Drug interaction

DRUG INTERACTIONS
Dr. Zarrin Ansari
First Year Resident
Department of Pharmacology
LTMMC & GH
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Table of Content
 Definition & Concepts
 Epidemiology
 Risk factors
 Causes of unwanted drug effect
 Classification of Drug Interaction (DI)
 Drug-Drug Interaction
Behavioral DI
Pharmaceutical DI
Pharmacokinetic DI
Pharmacodynamic DI
 Interactions involving Drug Transport Protein
 Interaction involving Therapeutic Proteins
 Food Drug Interaction
 Herb Drug Interaction
 Drug-Disease Interaction
 Drug interaction Management
 COVID 19 & DDIs

What is Drug Interaction?
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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
Ben D Snyder, Thomas M Polasek & Mathew P Doogue. Drug Interactions: Principles & Practices. Aust Prescr 2012;35
Unanticipated, Unrecognized/Mismanaged drug interactions
Contributes to preventable morbidity and mortality
Mongthuong Tran & Joseph A Grillo. Translation of Drug Interaction Knowledge to Actionable Labeling. Clin Pharmacol Ther. 2019; 105: 1292-1295

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Lets see some numbers (Epidemiology)
Drug Interactions are estimated to represent 3-5%
of preventable in-hospital adverse reactions
Patrick J McDonnell & Michael R Jacobs. Hospital admissions resulting from preventable adverse drug reactions Ann. Pharmacotherapy. 2002; 36: 1331-1336
A retrospective study reported 26% of total hospital
admissions directly due to adverse drug reaction
involved a Drug Interaction

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Risk Factors for Drug Interactions
LARS BJERRUM, BEATRIZ GONZALEZ LOPEZ-VALCARCEL & GERT PETERSE. Risk factors for potential drug interactions in general practice
European Journal of General Practice. 2008; 14: 23 29
Polypharmacy

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High number of prescribers per patient

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Drug Interactions- Principles, Examples and Clinical Consequences. Ingolf Cascorbi. Dtsch Arztebl Int. 2021; 109: 546-56
Increasing Age
An average 65 years old is on five drugs simultaneously
Prescription peaks in the 75-84 years age group
Potential interactions can arise at any age in life, but the
frequency of polypharmacy in older life increases the risk
substantially

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Causes of unwanted drug effects and interactions
Wrong choice of drug
Failing to take account into renal & hepatic function
Wrong dosage
Wrong route of administration
Errors in taking the drug
Transmission Errors

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Classification of Drug Interactions?
 Drug – Drug Interaction
 Food – Drug Interaction
 Drug – Disease Interaction
Classifying Drug Interaction. J.K Aronson. Br J Clin Pharmacol. 2004; 58: 342-3
Rabia Bushra, Nousheen Aslam & Arshad Yar Khan. Food-drug Interaction. Oman Medical Journal. 2011; 26: 77-83
 Drug – Herb Interaction

Behavioral Drug
Interaction
Pharmaceutic Drug
Interaction
Pharmacokinetic
Drug Interaction
Pharmacodynamic
Drug interaction
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Drug-Drug Interactions

One drug alters the patient’s behavior to modify
compliance with another drug. For example, a
depressed patient taking an antidepressant may
become more compliant with medication as
symptoms improve
Behavioral Drug Interaction
Arch Intern Med 2005;165:2497-503.
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Pharmaceutic Drug Interaction
The formulation of one drug is altered by another
before it is administered.
Leads to precipitation or inactivation of active
principles
For e.g.
 Precipitation of sodium thiopentone and
vecuronium within an intravenous giving set
 Ampicillin, Chlorpromazine and barbiturates
interact with dextrans in solutions
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Pharmacodynamic drug–drug interactions occur when
interacting drugs have either additive effects, in which case the
overall effect is increased, or opposing effects, in which case
the overall effect is decreased or even ‘cancelled out’.
Pharmacodynamic Drug Interactions
Pharmacodynamics means what the drug does to the
body
They often seem obvious and predictable based on an understanding
of the mechanisms of action of the interacting agents

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Additive or Synergistic Effects
Ginkgo Biloba (Herbal Memory Enhancer) has property of inhibition
of platelet aggregation.
It is often consumed by Elderly who are on anticoagulants like
Warfarin, thereby increasing the risk of bleeding
Alcohol used with other CNS depressants viz. BZDs can impair
cognition and can be dangerous combination for those who are
performing activities that require attention.

