llefebvre01-
what is the medical usage of CNS drugs?
pain relief, seizures, anaesthesia
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what is the recreational usage of CNS drugs?
stimulant/depressant, euphoria, hallucinations
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how does the CNS drugs effects work?
effects on individual neurons (excitation/depression) does not equal overt functional effects
ex: alcohol is a depressant but produces overt stimulant effect -> depresses activity in frontal lobe that is responsible for impulse control
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what are characteristics of BBB?
free lipid soluble > ionize/protein bound drugs (for crossing BBB)
underdeveloped in infants -> vulnerable to CNS drugs
Protects against toxic substances
Impairs therapeutic Tx
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why is there uncertainty with CNS drugs?
limited CNS pathophysiology understanding = uncertainty of CNS agents action
multiple CNS transmitters with unclear precise roles
almost always alters synaptic neurotransmission
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what is neuronal plasticity and how does it affect CNS drugs?
brain is always changing
1. decreased drug effects over time: decreases therapeutic effects (=tolerance) and decreases adverse effects (=habituation)
2. behaviour changes and addiction: withdrawal Sx (physical dependence), cravings (psychological dependence), highjacking of motivation + reward pathways (most drugs of abuse are CNS drugs)
3. delayed onset efficacy: increases drug effects over time, beneficial response from CNS adaptation rather than direct synaptic transmission alterations
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what are antipsychotics? what are the 2 types?
drugs of choice for schizophrenia
1st generation (FGA) and 2nd generation (SGA)
FGA has higher EPS than SGA
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what is EPS?
extrapyramidal symptoms
early reactions = acute dystonia, Parkinsonism, akathisia
late reactions = tardive dyskinesia
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what is the MoA of FGA?
dopamine (D2) antagonists -> block dopamine receptors
reduced dopamine synthesis and release = antipsychotic effect
remember SCZ hypothesis = too much dopamine
but remember decrease in dopamine = Parkinson, motor impairments
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what are the side effects of FGA and why do they happen?
EPS
sedation -> histamine receptors
orthostatic hypotension -> NE
anticholinergic effects -> acetylcholine
QT prolongation + cardiac effects
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explain toxicities of chlorpromazine and haloperidol
potency : low
EPS: moderate
sedation: high
orthostatic hypotension: high
anticholinergic effects: moderate
potency : high
EPS: very high
sedation: low
orthostatic hypotension: low
anticholinergic effects: low
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what are the differences of SGA to FGA?
believed to have superior efficacy
lower EPS
higher metabolic effects (diabetes, dyslipidemia)
cost 10-20x more
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what is the MoA of SGAs?
act on mesolimbic pathway (this is unregulated in schizo)
dopamine (D2) and serotonin (5HT2A) antagonists
also block histamine, NE and Ach receptors
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what are the use and selection guides for SGA?
abort and prevent acute psychosis: onset 1-2 days, peak effects 2-4 weeks
select agent based on toxicity profile to maximize adherence
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what are the side effects of SGA?
EPS
sedation
orthostatic hypotension
anticholinergic effects
metabolic effects
significant QT prolongation
prolactin elevation
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what are toxicities of clozapine?
EPS: very low
sedation: high
orthostatic hypotension: moderate
anticholinergic effects: high
metabolic effects: high
significant QT prolongation: yes
prolactin elevation: low
metabolized by CYP3A4
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what are toxicities of risperidone?
EPS: moderate
sedation: low
orthostatic hypotension: low
anticholinergic effects: none
metabolic effects: moderate
significant QT prolongation: yes
prolactin elevation: high
NOT metabolized by CYP3A4
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what are toxicities of olanzapine?
EPS: low
sedation: moderate
orthostatic hypotension: moderate
anticholinergic effects: moderate
metabolic effects: high
significant QT prolongation: no
prolactin elevation: low
NOT metabolized by CYP3A4
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what are uses of clozapine? what is safety alert?
most effective at improving Sx
weak D2 antagonist = decreased EPS
excellent for pt with severe EPS
fatal agranulocytosis
onset 6 months, mechanism unknown
monitor WBC weekly !!!
