APS Flashcards

1
Q

schizo – theory

A

1) dopamine theory: Amphetamine (overactive DA) produce similar sx to acute schizophrenia
* All antipsychotic drugs are D2 antagonists

2) 5HT theory: LSD (blocks 5HT) produce schizo sx

3) glutamate theory: ketamine (block NMDA receptor) produce schizo sx

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2
Q

5 schizo sx domains

A

1) +ve sx (abnormal behaviour)
2) -ve sx (substracted normal behaviour)
3) aggressive sx
4) ANX/ DEP
5) cognitive sx

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3
Q

DA pathways (1) DA theory

A

Nigrostriatal pathway (D1, D2)
- substantia nigra –> dorsal striatum

Mesolimbic pathway (D2, 3)
- ventral tegmental area (VTA) –> Limbic (emotional) brain

Mesocortical (D4)/ mesolimbic pathway
- ventral tegmental area (VTA) –> prefrontal cortex (emotional)

Tuberoinfundibular pathway (D3)
- hypothalamus –> anterior pituitary

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4
Q

Nigrostriatal pathway

A

substantia nigra –> dorsal striatum

Voluntary movement , prevent other movements

  • inhibit D2: EPSE (pseudo-parkinsonism)
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5
Q

Mesolimbic pathway

A

ventral tegmental area (VTA) –> Limbic (emotional) brain
Reward and emotion

  • inhbit D2: reduce +ve sx, reduce schizo sx
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6
Q

Mesocortical pathway

A

ventral tegmental area (VTA) –> prefrontal cortex

motion, cognition, attention
- Higher order thinking
- Executive functions

  • inhibit D2: hypofunction, results in -ve sx
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7
Q

Tuberoinfundibular pathway (D3)

A

hypothalamus –> anterior pituitary (infundibular)

DA inhibits prolactin secretion into blood circ

  • inhibit D2: hyperprolactinemia (more prolactin released)
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8
Q

1st vs 2nd gen

A

BOTH: block dopamine pathways = Control +ve sx of schizo

EPSE in 1st gen > 2nd gen

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9
Q

FGA eg

A

chlorpromazine
haloperidol
sulpiride

  • D2 antagonism
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10
Q

SGA eg

A

clozapine
olanzapine
quetiapine
risperidone
amisulpride
brexipiprazole

  • serotonin-dopamine antagonism (SDA: 5HT, DA) + complex mix
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11
Q

FGA SE

A

○ M1: dry mouth, constipation, blurred vision
○ H1: sedation, weight gain
○ A1: postural hypotension, dizzy
○ DA: EPSE, prolact

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12
Q

EPSE

  • Pyramidal motor pathway is output from primary motor cortex
    ○ via pyramids of medullar oblongata –> spinal cord
    ○ Involves basal ganglia: (striatum, substantia nigra)
A
  • (Tardive dyskinesia + Akathisia) Occur in 20-40% of pt on typical antipsychotics, IRREVERSIBLE dyskinesia
    Upregulation or super sensitivity of dopamine receptors in nigrostriatal system
  • (parkinsonism) block D2 receptor in nigrostriatal, where DA neurons terminate
  • (dystonia) DA hyperactivity in basal ganglia
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13
Q

EPSE description

A
  • Acute dystonia – (posture, spasm)
    * Parkinson-like sx: cogwheel rigidity and tremor at rest, abnormal muscle tone
    * 1st few wks of tx
    * Reversible when drug is stopped
    - Caused by D2 antagonism in nigrostriatal pathway
  • Tardive dyskinesia – uncontrolled facial, jaw movements
    * Slow (tardive) over mnths/ yrs of tx
    * Repetitive (dyskinesia)
    * irreversible
    - stereotyped involuntary movements of face, tongue, limbs
  • Akathisia – restlessness
    * Involuntary movements (akathisia)
    * compulsion assoc with restlessness, ANX, agitation
    - Correlates directly to duration on meds
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14
Q

