A presentation on:

Drug Interaction

Made by: Gauri Deshmukh .

Enrollment no: 172280820017
Guided by: Dr. Manish Patel
Dr. Praful Bharadiya

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 Contents
• Introduction to drug interaction
• The effect of protein binding interaction
• Cytochrome p450 based drug interaction

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• Drug interaction is a condition in which a substance alters the activity of
another drug when both are concurrently administered.
• This altered action can be synergistic (action of the drug is elevated) or
antagonistic (action of the drug is decreased).
• There are different types of interactions between drugs and other
substances such as food, dietary supplements, herbs, alcohol, tobacco
etc...
• Drug interactions usually occur accidentally or due to lack of knowledge
about the drugs being used.
• In drug interactions the therapeutic efficacy of a drug is altered by
another drug which is simultaneously administered to the patient.
• Certain drug interactions can lead to enhanced toxicity and can affect the
patient psychologically and can be fatal .
• Interactions play a Key role in patients who use drugs which may interact
with biologicals . 3
MECHANISMS OF DRUG INTERACTIONS
• There are several mechanisms through which drugs interact and they
can be divided into two categories:
• pharmacokinetic and pharmacodynamic interactions
1. Pharmacokinetic drug interactions:
a. Drug absorption interactions - Alteration in gastric absorption
b. Drug distribution interactions
c. Drug metabolism interactions - Enzyme induction and Enzyme
inhibition
d. Drug excretion interactions – Alteartion in clearance of the drug
from the body

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2. Pharmacodynamic drug interactions
• Narrow therapeutic index drugs are the major objects for drug interactions.
• Ex: warfarin , fluoroquinolones , antiepileptic drugs, oral contraceptives
• Drug interactions are more to occur in patients suffering with chronic non-
curable illness like diabetes mellitus, hypertension, and in such cases use of
multiple-dose treatment becomes a major cause for drug interactions
• Improper usage of OTC drugs is responsible for lack of adherence and
severe drug interactions leading to adverse effects .
• Alterations in pharmacological variables in elderly patients
• Certain chemical modifiers interact with certain drugs and cause
modification in the chemical structure of the drug and result in adverse drug
reactions

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 PERSON TO PERSON VARIATIONS

Variations from person to person are seen due to several factors like:
• Allergies
• Body mass
• Genes
• Gender
• Physiology
• Pregnancy
• Age
• Lifestyle
• Diseases
• Drug doses
• Combined therapy and
• Administration timing of two substances

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 COMMON DRUG INTERACTIONS

• Drug – Food interactions – Grape juice, Licorice, Chocolate, No

aspirin on empty stomach
• Grapefruit juice inhibits the activity of cytochrome P450 3A4
(CYP3A4) enzymes which is responsible for metabolism of drugs
and toxins
• Drugs – Alcohol interactions
• Tobacco – drug interactions
• Drug – Drug interactions
• Herb – Drug interactions – Ginseng, Licorice, Black cohosh, Green
tea, Kava, Saw palmett, Chinese herbal medicines
• Drug – vitamin supplements - Vitamin E, Iron and calcium pills

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 Dangerous drug interaction
• Antihistamines and Alcohol - Causes severe drowsiness
• Bronchodilators and Alcohol - CNS stimulator
• NSAIDS and Alcohol - exaggerate gastric irritation
• Grape juice and citrus fruits with Drugs - Causes severe adverse
effects
• The Acetaldehyde Syndrome is a very harmful and fatal drug
interaction caused upon the ingestion of alcohol and aldehyde
dehydrogenase inhibitors leading to the toxic accumulation of
aldehyde
• Serum levels of propranolol, an anti hypertensive drug increases
with the intake of high protein diet.
• Corticosteroids along with NSAIDS increase the chances of gastric
ulcers.
• Corticosteroids along with antidiabetics reduce the efficacy of
antidiabetic drugs. 8
 Protein binding
• Many drugs interact with plasma or tissue proteins or
with other macromolecules, such as melanin and
DNA, to form a drug–macromolecule complex.
• The formation of a drug protein complex is often
named drug–protein binding.
• Drug–protein binding may be a reversible or an
irreversible process.
• Irreversible drug–protein binding is usually a
result of chemical activation of the drug, which then
attaches strongly to the protein or macromolecule by
covalent chemical bonding.
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• Irreversible drug binding accounts for certain types
of drug toxicity that may occur over a long time
period.
• For example, the hepatotoxicity of high doses of
acetaminophen is due to the formation of reactive
metabolite intermediates that interact with liver
proteins
• Reversible drug–protein binding implies that the
drug binds the protein with weaker chemical bonds,
such as hydrogen bonds or van der Waals forces.
• Most drugs bind or complex with proteins by a
reversible process. The amino acids that compose the
protein chain have hydroxyl, carboxyl, or other sites
available for reversible drug interactions. 10
• Reversible drug–protein binding is of major interest
in pharmacokinetics.
• The protein-bound drug is a large complex that
cannot easily transverse cell or possibly even
capillary membranes and therefore has a restricted
distribution
• The protein-bound drug is usually pharmacologically
inactive. In contrast, the free or unbound drug crosses
cell membranes and is therapeutically active.

