BPHM2004 L25 Drug Interactions 29Nov2013

8/10/2019 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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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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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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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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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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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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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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Wilkinson GR, N. Engl. J. Med.352:2211-21 (2005)


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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

MMXIII@HKU

BPHM2004 L25 Drug Interactions 29Nov2013

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