ϖ Definition & Concepts
ϖ Epidemiology
ϖ Risk factors
ϖ Causes of unwanted drug effect
ϖ Classification of Drug Interaction (DI)
ϖ Drug-Drug Interaction
Behavioral DI
Pharmaceutical DI
Pharmacokinetic DI
Pharmacodynamic DI
ϖ Interactions involving Drug Transport Protein
ϖ Interaction involving Therapeutic Proteins
ϖ Food Drug Interaction
ϖ Herb Drug Interaction
ϖ Drug-Disease Interaction
ϖ Drug interaction Management
COVID-19 & Drug Interaction
2. 2
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
3. What is Drug Interaction?
3
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
4. 4
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
Mongthuong Tran & Joseph A Grillo. Translation of Drug Interaction Knowledge to Actionable Labeling. Clin Pharmacol Ther. 2019; 105: 1292-1295
5. 5
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
6. 6
Risk Factors for Drug Interactions
High number of prescribers per patient
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
7. 7
Risk Factors for Drug Interactions
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
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
8. 8
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
Drug Interactions- Principles, Examples and Clinical Consequences. Ingolf Cascorbi. Dtsch Arztebl Int. 2021; 109: 546-56
9. 9
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
Ben D Snyder, Thomas M Polasek & Mathew P Doogue. Drug Interactions: Principles & Practices. Aust Prescr 2012;3
11. 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.
11
Ben D Snyder, Thomas M Polasek & Mathew P Doogue. Drug Interactions: Principles & Practices. Aust Prescr 2012;3
12. 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
12
Ben D Snyder, Thomas M Polasek & Mathew P Doogue. Drug Interactions: Principles & Practices. Aust Prescr 2012;35
13. 13
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
Ben D Snyder, Thomas M Polasek & Mathew P Doogue. Drug Interactions: Principles & Practices. Aust Prescr 2012;35
14. 14
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.
Drug Interactions- Principles, Examples and Clinical Consequences. Ingolf Cascorbi. Dtsch Arztebl Int. 2021; 109: 546-56
15. 15
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
Drug Interactions- Principles, Examples and Clinical Consequences. Ingolf Cascorbi. Dtsch Arztebl Int. 2021; 109: 546-56
16. 16
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.
Drug Interactions- Principles, Examples and Clinical Consequences. Ingolf Cascorbi. Dtsch Arztebl Int. 2021; 109: 546-56
17. 17
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
Drug Interactions- Principles, Examples and Clinical Consequences. Ingolf Cascorbi. Dtsch Arztebl Int. 2021; 109: 546-56
18. 18
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.
Drug Interactions- Principles, Examples and Clinical Consequences. Ingolf Cascorbi. Dtsch Arztebl Int. 2021; 109: 546-56
20. 20
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
21. 21
Pharmacokinetic Drug Interaction: Absorption
Direct reduction of
absorption
Indirect reduction
of absorption
Chelation
Binding
Gastric pH
GI motility
Transport
protein
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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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PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION
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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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PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION
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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.
28. 28
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
36. 38
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.
PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
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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
PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
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PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
Chapter 4. Applied Pharmacology. Stan K Berdal, Jason E. Waechter, Douglas S. Martin
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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
PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
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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.
PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
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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
PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
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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.
PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
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PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION
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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
47. 49
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
Chapter 4. Applied Pharmacology. Stan K Berdal, Jason E. Waechter, Douglas S. Martin
48. 50
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
Chapter 4. Applied Pharmacology. Stan K Berdal, Jason E. Waechter, Douglas S. Martin
49. 51
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
Chapter 4. Applied Pharmacology. Stan K Berdal, Jason E. Waechter, Douglas S. Martin
50. 52
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.
Chapter 4. Applied Pharmacology. Stan K Berdal, Jason E. Waechter, Douglas S. Martin
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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.
PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
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PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
Chapter 4. Applied Pharmacology. Stan K Berdal, Jason E. Waechter, Douglas S. Martin
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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PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
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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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PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
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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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PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
Chapter 4. Applied Pharmacology. Stan K Berdal, Jason E. Waechter, Douglas S. Martin
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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PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
Chapter 4. Applied Pharmacology. Stan K Berdal, Jason E. Waechter, Douglas S. Martin
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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PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
Chapter 4. Applied Pharmacology. Stan K Berdal, Jason E. Waechter, Douglas S. Martin
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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PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
Chapter 4. Applied Pharmacology. Stan K Berdal, Jason E. Waechter, Douglas S. Martin
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
PRINCIPLES OF CLINICAL PHARMACOLOGY, THIRD EDITION DOI: http://dx.doi.org/10.1016/B978-0-12-385471-1.00015-5
63. 66
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
64. 67
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
65. 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
66. 70
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.
