Pharmacogenetic Considerations for Psychiatric Drugs Flashcards
Generic
aripiprazole
BRAND
Abilify
Abilify Maintena
aripiprazole (Abilify, Abilify Maintena)
Biomarker - CYP2D6
aripiprazole (Abilify)
Dosage note
Poor metabolizers (PMs): initially reduce
dose to ½ the usual dose; adjust based on
clinical response.
aripiprazole (Abilify Maintena)
Dosage note
PMs: 300mg once monthly.
aripiprazole (Abilify)
administration note
Concomitant strong CYP3A4
inhibitors: reduce aripiprazole dose to ¼ the
usual dose.
Generic
atomoxetine
Brand
Strattera
aripiprazole (Abilify Maintena)
Admin note
Concomitant CYP3A4 inhibitors: 200mg once monthly. See
full labeling.
atomoxetine (Strattera)
Biomarker
CYP2D6
atomoxetine (Strattera)
Children & Adolescents (PMs greater than 70 kg) or concomitant strong CYP2D6 inhibitors in
adults
initially 40mg/day; titrate to usual target dose of 80mg/day after 4wks if needed.
atomoxetine (Strattera)
Children & Adolescents
PMs less than 70kg or concomitant strong CYP2D6 inhibitors:
initially 0.5mg/kg/day; titrate to usual target
dose of 1.2mg/kg/day after 4wks if needed.
Generic
carbamazepine
Brand
Tegretol
carbamazepine (Tegretol)
Biomarker
HLA-B*1502
carbamazepine (Tegretol)
Chinese ancestry: studies have found strong
association between HLA-B1502 and the risk
of developing SJS/TEN. Test for HLA-B1502 prior to initiation of Tegretol; should not be used if HLA-B*1502-positive.
carbamazepine (Tegretol)
Other antiepileptic drugs (phenytoin): limited evidence suggests that HLA-B1502 may be a risk factor for the development of SJS/
TEN. Consider avoiding use of other drugs associated with SJS/TEN in HLA-B1502-positive
patients, when alternative therapies are equally
acceptable.
Generic
citalopram
Brand
Celexa
citalopram (Celexa)
biomarker
CYP2C19, CYP2D6
citalopram (Celexa)
CYP2C19 PMs, concomitant cimetidine or
other CYP2C19 inhibitors, hepatic impairment, or >60yrs: max 20mg/day due to the
risk of QT prolongation.
citalopram (Celexa)
CYP2D6 PMs and EMs: levels not significantly different.
Generic
clobazam
Brand
Onfi
clobazam (Onfi)
biomarker
CYP2C19
clobazam (Onfi)
PMs: initially 5mg/day; titrate according to
weight but to ½ the usual dose, an additional
titration to max dose (20mg/day or 40mg/day,
depending on weight) may be started at Day 21
chlordiazepoxide/
amitriptyline
Biomarker
CYP2D6
chlordiazepoxide/
amitriptyline
PMs: normal metabolizers (NMs) may resemble PMs since certain drugs inhibit CYP2D6. Caution with concomitant SSRIs or when switching
from one class to the other. Sufficient time (at
least 5wks) must elapse before initiating TCAs
in patients being withdrawn from fluoxetine.
Concomitant CYP2D6 inhibitors: may need to
adjust dose of either drug; if withdrawn, may
need to increase TCA dose (monitor).
Generic
clomipramine
Brand
Anafranil
clomipramine (Anafranil)
Biomaker
CYP2D6
clomipramine (Anafranil)
Interactions
PMs: normal metabolizers (NMs) may resemble PMs since certain drugs inhibit CYP2D6. Caution with concomitant SSRIs or when switching
from one class to the other. Sufficient time (at
least 5wks) must elapse before initiating TCAs
in patients being withdrawn from fluoxetine.
Concomitant CYP2D6 inhibitors: may need to
adjust dose of either drug; if withdrawn, may
need to increase TCA dose (monitor).
Generic
clozapine
Brand
Clozaril,
FazaClo
clozapine
(Clozaril, FazaClo)
Biomarker
CYP2D6
clozapine
(Clozaril, FazaClo)
PMs: may need to reduce dose. Increased clozapine levels possible since it’s completely
metabolized and then excreted.
Generic
desipramine
Brand
Norpramin
desipramine (Norpramin)
BioMarker
CYP2D6
desipramine (Norpramin)
PMs: normal metabolizers (NMs) may resemble PMs since certain drugs inhibit CYP2D6. Caution with concomitant SSRIs or when switching
from one class to the other. Sufficient time (at
least 5wks) must elapse before initiating TCAs
in patients being withdrawn from fluoxetine.
