Antipsychotics

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Antipsychotics

• Actions, uses and side effects

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Aims

• Overview of dopamine physiology
• Antipsychotic classifications
• Movement disorders neuroleptic malignant
  syndrome
• Stroke and mortality risk
• PCF/NICE guidelines delirium challenging
  behaviour in dementia
• Conclusions

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Dopamine Physiology

• 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)

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Mesolimbic mesocortical pathways

• Mesolimbic (midbrain limbic cortex)
• Pleasure, motivation and reward
• Increase in dopamine leads to positive symptoms
  of psychosis
• Mesocortical (midbrain to prefrontal cortex)
• Mood, cognitive function, concentration
• Decrease in dopamine leads to negative symptoms
  of psychosis

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Thalamic Sensory Gating

• Arousal, motivation and attention regulated by a
  two way loop between mesolimbic/cortical systems
  and thalamus
• Thalamus acts as a filter to allow relevant
  information through to cerebral cortex
• gate formed by GABAergic neurones which are
  switched off by dopamine to allow salient
  information through
• Dopamine excess leads to excessive throughput
  resulting in hallucinations and delusions

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Nigrostriatal Pathway

• Nigrostriatal (Substantia nigra corpus
  striatum)
• as part of the extrapyramidal nervous system,
  controls movements
• degenerates in Parkinsons disease
• Blockade of D2 receptors in this pathway causes
  the drug-induced movement disorders

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Tubero-infundibular pathway

• Tubero-infundibular pathway (hypothalamus
  pituitary)
• 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.

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Effect of D2 receptor antagonism
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Classification of antipsychotics

• Typical
• Phenothiazines Levomepromazine, chlorpromazine,
  prochlorperazine
• Butyrophenones Haloperidol
• atypical
• Aripripazole, clozapine, olanzapine, quetiapine,
  risperidone

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Typical Vs. Atypical

• Variation within and overlap between classes
• ALL D2 antagonists to varying degrees
• Variable effects on other receptors
• Muscarinic (dry mouth, constipation etc)
• Adrenergic (postural hypotension)
• Histamine (drowsiness)
• Serotoninergic (weight gain)

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Typical Vs. Atypical

• 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

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5HT2 Antagonism

• Serotonin regulates dopamine release in dopamine
  pathways apart from mesolimbic
• serotonin inhibits the release of dopamine in
  those pathways
• When serotonin receptors are blocked dopamine
  levels increase.
• 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)

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Antipsychotic Receptor Affinities

• Decreasing levels of movement disorders as you
  get lower down the list

D2 5HT2a 5HT2c 5HT3 H1 a1 a2 AChm
Haloperidol
Levomeprozine
risperidone
olanzapine
quetiapine
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Antipsychotic Tolerability

• 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

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Movement Disorders

• Acute Dystonia (spasms)
• 10 of patients treated with antipsychotics
  (commoner in young adults)
• Starts abruptly within days accompanied by
  anxiety
• 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)

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Movement Disorders

• Acute Akathisia (motor restlessness)
• 20 when using typical antipsychotics
• Within days and resolves within week of stopping
• Restless, pacing, rocking from foot to foot,
  fidgety movements, inability to sit or stand for
  a few minutes
• Propranolol 10mg tds /- benzodiazepine

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Movement Disorders

• Parkinsonism
• 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

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Movement Disorders

• Tardive Dyskinesia
• 20 when using typical antipsychotics long term
  (gt 3 months or gt 1month in elderly)
• Involuntary stereotyped chewing movements tongue
  and orofascial muscles reduced by sleep,
  torticollis, lordosis, akathesia (25)
• Early sign inability to hold tongue out for more
  than a few seconds and worm like movements
• Resolution 30 3 months, further 40 5 years,
  sometimes irreversible especially elderly
• Specialist advice on treatments (tetrabenazine,
  levodopa, clonidine, baclofen, diazepam,valproate,
  pyridoxine)

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Neuroleptic Malignant Syndrome

• Caused by acute dopamine depletion
• Usually within two weeks of starting or dose
  increase of antipsychotic
• Occurs less than 1 of patients on antipsychotics
• Death occurs in 20 and bromocriptine halves
  mortality
• Self limiting and resolves in 1-2 weeks if causal
  drug stopped
• Subsequent antipsychotic use has a 30-50 chance
  of causing a reoccurance

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Neuroleptic Malignant Syndrome

• Bradykinesia immobilisation akinsesia
  stupor accompanied by lead pipe rigidity, fever
  and autonomic instability
• Essential features severe muscle rigidity,
  pyrexia /- sweating
• Additional muteness/stupor, tachycardia, labile
  BP
• Management stop causal drug, benzo /-
  bromocriptine, may need IVI
• If acidosis, hypoxia, renal failure may need
  acute management/ICU

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Other considerations

• Stroke/All cause mortality risk
• 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

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Other considerations

• Parkinsons
• Try and avoid antipsychotics but if needed use
  queitiapine (could try trazadone or benzo)
• Epilepsy
• All antipsychotics cause dose dependent reduction
  in seizure threshold. Lowest risk with
  Haloperidol

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NICE Guidelines Delirium

• Find and treat reversible causes
• Use environmental factors to help keep patient
  from distress
• 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.

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PCF4 Delirium

• 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.

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Nice Guidelines Dementia

• 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 riskbenefit
  analysis
• start low and titrated upward
• treatment is time limited and regularly reviewed

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PCF4 Agitation in Dementia

• Treat causes (inc infection/pain)
• Environmental factors first
• Drugs as a last resort, evidence of benefit
  modest at best and risks are significant
• If drugs needed lowest dose for shortest period
• Haloperidol, olanzapine, queitapine, risperidone

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Individual Drug Properties
  bio-availability 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)
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Interesting facts!

• Haloperidol
• 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 NV in post op and gastroenterology
  not palliative care

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Interesting facts!

• Levomepromazine
• Licensed for pain!
• Olanzapine
• 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)

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Conclusions

• 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)
• Look out for movement disorders and dont miss
  NMS!
• Be aware of different profiles of typicals vs
  atypicals
• 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