Summy 2

ADHD

• neurodevelopmental disorder, inappropriate patterns of inattention, hyperactivity, and impulsivity

  • can impair social, academic, occupational functioning

executive dysfunction

• inhibition

• shift

• emotional regulation

• initiation and persistence

• working memory

• planning and organization

• organization of materials

• self monitoring

Methylphenidates

NE and DA reuptake inhibitor

• ddis → cyp1a2, most relevant is honestly caffeine

Amphetamines

NE and DA reuptake inhibitor, release 5HT at higher doses

• ddis → cyp2d6 substrate

  • amps are ph sensitive, alkalizers increase levels and vv

stimulant ddis

• absolute

  • maoi use within 14 days → we hate these guys, can increase risk of hypertensive emergency due to additive effect

  • serious structural cardiac abnormalities and such

  • active psychotic episode

• relative

  • htn, hr, recent mi, etc

  • bipolar disorder → distinguish from manic episode, use is ok if pt is controlled

stimulant ses

• appetite loss → lifestyle mods, eat small and calorie rich meals, protein shakes, etc

• abdominal pain

• constipation, dry mouth

• headaches

• sleep disturbances → note this is also an ADHD sx, need to differentiate between se and efficacy issue

stimulant monitoring

• bp/hr duh

• appetite

• height/weight

• sleep

• ekg if theres a compelling indication, not really recommended normally anymore

Alpha-2 Agonists

decrease firing rate of presynaptic neurons and release ne into the pfc

• only use er for adhd, dosed at bedtime to reduce risk of ses

• onset 2-4 weeks

• ses

  • hypotension

  • dizziness

  • drowsiness

NRI

• onset 8-12 weeks for ato, 4 weeks for vilox

• ses

  • nv, abdominal pain, constipation

  • constipation, dry mouth, decreased appetite

• ddis

  • strattera is a cyp2d6 substrate

  • qelbree is a strong cyp1a2 inhibitor, some cyp2d6/3a4 inhibition

• BBW for si in children and adolescents

random concerta fact

• oros or osmotic release oral system

• has an ir drug coat which dissolved within an hour

• then theres an osmotically active component that swells and pushes out more active drug through a hole in the capsule

• capsule itself isnt absorbed and appears in stool

jornay

• useful if issues with morning functionality/actually getting out of bed

  • dose at bedtime and onset occurs 8-10hrs post admin

switching between stimulants

• for mph to mph or amp to amp, just try and keep tdd the same

• for normal to dex, decrease dose by half bc its just one enantiomer

• for mph to amp, decrease by half since amp is 2x more potent

icer ratio

• how much money do we need to spend to gain one more qaly

  • cost b - cost a / effect b - effect a

cost-effective

below threshold, ~150k/qaly

dominant

less costly and better outcomes

Positive Symptoms

excess/distortion of normal functioning

• psychosis

  • delusions

  • hallucinations

• disorganization

  • in speech or behavior

Negative Symptoms

decrease of normal functioning

• flat/reduced affect

• avolition, lack of motivation for goal directed activities

• lack of socialization

• decreased executive functioning

NTs in schizophrenia

d2r is gi coupled → inhibitory

• 5ht1a is gi coupled → inhibitory, decreases 5ht release

  • less 5ht, less binding of 5ht2ra, increasing da release

  • so we like 5th1a agonists

  • lowkey dont talk about these tho

• 5ht2a is gq coupled → on presynaptic DA neuron, inhibits DA release

  • blocking 5ht2a activity disinhibits da release, so more da

  • we like 5th2a antagonists

schizophrenia hypotheses

Dopamine Hypothesis → da dysfunction is what underlies schizophrenia

Glutamate Hypofunction Hypothesis

Serotonin Hypothesis

Mesolimbic

excess DA results in positive sx

• related to pleasure, reward, and goal-directed behavior

Mesocortical

insufficient DA results in negative sx

• related to motivational and emotional responses

Nigrostriatal

insufficient DA leads to involuntary movements, EPS or parkinson’s like

• related to coordination of movement

Tuberoinfundibular

insufficient DA increases prolactin release

• regulates prolactin secretion by the pituitary, involved with production and discharge of breast milk

  • also increases free testosterone among other things

  • regulated by d2r (inhibitory) and 5ht2a (excitator)

  • fgas thus block d2r and disinhibit prolactin release, leading to excess stimulation

