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Drug-Drug Interactions (DDIs

)

Marc Imhotep Cray, M.D.
Learning Objectives
By the end of this presentation the learner will be able to:
1. Explain the clinical relevance of adverse drug-drug interactions (DDIs)
and provide some classic examples.
2. Explain the concept that the effects of one drug can be modified by the
prior, or simultaneous, administration of a second drug.
3. Provide five examples of clinically useful drug-drug interactions.
4. Provide a classification of adverse drug-drug interactions based on
mechanism and give examples in each class.
5. Explain the role that enzyme induction and inhibition of metabolic
enzymes play in drug metabolism and adverse drug-drug interactions.
6. List some drug that are enzyme inducers and enzymes inhibiters along
with their substrate(s) and the possible clinical consequences of their co-
administration.

Marc Imhotep Cray, M.D. 2
Topics Outline
 Introduction
 Useful drug interactions
 Trivial drug interactions
 Harmful drug interactions
 Adverse drug interactions grouped by mechanism
• Interaction of Absorption
• Interaction of Protein Binding
• Interaction of Metabolism
• Interaction of Receptor Binding
• Interaction of Excretion

Marc Imhotep Cray, M.D. 3
List of drugs / drug classes referenced in this presentation.
6-mercaptopurine Gentamicin Phenylbutazone
ACE-Inhibitors Heparin Phenytoin
Alcohol Imipenem Potassium-sparing
Allopurinol Indomethacin Diuretics
Amoxicillin Isoniazid Probenecid
Aspirin Levodopa Propantheline
Azathioprine Lidocaine Quinidine
Benzodiazepines Lithium Ritonavir
Beta blockers Losartan Salbutamol
Carbidopa Methotrexate Saquinavir
Cholestyramine Metoclopramide Spironolactone
Cilastin Metolazone Sulfamethoxazole
Cisplatin Naloxone Sulfonamides
Clavulanic acid NSAIDs Tetracycline
Cyclosporine Paclitaxel Theophylline
Digoxin Penicillin Trimethoprim
Furosemide Phenelzine Verapamil
Warfarin
Marc Imhotep Cray, M.D. 4
“Clinical Importance of DDIs in a Capsule”
A clinically relevant Drug-Drug Interaction (DDI) occurs when the effectiveness or toxicity of
one medication is altered by administration of another medicine or a substance that is
administered for medical purposes… Adverse consequences of DDIs may result from either
diminished therapeutic effect or toxicity. Among the various types of medical errors, the
occurrence of adverse DDIs is one that is usually preventable. It is therefore essential that
health professionals be able to evaluate the potential for DDIs and, when detected, to
determine appropriate prevention or management strategies. The potential for clinically
important DDIs can often be predicted based on the drug properties, method of drug
administration, and patient specific parameters. Consequently, adverse outcomes resulting
from DDIs can be prevented by making patient- and situation-specific assessments and, if
appropriate, avoiding concomitant administration by implementing alternative therapeutic
strategies, or taking precautionary measures such as dosage adjustments and increased
monitoring.
From: CredibleMeds : Common Drug-Drug Interactions [Emphasis mines.]
Available at https://www.crediblemeds.org/healthcare-providers/drug-drug-interaction/
Accessed 2 April, 2017

Marc Imhotep Cray, M.D. 5
Introduction
Definition of DDI
 A Drug-Drug Interaction (DDI) is modification of action of one
drug by another

 There are three kinds of mechanism for DDIs:
1. pharmaceutical
2. pharmacodynamic
3. Pharmacokinetic

 Drug interactions can be useful, of no consequence, or harmful

Marc Imhotep Cray, M.D. 6
Introduction (2)
Pharmaceutical interactions occur by chemical reaction or physical
interaction when drugs are mixed
Pharmacodynamic interactions occur when different drugs each influence
same physiological function (e.g. drugs that influence state of alertness or
blood pressure)
 Result of adding a second such drug during treatment w another may be to increase
effect of first (e.g. alcohol increases sleepiness caused by benzodiazepines)
 Conversely for drugs w opposing actions result may be to reduce effect of first (e.g.
indomethacin increases blood pressure in HTN pts. treated w an anti-HTN drug such
as losartan)
Pharmacokinetic interactions occur when one drug affects PKs of another
(e.g. by reducing its elimination from body or by inhibiting its metabolism)
 These mechanisms are discussed more fully in section on adverse
interactions grouped by mechanism A drug interaction can result
from one or a combination of these mechanisms
Marc Imhotep Cray, M.D. 7
Introduction (3)
 Drug interactions are important b/c, whereas careful use of
more than one drug at a time can greatly benefit patients,
adverse interactions are not uncommon, and may be
catastrophic, yet are often avoidable

