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DRUG INTERACTIONS
Dr. Jorge Zimbron
ST5 in General Adult Psychiatry
Clinical experience
Outline
• Definitions
• At risk groups
• Types of drug interactions
• Clinical tips
• Example questions
• References
Definitions
• Drug interaction
• Modification of the action of one drug by another.
• Can increase or decrease the effect of a drug.
• Can be beneficial.
• Not all clinically significant.
• Pharmacodynamics
• Pharmacokinetics
Definitions
• Pharmacokinetics may be simply defined as what the
body does to the drug, as opposed to…
• pharmacodynamics which may be defined as what the
drug does to the body
At risk groups
• Elderly
• Chronic illness
• Prescribed more drugs
• Poor kidney and liver function
• People with drug and alcohol problems
• People in/from developing countries
• People on drugs with narrow therapeutic index.
Narrow therapeutic index drugs
• Lithium 1.5:1
• Phenytoin
• Warfarin
• Digoxin 2:1
• Gentamicin
• Vancomycin
• Amphotericin B
Types of drug interactions
• Pharmaceutical
• Pharmacodynamic
• Pharmacokinetic
• P-Glycoprotein interactions
Pharmaceutical interactions
• Mixing of two incompatible drugs outside the body.
• Eg. Mixing haloperidol and lorazepam im in one syringe.
• No known hazardous interactions in psychotropic drugs.
Pharmacodynamic interactions
• Drugs competing for same target.
• Commonest type of interactions.
• Types:
• Antagonistic
• Antipsychotics vs levodopa in Parkinson’s.
• Synergistic
• Alcohol and TCAs – CNS depression
• SSRIs & aspirin – inhibition platelet aggregation
• Duration tends to depend on half-life or enzyme
production.
Pharmacokinetic interactions
Absorption, distribution,
metabolism or elimination of a
drug is influenced by another.
• Absorption
– Phenothiazines or sulpiride with
antacids.
• Distribution
– Protein bound drugs (>90%)
• Phenytoin is displaced by diazepam
– Short lived effect due to increase in
metabolism.
– Lysosomal trapping
• Thioridazine + antidepressants
Lysosomal trapping
• Tissues with high lysosomal content
• Lungs
• Liver
• Kidneys
• Astrocytes
• Tissues with low lysosomal content
• Heart
• Neurons
Pharmacokinetic interactions
•
Metabolism (cytochrome p450 &
UGTs*)
– Phase 1 metabolism (oxydation,
reduction, hydrolysis →
conjugation → excretion).
• Enzyme induction (not usually
hazardous)
– Carbamazepine: ↑ metabolism of
TCAs and antipsychotics.
• Enzyme inhibition
*uridine diphosphate glucuronosyltransferases: phase 2 conjugation reactions. Covalent
bond between drug and endogenous substrate (eg. glucuronide). Poorly understood.
Cytochrome p450 enzymes
• 11 important. 5 to remember in Ψ:
– CYP1A2
– CYP2C9*
– CYP2C19*
– CYP2D6*
– CYP3A4
*Polymorphisms = varying activity levels
• Poor, extensive (normal), and ultrarapid metabolisers.
– Implications for drugs and pro-drugs
CYP enzyme induction
• CYP3A4 – induced by carbamazepine, phenobarbital,
phenytoin, rifampicin, St. John’s Wort.
• Reduced efficacy of haloperidol
CYP enzyme inhibition
• Most likely to cause life-threatening interactions.
• Usually due to competition at binding site.
• Usually 1 inhibitor doesn’t affect more than 1 CYP protein.
• Eg sodium valproate inhibits CYP3A4.
• Leads to increased skin reactions with lamotrigine.
p450 issues
• Drugs usually metabolised by more than 1 CYP enzyme.
• No tests for individual genetic CYP makeup.
• Impossible to predict responses clinically
Pharmacokinetic interactions
• Absorption
• Distribution
• Metabolism
• Excretion (kidney)
– Lithium (re-absorbed proximal convoluted tubule with Na)
• Thiazides ↑Na excretion → compensation by PCT ↑absorption ↑lithium
P-Glycoprotein interactions
• Involved in absorption,
distribution, and excretion.
• Member of the ATP binding
cassette (ABC) transporter
superfamily.
– Efflux pump (intracellular to
extracellular matrix)
– Present throughout the body
– ↓ absorption by excreting
drug into intestinal lumen.
– Excrete drug from liver to bile
and from kidney to urine.
– Present at BBB and reduces
drug access to CNS
Common effects of interactions
• Oversedation (eg. inhibition of CYP3A4)
– Elderly
– RTAs
– DVTs
• Serotonin syndrome
• Seizures
– Antipsychotics
– St. John’s Wort induces metabolism of carbamazepine and
phenytoin.
Common effects of interactions
• Hypotension
• Falls
• Ischaemia
• Hypertension
• Eg MAOi + TCAs
• Arrhythmias (QTc)
Clinical points
• Impossible to remember.
– Always check!
– Eg tramadol + SSRI
• Impossible to predict
– f/u essential
• Hospital vs community prescribing
• Theoretical interactions not always clinically significant
– Based on animal experiments & case reports
Drug interaction checkers
• www.drugs.com
• http://wiki.psychiatrien
et.nl/index.php/Main_P
age
• Epocrates
• Bazire
• (BNF)
Common interactions in clinical practice
• IM olanzapine and IM benzodiazepines
• Lithium and NSAIDs
• Lithium and haloperidol (commonly used)
• Lithium and diuretics
• Thiazides
• K sparing
• Lithium and ACEi
• SSRIs and MAOi
Questions
1 A hazardous drug interaction is more likely to occur:
• a if the drug in question has a wide therapeutic index
• b with inhibition rather than induction of drug metabolising
enzymes
• c with drugs that are renally excreted
• d during long-term therapy with both drugs
• e in elderly people.
Questions
2 Inhibitors of the cytochrome P450 enzyme system:
• a affect all enzymes equally
• b have a slow onset of action on the enzymes
• c produce predictable effects on the metabolism of drugs
that are metabolised by CYP enzymes
• d include cimetidine and omeprazole
• e are less likely to produce drug interactions than are
inhibitors of UGTs.
Questions
3 P-glycoprotein:
• a is a hepatic drug-metabolising enzyme
• b can be inhibited or induced by drugs
• c is involved in maintenance of the blood–brain barrier
• d is involved in the renal excretion of lithium
• e has a well-defined role in the genesis of interactions
involving psychotropic drugs.
Questions
4 Elderly mentally ill people who have concomitant physical
illnesses:
• a can be treated safely with simvastatin while taking paroxetine
• b need pose no concerns if treated with nefopam and an MAOI
• c are at increased risk of hip fractures while receiving
thioridazine and lorazepam
• d are at greater risk of death if they are taking St John’s wort
and require theophylline for a severe asthmatic attack
• e have an increased chance of developing agranulocytosis if
fluvoxamine is co-administered with clozapine.
Questions
5 Patients in general can be:
• a safely treated with a combination of penicillin and
antidepressants that have epileptogenic potential
• b legally prevented from driving if they are prescribed
carbamazepine together with trifluoperazine
• c in danger of torsade de pointes if they have alcohol
dependence and are treated with sertraline
• d safely co-prescribed lithium and thiazide diuretics
Answers
References