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explain NMS and their management
neuroleptic malignant syndrome: fatal syndrome more likely w/high potency FGA
Sx: rigidity, fever, autonomic dysfunctions
dantrolene (muscle relaxant) + bromocriptine (DA agonist)
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explain anticholinergic effects
dry mouth, consitpation, urinary retention
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explain orthostatic hypotension and their management
via blockage or alpha1-adrenergic receptors -> no compensatory vasoconstriction
monitor BP and pulse
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explain sedation
via blockade of histamine H1 receptors -> decreases over time
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explain increased prolactin levels
via DA inhibition -> DA cannot inhibit prolactin release
manifestations: menstrual irregularities/ breast growth/ galactorrhea
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explain increased seizure risk + management
problematic in pt w/seizures disorders
adjust anti-seizure meds dosage up if necessary
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explain sexual dysfunction
decreased libido + erectile dysfunction -> decreased pt adherence
low potency FGA > high potency FGA
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explain agranulocytosis + management
very rare -> monitor WBC count if sign of infection
most likely with chlorpromazine + clozapine
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explain QT prolongation + management
chlorpromazine + haloperidol prolong QT interval
ECG + potassium determination before + after Tx
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explain effects on dementia patients
off label use -> double mortality risk -> avoid at all costs
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explain teratogen + management
risk of EPS to baby if exposed during 3rd trimester
not recommended to discontinue TX -> monitor instead
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explain physical dependence + management
addiction and abuse are unlikely
mild withdrawal Sx if abruptly stopped -> taper off gradually
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explain drug interactions
anticholinergic drugs -> increased anticholinergic effects
alcohol + CNS depressants -> additive effects
L-dopa -> antagonistic effects and vice versa
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what are the 3 major objectives of schizophrenia management?
acute episode suppression
prevention
improve QoL
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how do you select drug for SCZ?
individualized based on efficacy/toxicity/cost
history of diabetes -> avoid Rx w/metabolic effects
resistant to initial Tx -> clozapine, olanzapine
no contraindications -> cheaper Rx
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what are the administration strategies for drug for SCZ?
bedtime dosing decreases daytime drowsiness/sedation
higher dose for acute psychosis vs lowest effective dose for maintenance
acute therapy: PO (liquid therapy has to be diluted)
prevention: IM depot -> increased adherence and decreased toxicity
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what is acute therapy for SCZ?
Sx decrease in 1-2 days
1-2 wks for significant improvement
full effect over few months
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what is maintenance therapy for SCZ?
treat at least for 12 moths post acute episode -> poor adherence
if Sx-free: taper off gradually for less withdrawal
favour IM depot (long acting)
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how do you promote adherence + non drug therapy?
1. Cognitive behaviour therapy: forming therapeutic alliance + support system
2. pt + family education: strict schedule + adherence; low risk of addiction
3. vocational training: provide feelings of agency, productivity + independence
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what are adjunct drugs for SCZ?
benzodiazepines: decreased anxiety + stabilize sleep
antidepressants for depressive Sx
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why is there disputed efficacy for antidepressants?
clear benefits only for severe depression, unclear for mild/moderate
adaptive neuronal changes > enhanced neuronal transmission = the efficacy of drug
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what is the treatment response of antidepressants?
delayed therapeutic response:
initial effects around 1-3 weeks
full effects around 12 weeks
try for at least 1 month
do not administer PRN -> might halt or create abnormal neural changes
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what are new agents? old agents?
new: SSRIs -> safer !!!
old: TCAs, MAOIs
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what are the most efficient antidepressants?
angomelatine
amitriptyline
mirtazapine
escitalopram
paroxetine
vortioxetine
venlafaxine
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what are the most tolerated antidepressants?
agomelatine
citalopram
escitalopram
fluoxetine (only efficient option for minors)
sertaline
vortioxetine
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how do you manage treatment with antidepressants?
start low dose + increase gradually:
- if inefficient after 4-8 wks, switch Rx
- Tx for 4-9 months minimum
- taper off gradually over several wks
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what is a risk for all antidepressants?
suicide, mostly to pt under 25 years
if suicide risk is high, hospitalization is best option!
suicide risk of untreated depression > antidepressant suicide risk
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how do you mitigate suicide risk?
frequent follow ups with medical team
daily monitoring by family members
watch for rapid Sx deterioration
prescribe small amounts at a time
watch out for checking (putting meds in cheek)
suicide hotline
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what is peripartum depression?
