Transcript Psychopharmacology What you should know to survive the LMCC

Psychopharmacology
What you should know to survive the
LMCC and Internship
Kate Huntington, MD
April 2008
Objectives
To review:
• indications for
• mechanism of action
• side effects (remember not everyone gets
these)
• monitoring parameters
for the major classes of psychotropic
medications
SSRI’s: Indications
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MDD
GAD
Social phobia
PTSD
OCD
Augmentation in BD
Premenstrual Dysphoric Disorder
Panic Disorder
SSRI: Mechanism of Action
• In depression, the serotonin neuron has a relative deficiency of
serotonin and the autoreceptors and postsynaptic receptors are
increased in number & sensitivity
• When the reuptake pump is blocked, the level of serotonin increases in
the somatodendritic area, causing autoreceptors (the brakes) to
decrease in number & sensitivity
• This turns off the brake on the serotonin neuron and electrical impulses
flow down the axon, releasing more serotonin at the axon terminal
• Increased levels of serotonin in the synapse leads to down regulation
(decreased number and sensitivity) of postsynaptic receptors & other
downstream changes
SSRI: Side Effect Profile
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Headache
Anxiety (limbic projections) and Agitation (basal ganglia projections)
Nausea (chemoreceptor trigger zone)
Diarrhea (peripheral GI 5HT3 & 5HT4 receptors)
Sexual dysfunction (spinal projections) and Sleep disruption or
Somnolence (Brainstem sleep centre)
SSRI: Rare but Dangerous Side Effects
• UGI bleeding (platelet dysfunction)
• SIADH
• SSRI discontinuation syndrome (slow taper)
• Serotonin syndrome
Norepinephrine & Dopamine Reuptake
Inhibitor:Mechanism of Action
(Bupropion/Wellbutrin)
• Blockade of norepinephrine and dopamine reuptake pumps, leads to
similar cascade as with SSRI’s
NDRI: Side Effect Profile
• Seizures (not with SR formulation & following correct
dosing; contraindicated with Bulimia or electrolyte
disturbances)
• Headache
• Agitation (limbic cortex)
• Rash
• Emesis
• Sleep disruption (limbic cortex) and Shaking (cerebellum)
Serotonin & Noradrenergic reuptake
Inhibitors: Mechanism of Action
(Venlafaxine/Effexor)
• Blockade of serotonin reuptake up to about 150 mg
• Blockade of serotonin and norepinephrine reuptake from about 150225mg
• Blockade of serotonin, norepinephrine and dopamine reuptake above
225 mg
SNRI: Side Effect Profile
• Same as SSRI up to 150 mg
• >150 mg, may also see sustained increase in diastolic BP & other
noradrenergic-type side effects (see NDRI)
SNRI: Rare but Dangerous Side Effects
• As with SSRI’s
NaSSA: Mechanism of Action
• Blocks Alpha 2 autoreceptors on norepinephrine neurons &
heteroreceptors on Serotonin neurons, causing more NE & 5HT to be
released (puts the brakes on the brakes)
• NE neurons from the locus coeruleus innervate midbrain raphe 5HT
neurons. Therefore, increased NE causes a further increase in 5HT
release
• Blocks 5HT2 receptors, having an anxiolytic effect & blocking sleep &
sexual side effects
• Blocks 5HT3, blocking GI side effects from peripheral receptors &
from brainstem chemoreceptor trigger zone
• Blocks H1 histamine receptors, causing sedation & weight gain
NaSSA: Side Effect Profile
• Weight gain (H1 blockade)
• Anticholinergic: constipation, urinary retention, dry mouth,
blurred vision, drowsiness, sinus tachycardia,
confusion/delirium, fever (red as a beet, dry as a bone, blind as
a bat, mad as a hatter, hot as a hare; bowel & bladder lose
their tone & the heart goes off alone)
• Drowsiness (H1 blockade)
• Equilibrium
NaSSA: Rare but Dangerous Side Effects
• Neutropenia
• Serotonin syndrome
• Hepatotoxicity
• Possibly SIADH
SARI: Mechanism of Action
Serotonin 2A antagonists/reuptake inhibitors (Trazadone/Desyrel)
• Primarily blocks 5HT2A, reducing sexual dysfunction & sleep
disruption & increasing effect of 5HT1A stimulation (5HT2A &
5HT1A oppose one another)
• Weak 5HT reuptake inhibitor, increasing 5HT stimulation of 5HT1A
(therapeutic effects)
• H1 blockade causes sedation
• Alpha One blockade leads to orthostatic hypotension
SARI: Side Effect Profile
• Orthostatic hypotension
• Sedation
SARI: Rare but Dangerous Side Effects
• Serotonin syndrome
TCA: Mechanism of Action
Tricyclic antidepressants: 3° amines (eg amitriptyline, imipramine, doxepine) 2°
amines (eg nortriptyline, desipramine)
• Therapeutic effects and side effects from blocking Serotonin,
