renal excretion:

Renal excretion of one drug may be raised or lowered by co-administration of another
drug. Most lipid-soluble drugs are metabolized by the liver to inactive, water-soluble
metabolites before renal excretion. The mechanisms involved in these interactions
shall include:

6
a. Competition for active tubular secretion: for a drug that passes from systemic
circulation to tubular lumen, the drug is transported by combination with protein.

Since each protein has a certain affinity to anion or cation, drugs that use a similar
transport system appear to interact through competitive inhibition of transport
proteins.

Saturation of the transport system by precipitant drug may decrease the secretion of
the object drug by the tube.

Examples: Probencid impairs the tubular secretion of methotrexate, where its serum
levels have been reported to increase from three to four-fold during the concomitant
administration of probencid. Quinidine reduces the renal and biliary clearance of
digoxin by 30 to 40%.

b. PH-dependent passive tubular reabsorption: Drug excretion and reabsorption

usually occurs through passive diffusion, where non-ionized drug molecules are
preferably reabsorbed over ionized drugs. Strongly acidic and basic drugs tend to be
ionized at urinary pH (5 to 8), while the degree of ionization of weak acids and bases
varies with the pH of the urine. As a result, an increased amount of weakly acidic
drugs will be absorbed into the body from acidic urine, while basic drugs will be
excreted. The opposite is true of the basic urine.

Examples: Sodium bicarbonate increases lithium renal clearance. Chronic antacid

therapy with a combination of magnesium and aluminum hydroxide helps to increase
the salicylate approval resulting in a 30 to 70% decrease in serum salicylate levels(6).

7
Summary
A change in the effect of a drug on the body when a drug and a second one are taken
together.

Interaction between drugs may delay, decrease or improve the absorption of either
drug. This may reduce or increase the action of either the drug or both, or may cause
adverse effects.

Drug interactions could have life-threatening consequences Implications for older

people who may take several drugs at once.

Elderly people consume a disproportionate proportion of prescription and over-the-

counter drugs compared to young people.

These factors, combined with moderate changes in pharmacokinetic and

pharmacodynamic parameters, make the elderly more susceptible to drug interactions.
Therefore, when elderly people receive medicinal therapy, it should be absolutely
critical to attain well-defined objectives and to be administered at the lowest possible
dose levels.

8
References

(1) Rao, K. Krishna. "Clinical Drug Interactions." J Indian Medical (2015):

42-44.
(2) Cascorbi, Ingolf. "Drug interactions—principles, examples and clinical
consequences." Deutsches Ärzteblatt International 109.33-34 (2012):
546.
(3) https://www.fda.gov/media/76562/download
(4) Zevin, Shoshana, and Neal L. Benowitz. "Drug interactions with tobacco
smoking." Clinical pharmacokinetics 36.6 (1999): 425-438.
(5) Cascorbi, Ingolf. "Drug interactions—principles, examples and clinical
consequences." Deutsches Ärzteblatt International 109.33-34 (2012):
546.
(6) Bailey, David G., et al. "Grapefruit juice–drug interactions." British
journal of clinical pharmacology 46.2 (1998): 101-110.
(7) Hospital pharmacy Lecturer Notes of Faculty of Pharmacy Al Azhar
University of Cairo.