SGA – atypical

A

produce less EPSE. more metabolic (-ine)
complex mixtures of actions:

  • greater affinity for 5HT2 receptors
  • greater affinity at D4 receptors
  • mixed antagonism: a-adrenoceptor, H1, M1, 5HT2 receptor
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15
Q

diff SGA drug, diff receptor affinity – SE, efficacy

A
  • Amisulpride (D2, D3, reported 5HT7)
    • Fewer SE due to D2,3 receptor selectivity
      ○ D2,3 antagonist: prolactin release incr (breast pain, swell, lact)
      ○ Absence of a1, H1, M1 antagonist SE
  • Clozapine
    • M1: dry mouth, constipation, blurred vision
    • H1: sedation, weight gain
    • A1: postural hypotension, dizziness
      • D1,2,3,4
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16
Q

clozapine ADR

A

Clozapine-induced agranulocytosis
○ <1% of pt but fatal
○ Lack of granulocyte type WBC (monitor regular blood counts)

–> olanzapine (similar effect w/o this ADR)

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17
Q

drug-induced DM

A

clozapine, olanzapine, risperidone

(amisulpride exception)

MOA: unknown - may involve 5HT antagonism
* in hypothalamus
* in pancreatic beta cells

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18
Q

drug-induced weight gain

A

SGA: clozapine, olanzapine, risperidone

MOA: sedation (H1 antagonism) –> incr sedentary behaviour
maybe: A1 , 5HT2 antagonism on hypothalamus & feeding behaviour

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19
Q

WHY SGA < FGA EPSE

A
  • more 5HT2A receptor antagonism > D2 antagonism = less EPS, less -ve sx too
  • high D3 to D2 antagonism ratio (more action on nucleus accumbens > striatum = more DA receptor for EPSE)
  • high D4 to D2 antagonism ration (action in prefrontal cortex > striatum)
    /targets emotion, +ve sx control
  • high D2 to D1 antagonism ratio (less complete blockade of DA function as D2 antagonism at presynapse will iNCR DA RELEASE)
    / presynaptic D2 receptor as a feedback regulation
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20
Q

additional benefits of SGA

A
  • more effective against -ve sx (clozapine, olanzapine, risperidone)
  • cognitive dysfunction sx control (clozapine, risperidone)
  • mood stabilisation (clozapine, olanzapine, risperidone)

FGA: more on +ve sx control (not much for -ve sx, cognition and mood stability)

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21
Q

PK of APS and onset (tmax)

BAO

A
  • SGA
    * (long tmax) olanzapine 6hrs, aripiprazole 3-5hrs, brex 4hrs
  • most FGA, SGA: tmax= 1-3hrs
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22
Q

PK of APS and dosing freq (t1/2)

A

(divided dosing due to risk of hypoTEN, seizure)

  • FGA
    * (divide dose): chlorpromazine, sulpiride
  • SGA
    * (divided dose): amisulpride, clozapine, quet, ziprasidone

most FGA, SGA
* long t1/2: OD dosing
eg haloperidol 12-36hrs

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23
Q

PO APS potency

HOR

A

low potency: sulpiride, chlorpromazine, Amisulpride, clozapine, quetiapine

high potency: risperidone (2-6mg), haloperidol, olanzapine (5-15mg)

24
Q

dosing freq of LAI

A
  • haloperidol decanoate: 2-4w
  • risperidone: 2wk, suppl PO for first 3 wks reach stabilisation
  • paliperidone: 3mnths
25
Q

relative SE

A
  • FGA
    • EPSE – MOST
    • Prolactin – ALL
    • Weight gain – chlorpromazine, perphenazine
    • Pro convulsation – chlorpromazine, cloxapine
    • Cardiac – thioridazine
    • Anticholinergic – chlorpromazine
    • Hypotension: chlorpromazine
  • SGA
    • Weight gain : clozapine, olanzapine
    • Anticholinergic : clozapine
    • Cardiac: clozapine, ziprasidone
    • Sedation: clozapine
26
Q