any form of depression around the time of delivery
more than 2 weeks
moderate to sever dysfunction
favour initial therapy with SSRIs
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what are the 4 classes of antidepressants?
reuptake inhibitors: selective serotonin and serotonin + NE
tricyclic (TCA)
monoamine oxidase inhibitors (MAOI)
atypical
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class 1: what is SSRI?
selective serotonin reuptake inhibitor: prevents reuptake of serotonin, so continues to float in synaptic cleft, will activate receptors on other neuron, increase activity on neuron
most commonly prescribed antidepressants
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class 1: what is SNRI?
serotonin + NE reuptake inhibitors
- block reuptake of serotonin AND NE
- similar efficacy + adverse effects as SSRIs
- but inferior tolerability
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what are the high risk adverse drug reactions in adults of SSRIs and SNRIs?
serotonin syndrome:
risk of death
onset 2-72h post start
altered mental states, sweating, fever, tremors
DISCONTINUE Rx ASAP
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what are the high risk adverse drug reactions in newborns of SSRIs and SNRIs?
persistant pulmonary hypertension:
risk of death or cognitive impairment
ventilatory support + close monitoring
neonatal abstinence syndrome:
respiratory distress + seizures
monitor closely for min 48 hrs
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what are the common adverse drug reactions of SSRIs and SNRIs?
sexual dysfunction: affects 70%
manage: patient education, drug holidays, dose decrease
weight gain: due to decreased sensitivity of appetite regulating 5-HT receptors
withdrawal Sx: taper off gradually
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what are the drug interactions of SSRIs and SNRIs?
other antidepressants:
MAOIs: together increase serotonin levels + risk of serotonin syndrome
TCAs: SSRIs increase concentration
antipsychotics:
lithium: SSRIs increase concentration
others:
anti platelet + anticoagulation: increase bleeding risk
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what are uses of tricyclic antidepressants?
major depression - 2nd line Rx
neuropathic pain
fibromyalgia
ex: amitriptyline
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what is MoA tricyclic antidepressants?
blocks serotonin re-uptake transporter
blocks noradrenaline re-uptake transporter
blocks histamine receptors transporter
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what are adverse drug reactions tricyclic antidepressants?
orthostatic hypotension -> adrenergic
sedation -> histamine
anticholinergic, cardiac toxicity -> acetylcholine
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what are interactions of tricyclic antidepressants?
MAOIs cause severe hypertension
sympathomimetic + anticholinergic Rx
other sedatives (ex: alcohol, opioids)
overdose risk (TI around 8)
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what are therapeutic uses of MAOIs?
major depression - 2/3rd line Rx
atypical depression - 1st choice Rx
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what is MoA of MAOIs?
monoamine oxidase A inactivates NE and 5-HT (instead of blocking reuptake, blocking breakdown) -> anti depressive effect
monoamine oxidase B inactivates DA -> antiparkison effect
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what are ADRs of MAOIs? drug interactions?
orthostatic hypotension -> more NE in CNS reduces sympathetic firing
other antidepressants (SSRIs, TCAs)
antihypertensive drugs
many others...avoid all Rx unless also prescribed
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what are MAOIs food and drink interactions?
foods + drinks high in tyramine -> can cause hypertensive crisis
tyramine is precursor of NE, MAO is responsible to metabolize, but MAOI blocks MAO, so tyramine never gets metabolized
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what is Mirtazapine atypical antidepressant?
chemistry similar to TCAs but effect like SSRI but faster onset
blocks presynaptic alpha2-receptors (increases 5-HT + NE release)
generally well tolerated
ADR: sedation + weight gain due to histamine block
interactions: CNS depressants + MAOIs increase sedation
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what is Agomelatine atypical antidepressant?
action: melatonin agonist + 5-HT antagonist
- melatonin action normalizes sleep cycle
- 5-HT antagonism increases DA + NE release in frontal lobe
- called 'DA_NE distributor'
toxicity: well tolerated, potentially less toxic
ADRs:
- possible hepatoxicity (monitor ALT and AST)
- sleep disturbances + nightmares
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what are the dietary supplements used as antidepressants?
