Download Mechanism of DI

Drug interactions
Jiří Slíva, M.D., PhD.
Agenda
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epidemiology
classification and mechanism of drug
interactions (DI)
recent cases
 cisapride,
statins, grape-fruit juice, St. John´s worth
etc.

quality of information on DI
Epidemiology of DI

hospitalized
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
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7 % of ADRs during hospitalization
0.2 % serious and life-threatening DI
ambulatory
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follow-up of 2422 patients during 2 months
4.7 % potentially risky combinations
0.3 % DI
Definition & classification

LI =…administration of substance (drug) A
influences substance B

pharmacodynamic DI – change of effect without influence
of pharmacokinetics
pharmacokinetic DI – influence of pharmacokinetics
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clinically important / unimportant
advantageous (analgesics, antihypertenzives, ICS +
LABA)
harmful
synergic / antagonistic
Pharmacodynamic interactions
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Diuretics + digoxine: hypokalemia -  toxicity of
glycosides
IMAO + ephedrine, thyramine: hypertensive reaction
warfarine + ASA (NSAIDs):  bleeding
NSAIDs + antihypertensives:  antihypertensive effect
non-sedative antihistaminics + alcohole:  sedace
Parmacokinetic interactions
Absorption
 Distribution
 Biotransformation
 Excretion

Absorption

Influence of GI motility, stomach evaluation
 acceleration - metoclopramide, cisapride
 deceleration - atropine, opioids

Inhibition of resorption
 cholestyramine x warfarine, digoxin
 epinephrine in local anesthetics
Distribution

Plasma protein binding – mostly clinically non-important
(+  elimination)
 ASA,
NSAIDs, OADs, sulfonamides, fenytoine
 phenylbutazone
x warfarine = displacement from a
bound to albumine + inhibition of metabolism of Swarfarine
 salicylates
secretion
+ methotrexat: + inhibition of tubular
Biotransformation
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Cytochrome P-450 - isoenzymes CYP 3A4, 2D6, 1A2, 2C9
INDUCTION (barbiturates, rifampicine, fenytoine,
carbamazepine, ethanole)
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INHIBITION (cimetidine, macrolides, imidazoles, SSRIs,
grape-fruit juice – 3A4; 2D6 - verapamile, amiodarone)
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Xantinoxidase - allopurinole x azathioprine
Aldehyddehydrogenase - disulfirame x warfarine
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Different contributions of various CYP isoforms in liver
in total
active in drug metabolism
Genetic polymorphism

metabolisers – slow, intermediary, fast, ultra-fast
CYP 1A2, 2C9, 2D6, 2E1
xantinoxidase, alcoholdehydrogenase, COMT, AChE
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phenotypisation – individualized therapy
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Excretion
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Change of plasma protein binding -  free fraction
-  filtration - excretion
Inhibition of tubular secretion
 probenecide x peniciline, AZT
Change of volume & pH of urine
 diuretics
Genetic susceptibility to ADRs
pharmacogenetics
Mibefradil
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CCB blocking Tchannels –
hypertension, CHF 1997
recall after 1 year
due to DI
historically first recall
due to DI only,
minimal toxicity
strong inhibitor of
CYP3A4
DI and risk of QT interval
prolongation
cisapride
 non-sedative antihistaminics – astemizole,
terfenadine
 …..ventricle arrhythmias – torsade de
pointes ………..fibrilation !!!
 astemizole, terfenadine…….recall
 cisapride …..recall
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DI of statins & rhabdomyolysis
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cerivastatin
 recall
due to rhabdomyolysis and interactions
with CYP3A4 inhibitors and fibrates
(gemfibrozile)
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imidazoles, macrolides, diltiazem,
verapamil, ciclosporin, grapefruit etc.
Rhabdomyolysis due to DI of
statins and fibrates
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August 2001 – recall of cerivastatine as a result of high
risk of rhabdomyolysis
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most lipophilic and highest bioavailability (60 %)
in USA very often combined with gemfibrozile
administered at relatively high doses
Absolute risk of rhabdomyolysis
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incidence for all statins
 0.15
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deaths / 1 million prescriptions
cerivastatine
 21fold
higher risk than others
 31.9 % of all deaths due to statins in spite of
its short-time use
……………….White CM, 2002
Food supplements, phytopharmacs
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Grape-fruit juice
 an
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St. John´s wort
 an
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inhibitor of 3A4
inductor of 3A4
smoking – induction of 1A2 (imipramine,
clozapine, propranolole)
ethanole - 2E1
Interesting DI I.
Crataegus levigata, Cr. monogyna (hawthorn)

concomitant administration with digoxine at dose 0.25 mg
for 10 days or combination of digoxine with an extract of
leaves & flowers 450 mg bid (1 dose = 84.3 mg of
oligomeric procyanides) led to decrease of maximal plasma
concentration of digoxine by 14 % and minimal plasma
concentration by 23 %