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Antagonistic Effects
(Often happens with Drugs via the same receptors)
Salbutamol (Beta-2 agonist) prescribed for asthma administered
along with non-selective Beta Blockers viz. Propranalol. It works as
an antagonist at both Beta-1 and Beta-2 receptors.
Warfarin has narrow therapeutic index. MOA is by Vitamin K
antagonism. Green leafy vegetables viz. broccoli contain Vitamin K,
thereby antagonizing the effects of Warfarin

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Pharmacodynamic interactions of NSAIDS
NSAIDS increases COX-1 mediated inhibition of Thromboxane
synthesis, thereby increasing the risk of GI bleeding
Ibuprofen reversibly binds to COX-1, which prevents the
acetylsalicyclic acid (ASA) from acetylating the serine residue of the
COX-1 protein.
Irreversible and hence long-lasting inhibition of COX-1 mediated
thrombaxane A2 synthesis by ASA can thus be prevented.
Cardiac risk of patients with CHD can increase.
Long term ibuprofen/ naproxen should be avoided in patients with
CHD and on ASA prophylaxis.

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Pharmacodynamic interactions of NSAIDS (Contd….)
NSAIDS can reduce the blood-pressure lowering effect of ACE
inhibitors.
There is reduction in glomerular perfusion through reduction of
prostaglandin E2 synthesis with corresponding reactive secretion of
renin.
NSAIDS given with SSRIs can increase the risk of GI bleeding. SSRIs
inhibit the transport of serotonin in platelets, leading to further
impairment of function and doubling the risk of bleeding

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Pharmacodynamic interactions of Inhibitors of RAAS
Aldosterone-antagonistic effect of ACE inhibitors and AT1 receptor
antagonists in combination with potassium-sparing diuretics or
specific aldosterone antagonists viz. spironolactone and eplerenone,
induce dangerous hyperkalemia or renal failure.

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Pharmacokinetic Drug Interaction
Pharmacokinetic drug–drug interactions
occur when one drug changes the systemic
concentration of another drug, altering ‘how much’
and for ‘how long’ it is present at the site of action.
•Absorption
A
• Distribution
D
• Metabolism
M
• Excretion
E
Ben D Snyder, Thomas M Polasek & Mathew P Doogue. Drug Interactions: Principles & Practices. Aust Prescr 2012;35:85–8

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Pharmacokinetic Drug Interaction: Absorption
Direct reduction of
absorption
Indirect reduction
of absorption
Chelation
Binding
 Gastric pH
 GI motility
Transport
protein
PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION
DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5

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Chelation
A chelator is an organic chemical that bonds with and
removes free metal ions from solution.
Typically the molecule being chelated will be a
divalent cations e.g. Ca+2, Mg+2, Fe+2
Tetracycline, which is chelated by calcium.
Absorption inhibited. Antibacterial activity inhibited
Ciprofloxacin absorption decreased by 50-70% when
given within 2 hours of aluminum hydroxide or
calcium carbonate tablets

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PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
Binding
Drugs may bind other drugs, though rare.
E.g. Cholestyramine lowers cholesterol by binding to negatively
charged bile acids in the gut.
It binds to other negatively charged drugs in the gut (thiazide
diuretics, digitalis preparations, beta-blockers, coumarin
anticoagulants, thyroid hormones, fibric acid derivatives and
certain oral antihyperglycaemia agents)
Phenytoin absorption is decreased by sucralfate due to binding in
the GI lumen.
J A Farmer & A M Gotto Jr. Antihyperlipidaemic agents. Drug interactions of clinical significance. Drug Saf. 1994 Nov;11(5):301-9.