 Multiple drug use (polypharmacy) is very common, so
potential for drug interactions is vast
 For example One study showed that on average 14 drugs were
prescribed to medical in-patients per admission

Marc Imhotep Cray, M.D. 8
Introduction (4)
Problem of polypharmacy will remain, for several reasons:
1. Many drugs are not curative, but rather ameliorate chronic
conditions (e.g. arthritis)
 Populations are ageing, and elderly individuals not uncommonly
have several co-morbid conditions requiring multiple medications

2. It is easy to enter an iatrogenic spiral where a drug results
in an adverse effect that is countered by introduction of
another drug... and so on
NB: An out-patient visit or hospital admission provides the best
opportunity for a healthcare provider to review all medications that
any patient is receiving, as to ensure the overall regimen is rational.
Marc Imhotep Cray, M.D. 9
Introduction (5)
Out-patients also often receive several prescribed drugs, plus
OTC medicines, “alternative” remedies and “lifestyle” drugs

Greater number of drugs taken, more likely things can go wrong
(See next slide)

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Introduction (6)
Relationship of number of drugs administered
to (a) adverse drug reactions, (b) mortality rate
and (c) average duration of hospital stay.

Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London: Hodder Arnold, 2008.
Marc Imhotep Cray, M.D. 11
Useful Drug Interactions
Increased Effect
 Drugs can be used in combination to enhance their
effectiveness

 Disease is often caused by complex processes drugs that
influence different components of disease mechanism may
have additive effects (e.g. an antiplatelet drug w a
fibrinolytic in treating myocardial infarction)

 Another example is use of a β2 agonist w a glucocorticoid in
treatment of asthma (to cause bronchodilation and suppress
inflammation, respectively)
Marc Imhotep Cray, M.D. 12
Useful Drug Interactions (2)
Increased Effect cont.
Combinations of antimicrobial drugs are used to prevent
selection of drug-resistant organisms
 TB is best example of a disease whose successful Tx requires this
approach

Drug resistance via synthesis of a microbial enzyme that
degrades antibiotic (e.g. penicillinase producing
staphylococci) can be countered by using a combination of
antibiotic w an inhibitor of enzyme:
 co-amoxiclav = a combination of clavulanic acid, an inhibitor of
penicillinase, with amoxicillin

Marc Imhotep Cray, M.D. 13
Useful Drug Interactions (3)
Increased Effect cont.
Increased efficacy can result from pharmacokinetic interaction
 Imipenem is partly inactivated by a dipeptidase in kidney
o This is overcome by administering imipenem in combination w
cilastin ( a specific renal dipeptidase inhibitor)

 Another example is use of combination of ritonavir and
saquinavir in antiretroviral therapy
 Saquinavir increases systemic bioavailability of ritonavir by inhibiting
its degradation by GI CYP3A and inhibits its fecal elimination by
blocking P-glycoprotein that pumps it back into intestinal lumen

Marc Imhotep Cray, M.D. 14
Useful Drug Interactions (4)
Increased Effect cont.
 Some combinations of drugs have a more than additive effect =
synergy
 Several antibacterial combinations are synergistic, including
sulfamethoxazole w trimethoprim (co-trimoxazole), used in Tx of
Pneumocystis carinii
 Several drugs used in cancer chemotherapy are also synergistic, e.g.
cisplatin plus paclitaxel

Marc Imhotep Cray, M.D. 15
Useful Drug Interactions (5)
Increased Effect cont.
Therapeutic effects of drugs are often limited by activation of
a physiological control loop particularly in case of CV drugs
 use of a low dose of a second drug that interrupts this
negative feedback may enhance effectiveness substantially
o Examples include combination of an angiotensin converting
enzyme inhibitor (to block renin-angiotensin system) w a diuretic
(effect of which is limited by activation of renin-angiotensin
system) in treating hypertension