Mechanism of DI – influence of P-glycoprotein
…Tankanov R, 2003
Interesting DI II.
Ginseng

higher risk of bleeding when combined with warfarin
…Janetzky K, 1997

lower efficacy of diuretics
…Becker BN, 1996

higher pl. levels of digoxine
…Mc Rae S, 1996
Interesting DI III.
Gingko biloba

2 case reports of fatal bleeding:
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man, 71 y, ibuprofen 600 mg/d, Gingko biloba 40 mg
bid, 4 weeks => fatal intracerebral bleeding
woman, 70 y, warfarin for 5 y, then 2 months Gingko
biloba => intracerebral bleeding
…Matthews MK, 1998
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Mechanism of DI – inhibition of PAF etc.
stimulation of CYP2C19 – faster metabolism of omeprazole
…Yin OQ, 2004
Interesting DI IV.
Hypericum perforatum
Mechanism of DI

pharmacokinetic
- induction of cytochrome P450 in liver (esp.
CYP1A2, CYP2C9 & CYP3A4)
- induction of P-glycoprotein
- inhibition of MAO

pharmacodynamic
- in synapsis – elevation of 5-HT – DI with triptans,
antidepressants
Interesting DI V.
Hypericum perforatum
Drugs
Result of DI
antihistamines (fexofenadin, loratadine)
lower efficacy (fexofenadine), delirium
(loratadine)
antivirotics (efavirenz, indinavir, lamivudin,
nevirapin, stavudin)
lower virostat eff.
digoxine
lower eff. of digoxine
imatinibe
lower eff. of imatinibe
immunosuppressants (ciclosporin, tacrolimus)
lower immunosuppressive eff.
midazolam
lower eff. of midazolam
peroral contraceptives
gravidity, womb bleeding
simvastatine
lower lipid-lowering eff.
SSRI, triptans, dextromethorphane
serotonin syndrome
verapamile
lower eff. of verapamile
warfarine
lower anticoagulatory eff.
Grape-fruit juice

a strong inhibitor
of CYP3A4 & Pglycoprotein
Where do I find information
about DI ?
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Selected resources:
BNF & AISLP – SPCs
 database Micromedex – accessible via
Onelog
 Stockley’s Drug Interactions
 Interakce InfoPharm
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Quality of information about DI
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Clinical relevance:
 A...probably non-serious
 B…so far not confirmed (theoretical)
 C…moderate
 D…serious
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Level of documentation
 1...uncomplete case-reports
 2…good documented case-reports
reports
 3…studies with healthy volunteers
 4…controlled study with patients
or series of case-
Adverse drug
reactions (ADRs)
Reasons of ADRs
 Drug
 Patient
 Inappropriate drug combination
 Inappropriate indication
Classification of ADRs I.
Serious
 Death /life threatening
Nonserious
 Serious deterioration of health
 Permanent aftereffect
 Hospitalization
 Hospitalization prolongation
 Disability
 Congenital abnormality
Others
Classification of ADRs II.
Expected
Unexpected
ADRs mentioned in current SmPC
Others
PSUR (Periodic Safety Update Report)
Legislative in EU
(Eudralex Vol. 9 Pharmacovigilance, Commission Directive
2001/20/E, CPMP/PhVWP/108/99 etc.)
+ local requirements of regulatory authorities
Pharmacovigilance
 registration holder
 regulatory body
 health professionals
System of reporting in the
Czech Republic
Registration holder
Health professionels
Serious ADR
Serious or
unexpected ADR
Serious ADR (up to 15 d.)
Non-serious ADR (PSUR)
Reg. author.
Minimal data needed for ADR
reporting
 Drug suspected
 Patient information (age, sex)
 Reaction description
 Source of reporting