Transcript Antipsychotics - Yorkshire and the Humber Deanery

Antipsychotics
Actions, uses and side effects
Aims
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Overview of dopamine physiology
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Antipsychotic classifications
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Movement disorders +neuroleptic malignant syndrome
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Stroke and mortality risk
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PCF/NICE guidelines delirium + challenging behaviour in
dementia
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Conclusions
Dopamine Physiology
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Neurophysiology of dopamine underpins an
understanding of the therapeutic uses and side
effects of dopamine antagonists
Mesolimbic
mesocortical pathway
Nigrostriatal pathway
tubero-infundibular pathway
(chemoreceptor trigger zone)
Mesolimbic + mesocortical pathways
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Mesolimbic (midbrain – limbic cortex)
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Pleasure, motivation and reward
Increase in dopamine leads to ‘positive’ symptoms of
psychosis
Mesocortical (midbrain to prefrontal cortex)
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Mood, cognitive function, concentration
Decrease in dopamine leads to ‘negative’ symptoms
of psychosis’
Thalamic Sensory Gating
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Arousal, motivation and attention regulated by a two
way loop between mesolimbic/cortical systems and
thalamus
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Thalamus acts as a filter to allow relevant information
through to cerebral cortex
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gate formed by GABAergic neurones which are switched
off by dopamine to allow salient information through
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Dopamine excess leads to excessive throughput resulting
in hallucinations and delusions
Nigrostriatal Pathway
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Nigrostriatal (Substantia nigra – corpus striatum)
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as part of the extrapyramidal nervous system,
controls movements
degenerates in Parkinson’s disease
Blockade of D2 receptors in this pathway causes the
drug-induced movement disorders
Tubero-infundibular pathway
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Tubero-infundibular pathway (hypothalamus – pituitary)
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Dopamine acts on the pituitary as an inhibitor of
prolactin secretion
Blockade of D2 receptors by typical antipsychotics
and risperidone can cause hyperprolactinaemia
Other atypical antipsychotics do not cause sustained
hyperprolactinaemia because of their lower affinity for
D2 receptors.
Effect of D2 receptor antagonism
Classification of antipsychotics
 ‘Typical’
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Phenothiazines – Levomepromazine, chlorpromazine,
prochlorperazine
Butyrophenones – Haloperidol
‘atypical’
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Aripripazole, clozapine, olanzapine, quetiapine,
risperidone
Typical Vs. Atypical
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Variation within and overlap between classes
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ALL D2 antagonists to varying degrees
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Variable effects on other receptors:
 Muscarinic (dry mouth, constipation etc)
 Adrenergic (postural hypotension)
 Histamine (drowsiness)
 Serotoninergic (weight gain)
Typical Vs. Atypical
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Atypical generally have lower affinity and
shorter duration of D2 antagonism
Atypicals generally have greater seretonin
receptor antagonism (5HT2) than D2
antagonism
Atypicals have greater seretonin receptor
antagonism than typicals
5HT2 Antagonism
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Serotonin regulates dopamine release in dopamine pathways apart
from mesolimbic
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serotonin inhibits the release of dopamine in those pathways
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When serotonin receptors are blocked dopamine levels increase.
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naturally occurring dopamine then fills D2 receptors preventing
blockade by the antipsychotic agent.
Less D2 blockade therefore no worsening of negative symptoms,
less movement disorders and less hyperprolactanaemia (apart from
risperidone)
Antipsychotic Receptor Affinities
D2
Haloperidol
5HT2a
5HT2c 5HT3 H1
+++ +
Levomeprozine ++
α1
α2
AChm
++
+++
+++ +++ +
risperidone
+++ +++
++
olanzapine
++
+++
+
quetiapine
+
+
+
+
++
+
+++
+
++
+
++
+
++
++
++
* Decreasing levels of movement disorders as you get lower down the
list
Antipsychotic Tolerability
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Movement disorders/ extrapyramidal; side effects. Worst
haloperidol, best quetiapine.