First Generation Antipsychotics

D2 antagonism

other receptors include mu opioid, alpha 1, histamine 1

• eps → parkinsons like sx bc were blocking da

  • acute dystonia → facial grimacing, muscle spasms (dangerous bc airway can spasm and get compromised)

    • onset minutes to hours

  • akathisia → restlessness, trouble standing still

    • onset days

  • pseudoparkinsonism → bradykinesia, rigidity, tremors

    • weeks to months

  • increased risk with high dose, fast titration, or high potency fgas

  • reversible with dose decrease or stopping

  • can also treat sx with anticholinergics, benadryl or benztropine, or bb for akathisia

• tardive dyskinesias → involuntary movement of the body and extremities

  • eg protrusion or rolling of lips, facial dyskinesias, chewing motions

  • onset months to years

  • potentially permanent even after cessation of fga

• hyperprolactinemia

  • can reduce dose or switch to sga (except for risp or pali which randomly share the same risk as fgas)

• qtc prolongation

• seizures

Second Generation Antipsychotics

mixed D2 and 5HT2A antagonism

• metabolic effects

  • new onset or worsening diabetes

  • hypercholesterolemia

  • lower eps risk

highest potency fgas

haloperidol, fluphenazine, thiothixene

d22 affinity » all the others

generally more risk for eps, but less risk of anticholinergic ses, sedation, or orthostasis

medium potency fgas

perphenazine, loxapine

low potency fgas

chlorpromazine, thioridazine

all other » d2 affinity

less eps risk but greater anticholinergic, sedation, orthostasis risk

acute agitation in psychotic episode associated with schizophrenia

• haloperidol preferred, can also do fluph, chlor, olan, or zip

• if fga, coadmin with benadryl to reduce risk of eps → monitor carefully

• ses, sedation, qtc prolongation

antipsychotic choice

• guidelines recommend starting with SGA

• see effect with first 2 weeks, 3-4 weeks for max effect on - sx

  • can titrate up q2-3 days if inpatient

• metabolic monitoring for pt on sgas

  • baseline: weight, bmi, waist circumference, bp, glucose, lipids

sga bbw

increased mortality in pts with dementia-related psychosis

clozapines

• supa crazy se profile and troublesome monitoring parameters

  • so anticholinergic to the fact that pts need to be on musher and pusher like stat

  • lowers seizure threshold

  • agranulocytosis → need anc monitoring

  • metabolized by cyp1a2

  • requires titration, even if you miss like two days

  • but its da most effective antipsychotic we have, reserve for pts who fail like 2+ meds

sga se profile

	weight gain/metabolic	eps	anticholinergic	orthostatic hypotension
high	clozapine olanzapine	risperidone	clozapine olanzapine quetiapine	clozapine quetiapine risperidone
medium	quetiapine risperidone	akathisia: aripiprazole lurasidone
low	aripiprazole zip/lurasidone	clozapine	risperidone aripiprazole zip/lurasidone	olanzapine aripiprazole zip/lurasidone

abilify

• generally has a milder se profile, except for its akathisia risk

  • long half life like 3 days

  • gotta take in da am, a for activating

  • BBW → impulse control disorders

ziprasidone

• can cause qtc prolongation

• need to take with food, bid with greater than or equal to 500 cals

lurasidone

also need to take with food, within 30 mins of a 350 cal meal

risperidone

• has an se profile kinda similar to fgas

  • pali is the active metab of risp

  • can cause headache, tachy, and somnolence

olanzapine

• a cyp1a2 metabolite, induced by smoking

  • p effective, but great risk of sedation and weight gain up to 50 pounds broh

seroquel

basically no eps risk

lithium

• broadly, lithium seems to inhibit excitatory stimulus and promote inhibitory stimulus

  • has several effects on down stream second messenger pathways

• ses → to treat, dry reduce dose (maybe not good for mania/depression), do er, take at night

  • acute → n/d, sedation, polyuria+polydipsia

    • gi ses usually transient, if the d comes back then it might be toxicity

    • poly most annoying for adherence, can start pts on ir bid to establish tolerance then switch to er qd dosing

      • due to li blocking adh

  • chronic → weight gain, hypothyroidism, tremor (supa common, dose dependent)

    • hypothyroidism bc li inhibits t4→t3 conversion and reduces tsh release

    • also get leukocytosis with no left shift whatever that means

  • toxicity → n/v, profuse diarrhea, coarse tremor, ataxia, renal failure

mania sx digfast

• distractibility

• involvement in pleasurable activities

• grandiosity

• flight of ideas

• agitation (psychomotor)