Lars E Schmidt & Kim Dalhoff. Food-Drug Interaction. Drug 2002; 62 (10): 1481-1502
67. 72
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.
Lars E Schmidt & Kim Dalhoff. Food-Drug Interaction. Drug 2002; 62 (10): 1481-1502
68. 75
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”.
Lars E Schmidt & Kim Dalhoff. Food-Drug Interaction. Drug 2002; 62 (10): 1481-1502
69. 76
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.
Lars E Schmidt & Kim Dalhoff. Food-Drug Interaction. Drug 2002; 62 (10): 1481-1502
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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-
72. 79
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
73. 80
Translation of Drug Interaction Knowledge
to Actionable Labelling
1. Drug interaction
2. Clinical Pharmacology
3. Dosage & Administration
4. Contraindications
5. Warnings & Precautions
Mongthuong Tran & Joseph A Grillo. Translation of Drug Interaction Knowledge to Actionable Labeling. Clin Pharmacol Ther. 2019; 105: 1292-1295
74. 81
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
Mongthuong Tran & Joseph A Grillo. Translation of Drug Interaction Knowledge to Actionable Labeling. Clin Pharmacol Ther. 2019; 105: 1292-1295
75. 82
Translation of Drug Interaction Knowledge
to Actionable Labelling
Mongthuong Tran & Joseph A Grillo. Translation of Drug Interaction Knowledge to Actionable Labeling. Clin Pharmacol Ther. 2019; 105: 1292-1295
76. 83
Translation of Drug Interaction Knowledge
to Actionable Labelling
Mongthuong Tran & Joseph A Grillo. Translation of Drug Interaction Knowledge to Actionable Labeling. Clin Pharmacol Ther. 2019; 105: 1292-1295
77. 84
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
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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.
Unclear prescriptions, Inappropriate use of drugs, Improper storage of drugs, Drug expiration date exceeded, Patient error, Miscommunication among health care providers
sodium thiopentone: general anaesthetic
Vecuronium: Adjunct to general anesthesia-induced muscle relaxation for endotracheal intubation, mechanical ventilation
Phenprocoumon is a long-acting oral anticoagulant drug, a derivative of coumarin. It is a vitamin K antagonist that inhibits coagulation by blocking synthesis of coagulation factors II, VII, IX and X. It is used for the prophylaxis and treatment of thromboembolic disorders (thrombosis/pulmonary embolism). It is the standard coumatin used in Germany.
Phenprocoumon is a 4-hydroxycoumarin and inhibits vitamin K epoxide reductase.
Glucocorticoid impairs gastric mucus production, and gastric bicarbonate production thereby leading to gastric ulcers.
Triptans are serotonin receptor agonist.
Alluminium Hydroxide is antacid
Calcium carbonate is dietary supplements sometimes used as antacids for relief of heartburns
Cholestyramine not used currently. Statins used
Check buffered drugs
Atazanavir: Antiretroviral used in HIV AIDS
Alteration of gut motility by atropinic drugs, TCAs, opioids and prokinetic drugs like metoclopramide can also affect drug absorption
The clinical outcome of displacement interactions is generally significant only when displacement extends to tissue binding site as well, or is accompanied by inhibition of metabolism or excretion.
Quinidine has been shown to reduce the binding of digoxin to tissue protein as well as its renal and biliary clearance by inhibiting the efflux transporter P-glycoprotein, resulting in nearly doubling of digoxin blood levels and toxicity.
Based on their hepatic extraction ratio and unbound fraction in plasma or blood, drugs can be categorized as being restrictively or non-restrictively eliminated. The general perception is that drugs with very small plasma clearances and extensive plasma protein binding, such as warfarin, are eliminated restrictively. However, based on literature data for 18 non-steroidal anti-inflammatory drugs (NSAIDs) with low plasma clearances (< 60 ml/min), we have shown that most of these low-extraction compounds are non-restrictively eliminated, i.e. their hepatic extraction ratio exceeds their unbound fraction in plasma. For 4 NSAIDs considered in this survey, i.e. phenylbutazone and the oxicams piroxicam, isoxicam and tenoxicam, the hepatic extraction ratio is smaller than their unbound fraction in plasma, and their hepatic elimination, therefore, is restrictive. Our conclusion that most low-clearance NSAIDs are non-restrictively extracted is based on a number of realistic assumptions concerning their pharmacokinetic characteristics: 1. their elimination is exclusively hepatic, 2. bioavailability of their oral dosage form is complete, and 3. they do not undergo extensive reversible biotransformation or enterohepatic circulation.
Drugs are ca
Drugs are inactivated by glucoronidation in the liver. These glucoronides are delivered to the intestine from the liver via the bile. In the intestine they are hydrolized releasing gthe active drug. Active drugs are reabsorped and this is called entero-hepatic circulations.