Marc Imhotep Cray, M.D. 16
Useful Drug Interactions (6)
Minimize Side Effects
There are many situations (e.g. hypertension) where low doses
of two drugs may be better tolerated, as well as more
effective, than larger doses of a single agent

Sometimes drugs w similar therapeutic effects have opposing
undesirable metabolic effects can-to some extent- cancel
out when drugs are used together
 For example combination of a loop diuretic (e.g. furosemide=K+
depleting) w a K+ sparing diuretic (e.g. spironolactone)

Marc Imhotep Cray, M.D. 17
Useful Drug Interactions (7)
Minimize Side Effects cont.
Predictable adverse effects (AEs) can sometimes be averted by
use of drug combinations
Examples
 Isoniazid neuropathy is caused by pyridoxine deficiency prevented
by prophylactic use of this vitamin (B6)
 Combination of a peripheral dopa decarboxylase inhibitor (e.g.
carbidopa) w levodopa permits an equivalent therapeutic effect to be
achieved w a lower dose of levodopa than is needed when it is used as
a single agent while also reducing dose-related peripheral side
effects of nausea and vomiting

Marc Imhotep Cray, M.D. 18
Useful Drug Interactions (8)
Block Acutely an Unwanted (Toxic) Effect
 Drugs can be used to block an undesired or toxic effect
For example
 When an anesthetist uses a cholinesterase inhibitor to
reverse neuromuscular blockade
 When antidotes such as naloxone are used to treat
opioid overdose
 Uses of vitamin K or of fresh plasma to reverse effect of
warfarin

Marc Imhotep Cray, M.D. 19
Trivial Interactions
 Many interactions are based on in vitro experiments results
of which cannot be extrapolated uncritically to clinical
situation
 Many such potential interactions are of no practical
consequence especially true of
o Drugs w shallow dose–response curves and
o Interactions that depend on competition for tissue binding to
sites that are not directly involved in drug action but which
influence drug distribution (e.g. to albumin in blood)

Marc Imhotep Cray, M.D. 20
Trivial Interactions (2)
Shallow Dose–Response Curves
 Interactions are only clinically important when there is a
steep dose–response curve and a narrow therapeutic
window betw. minimum effective dose and minimum toxic
dose of one or both interacting drugs This is often not the
case
 For example, penicillin is so non-toxic that usual dose is more than
adequate for therapeutic efficacy, yet far below that which would
cause dose-related toxicity=Wide therapeutic index (TI)
o Consequently, a second drug that interacts w penicillin is unlikely
to cause either toxicity or loss of efficacy

Marc Imhotep Cray, M.D. 21
Drug dose–response curves illustrating likelihood of adverse
effect if an interaction increases its blood level.

Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London: Hodder Arnold, 2008.
22
Trivial Interactions (4)
Plasma and Tissue Binding Site Interactions
 One large group of potential drug interactions that are seldom
clinically important consists of drugs that displace one another
from binding sites on plasma albumin or α-1 acid glycoprotein
(AAG) or within tissues
 This is a common occurrence and can readily be demonstrated in
plasma or solutions of albumin/AAG in vitro
However,
 Expectation displacing drug will ↑ effects of displaced drug by ↑ its
free (unbound) concentration is seldom evident in clinical practice
o This is b/c drug clearance (renal or metabolic) also depends directly on
concentration of free drug…

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Trivial Interactions (5)
Plasma and Tissue Binding Site Interactions cont.
 Consider a pt. receiving a maintenance dose (MD) of a drug
 When a second displacing drug is started free conc. of first drug
rises only transiently before ↑ renal or hepatic elimination reduces
total (bound plus free) drug and restores free conc. to that which
prevailed before second drug was started
o Consequently, any ↑ effect of displaced drug is transient, and is
seldom important in practice
• It must, however, be taken into account if therapy is being guided by
measurements of plasma drug concs. as most such determinations are
of total (bound plus free) rather than just free conc. of drug