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Gastric pH
Some drugs require acidic medium for their
dissolution. Drugs that increase gastric pH reduce the
absorption of these agents
E.g. Atazanavir and azoles (Ketoconazole and
Itraconazole) require an acidic environment for
adequate absorption. These should be administered
2 hours before or 1 hour after antacids

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Gastro Intestinal Motility
Both food and drug can alter the GI motility,
enhancing or inhibiting the absorption of other
agents
Small intestine, large surface area, key area for drug
absorption. Anticholinergics decrease GI motility,
may decrease the rate of absorption by delaying
gastric emptying. Slowing rate of absorption may
have an impact on drugs that are required to work
quickly viz. analgesics

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PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION. DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
Gastro Intestinal Motility (Contd…)
Metoclopramide (prokinetic) increases the rate of
drug transport through the gut, thereby increasing
the rate of absorption of certain drugs
E.g. Despite no change in cyclosporine elimination,
the AUC and Cmax increased by 22% and 46%
respectively, when it was given with metoclopramide
to 14 kidney transplant patients
N K Wadhwa, T J Schroeder, E O'Flaherty, A J Pesce, S A Myre, M R First. The effect of oral metoclopramide on the absorption of cyclosporine.
Transplant Proc 1987; 19: 1730-3

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Pharmacokinetic Drug Interaction: Distribution
Only the unbound portion of a drug crosses cell membranes
and is able to exert a pharmacological effect.
Drugs compete with each other for binding to plasma
proteins.
If a given drug, drug A, displaces drug B from its binding site,
this will increase the amount of drug B that is unbound and
free to exert pharmacological effect.

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Displacement from plasma proteins plays a minimal role in
drug interactions.
Couple of theoretical reasons why its not expected to see
displacement from plasma proteins causing major problems
in clinical settings.
 Free drug is also free to be metabolized and/or excreted
from the body
 Free drug distributes very rapidly into tissues, quickly
reducing plasma levels.
Distribution (Contd…)

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Distribution (Contd…)
Warfarin is bound extensively to plasma albumin (>97%).
Warfarin may be displaced by acidic compounds that are also
highly bound to albumin, such as, valproic acid, resulting in
transient increases in free warfarin and increases in INR.
As free warfarin increases, so does its elimination from the
body, thus resulting effect is often transient.

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Pharmacokinetic Drug Interaction: Metabolism
Metabolism
Phase I Phase II
CYP Enzyme Family
 Hydrolysis
 Oxidation
 Reduction
Conjugation by
 Glucuronidation
 Sulfation
 Methylation
 Acetylation
 Glycine conjugation

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Cytochrome P-450 Enzyme
 CYP 450 enzymes are categorized according to a number-
letter-number system (e.g., CYP3A4)
 There are at least 40 CYP 450 enzymes
 The most common & relevant isozymes are 3A4, 2D6, 2C9,
2C19 and 1A2
 Clinically significant drug interaction occur from either
induction or inhibition of these enzymes

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Enzyme Inhibition
Inhibition of a CYP 450 enzyme will result in increased levels of
substrate (drug) that is metabolized by the enzyme
Reversible Irreversible
Enzymatic activity is regained
by the systemic elimination of
inhibitor.
 Competitive
 Non-Competitive
 Uncompetitive
It occurs when either a parent
compound or a metabolic
intermediate binds to the reduced
ferrous heme portion of P450
enzyme, thereby inactivating it.
 Irreversible
 Quasi-irreversible

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Reversible Enzyme Inhibition
Competitive
Inhibition
Non-competitive
(Allosteric) Inhibition
It is characterized by competition
between substrate & inhibitor for
the enzymes active site.
Competition for enzyme binding
site can be overcome by increasing
the conc. of substrate, thereby
sustaining the velocity of enzymatic
reactions despite presence of
inhibitor
A drug inhibits an enzyme that it itself
is not metabolized by. This inhibition
occurs at an allosteric site (not where
the substrate binds). This inhibition
cannot be overcome by increased
substrate concentration.
Uncompetitive
Inhibition
Inhibitor binds to
enzyme-substrate
complex. Rare in
clinical scenario.