S-adenosylmethionine (SAMe): superior to TCA and improved Sx in SSRI-resistant pt
MoA: increased synthesis of NE, 5-HT, DA in CNS
St-John's wort: superior to placebo for mild moderate depression
unclear action, p450 + P-glycoprotein inducer
BUT limited efficacy or insufficient evidence
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what is electroconvulsive therapy (ECT)?
produces generalized seizure for 20-30s to reset brain
requires 6-12 treatments
short acting muscle relaxant + IV anesthetic for safety
consciousness unnecessary for benefits
ADRs: transient amnesia, cognitive impairment
relatively safe + fast benefits: 8% relapse with ECT vs 73% without
good for severe depression unresponsive to Rx
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what are other therapies for depression?
transcranial magnetic stimulation
vagus stimulation: developed as anti-seizure but less Sx of depression, super $$$$
light therapy: increases 5-HT transmission, response proportional to light intensity, low cost
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what is the best thing for mental health disorders?
healthy lifestyle
exercise is more efficient than drugs for depressive Sx
medication reduces activity of DMN
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what are general considerations for anxiety management?
best therapy = psychotherapy + pharmacotherapy
1st line drug option = SSRIs
significant SBN potential: health life, social support, education, foster collaborative relationship
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what are the preferred drugs for long term management of anxiety?
SSRIs and buspirone -> delayed effects
- best for cognitive + psychic Sx
- low abuse potential
- no interactions with CNS depressants
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what are the preferred drugs for rapid stabilization of anxiety?
benzodiazepines -> rapid relief
- best for somatic Sx alleviation
- abuse potential explains declined use
- gradual tapering off = crucial to avoid withdrawal
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what is panic disorder therapy?
1st line: SSRIs
- decrease anticipatory anxiety, avoidance behaviours, frequency + intensity of attacks
- transient rebound anxiety upon initiation -> start w/low dose
2nd line: TCA/MAOI/benzodiazepine
- efficient but less well tolerated vs SSRI
Non drug:
- CBT + MBSR
- avoid stimulants
healthy lifestyle
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what is OCD therapy?
1st line: SSRIs
- benefits via increased 5-HT transmission
- delayed onset
- continue for at least 1 year
non drug Tx:
- fear control exercises -> very efficient
- deep brain stimulation for severe cases
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what is social anxiety therapy?
1st line: SSRIs
- delayed onset around 4 weeks
-very useful for pt obliged to face frequent anxiety situations
2nd line: benzodiazepines + B-blockers
- rapid onset
- useful for performance anxiety
Non drug:
- gradual social exposure exercises
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what is PTSD therapy?
remember 3 core Sx: re-experiencing event, avoiding reminders, hyperarousal
1st-line: SSRIs
2nd line: mirtazapine, TCA or MAOI
no evidence for: buspirone, buproprion, benzodiazepines
new evidence: MDMA + psychedelics
non drug:
- trauma focused exposure therapy
- stress inoculation training
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what are the 3 major Rx class for BPD therapy?
mood stabilizers: lithium, valproate, carbamazepine
- 1st line: abort manic episodes, prevent recurrence
antipsychotics: SGA>FGA
- adjunct to mood stabilizers for severe mania
antidepressants: SSRIs, bupropion
- adjunct to mood stabilizers for severe depressive
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what is Lithium?
used to abort + prevent manic episodes
MoA unknown
very short T1/2 + very narrow TI
administer PO in divided daily doses
kidney excretion: watch for renal impairment + sodium levels
NEED TO MONITOR PLASMA LEVELS -> keep below 1.5, this is superrrrrrr important, can die
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what is Lithium adverse drug reactions + interactions?
CNS
- teratogen: avoid during 1st
- tremors: mitigate w/B-blockers
GI
- Disturbances: common but transient
Renal
- toxicity: mostly w/chronic lithium therapy
- antagonism of ADH, must drink frequently
Interactions
- diuretics: increase Na+ loss leads to lithium accumulation
- NSAIDs: increase lithium renal reabsorption (except aspirin)
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what is valproate?
anti epileptic drug w/mood stabilizing effect
compared to lithium
- better onset + safety
- more effective vs manic Sx
- less effective vs suicidal ideation
- less effective vs depressive Sx
- higher rate of relapse
ADR: hepatoxicity, teratogen
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what is carbamazepine?
anti epileptic drug w/mood stabilizing effect
slightly inferior alternative to valproate
ADR:
mild neurologic effects (common)
severe hematologic effects (rare)
many interactions w/P450 enzymes