Marc Imhotep Cray, M.D. 24
Trivial Interactions (6)
Plasma and Tissue Binding Site Interactions cont.
An exception, where a transient ↑ in free conc. of a circulating
substance (albeit not a drug) can have devastating
consequences= bilirubin in premature babies whose ability to
metabolize bile pigments is limited
 Unconjugated bilirubin is bound by plasma albumin injudicious Tx w
drugs, such as sulfonamides, that displace bilirubin from albumin
permits diffusion of free bilirubin across immature blood–brain
barrier (BBB) consequent staining of and damage to basal ganglia
(kernicterus)  Acute bilirubin encephalopathy (ABE) in baby

Marc Imhotep Cray, M.D. 25
Trivial Interactions (7)
 Instances where clinically important consequences do occur
on introducing a drug that displaces another from tissue
binding sites are in fact often due to additional actions of
second drug on elimination of first
 For example, quinidine displaces digoxin from tissue binding sites
can cause digoxin toxicity but only b/c quinidine simultaneously
reduces renal clearance of digoxin by a separate mechanism

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Trivial Interactions (8)
Phenylbutazone (NSAID reserved for ankylosing spondylitis
unresponsive to other drugs) displaces warfarin from binding sites
on albumin causes excessive anticoagulation
 However, only b/c it also inhibits metabolism of active isomer of warfarin
(S-warfarin) causing S-warfarin to accumulate at expense of inactive
isomer

Indomethacin (another NSAID) also displaces warfarin from
binding sites on albumin but does not inhibit its metabolism and
does not further prolong prothrombin time (PT) in pts. treated w
warfarin
 although indomethacin can cause bleeding by causing peptic ulceration and
interfering w platelet function

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Harmful Interactions
It is not possible to memorize reliably the many clinically
important drug interactions thus, physicians and other
prescribers should use suitable references (e.g. Physicians'
Desk Reference [PDR] or National Formulary) to check for
potentially harmful interactions
NB: Frequency and consequences of an adverse interaction when two
drugs are used together are seldom known precisely every individual
has a peculiar set of characteristics that determine their response to
therapy (inter-individual variation)

Marc Imhotep Cray, M.D. 28
Harmful Interactions (2)
 There are certain drugs w steep dose–response curves and serious dose-
related toxicities for which drug interactions are especially liable to
cause harm and where special caution is required w concurrent therapy
These include:
 warfarin and other anticoagulants
 anticonvulsants
 cytotoxic drugs
 drugs for HIV/AIDS
 immunosuppressants
 digoxin and other anti-dysrhythmic drugs
 oral hypoglycaemics agents
 xanthine alkaloids (e.g. theophylline)
 monoamine oxidase inhibitors
Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical
Pharmacology and Therapeutics 5th Ed. London: Hodder Arnold, 2008.

Marc Imhotep Cray, M.D. 29
Harmful Interactions (3)
Risk of Adverse Drug Interactions
 In the Boston Collaborative Drug Surveillance Program
(BCDSP), 234 of 3600 (about 7%) adverse drug reactions
(ADRs) in acute-care hospitals were identified as being due
to drug interactions

 In a smaller study in a chronic-care setting, prevalence of
adverse interactions was much higher (22%) probably b/c
of more frequent use of multiple drugs in elderly pts w
multiple chronic pathologies

Marc Imhotep Cray, M.D. 30
Harmful Interactions (4)
Severity of Adverse Drug Interactions
 Adverse drug interactions are diverse, including
 Unwanted pregnancy (from failure of contraceptive pill due to
concomitant medication)
 Hypertensive stroke (from hypertensive crisis in pts on monoamine
oxidase inhibitors)
 Gastrointestinal or cerebral hemorrhage (in patients receiving
warfarin)
 Cardiac arrhythmias (e.g. secondary to interactions leading to
electrolyte disturbance or prolongation of QTc)
 Blood dyscrasias (e.g. from interactions betw. allopurinol and
azathioprine)

Marc Imhotep Cray, M.D. 31
Key points
Drug interactions may be clinically useful, trivial or adverse.

Useful interactions include those that enable efficacy to be
maximized, such as addition of an angiotensin converting
enzyme inhibitor to a thiazide diuretic in a patient with
hypertension inadequately controlled on diuretic alone. They
may also enable toxic effects to be minimized, as in use of
pyridoxine to prevent neuropathy in malnourished patients
treated with isoniazid for tuberculosis, and may prevent the
emergence of resistant organisms (e.g. multi-drug regimens for
treating tuberculosis).

