BPHM2004 L25 Drug Interactions 29Nov2013
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Transcript of BPHM2004 L25 Drug Interactions 29Nov2013
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Drug Interactions
(Lecture 25)
W.M. TomDepartment of Pharmacology & Pharmacy
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Drug Interactions
modification of the action of one drug by another
consequence
beneficial enhancement of therapeutic effectiveness
diminution of toxicity
e.g. combinations of different anticancer drugs
adverse diminution of therapeutic effectiveness
enhancement of toxicity
dose alteration may be necessary
or alternative medications prescribed
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Adverse Drug Interactions
represent 3-5% of preventable in-hospital ADRs
patients on six or more drugs have an 80% chance of ADRs
ADRs are most important for drugs with a low therapeutic index
the sicker the patient, the greater the risk of an ADR
drugs removed from the market because of ADRs
terfenadine (1998); mibefradil (1998); astemizole (1999); cisapride
(2000)
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Classification
Site of interactions
external
physicochemical incompatibilities
e.g. drugs mixed in IV infusion vialsprecipitation or
inactivation
internal can be a body site or system or the site of action
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Pharmaceutical interactions
physicochemical interactions may occur prior to systematic availability
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Classification
Mechanism
pharmacokinetic interactions
changes in the pharmacokinetics of one drug that are produced by the
presence of another drug
change in blood concentration occurs causing a change in effect
pharmacodynamic interactions
drug-induced changes in the effects of other drugs
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Interactions based on Absorption
one drug affects the rateor extentof absorption of the other drug
changes in the rate of absorption affect the peak concentration but
not usually the extent of absorption
altered rate is of little importance unless immediate effect is required,
e.g. analgesics or sedatives-hypnotics
a change in the extent of drug absorption that exceeds 20% isgenerally considered clinically significant
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Interactions based on Absorption
Gastrointestinal absorption
physicochemical interactions
changes in GI pH
chelation
exchange resin binding
adsorption
dissolution
changes in GI motility increased gastric emptying and
intestinal motility
decreased gastric emptying and
intestinal motility
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Interactions based on Absorption
changes in the rate ofabsorption
e.g. increasing or decreasinggastric emptying or intestinal
motility
e.g. metoclopramide
(prokinetic agent) hastens
gastric emptying
e.g. opioid analgesics, TCAs
(antimuscarinic) delays gastric
emptying
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Interactions based on Absorption
changes in the extent ofabsorption
iron, calcium and other divalent or
trivalent ions may form chelate
complex with some drugs
e.g. quinolones and tetracyclines are
chelated by antacids, and by calcium
in milk
decreasing extentof absorption can
be prevented if the doses are
separated by at least 2 hrs
Mn+
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Interactions based on Absorption
changes in the extent of absorption
e.g. inhibition of drug transporters in the wall of the intestine
some drugs inhibit the P-glycoprotein drug transporter and increase the net
absorption of drugs that are normally expelled by the transporter
e.g. induction of metabolism in gut lumen, gut wall or liver
agents induce CYP3A4
e.g. altered bacterial flora by antimicrobials
erythromycin reduces gut flora that degrade digoxin
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Interactions based on Distribution and Binding
competition for the non-specific binding sites on plasma proteins
interactions affecting plasma protein binding are of greatest importance
when the displaced drug
is highly protein bound
has a narrow therapeutic index
has a low apparent volume of distribution
is of low potency
limited clinical relevance
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Interactions based on Distribution and Binding
altered drug distribution is notusually a major problem
because distribution is not
relevant to steady-state plasma
concentrations
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Valproic acid-phenytoin interaction
plasma protein binding of
phenytoin is decreased when
valproic acid is administered
chronically to a group of
patients stabilized on
phenytoin
a resultant fall in the steady-
state plasma phenytoin
concentration
no substantial change in the
unbound phenytoinconcentration
no need to alter the dosing
rate of patients receiving
valproic acid
mg valproic acid dailycontrol
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Displacement interactions
administration of a dose of displacerto a patient already stabilized on a drug
?