Concomitant CYP2D6 inhibitors: may need to
adjust dose of either drug; if withdrawn, may
need to increase TCA dose (monitor).
Generic
dextromethorphan/
quinidine
Brand
Nuedexta
dextromethorphan/
quinidine (Nuedexta)
Biomarker
CYP2D6
dextromethorphan/
quinidine (Nuedexta)
PMs: quinidine component does not contribute
to the effectiveness of Nuedexta in PMs but a
possible risk of significant toxicity is present.
Consider genotyping to determine PM status
prior to initiation.
Generic
doxepin
Brand
Silenor
doxepin (Silenor)
Biomarker
CYP2D6, CYP2C19
doxepin (Silenor)
Special populations
PMs: may have higher doxepin plasma levels
than NMs
Generic
fluoxetine
Brand
Prozac
fluoxetine (Prozac)
Biomarker
CPY2D6
fluoxetine (Prozac)
Concomitant drugs metabolized by
CYP2D6 or narrow therapeutic index: NMs may resemble PMs since fluoxetine is a CYP2D6
inhibitor. Initiate lowest effective dose if receiv-
ing fluoxetine or have taken it in previous 5wks.
If already taking drugs metabolized by CYP2D6
and fluoxetine is added afterwards, consider
decreasing dose of original drug.
Generic
fluoxetine/
olanzapine
Brand
Symbyax
fluoxetine/
olanzapine (Symbyax)
biomaker
CYP2D6
fluoxetine/
olanzapine (Symbyax)
Concomitant drugs metabolized by
CYP2D6 or narrow therapeutic index: NMs may resemble PMs since fluoxetine is a CYP2D6
inhibitor. Initiate lowest effective dose if receiv-
ing fluoxetine or have taken it in previous 5wks.
If already taking drugs metabolized by CYP2D6
and fluoxetine is added afterwards, consider
decreasing dose of original drug.
fluvoxamine
Biomarker
CYP2D6
fluvoxamine
PMs: caution with fluvoxamine and other
concomitant drugs known to inhibit CYP2D6.
Generic
galantamine
Brand
Razadyne
galantamine (Razadyne)
Biomarker
CYP2D6
galantamine (Razadyne)
PMs: similar pharmacokinetics parameters com-
pared to EMs. No dosage adjustment needed
in PMs since the dose is individually titrated to
tolerability.
Generic
iloperidone
Brand
Fanapt
iloperidone (Fanapt)
Biomarker
CYP2D6
iloperidone (Fanapt)
PMs: higher exposure to iloperidone vs. EMs.
Reduce dose by ½. Lab tests are available to
identify CYP2D6 PMs.
Generic
imipramine
Brand
Tofranil
imipramine (Tofranil)
Biomarker
CYP2D6
imipramine (Tofranil)
PMs: normal metabolizers (NMs) may resemble PMs since certain drugs inhibit CYP2D6. Caution with concomitant SSRIs or when switching
from one class to the other. Sufficient time (at
least 5wks) must elapse before initiating TCAs
in patients being withdrawn from fluoxetine.
Concomitant CYP2D6 inhibitors: may need to
adjust dose of either drug; if withdrawn, may
need to increase TCA dose (monitor).
Generic
modafinil
Brand
Provigil
modafinil (Provigil)
Biomarker
CYP2D6
modafinil (Provigil)
PMs: metabolism by CYP2C19 may be substantially increased. Provigil may cause elevation in
tricyclic levels; may need to reduce dose of tricyclics.
Generic
nortriptyline
Brand
Pamelor
nortriptyline (Pamelor)
Biomarker
CYP2D6
nortriptyline (Pamelor)
PMs: normal metabolizers (NMs) may resemble PMs since certain drugs inhibit CYP2D6. Caution with concomitant SSRIs or when switching
from one class to the other. Sufficient time (at
least 5wks) must elapse before initiating TCAs
in patients being withdrawn from fluoxetine.
Concomitant CYP2D6 inhibitors: may need to
adjust dose of either drug; if withdrawn, may
need to increase TCA dose (monitor).
Generic
phenytoin
Brand
Dilantin
phenytoin (Dilantin)
Biomarker
HLA-B*1502
phenytoin (Dilantin)
Chinese ancestry: limited evidence suggests
that HLA-B1502 may be a risk factor for the
development of SJS/TEN. Consider avoiding
phenytoin as an alternative for carbamazepine
if HLA-B1502-positive. Use of HLA-B*1502
genotyping has important limitations and must
never substitute for appropriate clinical vigilance and patient management.
perphenazine
Biomarker
CYP2D6
perphenazine
(PMs)
PMs: metabolize perphenazine slower and
have higher concentrations vs. NMs or extensive
metabolizers (EMs).
perphenazine
(elderly)
Elderly: PMs have higher plasma concentra-
tions of antipsychotics at usual doses, which
may correlate with the emergence of side
effects. Prospective phenotyping prior to initiation may identify those at risk for adverse events.