EPSE

A
  • acute dystonia (abnormal, prolonged contraction of any muscle grp)
    ○ anticholinergics
  • parkinsonism (tremor, muscular rigidity, flattended effect, loss of movement, bradykinesia)
    ○ anticholinergics
  • akathisia (restlessness, fidget)
    ○ BZP, propranolol
  • tardive dyskinesia (involuntary orofacial muscle)
    ○ valbenazine
27
Q

EPSE – dystonia (muscle spasm)

A
  • IM/IV > PO hrs
  • Risk: high potency, neuroleptic naïve pt, young M
  • Manage: IM anticholinergics (benztropine, diphenhydramine)
28
Q

EPSE - pseudo parkinsonism manage
(tremor, rigid, bradykinesia, salivation)

A

○ Risk: elder F, previous neurological damage (head injury, stroke)

○ Manage: decr antipsychotic dose, switch to sga
○ Anticholinergics PRN (benztropine)

29
Q

EPSE - tardive dyskinesia (orofacial movement, chew/ tongue protusion, repetitive. Late onset 3-6mnths)

A
  • Risk: FGA > SGA, those develop acute EPSE when started on FGA. Worsens with anticholinergic. May be irreversible
  • Manage: discontinue anticholinergics
    ○ Decr dose, switch to SGA (clozapine)
    ○ Reversible inhibitor of vesicular MAO transporter 2 (VMAT2) = valbenazine 40-80mg/ day
    ○ BZP: Clonazepam PRN
30
Q

hyperprolactinaemia

A
  • Galactorrhea, amenorrhea, decr libido, gynecomastia (M)
  • Risk: FGA (Pali =/> RISP > OTHERS)
  • Manage: decr FGA dose, dopamine agonist (amantadine, bromocriptine)
    * Switch to aripiprazole
31
Q

metabolic SE

A
  • Weight gain (>7% from baseline), DM incr lipids
  • Risk: OLAN, CLOZ > CPZ, QUET, RISP >
  • Manage: lifestyle, tx DM (metformin) & hyperlipidemia
  • Switch to lower risk agents (Ari, Lura, Zip, Halo)
32
Q

manage CVS - ortho hypoTENsion

A
  • orthostatic hypotension
    * CPZ, CLOZ > RISP, PALI, QUET
    * get up slow; switch to olan, zip, ari, sulpiride
33
Q

manage CVS -QTc

A
  • high doses, IV haloperidol, low K+, IHD, Female
  • avoid: Thio > chlorpromazine > Halo > quet > risp> olan
  • lower risk agents: Aripiprazole
34
Q

CVS - VTE/ PE

A
  • avoid: low potency FGA: sulpiride, chlorpromazine
  • prevent, monitor and tx DVT
35
Q

CNS - sedation

A

Risk: CPZ > CLOZ > QUET > OLAN

Manage: switch to lower risk agents. (RISP, PALI, ZIP, ARI)

36
Q

CNS seizure

A
  • Risk: CLOZ > CPZ> OTHERS SGA
  • High doses, rapid titration, hx of epilepsy
  • Manage: switch to high potency agents (HALO, RISP)
37
Q

neuroleptic malignant syndrome is __

caused by ___

A
  • DA blockade, cause hypothalamic dysfunction. muscle contraction & temp dysregulation
  • Muscle rigidity, fever, altered consciousness, high CK, autonomic dysfunct (PR, BP, diaphoresis)
  • Risk: high potency anticholinergics
    • Rare, potentially lethal
    • Onset: hrs - 3days (within 30d)
  • Other possible causes
    1. Succinylcholine/ suxamethonium (muscle relaxant)
    2. Antipsychotics D2 blocker
    3. Sudden discontinuation Levodopa (LT dopamine agonist)
38
Q

manage NMS

A
  • Manage: IV dantrolene 50mg TDS, PO dopamine agonists (amantadine, bromocriptine)
  • Supportive measures
  • Switch to SGA
39
Q