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Irreversible Enzyme Inhibition
Irreversible
Inhibition
Quasi-irreversible
Inhibition
Also called as “suicidal inhibition”. The intermediate forms a covalent bond with
CYP protein or its heme component, causing permanent inactivation.
In quasi irreversible, the intermediate forms a very tight bond with the CYP
protein, it is practically irreversible. These are indistinguishable in clinical practice.
Also called as “time-based” or “mechanism based” inhibition, the time to
metabolic recovery depends upon the synthesis of the new enzyme, rather than
dissociation and elimination of the inhibitor.
E.g. Macrolides viz. erythromycin & clarithromycin and HIV protease inhibitor

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Categories of Enzyme Inhibitors
Based on their potency of their inhibition of CYP450 enzymes
Strong Inhibitors: Increase the AUC of a sensitive substrate
in vivo by ≥ 5-folds
Moderate inhibitors: Increase AUC of a sensitive substrate
by ≥ 2 folds but < 5 fold.
Weak inhibitor: Increase in AUC of a sensitive substrate by
≥ 1.25 fold but < 2 fold

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Enzyme Induction
An inducer stimulates increased production of CYP 450 enzyme.
These effect can be seen in days but often takes 2 to 3 weeks to
be established.
If the drug is inactivated by that enzyme for the purpose of
excretion, an inducer will result in reducing circulating levels of
active drug.
This will reduce biologic activity of the drug, perhaps leading to
therapeutic failure.
Chapter 4. Applied Pharmacology. Stan K Berdal, Jason E. Waechter, Douglas S. Martin

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Enzyme Induction
A patient is stable on drug A and drug B. Drug B induces the
metabolism of drug A.
The dose of drug A was increased to accommodate the effects
of the enzyme inducer.
On stopping drug B, the dose of drug A should be reduced in
order to avoid toxicity due to increased plasma level of drug A

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Mixed Inhibitors and Inducers
Significant increases in the concentration of a co-
administered substrate may be apparent in the first few days
of concomitant dosing,
followed by relative decrease in substrate exposure as
induction of metabolizing enzymes kicks in and overcomes
the inhibitory effect.
e.g. Ritonavir at high doses

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Prodrugs (Exception to this rule)
Prodrugs require metabolic enzymes for transformation to
an active metabolite
An enzyme inhibitor would lead to a reduction in levels of
active drug, in turn reducing the biologic activity of the
drug.
An enzyme inducer would lead to more activation to the
active drug, leading to exaggerated effect.

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Other Metabolic Interactions
Drugs that interfere with enterohepatic (EH) circulation will
potentially reduce the activity of any drug that undergoes
this process.
Bacteria in the gut play an imp role in the hydrolysis of
glucoronides. Antibiotics (broad spectrum) kill these
bacteria, interfere with the EH circulation.
E.g. Drug levels of OC pills are interfered due to antibiotics
as OC pills depends upon the gut bacteria for EH circulation

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Other Metabolic Interactions
Wine-cheese reaction
MAOIs (previously used as anti-depressants)
MAO breaks down norepinephrine, dopamine, serotonin
and tyramine.
When patient on MAOIs consume cheese or wine (rich in
tyramine), they would often experience a sudden and
dangerous increase in blood pressure, sometimes leading to
stroke or even death.

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Pharmacokinetic Drug Interaction: Excretion
A drug can affect excretion of another drug in various ways:
 Filtration-by altering plasma protein binding
 Secretion-By inhibiting tubular secretion
 By altering reabsorption
 By altering urine pH

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Filtration
Drugs that are bound to plasma proteins cannot be
filtered and excreted by the kidney.
Displacement of a drug will therefore facilitate its
filtration & subsequent excretion
This forms a very minor role in drug interaction

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Secretion
Drugs are secreted into the renal tubules, leading to their
excretion.
One drug may inhibit the secretion of another, hence
reducing its rate of excretion in urine
This DDI can be beneficial in some cases
Probenecid inhibits the renal tubular secretion of penicillin.
This prolongs the stay of penicillin in the body. Thus, longer
interval can be allowed between doses

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Reabsorption
Reabsorption of one drug can be enhanced by another.
E.g. Diuretics work by enhancing Na+ excretion. As a
compensation for this fluid reduction in fluid volume,
kidney reabsorbs Na+. Differentiation between Na+ and
Lithium by the kidneys is poor.
Thus, patients who are on Lithium and are volume depleted
or lacking Na+ will retain both Na+ and Lithium.
Lithium is toxic to the kidneys

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Urinary pH
Changes in the urine pH alter the ionization of weakly acidic
and basic drugs, thereby affecting the degree of passive
diffusion.
Since most weakly acidic and basic drugs are metabolized to
inactive compounds prior to renal excretion, changes in
urinary pH do not affect the excretion of most drugs.
Acidic compounds viz. phenobarbital and aspirin. Their
serum levels decreases on concurrent administration of
antacids or sodium bicarbonate. This has formed toxicology
principle for poisoning.