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 Protein binding of drug
• Drugs may bind to various macromolecular components in the
blood, including albumin, Globulin, α1-acid glycoprotein,
lipoproteins, immunoglobulins (IgG), and erythrocytes (RBC).
1. Albumin is a protein with a molecular weight of 65,000–69,000
Da that is synthesized in the liver and is the major component of
plasma proteins responsible for reversible drug binding.
• In the body, albumin is distributed in the plasma and in the
extracellular fluids of skin, muscle, and various other tissues.
• Interstitial fluid albumin concentration is about 60% of that in
the plasma.
• The elimination half-life of albumin is 17–18 days.
• Normally, albumin concentration is maintained at a relatively
constant level of 3.5–5.5% (weight per volume) or 4.5 mg/dL.
• Albumin is responsible for maintaining the osmotic pressure of
the blood and for the transport of endogenous and exogenous
substances. 12
Cont….
• As a transport protein for endogenous substances, albumin
complexes with free fatty acids (FFAs), bilirubin, various
hormones (such as cortisone, aldosterone, and thyroxine),
tryptophan, and other compounds.
• Many weak acidic (anionic) drugs bind to albumin by
electrostatic and hydrophobic bonds.
• Weak acidic drugs such as salicylates, phenylbutazone, and
penicillins are highly bound to albumin. However, the strength
of the drug binding is different for each drug.

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2. α - Acid glycoprotein (orosomucoid) is a globulin with a molecular
weight of about 44,000 Da.
• The plasma concentration of α -acid glycoprotein is low (0.4–1%)
and binds primarily basic (cationic) drugs such as propranolol,
imipramine, and lidocaine.Globulins (α, β, γ globulins) may be
responsible for the plasma transport of certain endogenous
substances such as corticosteroids.
• These globulins have a low capacity but high affinity for the binding
of these endogenous substances.

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 Determinants of Protein Binding

Drug–protein binding is influenced by a number of important factors,

including the following:
1. The drug
• Physicochemical properties of the drug
• Total concentration of the drug in the body
2. The protein
• Quantity of protein available for drug–protein binding
• Quality or physicochemical nature of the protein synthesized
3. The affinity between drug and protein
4. Drug interactions

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 Cytochrome p450
• Cytochrome P450 (CYP) enzymes form a gene superfamily that are
involved in the metabolism of a variety of chemically diverse
substances ranging from endogenous compounds to xenobiotics,
including drugs, carcinogens, and environmental pollutants.

• It is well known that several of the CYP genes are induced by many
drugs. This may cause variability in enzymatic activity, with
different groups of patients producing unexpected pharmacological
outcomes of some drugs as a result of drug-drug interactions .

• For example, induction of CYP3A has been shown to result in a

significant loss of efficacy for the contraceptive steroids

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• P450 enzymes can be found throughout the body, particularly at
interfaces, such as the intestine, nasal epithelia, and skin. The liver
and the intestinal epithelia are the predominant sites for P450-
mediated drug elimination and are also the sites worth considering
in most detail with respect to drug-drug interaction

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 Cytochrome p450 classification
• In man there are around 30 CYP enzymes which are responsible for
drug metabolism and these belong to families 1–4.
• It has been estimated that 90% of drug oxidation can be
attributed to six main enzymes: CYP 1A2, 2C9, 2C19, 2D6, 2E1
and 3A4 .
• The most significant CYP isoenzymes in terms of quantity are
CYP3A4 and CYP2D6.
• CYP3A4 is found not only in the liver but also in the gut wall,
where it may serve as a primary defence mechanism. The bulk of
drugs acting on the CNS with the exception of volatile anaesthetic
agents, are metabolized by this enzyme.

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Mechanism of pharmacokinetic drug-drug interaction

1. Inhibition
• Inhibition is reduced enzyme activity due to direct interaction
with a drug. This process usually begins with the first dose of the
inhibitor, and the start and finish of inhibition correlate with the
half-lives of the drugs involved .
• There are three basic types of enzyme inhibition (competitive,
non-competitive and uncompetitive), and clinical effects are
influenced by these basic mechanisms

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• The first type is competitive inhibition between inhibitor and substrate
for the same binding site on an enzyme. 
• For example, when single oral doses of metoprolol (50 mg), a beta-
adrenoceptor blocking agent and/or propafenone (150 mg) were
administered, or when the two drugs were given in combination to
healthy subjects, an approximately two-fold reduction in the oral
clearance of metoprolol was observed when propafenone was
included. The dose of metoprolol should be reduced when propafenone
is also given .
• Similar drug-drug interactions are seen in the combined administration
of thioridazine and propranolol (CYP2D6) , fluoxetine and desipramine
(CYP2D6) , omeprazole and diazepam (CYP2C19) , tolbutamide and
phenytoin (CYP2C9) , and diltiazem and cyclosporin (CYP3A) .