psychogenic polydipsia
self-induced water intoxication

A
  • avoid: anticholinergics
  • manage: fluid restriction, discontinue drug with anticholinergics effect (anta M1, Ach)
40
Q

temp dysregulation

A
  • avoid anticholinergics
  • manage: hydration, app clothes + shade
41
Q

hepatic SE

A
  • Incr LFT, cholestatic jaundice (CPZ)
  • Risk: CPZ (FGA), OLAN, QUET > OTHER SGA
  • Manage: jaundice develops = discontinue and switch to safer agents
    sulpiride, ami
42
Q

opthalmologic

A
  • Cornea/ lens changes, pigmentary retinopathy
  • Risk: phenothiazines (CPZ, THIO), Quet
  • Manage: pt on QUET (eye exam q6mnths)
43
Q

dermatologic

A
  • Maculopapular rash, photosensitive, pigmentation
  • Risk: CPZ
  • Manage: protective clothing, sunscreen
    * Consider switch to other antipsychotics
44
Q

hematologic

A
  • Decr WBC, agranulocytosis (absolute neut count ANC)
  • Risk: clozapine
  • Manage: discontinue antipsychotics if severe
    * WBC < 3x 109/L or ANC < 1.5x 109/L
45
Q

monitor SE

A

(every visit)
- vitals
* BP, PR, temp
- SE:
* EPSE exam, plasma prolactin (libido, gynecomastia)
- mental state:
* suicidality, MSE

(12wks, annual)
- metabolic:
* BMI, waist circumference, Fasting blood sugar, lipid panel
- ECG (Qtc prolongation)

(wkly 18wks, mnthly)
- WBC, ANC (clozapine)

46
Q

preg

A

avoid OLAN, CLOZ: Gestational DM

47
Q

breastfeed

A

OLAN, QUET suitable

CLOZ continue + not breastfeed

48
Q

renal impairment

A

oral aripiprazole

avoid: sulpiride, amisulpride

49
Q

hep impairment

A

sulpiride, amisulpride preferred

50
Q

elderly

A
  • Avoid drug with high propensity for a1 blockade = hypotension
  • Avoid drugs with Ach SE = Constipation, urinary retention, delirium
    ○ Start low, go slow. Simplify regime, avoid DDI, avoid long t1/2 drugs (split)
  • Caution: FGA, SGA - incr mortality, CVA in dementia pts
51
Q

PD int

(6)

A
  • CNS depressants: alcohol, codeine, hydroxyzine, psychotropics
  • additive effects: anti M1, H1, A1, DA (hypotension) BP meds
    * Parkinson (nullify effect): dopamine agonist, levodopa
  • 5HT augmenting agents (antagonise 5HT2A receptor block, decr DA release, worsen EPSE)
  • EPSE, NMS: metoclopramide, psychostimulants
  • seizure: lower the seizure threshold, incr seizure risk
  • incr toxicity: Li, TCAs
  • agranulocytosis (CBP + cloz)
52
Q

PK int

A
  • P1: oxidation, reduction, hydrolysis
    ○ CYPP450, 1A2, 3A4, 2D6
  • P2
    ○ Glucuronidation, coupling
53
Q

CYP1A2

A
  • inducers: rifampicin, PB, PT, smoke
  • inhibitors: fluvoxamine, ciprofloxacin, quinolones, macrolides, isoniazid, ketoconazole

(halo, cloz, olan, zip)

54
Q

CYP2D6

A
  • inducers: rifampicin, PB, PT, CBP
  • inhibitors: fluoxetine, paroxetine - ssri, duloxetine - snri

(halo, risp, ari, olan)

55
Q

CYP3A4

A
  • inducers: barbiturates, CBP, PT, rifampicin, st john’s
  • inhibitors: azoles, TCA, fluvoxamine, isoniazid, macrolides, grapefruit

quet, zip, Ari, Risp, brexipip