Norepinephrine & Dopamine Reuptake
• Some also have 5HT2 blocking ability (blocks sex & sleep side
effects)
• Side effects from blocking H1 histamine receptors, muscarinic
receptors, alpha one adrenergic receptors & sodium channels in the
heart & brain
TCA: Side Effect Profile
• Antihistamine – weight gain & sedation
• Anticholinergic – (remember toxidrome from NaSSA)
• Anti-alpha adrenergic – dizziness, orthostatic hypotension
• Blockade of fast sodium channels – prolongation of QTc (risk of
Torsades)
TCA: Rare but Dangerous Side Effects
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Torsades de Pointes
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EKG – rule out bradycardia and prolonged QTc
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Lytes – rule out electrolyte imbalance
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Make sure not on type 1 or 3 antiarrythmic drugs
SIADH
Serotonin Syndrome
MAOI: Mechanism of Action
Monoamine oxidase inhibitors:
“the classics” (phenylzine/nardil, tranylcypromine/parnate)
Reversible inhibitor: (moclobemide/mannerix)
• Irreversibly bind MAO (2 wks) & destroy its function, therefore
decrease monoamine breakdown, increasing 5HT, NE & DA
MAOI: Side Effect Profile
• Side effects related to increase in serotonin norepinepherine &
dopamine (see SSRI’s & NDRI’s)
• Orthostatic hypotension
MAOI: Rare but Dangerous Side Effects
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Blood dyscrasias
Hepatotoxicity
Teratogenicity
Serotonin Syndrome - (even more susceptable than with other
serotenergic antidepressants)
• When you see an MAOI, get a pharmacy consult, the patient
should consult their pharmacist about any over - the – counter
medications
• Hypertensive crisis
• Consult the dietician Re: MAOI diet
• Patients need to avoid all foods with tyramine (aged foods such as
cheese and wine)
Serotonin Syndrome
Major Criteria
Minor Criteria
Mental
Symptoms
impaired consciousness,
elevated mood,
coma/semicoma
restlessness,
insomnia
Autonomic
Symptoms
fever, sweating
Tachycardia, dyspnea,
diarrhea
Neurological
Symptoms
myoclonus, tremor,
shivering, rigidity,
hyperreflexia
uncoordination, dilated
pupils, akathisia
Co-incidence with the addition or increase of a serotenergic agent
Development of at least 4 major or 3 major plus 2 minor criteria
Hypertensive Crisis
• Norepinephrine is the amine most closely linked with control of blood
pressure
• MAO normally inactivates norepinepherine
• Tyramine, an amine present in aged foods, causes release of
norepinepherine
• In the presence of MAOI, this increased NE cannot be broken down,
resulting in a hypertensive crisis
Starting Antidepressants: General Guidelines
• Start with a reuptake inhibitor or mirtazepine (not a TCA or MAOI)
• Start at lowest possible dose (half of this with anxiety and in the
elderly and medically frail)
• Increase by this increment about every five half lives (or about once a
week) until one of the following endpoints:
• Intolerable side effects
• Full response
• Maximum dose
• Continue to monitor for therapeutic effects, side effects and safety
Course of Recovery From
Depression
Response
2-3 weeks:
3-4 weeks:
6-8 weeks:
Improved
sleep,
appetite,
vegetative
shifts
objective
improvement
energy
suicidal
ideation may 
subjective
improvement
Stimulants: Indications
• ADHD
• Narcolepsy
• (treatment resistant depression)
Stimulants: Mechanism of action
• Increases dopamine and NE actions by blocking
their reuptake and facilitating their release
• Action in DL prefrontal cortex improves attention,
concentration, executive function and wakefulness
• Action in Basal Ganglia may improve
hyperactivity
• Action in medial prefrontal cortex may improve
depression, fatigue and sleepiness
Stimulants:
Common Side Effects
• Headaches and Heart concerns(palpitations,
tachycardia and hypertension)
• Insomnia, Irritibility and Increased stimulation
• Dizziness
• Exacerbation of tics, tremor
• Stomach: anorexia, nausea, abdo pain, weight
loss, possibly slowing of normal growth in
children
Stimulants:
Rare Side Effects
• Psychosis
Stimulants:
Ongoing Monitoring
• Blood pressure at baseline and with dose
increases
• In children, ongoing monitoring of height
and weight
ECT: Indications
• Common
• MDE
• Mania
• Mixed state
• Catatonia
• Schizophenia with
prominent affective
symptoms
• Schizoaffective disorder
• Uncommon
• Delirium
• NMS
• Parkinson’s Disease
ECT: Indications (cont.)