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• The most typical example of the second type of drug-drug
interaction includes that of terfenadine and erythromycin .
• The combined use of these drug, terfenadine, and macrolides
(antibiotics) or ketoconazole prolongs electrocardiographic QT
intervals, thereby triggering a specific cardiac dysrhythmia known
as torsades de pointes’ .

• In non-competitive inhibition, the inhibitor binds at a site on the

enzyme distinct from the substrate, as happens in classical studies of
enzymology.
• Such examples include interactions between cimetidine and a
number of drugs. The duration of this type of inhibition may be
longer if new enzymes are synthesized after the inhibitor drug is
discontinued. Cimetidine is bound to P450 and produces a stable
cytochrome-substrate complex. It is the formation of this complex
which prevents access of other drugs to the P450 system.
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2. Induction
• The effect of induction is simply to increase the amount of P450
present and speed up the oxidation and clearance of a drug .
• It is rather difficult to predict the time-course of enzyme induction
because of several factors, including the drug half-life and enzyme
turnover, which determine the time-course of induction. A
complicating factor is that the time-course of induction depends on
the time required for enzyme degradation and new enzyme
production.

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• The short half-life of rifampicin results in enzyme induction
(CYP3A4, CYP2C), apparent within 24 h, whereas phenobarbital,
which has a half-life of 3–5 days, requires about1 week for
induction (CYP3A4, CYP1A2, CYP2C) to become apparent.
• These enzyme-induction reactions also occur with smoking and
long-term alcohol or drug consumption and can reduce the duration
of action of a drug by increasing its metabolic elimination

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 Clinical examples of cyt p450 based
interaction
• Cyclosporin is the most popular immunosupressant used in
organ transplantation. The major pathway of cyclosporin
metabolism is via CYP3A4 , with three major metabolites being
formed . Since cyclosporin is mainly used as an immunosuppressant
for organ transplantation, the CYP3A4 level in the donor's liver as
well as the recipient's liver, small intestine and other tissues must
always be taken into consideration.
 For example, Lucey et al. reported that a 40-year-old male liver
allograft recipient had neurological dysfunction and renal failure
while his cyclosporin blood levels were in the therapeutic range.
 CYP3A activity, using the [14C] erythromycin breath test, was
reduced compared with that in controls, including other liver
transplant recipients.

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 Pretreatment with rifampicin, an inducer of CYP3A, increased
enzyme activity. After treatment with rifampicin the patient was
able to be rechallenged with cyclosporin at a dose almost twice
that which had previously been toxic.
 The patient died during a second transplantation and the microsomal
CYP3A content was found to be low in the first transplant liver.
Lower blood levels of cyclosporin may have been achieved when
the drug used for enzyme induction (rifampicin) has been given
to the transplant patient for a long period

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• Rifampicin and isoniazid are key drugs used in the treatment of
tuberculosis, while rifampicin is highly effective in inducing
hepatic, drug metabolic P450 enzyme.
• When enzyme induction is achieved, the pharmacological effects of
a specific drug may be reduced, since not only the metabolism of
rifampicin itself, but also the metabolism of the other drug is
accelerated .
• The problem arises when doses are increased to reduce the effects
of the combined drugs: increased serum concentrations of the
combined drugs may possibly produce side-effects because of the
lost enzyme induction if rifampicin is discontinued.
• Rifampicin is also known to induce CYP3A4 and CYP2C9 (e.g.
cyclosporin, diazepam and steroids). As for dihydropyridine calcium
channel blockers, it is quite possible that interactions with
rifampicin may develop, since most of these drugs are metabolized
by CYP3A4
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References
• Papers:
1. Research and Reviews: Journal of Pharmacy and Pharmaceutical
Sciences , “Drug Interactions – Causes & Implications” Pratibha
Muntha*(RRJPPS | Volume 2 | Issue 3 | Oct – Dec, 2013)
2. Bibi, Zakia. “Role of Cytochrome P450 in Drug
Interactions.” Nutrition & Metabolism 5 (2008): 27. PMC. Web. 3
Apr. 2018.
Book:
• Drug-Drug Interactions (Second Edition) by A. David Rodrigues

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THANK YOU

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