• sleep decreased

• talkative

rapid cycling

• 4+ mood episodes within 12 months

  • can be either manic or depressive

  • harder to treat, prefer vpa/cbz over lithium

li ddis

• li clearance decreases with nsaids, aces/arbs, diuretics (esp thiazide)

  • if a pt needs to start on a thiazide, preemptively halve their li dose broh

• caffeine can increase li clearance

li and na

• elimination 100% renal → 75% reabsorbed in proximal tubule

  • treated very similarly to na

li monitoring

• renal function (bun, scr), electrolytes

• cbc with diff

• tfts

• urinalysis for lytes again

• ekg if >40 or otherwise indicated

• plus tdm

antipsychotics for bipolar

• better evidence in acute mania, not as much for maintenance

  • seroquel has best data for acute bipolar depression

• options → seroquel, abilify, lurasidone, haloperidol

li dosing

• dosing sched = CLli * Cpssli

  • dosing sched is your tdd basically

  • CLli = CLcr * 0.25, using tbw not ideal

  • Cpssli = goal between 0.6-1.2 meq/L, usually target like 0.8 or smth

• get concentrations after steady state, usually 3 days but yknow

• make sure to get labs at least 10h after a dose, otherwise levels may be high since youre sampling during distribution phase

bipolar maintenance

• first line → lithium, vpa

  • lamotrigine may be preferred as monotherapy if pt is mainly depressive

• second line → atypical antipsychotics

• third line → polypharmacy with 2 meds

• fourth line → polypharmacy with 3 meds, ect

bipolar depression

• treat for 12 weeks, a lot shorter than mdd

• options:

  • lithium duh, dose up if possible

  • lamotrigine, usually as adjunct

  • atypical antipsychotics, adjunct if lamictal dont work

  • ect

  • maybe antidepressants → ok if pt is stabilized on a mood stabilizer

parkinsons diagnostic criteria

• bradykinesia + at least one of the following

  • resting tremor

  • rigidity

  • postural instability

pd non motor sx

• autonomic dysfunction → orthostatic hypotension, sialorrhea

• sleep disorders → excessive daytime somnolence, rls

• sensory sx → olfactory, visual, auditory dysfunction

• neuropsychiatric problems → psychosis/hallucinations, cognitive impairment, anxiety, depression

sinemet

• indication → first line monotherapy for mild to moderate pts >65

• ses

  • peak-dyskinesias → abnormal wiggly movements

  • wearing off → exactly what it sounds like, med not providing adequate sx relief for long enough

  • nv → take with non protein food

  • hallucinations → schizophrenia like sx whenever we have excess da

  • vivid dreams

  • orthostatic hypotension

• clinical pearls

  • take on empty stomach or with non-protein meals

da agonists

• indication → monotherapy or sinemet adjunct therapy

  • for early or mild pd sx

  • may consider first line in pts <65

• options

  • pramipexole

  • ropinirole

• ses

  • nv

  • impulse control disorders → compulsive shopping, gambling, hypersexuality

  • excessive daytime sedation

  • hallucinations

  • leg swelling

  • orthostatic hypotension

• ci

  • pts with psychosis or memory disorders

mao-b

• indication → monotherapy or adjunct

  • early or mild pd sx

• options

  • selegiline → active metabolite is an amphetamine, avoid taking too late in the day

  • rasagaline

• ses

  • nv

  • hallucinations

  • dizzziness

  • orthostatic hypotension

comt

• indication → adjunct to sinemet

• options

  • entacapone

  • tolcapone

  • opicapone

• ses → look like sinemet bc it just prolongs duration of action

  • dyskinesias

  • hallucinations

  • orthostatic hypotension

  • entacapone → diarrhea and urine discoloration unique

  • tolcapone → hepatotoxicity, has a bbw

  • opicapone → constipation, insomnia, dry mouth, ck elevation

anticholinergics in pd

restore balance of ach and da in striatum

• indication → adjunct for younger pts with tremor or dystonia

• options

  • trihexyphenidyl

  • benztropine

• ci

  • elderly → beers

amantadine

NMDAR antagonist, potentially inhibits da reuptake

• indication → adjunct for peak dose dyskinesias

  • or monotherapy for mild pd

• ses

  • edema

  • insomnia

  • paranoia

  • confusion

  • hallucinations

  • orthostatic hypotension

Peak Dose Dyskinesias

• decrease dose of sinemet, or any adjunct meds

• if advanced dx with stable regimen, consider adding amantadine

Wearing Off Motor Fluctuations

• can try increasing sinemet dose or shortening dosing intervals

• may also switch to cr/er

  • even just nighttime dose swapping to er/cr could work if pt covered well in the mornings