• Indications for First Line Use:
• Need for rapid improvement (suicide, malnutritian, catatonia,
severe psychosis or agitation)
• When other treatments are more risky (elderly, pregnant)
• Patient preference
• Psychotic depression (gold standard – 95% response)
ECT: Relative Contraindications
(weigh pros & cons)
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Space occupying cerebral lesions
Increased ICP
Recent MI
Recent CVA
Aneurysm
Retinal detachment
Pheochomocytoma
ECT: Mechanism of Action
• Neurotransmitter theory
• Enhances DA, 5HT & NE neurotransmissiom
• Neuroendocrine theory
• Increased release of neurohormones including prolactin, TSH,
ACTH & endorphins
• Anticonvulsant theory
• Increase in seizure threshold during course of ECT; CSF of
animals receiving ECS is anticonvulsant when given IV to
recipient animals
ECT: Side Effect Profile
• Common
• Headache
• Muscle ache
• Nausea
• Memory impairment
• Delirium
• Amnesia (anterograde & retrograde)
• No longterm deficits
ECT: Side Effect Profile
• Rare:
• Mortality 1/10,000-0.2 / 100 000
• Cardiovascular
• 2° initial vagal stimulation
• Bradycardia / asystole / ectopic activity
• 2° sympathetic stimulation
• Increased HR & increased BP
• Prolonged apnea
• Pseudocholinesterase deficiency
• Prolonged seizure
• Treat with IV benzo
Mood Stabilizers: Indications
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Bipolar Affective Disorder (BD)
Migraine or cluster headaches
Chronic aggression or impulsivity
Lithium reduces suicidal risk in BD and
augments antidepressants in MDD and
OCD
Choice of Treatment in BD
(Bipolar Disorder)
• For first onset acute manic or mixed episodes, start lithium,
epival or an atypical antipsychotic; taper and discontinue
antidepressants if possible
• For acute bipolar depression, initiate either lithium or
lamotrigene
• For rapid cycling (more than four episodes per year),
initiate either lithium, epival or lamotrigene; taper and
discontinue antidepressants
• For maintenance therapy, lithium and epival are most
supported. Alternatives include lamotrigene,
carbamazepine, oxcarbazepine and M-ECT
Lithium: Mechanism of Action
• MOA is unclear
• Thought to be involved in:
• Modulating second messenger systems (ie G protein-coupled
receptors, through which most hormones and neurotransmitters
mediate their effects) which leads to:
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Increasing GABA activity
Reducing glutamate activity
Stabilizing catecholamine receptors
Blocking the effects of some hormones (eg. ADH and TSH) on end
organs
• Effective in treating classic, euphoric mania & BD with MD-E pattern
Lithium: Side Effect Profile
(THE MAGIC WAND)
• Tremor
• Hypothyroid (5%)
• EKG changes (bradycardia, reversible T-wave flattening or
inversion; contraindicated in sick sinus syndrome, can lead to
sinus node dysfunction)
• Muscle weakness
• Alopecia
• GI upset
• Increased WBC (transient)
• Cardiac abnormality: increased risk Ebstein’s anomaly
(0.1% vs 0.005%) in first trimester
Lithium: Side Effect Profile (cont.)