Acute extrapyrimadal side effects would be avoided in
one patient for every 3-6 patients treated with atypical
vs. typical
5 times lower risk of longer term extrapyramidal side
effects with atypicals vs. haloperidol
Overall discontinuation for undesirable side effects are
comparable
Movement Disorders
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Acute Dystonia (spasms)
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10% of patients treated with antipsychotics
(commoner in young adults)
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Starts abruptly within days accompanied by anxiety
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Retrocolis, torticolis, trismus, grimacing, tongue
dysfunction, oculogyric crisis, abnormal positioning
limbs or trunk
Diazepam 5mg IV (benzo) or Procyclidine 5-10mg
IV/IM (repeat after 30 min if needed)
Movement Disorders
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Acute Akathisia (motor restlessness)
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20% when using typical antipsychotics
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Within days and resolves within week of stopping
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Restless, pacing, rocking from foot to foot, fidgety
movements, inability to sit or stand for a few minutes
Propranolol 10mg tds +/- benzodiazepine
Movement Disorders
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Parkinsonism
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30-60% on long term antipsychotics
Any point other than first week but more usually
weeks to months
Coarse resting tremor, muscular rigidity, shuffling
gait, sialorrhoea, bradkinesia (face)
procyclidine 2.5mg-5mg tds
Movement Disorders
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Tardive Dyskinesia
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20% when using typical antipsychotics long term (> 3 months or >
1month in elderly)
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Involuntary stereotyped chewing movements tongue and orofascial
muscles reduced by sleep, torticollis, lordosis, akathesia (25%)
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Early sign inability to hold tongue out for more than a few seconds and
worm like movements
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Resolution 30% 3 months, further 40% 5 years, sometimes irreversible
especially elderly
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Specialist advice on treatments (tetrabenazine, levodopa, clonidine,
baclofen, diazepam,valproate, pyridoxine)
Neuroleptic Malignant Syndrome
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Caused by acute dopamine depletion
Usually within two weeks of starting or dose increase of
antipsychotic
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Occurs less than 1% of patients on antipsychotics
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Death occurs in 20% and bromocriptine halves mortality
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Self limiting and resolves in 1-2 weeks if causal drug stopped
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Subsequent antipsychotic use has a 30-50% chance of causing a
reoccurance
Neuroleptic Malignant Syndrome
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Bradykinesia – immobilisation – akinsesia – stupor accompanied by
lead pipe rigidity, fever and autonomic instability
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Essential features – severe muscle rigidity, pyrexia +/- sweating
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Additional – muteness/stupor, tachycardia, labile BP
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Management – stop causal drug, benzo +/- bromocriptine, may
need IVI
If acidosis, hypoxia, renal failure may need acute management/ICU
Other considerations
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Stroke/All cause mortality risk
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In dementia - Risk of stroke with olanzapine and
risperidone 2-3 times higher than placebo + doubling of all
cause mortality with olanzapine (meta-analysis)
Increase risk in all elderly patients for both typicals and
atypicals, greatest in those with dementia and within first
month of starting treatment and with higher doses
(metanalysis). (? Worse with typical)
Relative risk with individual drugs has yet to be
determined
Other considerations
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Parkinsons
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Try and avoid antipsychotics but if needed
use queitiapine (could try trazadone or benzo)
Epilepsy
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All antipsychotics cause dose dependent
reduction in seizure threshold. Lowest risk
with Haloperidol
NICE Guidelines Delirium
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Find and treat reversible causes
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Use environmental factors to help keep patient from distress
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If a person with delirium is distressed or considered a risk to
themselves or others and verbal and non-verbal de-escalation
techniques are ineffective or inappropriate, consider giving
short-term (usually for 1 week or less) haloperidol or
olanzapine.
Start at the lowest clinically appropriate dose and titrate
cautiously according to symptoms.
antipsychotic drugs such as haloperidol and olanzapine should
be used with caution or not at all for people with conditions
such as Parkinson‟s disease and/or Lewy-body dementia.
PCF4 – Delirium
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Delirium is distressing and associated with higher mortality,
reduced performance status and increased admissions to
nursing homes
Antipsychotics should be considered in ALL forms of delirium
alongside environmental measures (including hypoactive)
Reduce distressing symptoms, shortened the duration of
delirium and improved outcomes in ALL forms delirium (RCTs)
When antipsychotics alone insufficient or sedation needed for
hyperactive/frightened patients benzos or trazadone can be
added.
Nice Guidelines Dementia
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Do not use for mild-to-moderate symptoms
Consider for severe symptoms (psychosis and/or agitated
behaviour causing significant distress) only if:
 risks and benefits have been fully discussed
 changes in cognition are regularly assessed and recorded
 target symptoms identified and changes regularly assessed
and recorded
 comorbid conditions, such as depression, have been
considered
 drug is chosen after an individual risk–benefit analysis
 start low and titrated upward
 treatment is time limited and regularly reviewed
PCF4 – Agitation in Dementia
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Treat causes (inc infection/pain)
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Environmental factors first
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Drugs as a last resort, evidence of benefit modest at
best and risks are significant
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If drugs needed lowest dose for shortest period
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Haloperidol, olanzapine, queitapine, risperidone
Individual Drug Properties
bioavailability
Onset
Time to peak plasma
concentration
Half life
(Hr)
Duration
(Hr)
Haloperidol
45-75%
1hr (PO)
10-15 (SC)
2-6hr (PO)
10-20min (SC)
13-35
24+
Levomepromazine
20-40%
30min
1-3hr (PO)
30-90min (SC)
15-30
12-24
risperidone
99%
*
1-2hr (PO)
24
12-48
olanzapine
60%
*
5-8hr (PO)
34-52
12-48
quetiapine
100%
*
1.5hr (PO)
7-14
12h
*hours to days in delirium, days to weeks in psychosis
N.B all metabolised by various CP450 enzymes (liver)
Reduce doses in elderly, renal and liver impairment (generally half of usual
dose)
Interesting facts!
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Haloperidol
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Bioavailability 45-75% orally and 60-70% SC
? Should reduce dose by injection
Liquid is odourless, colourless and tasteless
Prolongs QT interval
Plasma concentration halved by carbamazepine
Evidence for N+V in post op and gastroenterology not
palliative care
Interesting facts!
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Levomepromazine
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Licensed for pain!
Olanzapine
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Evidence in phase 1 and phase 2 trial of efficacy for
vomiting with moderately and highly emetogenic
chemotherapy
Adversely affects diabetic control
Drowsiness and wt. gain most common side effects
Smoking can decrease plasma levels (as can omeprazole,
carbamazepine, rifampicin)
Conclusions
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Be aware of side effects and risks but keep them in
perspective and review need to continue drugs regularly(be
cautious but not to cautious)
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Look out for movement disorders and don’t miss NMS!
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Be aware of different profiles of typicals vs atypicals
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Use antipsychotics in agitated delirium, jury still out about
hypoactive delirium (? Use atypicals)
Be cautious in dementia but not to cautious and if using
anything use low doses and review regularly