Marc Imhotep Cray, M.D. 32
Key points
Many interactions that occur in vitro (e.g. competition for
albumin) are unimportant in vivo b/c displacement of drug
from binding sites leads to increased elimination by
metabolism or excretion and hence to a new steady state
where total conc. of displaced drug in plasma is reduced, but
concentration of active, free (unbound) drug is same as before
interacting drug was introduced.

Interactions involving drugs with a wide safety margin (e.g.
penicillin) are also seldom clinically important.

Marc Imhotep Cray, M.D. 33
Key points
Adverse drug interactions are not uncommon, and can have
profound consequences, including death from hyperkalemia
and other causes of cardiac dysrhythmia, unwanted pregnancy,
transplanted organ rejection, etc.

Marc Imhotep Cray, M.D. 34
Adverse Interactions
Grouped By Mechanism

Marc Imhotep Cray, M.D. 35
Pharmaceutical Interactions
 Occur by chemical reaction or physical interaction when drugs are mixed
 Inactivation when drugs are mixed (e.g. heparin w gentamicin)
 Drugs may also interact in lumen of gut (e.g. tetracycline w iron, and
cholestyramine w digoxin)

DDIs outside the body
Mixture Result
Thiopental and suxamethonium Precipitation
Diazepam and infusion fluids Precipitation
Phenytoin and infusion fluids Precipitation
Heparin and hydrocortisone Inactivation of heparin
Gentamicin and hydrocortisone Inactivation of gentamicin
Penicillin and hydrocortisone Inactivation of penicillin
Redrawn after: Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed.
London: Hodder Arnold, 2008.

Marc Imhotep Cray, M.D. 36
Pharmacodynamic Interactions
 PD interactions are common most have a simple
mechanism consisting of summation or opposition of
effects of drugs w similar or opposing actions (respectively)
 Since PD interaction depends on effect of a drug, rather than on its
specific chemical structure, such interactions are non-specific
o For example drowsiness caused by an H1-blocking antihistamine and by
alcohol  pts must be warned of dangers of consuming alcohol
concurrently when such antihistamines are prescribed (especially if driving
or operate machinery)

Marc Imhotep Cray, M.D. 37
Pharmacodynamic Interactions (2)

 Non-steroidal anti-inflammatory agents and
antihypertensive drugs provide another clinically important
example
 Anti-HTN drugs rendered less effective by concurrent use of
NSAIDs, irrespective of chemical group Anti-HTN belong
mechanism = b/c of inhibition of biosynthesis of vasodilator
prostaglandins in kidney

Marc Imhotep Cray, M.D. 38
Pharmacodynamic Interactions (3)
 Drugs w negative inotropic effects can precipitate heart failure
especially when used in combination
 Thus, beta blockers and verapamil may precipitate HF if used sequentially IV in
patients w supraventricular tachycardia (SVT)

 Warfarin interferes w hemostasis by inhibiting coagulation cascade,
whereas aspirin influences hemostasis by inhibiting platelet function
 Aspirin also predisposes to gastric bleeding by direct irritation and by inhibition of
prostaglandin E2 biosynthesis in t gastric mucosa
 There is therefore potential for serious adverse interaction betw. warfarin and
aspirin

Important DDIs can occur betw. drugs acting at a common receptor
 generally useful when used deliberately, for example use of naloxone to
reverse opiate intoxication

Marc Imhotep Cray, M.D. 39
Pharmacodynamic Interactions (4)
 One potentially important type of PD drug interaction
involves interruption of physiological control loops this
was mentioned above as a desirable means of increasing
efficacy
However,
 In some situations such control mechanisms are vital
 For example use of β-blocking drugs in pts. w insulin-requiring
diabetes is such a case, as these pts. may depend on sensations
initiated by activation of β-receptors to warn them of insulin-
induced hypoglycemia

Marc Imhotep Cray, M.D. 40
Pharmacodynamic Interactions (5)
 Alterations in fluid and electrolyte balance is an important source of
PD drug interactions
 Combined use of diuretics w actions at different parts of nephron (e.g.
metolazone and furosemide) is valuable in Tx of resistant edema but without
close monitoring of plasma urea levels such combinations readily cause
excessive intravascular fluid depletion and prerenal kidney failure

