Paul (Pharmacogenetics and mental health) Flashcards
Pharmacogenomics
Polymorphisms (>1% of population)
Common types of polymorphisms:
- SNPs (Single nucleotide)
- STRP (short tandem repeat)
- Gene deletion
- Copy number variant
These can affect protein structure and/or function
What proteins are involved with drug action?
Is their relationship with pharmacodynamics or pharmacokinetics?
- Transport or carrier proteins (PD/PK)
- Receptors (PD)
- Enzymes (PD/PK)
- Ion channels (PD)
- Human Leukocyte Antigen (HLA Complex)
- Hypersensitivity reactions to drugs
- Disease pathogenesis e.g. Cystic Fibrosis
Effects on pharmacokinetics (ADME)
Transporter/carrier proteins e.g.
- P-glycoprotein (efflux transporter)
Drug metabolising enzymes
- Cytochrome P450
- CYP239/CYP2C19/CYP2D6/CYP3A4
- Poor metabolisers, extensive, ultra rapid
Effects on pharmacodynamics
Receptors e.g. 5HT receptors
Enzymes e.g. VKORC1
- affects warfarin
Idiosyncratic reactions and disease
HLA complec
- Increase hypersensitivity to
- Carbamazepine
- Abacavir
- Lamogitrine
Cystic fibrosis
Prescribing in psychiatry
Evidence for efficacy
Evidence for safety
Concordance issues
Problems- (clinical trial is much shorter than the amount of time a patient will be on the drug i.e. lifetime)
Any family history of ADRs?
Why has psychiatry more to gain from personalised medicine than other disciplines?
- Complex conditions
- Symptom similarities between diseases
- Poor classification of mental illness
- Different genetic causes/biological mechanisms
- Nosologic insights to aid diagnosis
- No objective tests
- Greater adherence (Cloziping used in schizophrenia and you need blood tests every month so hard drug to be on)
- Time
- Poor response rates e.g. 35%-40% in schizophrenia and bipolar affective disorder
- High incidence of side effects
Pharmacogenomic targets
Pharmacodynamics
- Synthesis of serotonin transporter
- Opiate receptors
- Dopamine receptor
- Gene variant predicted response to clozapine
- Weight gain or other side effects
- Alzheimers and apolipoprotein E variants
Pharmacokinetics
- Variations in liver metabolism by CYP450
- 40+ fold differences in plasma concentrations of some drugs
- Variations in responsiveness and side effects
- Drug interactions susceptibility
Challenges
- Many psychiatric drugs employ a range of mechanisms e.g. largactil (blocks many receptors which can cause a lot of side effects) and antipsychotics
- Psychiatric drugs are metabolised by a range of different liver enzymes
- AEDs (anti-epileptic drugs)
DME (drug metabolising enzyme) genes
Tests for several are now routine
Prediction of pharmacokinetic phenotypes e.g.
- CYP4502D6 gene (in liver, phase 1 metabolism)
- CYP4502C19 gene
CYP4502D6 gene
22nd chromosome high allelic variability.
Primary metabolism of 70 medicines.
You usually inherit 1 copy from mother and 1 from father. However,
- Ultra metabolisers inherit an extra copy of the gene from either one or both parents.
- Poor metabolisers inherit 2 inactive copies
- Slower metabolisers inherit 1 inactive, 1 partially inactive
- Intermediate metabolisers inherit 1active, 1 inactive/partial
- Extensive metabolisers inherit 2 copies at normal doses
2D6 substrates
Predominantly 2D6 substrates:
- Despramine
- Nortriptyline
- Fluoxetine
- Paroxetine
- Venlafaxine
Partial 2D6 substrates
- Amitriptyline
- Imipramine
- Mirtazapine
- Duloxetine
- Bupropion
- Sertraline
- Trazodone
Minimal 2D6 substrates
- Citalopram
- Escitalopram
- Fluvoxamine
Multiple copies- ultra metabolisers
Other African and Mediterranean populations have a higher frequency of individuals who have multiple active copies of the 2D6 gene.
In Ethiopia and Somalia, up to 30% of the population are ultra rapid metabolisers.
These patients require higher than the standard recommended dosage of 2D6 substrate medications to obtain a therapeutic blood level.
CYP4502C19 gene
10th gene.
Less variable then 2D6 (8 variants).
Normal extensive metabolisers (2 copies of wild type 1).
Intermediate metabolisers (1 copy).
Poor metabolisers (2 deficient copies)
- Caution tricyclics (imipramine and amitriptylene) 60% of normal dose needed
Serotonin transporter (SLC6A4 gene)
17the chromosome.
SERT or 5HTTR.
31,000 nucleotide base pairs.
14 exons that define sequences for SERT.
43-base deletion polymorphisms (promoter region)
‘Short form’ is deletion of 43 base pairs.
3 classifications
- Long/long (more rapid re-uptake- better response- original structure)
- Long/short
- Short/short (more likely to develop depression under stress)