(THE MAGIC WAND)
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Weight gain (50%)
Acne (rashes in general)
Neurological (in toxicity)
Diabetes insipidus/Drinking more
• Early Toxicity
GI distress, hand tremor, fatigue, thirst,
headache, decreased concentration
• Late Toxicity
Ataxia
Stupor
Coma
myoclonic jerking
increase DTR’s
seizure
Lithium: Initial Work-up
• CBC ( can increase WBC)
• Lytes, BUN, Cr (renally excreted)
• TSH (5% hypothyroidism)
• EKG with rhythm strip(contraindicated with sick sinus syndrome)
Lithium: Ongoing Monitoring
• Lithium level every five days until steady state is reached then at 3-6
months, with signs of dehydration or toxicity or with change in
medications or salt intake
• Levels are increased by NSAIDS, thiazide diuretics, ACEI,
tetracycline, anticonvulsants
• Levels are decreased by osmotic diuretics (mannitol), carbonic
anhydrase inhibitors, caffeine, increased salt
• Repeat kidney functions, Li level, TSH and EKG every 6-12 months
• Target Li level is 0.5-1.2 in adults and 0.4-0.8 in the elderly
Why Use an Anticonvulsant as a Mood
Stabilizer: The Kindling Hypothesis
• Underlying pathophysiologic mechanisms in BD are poorly understood
• Mania and epilepsy may share the underlying mechanism of kindling
(repeated subthreshold stimuli generating an action potential leading to
seizure in epilepsy or mood states in BD)
• It is hypothesized that both disorders may be caused by dysfunctional
cation (Na &Ca) pumps, which leads to an imbalance between excitatory
(glutamate) & inhibitory (GABA) neurotransmitters
• Anticonvulsants are thought to prolong inactivation of cation channels
during activity such as seizure(or mood episode), preventing spread &
leading to downstream changes in GABA & glutamate
Epival: Side Effect Profile
(TURN SO BALD & FAT)
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Tremor (10-29%)
Unsteadiness
Rashes (incl. S-J-S)
Nausea (20%) / GI upset
• Sedation (31%)
• Oligomenorrhea/PCO (menstral irregularity in 45%)
Epival: Side Effect Profile (cont.)
(TURN SO BALD & FAT)
• Blood dyscrasia
• thrombocytopenia (always ask about bruising and bleeding)
• Anemia (macrocytic)
• Agranlocytosis(ask about symptoms of infection)
• Coagulopathies
• Alopecia (treat with Zn & selenium)
• LFT elevation (up to 44%) (always ask re.: nausea, vomiting,
edema, malaise)
• Dysarthria
• Fat (weight gain) / insulin resistance
• Ammonia levels can rise (can cause confusion, stupor, coma)
• Teratogen (5-15%)
Epival: Initial Work-up & Ongoing
Monitoring
• Initial
• CBC + LFT’s
• Epival level weekly until steady state reached
• Ongoing
• Repeat tests monthly x 6 months then Q6mos or if symptoms
(bruising/bleeding/infection/general malaise) develop
• Target range 350-800 umol
Lamotrigene: Side Effect Profile
• Rash – 0.3% adults / 1% in children. With slow titration risk was
reduced to 0.01% comparable to other anticonvulsants.
• Activation (3-8%), Ataxia
• Spaced out (cognitive slowing), Sedation, Sleep disturbances
• H/A, Hypersensitivity reactions
Lamotrigene: Rx
• Start with 25-50 mg/d
• Increase every 2 weeks by 25-50 mg
• Usual maintenance dose is 100-500 mg in 2 divided doses
Anxiolytics: Indications
eg. Benzodiazepines (lorazapam)
• Short term hypnotic (But decrease REM,
Stages 3 & 4 sleep)
• Anxiolytic
• Acute mania
• Alcohol withdrawal
• Catatonia
Anxiolytics:
Mechanism of action
• ↑ Affinity of GABA a receptor for GABA (a
positive allosteric modulator)
• Two main receptor types
• BZ1 – Located mostly in the cerebellum
– Anxiolytic and sedative-hypnotic actions
• BZ2 – Located mostly in the spinal cord,
striatum and limbic system
– Muscle relaxant actions
Anxiolytics: Side effects
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Memory decline
Addiction(dependency &withdrawal)
Ataxia/Falls
Drowsiness/dizziness/disinhibition
Anxiolytics:Contraindications
• With COPD or sleep apnea
• Avoid in the elderly; with long term use
taper by 25 % q-monthly after treating the
underlying anxiety disorder with an SSRI as
indicated
Novel hypnotics
(e.g. Imovane)
Indications: short term hypnotic agents
Mechanism of action:
• Higher affinity for BZ1 than BZ2 therefore
less side effects
• More specific to CNS vs. peripheral
receptors therefore less side effects
Side Effects: Same as benzodiazepines but
reported to be less
Antipsychotics: Indications
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Psychotic illness
Delirium
Mood disorder with psychosis
Severe agitation or aggression
Typical Antipsychotics:
Mechanism of action
• D2 blockade
• Produces antipsychotic effect in the mesolimbic pathway