 Thiazide and loop diuretics commonly cause mild hypokalemia
usually of no consequence
However,
 Binding of digoxin to plasma membrane Na+/K+ adenosine
triphosphatase (Na+/K+ ATPase)--and hence its toxicity-- is increased
when extracellular potassium concentration is low dysrrhythmias

Marc Imhotep Cray, M.D. 41
Pharmacodynamic Interactions (6)
 β2-Agonists, such as salbutamol, reduce plasma
potassium concentration esp. when used IV

 Conversely, potassium-sparing diuretics may cause
hyperkalemia if combined w potassium supplements
and/or ACE-I (which reduce circulating aldosterone), esp. in
pts. w renal impairment
NB: Hyperkalemia is one of most common causes of
fatal adverse drug reactions (ADRs).

Marc Imhotep Cray, M.D. 42
Interactions secondary to drug-induced alterations of fluid
and electrolyte balance.
Primary drug Interacting drug Result of effect interaction

Digoxin Diuretic-induced hypokalemia Digoxin toxicity

Lidocaine Diuretic-induced hypokalemia Antagonism of antidysrhythmic
effects
Diuretics NSAID-induced salt and water Antagonism of diuretic effects
retention
Lithium Diuretic-induced reduction in Raised plasma lithium
lithium clearance
Angiotensin Potassium chloride and/ or Hyperkalemia
converting enzyme potassium retaining diuretic
inhibitor induced hyperkalemia

Redrawn after: Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London:
Hodder Arnold, 2008.
Marc Imhotep Cray, M.D. 43
Pharmacokinetic Interactions
Absorption
 In addition to direct interaction within gut lumen (see above), drugs that
influence gastric emptying (e.g. metoclopramide, propantheline
[antimuscarinic]) can alter rate or completeness of absorption of a
second drug particularly if second drug has low bioavailability

 Drugs can interfere w enterohepatic recirculation of other drugs
 Failure of oral contraception can result from concurrent use of antibiotics, due to
this mechanism many different antibiotics have been implicated

 Phenytoin reduces effectiveness of cyclosporine partly by reducing its
absorption

Marc Imhotep Cray, M.D. 44
Pharmacokinetic Interactions (2)
Distribution
 As explained previously, interactions that involve only mutual
competition for inert protein- or tissue-binding sites seldom give
rise to clinically important effects
 Examples of complex interactions where competition for binding
sites occurs in conjunction w reduced clearance are mentioned in
slides below

Marc Imhotep Cray, M.D. 45
Pharmacokinetic Interactions (3)
Metabolism
 Decreased efficacy can result from enzyme induction by a
second agent
 Historically, barbiturates were clinically most important
enzyme inducers but w decline in their use, other
anticonvulsants, notably carbamazepine and
antituberculous drug rifampin, are now most common
cause of CYP450 enzyme induction
o These agents necessitate special care in concurrent therapy w
warfarin, phenytoin, oral contraceptives, glucocorticoids or
immunosuppressants (e.g. cyclosporine, sirolimus)

Marc Imhotep Cray, M.D. 46
Interactions due to enzyme induction
Primary drug Inducing agent Effect of interaction

Warfarin Barbiturates, Rifampin, Ethanol Decreased anticoagulation
Oral contraceptives Rifampin Pregnancy
Prednisolone/ Anticonvulsants Reduced immunosuppression
cyclosporine (graft rejection)
Theophylline Smoking Decreased plasma theophylline

Redrawn after: Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London:
Hodder Arnold, 2008.

Marc Imhotep Cray, M.D. 47
Pharmacokinetic Interactions (5)
Metabolism cont.
 Withdrawal of an inducing agent during continued admin. of a second drug
 can result in a slow decline in enzyme activity, w emergence of
delayed toxicity from second drug due to what is no longer an appropriate
dose
 For example, a pt. receiving warfarin may be admitted to hospital for an
intercurrent event and receive Tx w an enzyme inducer
 During hospital stay, dose of warfarin therefore has to be ↑ in order to
maintain international normalized ratio (INR) within therapeutic range
 Intercurrent problem is resolved, inducing drug discontinued and pt.
discharged while taking larger dose of warfarin
 If INR is not checked frequently, bleeding may result from an excessive
effect of warfarin days or weeks after D/C from hospital, as effect of
enzyme inducer gradually wears off
Marc Imhotep Cray, M.D. 48
Pharmacokinetic Interactions (6)
Metabolism cont.
 Inhibition of drug metabolism produces adverse effects
 time-course is often more rapid than for enzyme induction, since it
depends merely on attainment of a sufficiently high conc. of inhibiting
drug at metabolic site
 Xanthine oxidase is responsible for inactivation of 6-mercaptopurine
6-MP itself a metabolite of azathioprine
o Allopurinol markedly potentiates these drugs (6-MP &
azathioprine) by inhibiting xanthine oxidase
o Xanthine alkaloids (e.g. theophylline) are not inactivated by
xanthine oxidase, but rather inactivated by a form of CYP450