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Interactions Involving Drug Transport Proteins
Membrane Transporters
ATP Binding Cassette
(ABC)
Solute Carrier
(SLC)
 P-glycoprotein (P-gp)
 Breast Cancer Resistance
Protein (BCRP)
 Multidrug Resistance
Proteins (MRPs)
 Organic Anion Transporting
Polypeptides (OATPs)
 Organic Cation Transporter
(OCTs)
 Organic Anion Transporters
(OATs)

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P-glycoprotein (P-gp)
 Location: Canalicular surface of hepatocytes, apical surface
of renal tubular epithelial cells, apical surface of intestinal
and placental cells, luminal surface of the capillary
endothelial cells at the BBB, on lymphocytes.
 Frequently involved in absorption, distribution, metabolism
and excretion
 P-gp functions to limit systemic drug exposure, excreting
drug into the intestinal lumen, into the renal tubules, into
bile. P-gp also limits drug exposure to brain and
lymphocytes by extrusion.

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P-glycoprotein (P-gp) Inhibition
 Mechanism for inhibition involve competition of its drug
binding site and blockade of ATP hydrolysis that is necessary
for its transport function
 Administration of quinidine with P-gp substrate loperamide
was found to produce respiratory depression, despite no
change in plasma conc. of loperamide.
 Quinidine inhibits P-gp at the BBB, resulting in greater
penetration of loperamide in the CNS leading to neurotoxicity
without any change in plasma levels.
 Considerable overlap of DDIs between CYP3A4 and P-gp

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P-glycoprotein (P-gp) Inhibition (Research Implications)
 P-gp inhibition used to optimize pharmacotherapy with
anticancers and antivirals
 P-gp blockade to enhance chemotherapy uptake by cancer
cells expressing P-gp mediated drug resistance.
 To improve bioavailability, to increase exposure to tumors
protected by BBB
 P-gp inhibitors used to improve protease inhibitors uptake into
T lymphocytes in HIV patients

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P-glycoprotein (P-gp) Induction
 P-gp induction can happen at various sites viz. gut, liver, kidney
 Induction of P-gp leads reduced systemic conc. of the substrate
medication
 Similar to inhibition, considerable overlap occurs between P-gp
and CYP3A4 inducers viz. phenytoin, phenobarbital, rifampin,
dexamethasone, St. John’s wort etc.
 Induction of intestinal P-gp has been shown to reduce the
bioavailability of P-gp substrates.
 When given IV, digoxin PK was not altered in the presence of
rifampin. However, when given orally along with rifampin,
rifampin induction of P-gp resulted in reduction of AUC and
Cmax by 31% and 52% of digoxin

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Organic Anion Transporting Polypetides (OATPs)
 OATPs present in multiple organ system, but clinically relevant
DDIs occur primarily in the liver
 OATPs substrates include bile acids, thyroid hormones,
conjugated steroids, anionic peptides, xenobiotics like statins,
valsartan, repaglinide and fexofenadine.
 E.g. 1) Inhibition of OATP by cyclosporine increases AUC of
rosuvastatin, pravastatin and pitavastatin.
2) Lopinavir-ritonavir increases rosuvastatin AUC by 107%
3) Grapefruit, apple and orange juice inhibits OATPs thereby
60-80% reduction of bioavailability of fexofenadine

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Organic Cation Transporters (OCTs)
 Expressed in basolateral membrane of epithelial cells in the
kidney, liver & intestine.
 Transports hydrophilic, low molecular weight organic cations.
 Cimetidine is a inhibitor of OCT & associated with reduced
clearance of concomitant medications viz. metformin, pindolol
and dofetilide.
 This interaction doesn’t work in isolation and several other
mechanisms operate simultaneously.