• Causes worsening of negative and cognitive symptoms in
the mesocortical pathway, where a dopamine deficit is
thought to cause these symptoms
• Causes
EPS
(dystonia,
dyskinesia,
akathesia,
parkinsonism)in the nigrostriatal pathway
• Causes increased prolactin in the tuberoinfundibular
pathway (gynecomastia, galactorrhea and sexual
dysfunction)
Typical Antipsychotics: Side effects
High potency
EPS
Haldol
Pimozide
Loxapine
Perphenazine
Low potency
Mellaril
Antihistamine
Chlorpromazine
AntiAlphaAdrenergic
Anticholinergic
QT prolongation with pimozide, CPZ
Atypical Antipsychotics:
Indications
• Same as typicals
• Agitation/aggression in dementia
responding
to
adequate
pharmacological interventions
NOT
non-
Features of
Atypical Antipsychotics
• Block both D2 and 5HT2A
• Cause less EPS than typical antipsychotics
• Improve positive symptoms as well as
typical antipsychotics
Atypical Antipsychotics:
Mechanism of action
• 5HT2A, when stimulated, normally stops
dopamine release; when this is blocked, it
causes dopamine release
• The different dopamine pathways have
varying amounts of D2 and 5HT2A
receptors
Atypical Antipsychotics:
Mechanism of action cont…
• In pathways with more 5HT2A receptors to block, SDA’s
lead to dopamine release(i.e. the mesocortical pathway,
reducing negative and cognitive symptoms)
• In pathways with more D2 receptors to block, SDA’s cause
dopamine blockade (i.e.the mesolimbic pathway, with
antipsychotic effects)
• In pathways where receptor numbers are relatively equal,
there is no change in the amount of dopamine (i.e. in the
tuberoinfundibular pathway, preventing increased
prolactin)
• In the nigrostriatal pathway, there are just enough 5HT2
receptors to bring the D2 blockade down below 80%, the
critical number to prevent EPS.
Atypical Antipsychotics:
Side Effects
Less effects on:
• EPS, negative symptoms and cognition
A different set of concerns:
• Weight gain (get baseline weight)
• Akathisia
• Sedation
• Hyperglycemia/Hyperlipidemia(baseline fasting lipids
and glucose)
• Dizziness (orthostatic hypotension; check BP)
• In dementia increase mortality and risk of
cardiovascular events
• Risk of agranulocytosis and seizure (dose dependent)
with Clozapine
Atypical Antipsychotics:
Monitoring
• Obtain baseline weight and calculate BMI; BMI
monthly for three months and then q4mths
• Baseline personal and family history of obesity,
dyslipidemia, hypertension and cardiovascular
disease
• Baseline waist circumference at the umbilicus, BP,
fasting glucose and lipid profile; repeat at 3
months and then annually
Neuroleptic Malignant Syndrome
• Antipsychotic use (+) fever (+) rigidity (+) 2 of:
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↑ WBC
Lab evidence muscle injury (CK or myoglobinuria)
Diaphoresis
↑ HR
↑ or labile BP
Dysphagia
Tremor
Incontinence
Change in MS
Mutism
Cognitive Enhancers
Cholinergic Agents
- Donepezil
- Rivastigmine
- Galantamine
NMDA Antagonist
- Memantine
Cognitive Enhancers:
Indications
AChEI: early to moderate AD
Lewy Body Dementia
Mixed Dementia
Memantine: Moderate to severe AD
Cholinesterase Inhibitors: Indications
• Abilities
• Behaviour
• Cognition
• Decrease in caregiver time
• Entry into Nursing Home
Cholinesterase Inhibitors
Mechanism of Action
• Inhibits centrally-acting
acetylcholinesterase, making more
acetylcholine available
• This compensates in part for degenerating
cholinergic neurons that regulate memory
Cholinesterase Inhibitors:
Common Side Effects
Muscle Cramps
Insomnia
Nausea
Diarrhea
Cholinesterase Inhibitors:
use caution or consultation with:
• History of seizures
• History of bradycardia, sinus node
dysfunction or other serious conduction
abnormality
• History of PUD or other risk factors for GI
bleeding
• History of COPD or asthma
Memantine: Indications
Socialization
Household tasks
ADL
Persecutory ideation
Excessive activity (agitation)
Memantine:
Mechanism of action
• A dysfunction of glutamatergic neurotransmission,
manifested as neuronal excitotoxicity, is hypothesized to
be involved in the etiology of Alzheimer’s disease
• Memantine binds the NMDA receptor with a higher
affinity than Mg2+ (which are normally there), inhibiting a
prolonged influx of Ca2+ (thereby preventing
excitotoxicity)
• The receptor can still be activated by the relatively high
concentrations of glutamate released following
depolarization of the presynaptic neuron
Memantine: Common Side Effects
Confusion
Headache
Equilibrium (dizziness)
Constipation
Kidney function
Cognitive enhancers:
monitoring
• Response may be seen 1 month, typically 3
months
• Realistic expectation is to “maintain”