Marc Imhotep Cray, M.D. 49
Pharmacokinetic Interactions (7)
Metabolism cont.
 Theophylline has serious (sometimes fatal) dose-related
toxicities, and clinically important interactions occur w
inhibitors of CYP450 system
 notably several antibiotics, including ciprofloxacin and
clarithromycin
 Severe exacerbations in asthmatic pts are often precipitated by
chest infections so an awareness of these interactions before
commencing antibiotic Tx is essential, if pt. is on theophylline

Marc Imhotep Cray, M.D. 50
Interactions due to CYP450 or other enzyme
inhibition
Primary drug Inhibiting drug Effect of interaction
Phenytoin Isoniazid, Cimetidine, Chloramphenicol Phenytoin intoxication
Warfarin Allopurinol, Metronidazole, Phenylbutazone, Hemorrhage
Co-trimoxazole
Azathioprine, Allopurinol Bone-marrow suppression
6-MP
Theophylline Cimetidine, Erythromycin Theophylline toxicity
Cisapride Erythromycin, Ketoconazole Ventricular tachycardia

Redrawn after: Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London:
Hodder Arnold, 2008.

Marc Imhotep Cray, M.D. 51
Pharmacokinetic Interactions (9)
Metabolism cont.
 Hepatic CYP450 inhibition also accounts for clinically
important interactions
 w phenytoin (e.g. isoniazid) and
 w warfarin (e.g. sulfonamides)

 Non-selective MAO inhibitors (e.g. phenelzine) potentiate
action of indirectly acting amines such as tyramine, which is
present in a wide variety of fermented products (most
classically soft cheeses: =“cheese reaction”) CNS
stimulation and hypertensive crisis

Marc Imhotep Cray, M.D. 52
Pharmacokinetic Interactions (10)
Metabolism cont.
 Clinically important impairment of drug metabolism may
also result indirectly from hemodynamic effects rather than
enzyme inhibition
 Lidocaine is metabolized in liver and hepatic extraction ratio is
high consequently, any drug that reduces hepatic blood flow
(e.g. a negative inotrope) will reduce hepatic clearance of
lidocaine cause it to accumulate
o accounts for ↑ lidocaine conc. and toxicity caused by β-blocking drugs

Marc Imhotep Cray, M.D. 53
Pharmacokinetic Interactions (11)
Excretion
 Many drugs share a common transport mechanism in PCT
and reduce one another’s excretion by competition
 Probenecid reduces penicillin elimination in this way
 Aspirin and NSAIDs inhibit secretion of methotrexate into urine
as well as displacing it from protein-binding sites can cause
methotrexate toxicity
 Many diuretics reduce Na+ absorption in loop of Henle or DCT
this leads indirectly to ↑ PCT reabsorption of monovalent
cations
o ↑ PCT reabsorption of lithium in pts TX w lithium salts  can
cause lithium accumulation and toxicity

Marc Imhotep Cray, M.D. 54
Pharmacokinetic Interactions (12)
Excretion cont.
 Digoxin excretion is reduced by spironolactone, verapamil
and amiodarone all of which can precipitate digoxin
toxicity as a consequence
 several of these interactions have complex mechanism, involving
displacement from tissue binding sites, in addition to reduced
digoxin elimination

 Changes in urinary pH alter excretion of drugs that are
weak acids or bases, and administration of systemic alkalinizing
or acidifying agents influences reabsorption of such drugs
Marc Imhotep Cray, M.D. 55
Competitive interactions for renal tubular
transport
Primary drug Competing drug Effect of interaction
Penicillin Probenecid Increased penicillin blood level

Methotrexate Salicylates, Sulfonamides Bone marrow suppression
Salicylate Probenecid Salicylate toxicity

Indomethacin Probenecid Indomethacin toxicity
Digoxin Spironolactone, Amiodarone, Increased plasma digoxin
Verapamil
Redrawn after: Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London:
Hodder Arnold, 2008.