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Organic Anion Transporters (OATs)
 Expressed in basolateral membrane of epithelial cells in the
kidney, liver, brain and placenta.
 Transports zidovudine, cephalosporin, tetracycline,
salicyclates, cidofovir, cephradine, acyclovir, tenofovir,
furosemide, methotrexate, NSAIDs, histamine receptor
antagonist, prostaglandins, ACEIs etc.
 Probenecid inhibits OATs. Cidofovir, furosemide & acyclovir
clearance value were decreased by 32%, 66% & 32% by
concurrent probenecid administration.
 Probenecid protects against cidofovir mediated nephrotoxicity
by limiting its OAT mediated renal transport
 Other inhibitors include pravastatin, cimetdine, cephalosporin,
thiazides, loop diuretics, acetazolamide etc.

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Multidrug Resistance Protein (MRPs)
 Widely distributed in human tissues. MRPs have ability to confer
multidrug resistance to anticancer compounds.
 MRP is localized in the basolateral membrane of epithelial cells
in intestine, liver, brain, lung, peripheral blood mononuclear
cells, choroid plexus, kidney, testes, brain, placenta &
oropharynx
 Transports antineoplastic drugs, heavy metals, difloxacin,
grepafloxacin, leukotrines, prostaglandins, HIV protease
inhibitors, cidofovir, etoposide, mitoxantrone, valsartan
 Inhibited by atazanavir, lopinavir, ritonavir, cidofovir, adefovir,
saquinavir, lamivudin, tenofovir, nevirapine, efavirenz, abacavir,
delavirdine, probenecid, cyclosporine, furosemide.

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Breast Cancer Resistance Protein (BCRP)
 It was so named because it was initially cloned from a
multidrug-resistant breast cancer cell line where it was found
to confer resistance to chemotherapeutic agents such as
mitoxantrone and topotecan.
 Similar to P-gp it acts as an efflux protein
 Expressed in mammary cells, testis, placenta, GIT, kidney,
liver, brain
 Substrates: Mitoxantrone, methotrexate, topotecan, imatinib,
statin

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Interactions Involving Therapeutic Proteins
 Exogenously administered immunologic proteins viz. IFNs & ILs
may result in changes in metabolic capacity of liver (Simulating
acute infection or inflammation)
 Cytokines can suppress gene transcription resulting in
downregulation of P450 enzymes

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Food-Drug Interactions
Drug-food interaction is defined as alteration of PK or PD of a
drug or a nutritional element or a compromise in nutritional
status as a result of the addition of a drug.
 Majority of clinically relevant food-drug interactions are
caused by food-induced changes in bioavailability
• Alteration in absorption by fatty, high protein & fiber diets
• Chelation with components of food (commonest)
• Physiological increase in gastric acidity in response to food
intake may reduce or increase bioavailability of certain drugs
Food & Drug Interaction: Consequences for Nutrition/Health Status. Dieter Genser. Ann Nutr Metab. 2008; 52: 29-32

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Types of Food-Drug Interaction
Type Description
Type I Interaction between the drug & nutritional element or
formulation through biochemical or physical reactions viz.
hydrolysis, oxidation, neutralization or precipitation
Type II These affect absorption causing either increase & decrease in
bioavailability. Modification of enzymatic function, transport
mechanism, complexation or binding occurs.
Type III These affect the systemic or the physiological disposition.
Changes of the cellular or tissue distribution, systemic
transport, penetration of the specific tissues can occur
Type IV These affect the elimination. Involve antagonism, impairment
or modulation of renal and/or enterohepatic circulation
Food & Drug Interaction: Consequences for Nutrition/Health Status. Dieter Genser. Ann Nutr Metab. 2008; 52: 29-32

Agents Affecting Alimentary Tract and Metabolism
 Synthetic Prostaglandin analogue misoprostol with meal
 Antiemetic Ondansetron administered with meal
 Oral antidiabetic agent troglitazone with meal
 Warfarin and Vitamin-K rich food interaction. Vitamin K rich
food like broccoli, cabbage, liver and certain dietary
supplements.
 Calcium Channel Antagonists
Nifedipine with meal
Felodipine and grapefruit juice
Lars E Schmidt & Kim Dalhoff. Food-Drug Interaction. Drug 2002; 62 (10): 1481-1502

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Agents Affecting Cardiovascular System
 Cardiac Glycosides and Antiarrhythmics
Ingestion of high dietary fibre decreases the bioavailability of
digoxin by 32%. This may result in treatment failure requiring
dosage adjustment
 Diuretics
When potassium sparing diuretics are used, a high intake of
potassium rich foodstuff such as bananas and spinach may
result in hyperkalemia.