• assess if any food drug interactions

• if pt unlikely to tolerate adjustments to sinemet regimen, add adjunct meds to prolong duration of action

  • da agonist

  • mao-b

  • comt

• add rescue meds

  • apomorphine → da agonist, infusion for severe off period sx

  • levodopa monotherapy

both peak dose dyskinesias + wearing off

reduce dose AND dosing interval

rapid eye movement behavioral disorders

• physically acting out vivid dreams

  • establish safe sleeping environment

  • discontinue serotonergic antidepressants

  • can use melatonin or klonopin

excessive daytime somnolence

• if on da agonist try lowering dose or tapering off

  • can also try stimulates lawl

what meds to avoid in pd

antipsychotics → less da in alr da deficient disease state!!

antiemetics → metoclopramide, prochlorperazine, promethazine

• da antagonists

Donepezil

• ses

  • nvd

  • insomnia

  • vivid dreams

  • bradycardia

  • syncope

• clinical pearls

  • po goes up to 23mg, but not really clinically significant and has more se risk

  • no renal or hepatic dose adjustments

Rivastigmine

• ses

  • nvd

  • dizziness

  • anorexia

  • bradycardia

  • syncope

• clinical pearls

  • patch formulation has leastt gi ses of all acheis

  • avoid in liver impairment

Galantamine

• ses

  • nvd

  • dizziness

  • vivid dreams

  • bradycardia

  • syncope

• clinical pearls

  • take with food, bad gi ses

  • avoid in kidney or liver impairment

Memantine

NMDAR antagonist

• normally involved in learning and memory, blocks overstimulation of NMDARs and is potentially neuroprotective

• ses

  • hypertension

  • dizziness

  • constipation

  • hallucinations

  • somnolence

• clinical pearls

  • no gi ses

  • titrate qweek

  • renally dose adjusted

monitoring ad meds

• re-evaluate every 2-4 weeks with titration

• then at stable dose, monitor q3-6mos

what meds to avoid in ad

benzos

• can worsen dementia or delirium

• causes paradoxical agitation

anticholinergic agents → blocking ach in alr ach deficient dx is no go

• antihistamines

• benztropine

• oxybuytnin

• tcas

• antipsychotics

• etc

z drugs → ambien blackout

sleep disturbance in ad

• fluvoxamine

• duloxetine

• belsomra → specific fda indication !

aggression and agitation in ad

citalopram, sertraline

Lamotrigine

• na channel blocker

• ses

  • better se profile than cbz, vpa

  • sjs, ten

• clinical pearls

  • skin rash/sjs more common with higher starting doses + rapid escalations → go low and slow mans

    • also seen with concomitant vpa tpx

  • onset to therapeutic effect may take up to 10 weeks

• ddis

  • estrogen-containing contraceptives can reduce lamictal concentrations

  • lamictal can induce metabolism of progestin only contraceptives

  • metabolized via UGT

Valproic Acid

• ttype ca channel blocker

• ses → all dose related

  • gi discomfort

  • dizziness

  • tremor

  • weight gain

  • mild transaminitis

    • monitor lfts at baseline then periodically during the first six months

    • dc is lfts 3x baseline or if there are any signs of impairment to liver’s synthetic abilities

      • eg higher tbili, INR or decreased albumin

  • thrombocytopenia

  • sjs, ten

  • BBW → fulminant hepatitis

• ci → women of childbearing age, increases risk of fetal defects including neural tube defects, spina bifida

• ddis

  • PHT and ASA may displace VPA from plasma proteins → increase the free vpa conc, higher risk for toxicities

  • may inhibit metabolism of many other asd → not predictable, should not immediately dose adjust anything

    • phenytion

    • phenobarbital

    • carbamazepine

    • ethosuximide

how does amp effect 5ht

competitively inhibit VMAT2, triggering release of monoamine stores from vesicles and increasing the concentration of dopamine and norepinephrine (and to lesser degree serotonin) in the cytosol

metadate cd

release control membrane dissolves after 3 hr, so slower onset>

when may nris be preferred

if pt has hx of anxiety or depression
hypotension/bradycardia

when a2 agonists may be preferred

aggression

insomnia

hypertension

cyp2d6 inhibitors

parox, fluox, dulox, bup > sert, cit, esci

guanfacine

a2 agonist

cyp3a4 substrate

dominant

higher effect and lower cost