Marc Imhotep Cray, M.D. 56
Key Points Summary
There are three main types of adverse interaction:
• pharmaceutical
• pharmacodynamic
• pharmacokinetic
Pharmaceutical interactions are due to in vitro incompatibilities,
and they occur outside the body (e.g. when drugs are mixed in a
bag of intravenous solution, or in the port of an intravenous
cannula).
Pharmacodynamic interactions between drugs with a similar
effect (e.g. drugs that cause drowsiness) are common. In principle,
they should be easy to anticipate, but they can cause serious
problems (e.g. if a driver fails to account for the interaction
Marcbetween an antihistamine and ethanol).
Imhotep Cray, M.D. 57
Key Points Summary
Pharmacokinetic interactions are much more difficult to
anticipate. They occur when one drug influences the way in which
another is handled by the body:
a) absorption (e.g. broad-spectrum antibiotics interfere with
enterohepatic recirculation of estrogens and can cause failure
of oral contraception)
b) distribution – competition for binding sites seldom causes
problems on its own but, if combined with an effect on
elimination (e.g. amiodarone/digoxin or
NSAID/methotrexate), serious toxicity may ensue

Marc Imhotep Cray, M.D. 58
Key Points Summary
c) metabolism – many serious interactions stem from
enzyme induction or inhibition. Important inducing agents
include ethanol, rifampin, rifabutin, many of the older
anticonvulsants, St John’s wort, nevirapine and
pioglitazone. Common inhibitors include many
antibacterial drugs (e.g. isoniazid, macrolides, co-
trimoxazole and metronidazole), the azole antifungals,
cimetidine, allopurinol, HIV protease inhibitors;
d) excretion (e.g. diuretics lead to increased reabsorption of
lithium, reducing its clearance and predisposing to lithium
accumulation and toxicity)
Marc Imhotep Cray, M.D. 59
Case history
A 64-year-old Indian male was admitted to hospital with miliary
tuberculosis. In the past he had had a mitral valve replaced, and
he had been on warfarin ever since. Treatment was commenced
with isoniazid, rifampin and pyrazinamide, and the INR was closely
monitored in anticipation of increased warfarin requirements. He
was discharged after several weeks with the INR in the
therapeutic range on a much increased dose of warfarin. Rifampin
was subsequently discontinued. Two weeks later the patient was
again admitted, this time drowsy and complaining of headache
after mildly bumping his head on a locker. His pupils were unequal
and the INR was 7.0. Fresh frozen plasma was administered and
neurosurgical advice was obtained.
Marc Imhotep Cray, M.D. 60
Case history comment
This patient’s warfarin requirement increased during treatment
with rifampin because of enzyme induction, and the dose of
warfarin was increased to maintain anticoagulation.
When rifampin was stopped, enzyme induction gradually receded,
but the dose of warfarin was not readjusted. Consequently, the
patient became over-anticoagulated and developed a subdural
hematoma in response to mild trauma. Replacement of clotting
factors (present in fresh frozen plasma) is the quickest way to
reverse the effect of warfarin overdose.

Marc Imhotep Cray, M.D. 61
THE END

See next slide for further study tools and resources.
62
Companion study tools:
 MedPharm Syllabus| Digital Guidebook 2015: Unit 1: General Principles of
Pharmacology string (Pgs. 10-29).

Sources and further study:
 Karalliedde LD, Clarke SF, Ursula Gotel U, Karalliedde J, Eds. Adverse Drug
Interactions: A Handbook for Prescribers, 2nd ed. Boca Raton, FL: CRC Press, Taylor &
Francis Group, 2016.
 Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and
Therapeutics 5th ed. London: Hodder Arnold, 2008.
 Wecker L, Crespo L , et al. Brody’s Human Pharmacology : Molecular to Clinical , 5th
ed. Philadelphia, PA: Mosby-Elsevier, 2010.
E-learning resource center: IVMS Medical Pharmacology Cloud Folder

Marc Imhotep Cray, M.D. 63