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Dermatological Agents
 Isotretinoin: Bioavailability increases by 72-86% when
administered shortly after meal.
 Acitretin: Bioavailability with food increases by 91%. Thus,
administration with food preferred.

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Agents Affecting the Nervous System
 Phenytoin: Interindividual variability. Food decreased bioavailability
by 16% - increased bioavailability by 27%. Co-administration with
enteral feeds caused 72% reduction in serum conc.
Co-administration of phenytoin & jejunostomy feed results in 100%
malabsorption of phenytoin.
 Carbamazepine: Food increases bioavailability by 22%. Controlled
release formulation unaffected by food.
 MAOIs: Tyramine rich food…”Cheese reaction”.

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Summary of Food-Drug Interaction
 There is considerable variation in the extent and
clinical relevance of food-drug interaction.
 The most important interactions are those
associated with high risk of treatment failure arising
from a significantly reduced bioavailability in the fed
state (tetracycline, indinavir, bisphonates).
 For several drugs, the PK evidence of food drug
interaction is not accompanied by any major changes
in clinical effect.

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Herb-Drug Interaction
Concurrent use of herbs may mimic, magnify or oppose the effect of
the drugs
Herbal medicines are ubiquitous, there is dearth of reports of ADRs
and interactions (Under-reporting & benign nature of most herbs)
Experimental data on herbs are scare
Thus, true prevalence of herb-drug interaction is substantial but
unknown.
Plausible cases include:
• Bleeding (warfarin + Gingo biloba)
• Serotonin Syndrome (St John’s wort + SSRIs)
• Decreased bioavailability of digoxin, theophylline, cyclosporine
when combined with St. John’s wort
• Risk of HTN (TCAs + Yohimbine)
Adriane Fugh-Berman. Herb-drug interaction. Lancet 2000; 355: 134-38

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Drug-Disease Interaction
Drug-Disease Interaction occurs when a drug prescribed to treat one
condition subsequently exacerbates co-existing chronic conditions.
Clinical Implication from drug-drug and drug-disease interactions in older people. Danijela Gnjidic & Kristina Johnwell. Clinical & Experimental Pharmacology &
Physiology. 2013; 40: 320-325
Drug-disease interactions occur when a disease alters the PKPD of a
drug.
J. K. Aronson. Classifying Drug Interaction. Br J Clin Pharmacol. 2004; 58: 342-

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Drug Interaction Management
1. Improving the drug interaction knowledge of the HCPs
2. Improve computerized drug interaction screening system
3. Provide information on patient risk factors that increase the
chance of an adverse event.
4. Incorporate pharmacogenetic information into risk assessment
5. Provide information on drug administration risk factors that
increase the chance of adverse events. (dose, duration, dosing
time & sequence)
6. Improve patient education on drug interaction
P. D Hansten. Drug Interaction Management. Pharm World Sci 2003; 25(3): 94-97

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Translation of Drug Interaction Knowledge
to Actionable Labelling
1. Drug interaction
2. Clinical Pharmacology
3. Dosage & Administration
4. Contraindications
5. Warnings & Precautions

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Strategies to Enhance Communication of
DI related Information in Drug Labelling
1. Actionable & informative
2. Clear & inclusive of safety & efficacy data
3. Devoid of technical jargons
4. Format should be readable & should ensure clarity
and understandability

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Sciaccaluga C, et al. COVID-19 and the burning issue of drug interaction: never forget the ECG. Postgraduate Medical Journal 2021;97:180-184.
Drug Interaction during COVID Times
1. Scarcity of information
2. Hydroxychloroquine & QT prolongation
3. Lopinavir/Ritonavir & QT prolongation
4. Azithromycin & QT prolongation
5. Lopinavir/Ritonavir augment plasma level of digoxin via
P-gp inhibition
6. IL-6 inhibitor Tocilizumab- minimal effect on QT interval

85
QT Prolongation Management in COVID Times
Sciaccaluga C, et al. COVID-19 and the burning issue of drug interaction: never forget the ECG. Postgraduate Medical Journal 2021;97:180-184.

Drug interaction

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