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Interactions based on Distribution and Binding
may be altered by other drugs that compete for binding sites on
plasma proteins
e.g. antibacterial sulphonamides can displace methotrexate, phenytoin,sulphonylureas and warfarin from binding sites on albumin
changes in drug distribution can occur if one agent alters the size of
the physical compartment in which another drug distributes
e.g. diuretics, by reducing total body water, can increase plasma levels of
aminoglycosides and of lithium, possibly enhancing drug toxicities
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Interactions based on Metabolic Clearance
nearly always due to interaction at
phase I enzymes, rather than phase II
i.e. commonly due to interaction at
cytochrome P450 enzymes, some of
which are genetically absent
metabolic interactions includeenzyme induction or inhibition
Relative importance of phase I enzymes
in drug metabolism
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Examples of drugs withdrawnbecause of CYP-related drug interactions
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Drug interactions due to enzyme induction
enzyme induction by drugs increases first-pass metabolism, increases
clearance, decreases t1/2and lowers average steady-state
concentrations
Drug activation of nuclear receptors
PXR and CAR
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Interactions due to enzyme induction
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Drug interactions due to enzyme inhibition
enzyme inhibition causes less first-pass metabolism, decreasedclearance, longer t1/2and higher average steady-state concentrations
interactions arising fromsimple competition for thesame enzyme would only beimportant if the concentrationresulted in saturation of theenzyme system
examples of potent enzymeinhibitors: erythromycin, SSRIs,ketoconazole, cimetidine,grapefruit juice
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Drug interactions due to enzyme inhibition
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Interactions Based on Absorption
changes in the extentof absorption
e.g. inhibition of first passmetabolism
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First-Pass Metabolism after Oral Administration of Felodipine andIts Interaction with Grapefruit Juice
grapefruit juice selectively inhibits CYP3A in the
enterocyte, with the net result being a 3-fold
increase in the oral bioavailability of felodipine
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First-Pass Metabolism after Oral Administration of Felodipine andIts Interaction with Grapefruit Juice
Wilkinson GR, N. Engl. J. Med.352:2211-21 (2005)
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First-Pass Metabolism after Oral Administration of Felodipine andIts Interaction with Grapefruit Juice
Wilkinson GR, N. Engl. J. Med.352:2211-21 (2005)
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Drug interactions due to grapefruit juice
component(s) in grapefruit inhibits the CYP3A4 enzymes responsible for
metabolizing many drugs as they pass through the gut wall, leading to
large increases in serum concentrations of susceptible drugs
increases in the AUC of up to 16-fold have been reported,
e.g. lovastatin
drugs affected have the following characteristics
metabolized largely by CYP3A4
subject to marked first-pass metabolism
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Some Common Drugs with Low Oral Bioavailability andSusceptibility to First-Pass Drug Interactions
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Theoretical plasma concentrationtime profiles of drugin the presence of a CYP enzyme inducer and inhibitor
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Interactions based on Metabolic Clearance
metabolic clearance can be increased by other agents that cause theinduction of hepatic drug metabolizing enzymes
induction of drug metabolizing enzymes occurs predictably with the
chronic administration of barbiturates, carbamazepine, ethanol,phenytoin, or rifampin
the metabolism of some drugs may be decreased by other drugs thatinhibit drug metabolizing enzymes
such inhibitors of drug metabolizing enzymes include cimetidine,disulfiram, erythromycin, ketoconazole, propoxyphene, quinidine andsulphonamides
the CYP3A4 isozyme of cytochrome P450, the dominant form in thehuman liver, is particularly sensitive to such inhibitory actions
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Some other interactionsbased on metabolic clearance
drugs that reduce hepatic blood flow, e.g. propranolol, may also reducethe clearance of other drugs metabolized in the liver, especially thosesubject to flow-limited hepatic clearance such as morphine andverapamil
ability of some drugs to increase the stores of endogenous substancesby blocking their metabolism
sensitization of patients taking MAO inhibitors to indirectly actingsympathomimetics (amphetamine, phenylpropanolamine, etc.); suchpatients may suffer a severe hypertensive reaction in response toordinary doses of cold remedies, decongestants and appetitesuppressants
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Interactions based on Renal Function
Glomerular filtration drugs affecting renal perfusion or plasma protein
binding could give rise to interactions
pH-dependent reabsorption altered by drugs affecting urine pH (directly or
indirectly)
Renal tubular secretion competition for the transporter
e.g. aspirin interferes with the transport of both
endogenous compounds (uric acid) and drugs
(methotrexate)
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Competitive interactions for renal tubular transport
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Pharmacodynamic interactions
usually predictable
may relate to the principal site of action of the drug or secondary sitesof action that are responsible for the unwanted effects of the drug
drugs that are highly selective for a single site of action are less likely toproduce pharmacodynamic interactions than are drugs that show lowselectivity
e.g. ACEI and spironolactone combinationlife-threatening hyperkalemia
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Interactions based on Additive Effects
algebraic summing of the effects of 2 drugs
the two drugs may or may not act on the same receptor to produce
such effects
the combined use of tricyclic depressants with diphenhydramine or
promethazine predictably causes excessive atropine-like effects since all
of these drugs have significant muscarinic receptor- blocking actions
TCA may increase the pressor responses to sympathomimetics by
interference with amine transporter systems
additive depression of CNS function cause by concomitant administration
of sedatives, hypnotics, and opioids with each other or associated with
the consumption of ethanol
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Interactions based on Additive Effects
patient with moderate to severe hypertension maintained on one
drug is at risk of excessive lowering of blood pressure if another drug
with a different site of action is added at high dosage
additive effects of anticoagulant drugs can lead to bleeding
complications
e.g. in the case of warfarin, the potential for such adverse effects is
enhanced by aspirin (via an antiplatelet action), quinidine (additive
hypoprothrombinemia), thrombolytics (via plasminogen activation) and
the thyroid hormones (via enhanced clotting factor catabolism)
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Interactions based on Supra-Additive Effects
synergistic interactionoccurs if the result of interaction is greater
than the sum of the drugs used alone
e.g. antibiotic combinations such as sulphonamides and dihydrofolicacid reductase inhibitors such as trimethoprim
potentiationoccurs when a drugs effect is increased by another
agent that has no such effect
e.g. therapeutic interaction of -lactamase inhibitors such as clavulanic
acid with lactamase-susceptible penicillins
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Interactions based on Drug Antagonism
antagonismis often predictable
e.g. antagonism of bronchodilating effects of 2-adrenoceptor
activators used in asthma is to be anticipated if a -blocker is given for
another condition
e.g. action of a catecholamine on heart rate (via -adrenoceptor
activation) is antagonized by an inhibitor of acetylcholinesterase that
acts through ACh (via muscarinic receptors)
some antagonisms do not appear to be based on receptor
interactions
e.g. NSAIDs may decrease the antihypertensive action of ACE inhibitors
by reducing elimination of sodium
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Pharmacodynamic interactions
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The End
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