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Antipsychotics

INTRODUCTION

Decrease relapse

Treats Sx only

Not cure

2 classes:
o Dopamine-R
antagonist
(typical)
o Serotonin-dopamine antagonist
(atypical)
DOPAMINE HYPOTHESIS

D2 receptor block improves positive Sx

Mesolimbic and mesocotical tracts

Other transmitters:
o 5HT, NE, GABA, glutamate
4 DOPAMINE PATHWAYS:

Mesolimbic
(arousal,
memory,
behaviour)
o Hyperactivity
of
DA

hallucinations, delusions and


thought disorders
o Role in aggressive sx
o Drugs that DA psychotic sx
o Antipsychotics DA (blocks R)

Mesocortical (cognition, socialization)


o Related to mesolimbic
o Projects to different brain areas
o DA deficit role in negative &
cognitive sx
o Causes of DA:

Excite-toxicity
of
glutamate system

2 to inhibition by
excess serotonin

D2
block
by
antipsychotics
o Degenerative process here
could explain worsening of

INDICATIONS

Psychotic disorders

Dementia (especially behavioural Sx)

Augmentation of MDD & OCD

Tic disorders
PSYCHOSIS: ACUTE MANAGEMENT
Chemical restraints for aggression:

LORAZEPAM 2-4mg ii with:


IM acute onset antipsychotic:

Haloperidol 5-10mg/2-4h (max40mg/d)

Olanzapine (not with BZ) 10mg/2-4h


(max 30mg/d)

Ziprasidone 10-20mg/4h (max40mg/d)

Zuclopenthixol-acetate 50-100mg/72h
(max 400mg over 3 weeks)
Decide if admission is warranted or essential
CLASSES OF ANTIPSYCHOTICS
1st generation (typical)

D2 antagonism

Other: M1, H1, 1


antagonism

E.g.
haloperidol,
chlorpromazine

2nd generation (atypical)

5HT2A D2
antagonism

5HT1A agonism

other: M1, H1,


2HT2C, 1
antagonism

e.g. clozapine,
risperidone,
olanzapine

1ST GENERATION/ TYPICALS

Butyrophenone (haloperidol)

Phenothiazine
(chlorpromazine,
trifluperazine, fluphenazine)

Diphenylbutylpiperidine (pimozide)

Benzamine (sulpiride)

Thioxanthines
(flupenthixol,
zuclopenthixol)

Differ in molecular structure and


potency
Equal efficacy for positive sx
S/E profiles differ
Dosage:
o Chlorpromazine 200-800mg
o Haloperidol 0.5-15mg
o Trifluoperazine 2-15mg
o Pimozide 1-12mg
peak concentration
o oral within 1-4h
o parenteral 30-60min
high potency associated with:
o EPSE
o anti-Ach
o epileptogenic
DA receptor block is immediate but
antipsychotic effect takes weeks
D2 block responsible for:
o Antipsychotic (ML)
o Worsen negative sx (MC)
o Movement d/o & EPSE (NS)
o Hyperprolactinaemia (TI)
Muscarinic, cholinergic block
o Ach & DA reciprocal
relationship in NS pathway
o Cholinergic block mitigate
effects of D2 block in
nigrostriatal pathway = less
EPSE

2ND GENERATION / ATYPICALS

Clozapine (leponex)

Risperidone (Risperdal)

Olanzapine (Zyprexa)

Quetiapine (Seroquel)

Aripiprazole (Abilify)

Ziprasidone (Geodon)

Paliperidone (Invega)

Amisulpride (Solian) selective D2/3


agnoist

Sulpiride (Eglonyl)

5HT2A-D2 antagonist
lower affinity for D2, less EPSE
5HT1A agonism DA release in
prefrontal cortex; glutamate release
(Ziprasidone, Quetiapine, Clozapine)
S/E depend on relative receptor
affinities: DA, NA, H1, Ach
Daily dose ranges:
o Olanzapine 5-20mg
o Clozapine 100-800mg
o Risperidone 1-8mg
o Paliperidone 3-12mg
o Quetiapine 300-800mg
o Amisulpiride 100-800mg

Indications

Severe EPSE

Tardive dyskinesia

Young person with 1st episode

Better for negative sx (?)