Generic
pimozide
Brand
Orap
pimozide (Orap)
Biomarker
CYP2D6
pimozide (Orap)
Children
Children (>0.05mg/kg/day): perform
CYP2D6 genotyping. PMs: max 0.05mg/kg/day;
should not increase dose earlier than 14 days.
pimozide (Orap)
Adult
Adults (doses >4mg/day): perform CYP2D6
genotyping. PMs: max 4mg/day; should not increase dose earlier than 14 days
Generic
protriptyline
Brand
Vivactil
protriptyline (Vivactil)
Biomarker
CYP2D6
protriptyline (Vivactil)
PMs: normal metabolizers (NMs) may resemble PMs since certain drugs inhibit CYP2D6. Caution with concomitant SSRIs or when switching
from one class to the other. Sufficient time (at
least 5wks) must elapse before initiating TCAs
in patients being withdrawn from fluoxetine.
Concomitant CYP2D6 inhibitors: may need to
adjust dose of either drug; if withdrawn, may
need to increase TCA dose (monitor).
Generic
risperidone
Brand
Risperdal
risperidone (Risperdal)
Biomarker
CYP2D6
risperidone (Risperdal)
EMs and PMs have similar pharmacokinet-
ics even though EMs convert risperidone to
9-hydroxyrisperidone quicker than PMs.
Risperidone EMs half-life: 3hrs.
Risperidone PMs half-life: 20hrs.
Overall mean half-life: 20hrs.
Generic
tetrabenazine
Brand
Xenazine
tetrabenazine (Xenazine)
Biomarker
CYP2D6
tetrabenazine (Xenazine)
> 50mg/day: perform CYP2D6 genotyping to
determine PM or EM status prior to initiation.
Individualize dose based on PM or EM status.
EMs or intermediate metabolizers (IMs): max 37.5mg/dose or 100mg/day.
PMs: max 25mg/dose or 50mg/day.
Generic
trimipramine
Brand
trimipramine (Surmontil)
Biomarker
CYP2D6
trimipramine (Surmontil)
PMs: normal metabolizers (NMs) may resemble PMs since certain drugs inhibit CYP2D6. Caution with concomitant SSRIs or when switching
from one class to the other. Sufficient time (at
least 5wks) must elapse before initiating TCAs
in patients being withdrawn from fluoxetine.
Concomitant CYP2D6 inhibitors: may need to
adjust dose of either drug; if withdrawn, may
need to increase TCA dose (monitor).
thioridazine
Biomarker
CYP2D6
Psychopharmacology is the study of
how drugs interact with specific target sites in the nervous system to induce changes in mood, thinking, or behavior
are interested in a wide variety of drug classes that produce psychological side effects, such as antidepressants, stimulants, antipsychotics, hallucinogens, benzodiazepines, opiates, and hypnotics.
Pharmacodynamics - Potency
Potency is an index of the concentration required for a given effect - usually the EC50. It is not the same as effect.
Drugs that are highly potent require only small doses (concentrations) to achieve their effects.
High potency is often considered desirable because less drug (in molar terms) is available to cause adverse effects.
Pharmacodynamics - Efficacy
Efficacy is the desired effect (e.g. analgesia). Some drugs (e.g. morphine) have greater analgesic effect than others (e.g. paracetamol).
Pharmacodynamics - Therapeutic Index
The therapeutic index represents the relationship between concentrations causing adverse effects and concentrations causing desired effects.
Drugs with a high or large therapeutic index are desirable in practice
World Health Organization’s Six-Step Model of Rational Prescribing
Step 1: Define the patient’s problem.
Step 2: Specify the therapeutic objective.
Step 3: Choose the treatment.
Step 4: Start the treatment.
Step 5: Educate the patient.
Step 6: Monitor effectiveness.