A variety of efflux and uptake proteins are involved in clinically relevant DDIs. Membrane transporters are classified in two superfamilies
Increased exposure to digoxin after administration of the P-gp inhibitors viz. verapamil and quinidine.
Accordingly, P-gp inhibitors/blockers are potential enhancer for the cellular bioavailability of several clinically important anticancer drugs such as, anthracyclines, taxanes, vinca alkaloids, and podophyllotoxins.
Some naturally occuring P-gp inhibitors viz., flavonoids, coumarins, terpenoids, alkaloids and saponins.
Some common pharmacological inhibitors of P-glycoprotein include: amiodarone, clarithromycin, ciclosporin, colchicine, diltiazem, erythromycin, felodipine, ketoconazole, lansoprazole, omeprazole and other proton-pump inhibitors, nifedipine, paroxetine, reserpine, saquinavir, sertraline, quinidine, tamoxifen, verapamil,
A consistent finding in studies is that blockade or absence of intestinal P-gp results in decreased extrusion and increased systemic availability of drugs that are P-gp substrate; this may lead to toxicity or enhanced efficacy.
It should not be construed to suggest that all P-gp substrates will undergo reduced oral absorption in the presence of a P-gp inducer. Due to saturation of intestinal P-gp at clinically relevant doses, numerous drugs that are P-gp substrates exhibit reasonably good bioavailability. E.g. Vinblastine, digoxin, ritonavir, etoposide, indinavir and verapamil.
P-gp inhibition is infrequent source of clinically relevant DDIs. 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, ripampin induction of P-gp resulted in reduction of AUC and Cmax by 31% and 52%. Biopsies revelaed that duodenal P-gp content increased 3.5 fold after rifampin administration, confirming the role of inetstinal P-gp induction in this reaction.
OATPs represent an increasingly important group of transport proteins that should be routinely considered as a potential mediator of DDIs, especially in patients taking OATP inhibitors in combination with OATP substrates that have low therapeutic index.
Anions are negatively charged…Cations are positively charged…..
Fexofenadine is antihistaminic……
Dofetilide is an antiarrythmic…..
OATs and OATPs are proteins coded by different genes each having different substrates. At times their function might overlap.
Probenecid decreases CSF clearance of OAT substrate zidovudin, thus prolonging its half-life in the brain.
Type I: Interaction between the drug & nutritional element or formulation through biochemical or physical reactions viz. hydrolysis, oxidation, neutralization or precipitation. They usually occur in the delivery devices. Most common with drugs given IV.
Recommendations: Drugs should not be mixed directly with feeding enteral or parenteral formulation. Tubes should be flushed with water before or after drug administration. Preformulated oral solutions should be preferred over crushing of tablets when giving enteral feeds.
Elderly patient because many co-morbidities and resultant polypharmacy.
Administration off synthetic prostaglandin analogue misoprostol wiith food reduces its rate of absorption and consequently the height of its plasma peak conc. by 63% without affecting its bioavailability. Because the systemic adverse effects associated with misoprostol are related to high peak drug concentration taking the drug with food decreases the incidence of adverse effects, while maintaining the desired drug effect
The bioavailability of ondensetron is increased by 14% when given after meal, not clinically significant.
Taking oral anti-diabetic agent troglitazone with or shortly after meal increases its bioavailability by 59%, which may be reflected in an improved insulin effect.
The bioavailability of furosemide is reduced by 16-15% when taken with food. In one study it was associated with a reduction in diuretic response, whereas diuresis in another study was almost unaffected. Overall, this interaction with food and furosemide is of no clinical importance, but it may explain why some individuals with apparent furosemide resistance may respond to bumetanide. No food-drug interaction has been demonstrated with bumetanide.
When potassium sparing diuretics are used, a high intake of potassium rich foodstuff such as bananas and spinach may result in hyperkalemia.
High plasma peak concentration of nifedipine is associated with adverse effects viz. hypotension, flushing and headache. Nifedipine capsules or tablets with meals reduces the height of the initial plasma concentration and thereby the risk of developing adverse effects, while bioavailability and desired clinical effect are maintained.
Felodipine bioavailability increases by 284% when administered with grapefruit juice by inhibiting its first-pass metabolism. The clinical effect on BP and HR is doubled. A similar effect of grapefruit juice is seen with other dihydropyridine CCBs, but not with diltiazem or verapamil
Food intake decreases the bioavailability of captopril, but clinical hemodynamic effects of captopril not affected. Perindropril bioavailability affected by food ingestion. Clinically significant drug interactions. Enalapril, lisinopril unaffected by food. Hyperkalemia is a frequent complication of ACEIs and may be aggravated by intake of potassium rich food.