Treatment resistant: clozapine

Re-challenge after NMS

Unacceptable prolactin levels

Mood sx and suicide risk

Elderly with behavioural sx


S/E

negative sx over time


Nigrostriatal
o Part of extrapyramidal system
o Control motor movement
o DA = movement disorder &
EPSE
Tuberoinfundibular
o Controls prolactin secretion
o DA inhibits prolactin

Also block alpha1 & histaminergic-R


S/E
o Neuroleptic induced
movement disorders

Metabolic disturbances

IF S/E = REDUCE DOSE/ SWITCH MEDS/


Rx FOR SPECIFIC S/E

AKATHESIA

Develops within 1st few weeks

Subjective tension + objective


restlessness & agitation

Unable to sit still, fidgets, rocks,


paces

Must
be
distinguished
from
aggressive / agitated patient

Lower dosage if possible

B-blockers: Propanolol 10-30mg tds

BZ

Change to low potency typical or


SDA

ACUTE DYSTONIA

First 4-7 days / dose

risk: young male, high potency

Painful, prolonged contraction of muscles result in


abnormal movements/ posture:
o Torticollis (neck)
o Trismus (jaw)
o Protrusion of tongue
o Dysphagia
o Laryngo-pharyngeal spasm
o Oculogyrus crisis

Rx: Biperidine 5mg IVI/ IMI


PARKINSONISM

Tremors, rigidity & bradykinesia

If DA receptors blocked AChEPS

Rx: Anticholinergics
o Orphenadrine 50mg PO 1-3x/d OR

TARDIVE AKINESIA

Abnormal, involuntary movements

Oral movements, protrusion of


tongue, grimaces

Choreoatesosis of extremities &


abnormal postures (tardive dystonia)

Appears very late (>4weeks)

Irreversible

RF: female, elderly, high dose

Up-regulation of D2-R in NS pathway

Not alleviated by anticholinergic/


antiparkison drugs

Reduce dose, stop anticholinergics

Try SDA/ clozapine


NEUROLEPT MALIGNANT SYNDROME

Extremely rare (0.02% of people Rx


with antipsychotic)

Potentially lethal

Features of advanced parkinsonism


and catatonia

Exact mechanism unknown

Central DA blockade involved

Also other NT (GAMA, NE, 5HT, Ach)

Mostly in 1st week; 10-30% mortality

Muscle rigidity + fever with:

NMS Mx:

Emergency ICU; stop antipsychotics

Exclude serious conditions

Cool pt + aggressive hydration

Monitor vitals + NGT

Diazepam / lorazepam for muscle


rigidity

DVT prophylaxis

Beware of renal failure (CK/


myoglobin)

Dantrolene 3-5mg/kg IV divided dose

Bromocryptine 5mg qid (?L dopa)

If no response ECT

Rechallenge: low dose, atypical, ECT


OTHER SIDE EFFECTS
Anticholinergic (M antagonist)

Dry mouth

Blurred vision/ dry eyes

Constipation/ urinary retention

Cognitive dysfunction
Cardiovascular (1, M block)

Postural hypotension/ HR

ECG change: prolonged QT

risk sudden death (arrhythmia)

cardiomyopathy (clozapine)
Neurological (D2 antagonism)

lowers seizure threshold


Cognitive

sedation/ headache

decreased concentration

depression
sexual (D2, 1, M block)

decreased libido/anorgasmia

ED/ inhibit ejaculation


Endocrine

prolactin
(sexual
dysfx,
galactorrhoea, weight, /
glucose, SIADH)
Hypersensitivity reaction

METABOLIC SYNDROME
Co-occurrence of interrelated risks:

obesity

insulin resistance

dyslipidaemia

hypertension

pro-inflammatory
&
prothrombotic state
to continue SDA or not

lifestyle change (exercise, stop


smoking, diet)

benefit vs risk
CLOZAPINE

for Rx resistant schizophrenia,


intolerable EPS or tardive
dyskinesia

risk for agranulocytosis


monitor WBC

dangerous: myocarditis, toxic


megacolon, seizures at high
doses, metabolic sd

common:
hypersalivation,
constipation,
weight
gain,
sedation
DEPOT PREPARATIONS
Should not be used until response to oral
medication demonstrated
Lowest possible dose (IMI):

Flupentixol decanoate 10-60mg


2-4 weekly

Fluphenazine decanoate 6.2550mg 2-4 weekly

Zuclopenthixol decanoate 100400mg 2-4 weekly

Risperidone 25-50mg 2 weekly

Paliperidone
GENERAL PRINCIPLES

o Biperidine 2mg 1-3x/d


Lower dose of antipsychotics
If severe, replace with SDA

o
o
o
o
o
o
o
o
o

Diaphoresis
Autonomic instability
Tremor
Dysphagia
Mutism
Incontinence
Leucocytosis
Change in LOC
Injured muscle: CK (lab)

photosensitivity, skin reaction

agranulocytosis
ocular effects

retinitis pigmentosa
GI

weight gain, metabolic sd

constipation/ sialorrhoea

Start Rx early
Gradual increase of dose
Use lowest effective dose
Sufficient time (4-6w)
Prolonged use of prophylactic Rx (1st
episode = 2yrs, 2nd episode = 5/>yrs)
Non-compliance = depot injections