Brain Function & Deficits -
Cerebral Cortex (Frontal Lobes)
Functions
Functions:
– Consciousness (How we know what we are doing in our
environment)
– How we initiate activity in response to our environment
– Judgments we make about what occurs in our daily
activities
– Controls our emotional response
– Controls our expressive language
– Assigns meaning to the words we choose
– Involves word associations
– Memory for habits and motor activities
Brain Functions & Deficits
Cerebral Cortex (Frontal Lobes)
Observed problems
Observed Problems:
– Loss of simple movement of various body parts (Paralysis)
– Inability to plan a sequence of complex movements needed to complete multi-stepped tasks, such as making coffee (Sequencing)
– Loss of spontaneity in interacting with others. Loss of flexibility in thinking
– Persistence of a single thought (Perseveration)
– Inability to focus on task (Attending)
– Mood changes (Emotionally Labile)
– Changes in social behavior. Changes in personality
– Difficulty with problem solving
– Inability to express language (Broca’s Aphasia)
Brain Function & Deficits
Parietal Lobes
* Functions
Functions
–Location for visual attention
–Location for touch perception
–Goal-directed voluntary movements
–Manipulation of objects
–Integration of different senses that allows for
understanding a single concept
Brain Function & Deficits
Parietal Lobes
* Observed Problems
Observed Problems
– Inability to attend to more than one object at a time
– Inability to name an object (Anomia)
– Inability to locate the words for writing (Agraphia)
– Problems with reading (Alexia)
– Difficulty with drawing objects
– Difficulty in distinguishing left from right
– Difficulty with doing mathematics (Dyscalculia)
– Lack of awareness of certain body parts and/or surrounding space (Apraxia) that leads to difficulties in self-care. Inability to focus visual attention
– Difficulties with eye and hand coordination
Brain Functions & Deficits
Occipital Lobes
* Functions
Vision
Brain Functions & Deficits
Occipital Lobes
* Observed Problems
Observed Problems
– Defects in vision (Visual Field Cuts)
– Difficulty with locating objects in the environment
– Difficulty with identifying colors (Color Agnosia)
– Production of hallucinations Visual illusions - inaccurately seeing objects
– Word blindness - inability to recognize words
– Difficulty in recognizing drawn objects
– Inability to recognize the movement of an object (Movement Agnosia)
– Difficulties with reading and writing
Brain Functions & Deficits
Temporal Lobes
* Functions
Functions
–Hearing ability
–Memory acquisition
–Some visual perceptions
–Categorization of objects
Brain Functions & Deficits
Temporal Lobes
* Observed Problems
Observed Problems
– Difficulty in recognizing faces (Prosopagnosia)
– Difficulty in understanding spoken words (Wernicke’s Aphasia)
– Disturbance with selective attention to what we see and hear
– Difficulty with identification of, and verbalization about objects
– Short-term memory loss. Interference with long-term memory
Increased or decreased interest in sexual behavior
– Inability to categorize objects (Categorization)
– Right lobe damage can cause persistent talking
– Increased aggressive behavior
Brain Functions & Deficits
Brain Stem
* Functions
Functions
–Breathing Heart Rate Swallowing Reflexes to seeing
and hearing (Startle Response)
–Controls sweating, blood pressure, digestion,
temperature (Autonomic Nervous System)
–Affects level of alertness
–Ability to sleep
–Sense of balance (Vestibular Function)
Brain Functions & Deficits
Brain Stem
* Observed Problems
Observed Problems
–Decreased vital capacity in breathing, important for speech
–Swallowing food and water (Dysphagia)
–Difficulty with organization/perception of the environment
–Problems with balance and movement
–Dizziness and nausea (Vertigo)
–Sleeping difficulties (Insomnia, sleep apnea)
Brain Functions & Deficits
Cerebellum
* Functions
Functions
– Coordination of voluntary movement Balance and equilibrium
– Some memory for reflex motor acts
Brain Functions & Deficits
Cerebellum
* Observed Problems
Observed Problems
– Loss of ability to coordinate fine movements
– Loss of ability to walk
– Inability to reach out and grab objects
– Tremors. Dizziness (Vertigo)
– Slurred Speech (Scanning Speech)
– Inability to make rapid movements
Thalamus
– “central switching station” – relays incoming sensory information (except olfactory) to the brain
Hypothalamus
– controls the autonomic nervous system (maintains the body’s homeostasis)
Limbic System
– Emotional expression, particularly the emotional component of behavior, memory, and motivation
Amygdala
– Attaches emotional significance to information and mediates both defensive and aggressive behavior
Hippocampus
– involved more in memory, and the transfer of information from short-term to long-term memory
Glutamate –
– Glutamate is the major excitatory neurotransmitter in the brain.
– It is required for learning and memory.
– Low levels can lead to fatigue and poor brain activity.
– Increased levels of glutamate can cause death to the neurons (nerve cells) in the brain. Dysfunction in glutamate levels are involved in many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s, Huntington’s, and Tourette’s. High levels also contribute to Depression, OCD, and Autism.