Lovastatin and pravastatin: Bioavailability reduced with food
Lovastatin, Atorvastatin, Simvastatin: Excessive intake of grapefruit juices increases bioavailability by inhibiting first pass metabolism.
The bioavailability of the anti-acne agent isotretinoin is increased by 72-86% when administered with or shortly after meals. Because isotretinoin dosage is titrated according to the drug effect and the appearance of adverse effects, the drug should be taken in constant relationship to meals.
Acitretin is a second generation retinoid used for resistant psoriasis….
Penicillamine is a strong chelating agent. Food and iron supplemnets reduces the bioavailability. This is associated with a reduced clinical effect including reduced copper excretion, which is relevant to its use in Wilson’s disease.
Yohimbine: Derived from African tree barks…It is an alpha 2 adrenergic antagonist……
Bacterial resistance induced by antimicrobial drugs, another unusual aspect of which is that the effect in one individual alters the response in another. It has been said that the more rigorously a country controls infection and the supply n use of antimicrobials, lower the rate of resistance.
Reduction of drug clearance due to renal or hepatic impairment is the most common pharmacokinetic disease‐drug interactions.
On the other hand, the elevation of IL‐6 level in patients with autoimmune diseases and the IL‐6‐induced activity reduction of CYP450 enzymes is a rather insidious example for pharmacokinetic disease‐drug interaction. This interaction was only recognized when the patients' IL‐6 concentrations were successfully lowered by immunosuppressive therapy, which led to restoration of CYP450 enzyme function and concentration alterations of concomitantly administered drugs that are known to be the substrates of these enzymes.
Most healthcare providers feel overwhelmed by the amount of info available on drug interactions. There are plenty of sources where the information of drug interaction may be available. However, simply knowing that the two drugs may interact does not provide enough information for the healthcare provider to devise a plan to reduce the risk of an adverse outcome. Healthcare providers are often left on their own to come up with a plan to manage the interaction.
Since the discovery of cytochrome P450 isoenzyme and the ATP binding cassette (ABC) transporters, the number of drug interaction publication per year has increased substantially. It is not possible for individual healthcare workers to remember all drug interactions. They do, however, need to know how to use drug interaction information that is provided by computers, books and other sources. It is possible for the HCPs to remember the interactive properties of drugs they use frequently. If one knows that a drug is an enzyme inducer, or inhibits a particular cytochrome isoenzyme, it is possible to predict how this drug is likely to interact with other medications the patient takes.
Current computarized systems have their own deficiencies & its not yet proven whether they reduce drug interaction morbidity or mortality.
a) Computarized drug interaction screening systems detect a large number of interaction of questionable clinical significance.
b) Almost all drug classes interact heterogeneously because individual members of drug class are often not metabolized by the same cytochrome P450 isoenzyme as other
members of the class. It is common for reviews and computer systems to include all statins together as interacting with CYP3A4 inhibitors, even though the risk is primarily
limited to lovastatin and simvastatin.
c) Knowing is not enough, HCPs should have adequate guidelines to prevent the drug interactions viz. avoiding the combination entirely, adjusting the dosing of the object drug,
spacing dosing times to avoid interactions, monitoring for early detection.
Verapamil and simvastatin given together pose a higher risk of myopathy. This risk increases when there are patient factors involved like advanced age, low body weight and renal insufficiency
Incorporate pharmacogenetic information into risk assessment. The magnitude of drug interactions is known to differ markedly from person-to person, and some of this variability is due to pharamacogenetics factors. CYP450 isoenzymes are under genetic influences. There is considerable inter and intra individual variability.
The magnitude of most drug interaction is dependent upon the way the drugs are administered. There are couple of factors that increase the chance of drug interactions. The most known factors are dose, duration, dosing timings & sequence. Almost all drug interactions are dose related. Higher the dose, more likely the drug interaction. Example, a single glass of regular grapefruit juice for 3 days produces a modest increase in lovastatin serum concentration, while a double strenght grapefruit juice thrice daily produces a dramatic increase in lovastatin serum conc. Duration of therapy with the precipitant drug can be an important determinant to the outcome of drug interaction. A single dose of Cyp3A4 inhibitor e.g. Itraconazole will have no effect on the metabolism of simvastatin. Thus, 2-3 days of itraconazole therapy won’t cause myopathy when given with simvastatin. Dosing timings can influence drugs interaction, if the drugs interact in the GIT. In this case giving the drugs two hours apart can mitigate the drug interaction. The sequence of administration of the object and precipitant drug can be important when the object drug is titrated to an optimal therapeutic response.
Patient information can be parted to avoid drug interaction related adverse events. These information can be given via PILs, warning labels on packages, books etc. If the patients are warned about the myopathy associated with statins, they will tend to seek out help early in the course of the treatment. Also, drugs which have more tendency to interact, should not be given with OTC drugs. These things should be warned to the patients.