DRUG

INTERACTIONS
DR.OMER A.A.S. RIKABY
BSc Pharmacy
MSc Clinical Pharmacy
MBA
 Learning objectives
1 3 5
. .
General Principles
Introduction of Pharmacodynamic Other interactions
Interactions

2 4

General Principles
interactions of Pharmacokinetic
classification Interactions
 1-INTRODUCTION

A drug interaction occurs when a patient’s response to a drug is

modified by food, nutritional supplements, formulation
excipients, environmental factors, other drugs or disease.
Definition: A drug interaction is defined as a measurable
modification of the action of one drug by prior or concomitant
administration of another substance (including prescription and
nonprescription drugs, food, or alcohol) •

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 2-INTRODUCTION

May be harmful: toxicity, reduced efficacy

May be beneficial: synergistic combinations reduced toxicity reduction .

Drug interactions may result in antagonism or synergism.

Antagonism: means that the action of one drug is opposite to other drug action.

E.g: histamine and adrenaline on bronchi ( physiological non competitive antagonism)

Or the two drugs may compete for the same drug receptor like Morphine and Naloxone.

(Competitive antagonism)

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Synergism: two types
summation and potentiation

In summation 1+1=2

while in potentiation 1+1=3 ??(one drug increases the action of another drug like :

Trimeyhoprime {bacteriostatis} + Sulphonamide { bacteriostatis} = bactericidal

E.g for summation synergism bethanidine + a thiazide diuretic. They have additive
effects to each other.
3-INTRODUCTION
◦ Chances increase interaction
1. More number of drugs.
2. Patient with multiple diseases
3. Patient treated by multiple doctors
4. Patients with diminished physiologic
reserve (geriatric, neonate, HIV,
malnourished,)

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 2-Interactions classification
we focus our attention to the classification
of interactions by pharmacologic
mechanism.
These interactions are classified as
pharmacodynamic or pharmacokinetic in
character.

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3-General Principles of
Pharmacodynamic Interactions
 4-General Principles of
Pharmacodynamic Interactions
Pharmacodynamic drug interactions result in
an alteration of the biochemical or
physiological effects of a drug.

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 Pharmacodynamic drug interactions
Pharmacodynamic drug interactions can be either
beneficial or harmful to the patient. In general, drug
interactions of this type can be divided into four classes:
1. Interactions at the drug receptor (pharmacological).
2. Interactions via different cellular mechanisms acting in
concert or in opposition
3. Interactions due to alterations of the cellular
environment.
4. Chemical neutralization in the body
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 1-Interactions at the drug receptor (pharmacologica
antagonist at the level of the receptor: albuterol (a β-agonist used for
asthma) and timolol (a β-blocker used for hypertension and glaucoma).

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2-Interactions via different cellular
mechanisms acting with or opposite
(physiological).
An example of a beneficial effect is the use of β-
receptor agonists with methylxanthines (theophylline) to
relax bronchiolar smooth muscle
in contrast, an example of a harmful interaction is the
effect of amino-glycoside antibiotics to potentiate the
blockade of skeletal muscle (particularly respiratory) by
the neuromuscular blocking agents.

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3-Interactions due to alterations
of the cellular environment
Perhaps the best example of this mechanism is
the interaction between drugs that cause
potassium depletion and cardiac glycosides.
Several drugs, including diuretics can produce
hypokalemia, and thereby increase susceptibility
to digitalis toxicity

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 4-Chemical neutralization in
the body
A desirable interaction of this type is the use of protamine to
neutralize heparin.

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4-General Principles of
Pharmacokinetic Interactions
5-General Principles of
Pharmacokinetic Interactions
1. Drugs Interacting at Sites of Absorption
2. Drug Interactions Affecting Distribution
3. Drug Interactions that Alter Metabolism
4. Drug Interactions Affecting Excretion

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1. Drugs Interacting at Sites of
Absorption
1. Drugs Interacting at Sites of Absorption

The rate of absorption determines how fast drug enters

the blood and the peak concentrations obtained.

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2-Interactions affecting extent of absorption
Extent of absorption affects the total amount available
systemically.
A decreased extent of absorption can result in a substantial
decrease in circulating serum concentrations of a drug,
thereby compromising therapy.
An increase in absorption, though unusual, could subject the
patient to drug toxicity.

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Types of Interactions
Formation of drug complexes due to absorption; chelation, or
binding Interactions
1-Before Administration: Phenytoin precipitates in dextrose
solutions (e.g. D5W
2- In the GI Tract Sucralfate, some milk products, antacids, and
oral iron preparations block absorption of quinolones, tetracycline,
and azithromycin, thyroid hormone, and digoxin
3-Alterations in gastric pH Omeprazole, lansoprazole, H2-
antagonists can reduce absorption of ketoconazole, can reduce
ketoconazole absorption

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2.Drugs Interacting at Sites of
Distribution
 2. Drug Interactions Affecting
Distribution
Several drugs and disease states can alter serum protein binding
and, thus, shift the equilibrium and the amount of free drug in the
serum.
Phenylbutazone displaces warfarin from binding sites on serum
proteins thus increasing the likelihood of bleeding.
Patients may also be more susceptible to interactions involving
protein binding, since several disease states decrease available
binding sites. In patients with hypoalbuminemia, there is a decrease
in binding of phenytoin, furosemide, and digitoxin.

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3.Drugs Interacting at Sites of
Metabolism
 3. Drug Interactions that Alter
Metabolism
Phase I reactions include oxidation or reduction mostly by hepatic
microsomal cytochrome P450.
Phase II reactions "conjugate" a water soluble entity such as
acetate, sulfate or glucuronate onto the drug at the newly created.
forming a more polar and water soluble metabolite that can be
more easily excreted in the urine and/or bile.

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Cytochrome P450 1A2
include: theophylline
Inhibited by: cimetidine
Induced by: smoking tobacco
Cytochrome P450 2B6 Proportion of Metabolism
Substrates include: methadone
Induced by: phenobarbital, rifampcin

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Cytochrome P450 2C8
Drugs: rosiglitazone
Inhibited by: candesartan, clotrimazole, felodipine

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Cytochrome P450 2D6
Note: Responsible for the second largest number of
substrates.
Substrates include: metoprolol, timolol, amitriptylline,
Inhibited by:, chlorpheniramine

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Cytochrome P450 3A4
CYP3A metabolizes the largest number of drugs and is present
in the largest amount in the liver.
Substrates include: atorvastatin
Inhibited by: itraconazole
Induced by: carbamazepine

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3.Drugs Interacting at Sites of
Exeretion
4. Drug Interactions Affecting
Excretion
Filtration Many drugs are eliminated by
1- glomerular filtration;
particularly important are the aminoglycoside
antibiotics and digoxin. Theoretically, changes in
glomerular filtration rate (GFR) could importantly
affect handling of these and a host of other drugs.

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b. Active Secretion
The kidney is capable of secreting a number of drugs. Active
secretion of a variety of agents occurs in proximal tubule.
There appear to be two non-specific transport systems, one
for organic acids and one for bases, in which secreted drugs
can compete for transport with another drug within the
same group.
An additional important secretory pathway is that for
digoxin, which appears to be located in the distal tubule.

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c. Reabsorption
Reabsorption of drugs in the distal tubule and
collecting duct is related to urinary flow rate and
pH.
Carbonic anhydrase inhibitors or bicarbonate
administration causes an alkaline urine,
while ammonium chloride, potassium depletion
from diuretics, etc., induce acid urine.

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5-Other interactions
1-Drug-disease interactions

These include interactions between certain drugs

and specific disease states such as severe liver and
renal disease.
Although liver disease can diminish clearance of
some drugs, the capacity is relatively spared until
hepatic function is severely compromised.

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1-Drug-disease interactions
The effects of renal disease on elimination of
drugs that are primarily cleared renally are more
predictable and can be adjusted accordingly
usually based on a calculated creatinine
clearance.
Heart failure reduces liver blood flow and causes
a reduction in clearance for a small number of
drugs.

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2-Drug-food and drug-supplement interactions
The best characterized are those between
tetracycline and calcium containing foods,
warfarin and vitamin K containing foods and
grapefruit juice and drugs metabolized in the gut.

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