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Antipsychotics Actions, uses and side effects. Aims Overview of dopamine physiology Overview of dopamine physiology Antipsychotic classifications Antipsychotic.

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Presentation on theme: "Antipsychotics Actions, uses and side effects. Aims Overview of dopamine physiology Overview of dopamine physiology Antipsychotic classifications Antipsychotic."— Presentation transcript:

1 Antipsychotics Actions, uses and side effects

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

3 Dopamine Physiology Neurophysiology of dopamine underpins an understanding of the therapeutic uses and side effects of dopamine antagonists Neurophysiology of dopamine underpins an understanding of the therapeutic uses and side effects of dopamine antagonists Mesolimbic Mesolimbic mesocortical pathway mesocortical pathway Nigrostriatal pathway Nigrostriatal pathway tubero-infundibular pathway tubero-infundibular pathway (chemoreceptor trigger zone)

4 Mesolimbic + mesocortical pathways Mesolimbic (midbrain – limbic cortex) Mesolimbic (midbrain – limbic cortex) Pleasure, motivation and reward Pleasure, motivation and reward Increase in dopamine leads to ‘positive’ symptoms of psychosis Increase in dopamine leads to ‘positive’ symptoms of psychosis Mesocortical (midbrain to prefrontal cortex) Mesocortical (midbrain to prefrontal cortex) Mood, cognitive function, concentration Mood, cognitive function, concentration Decrease in dopamine leads to ‘negative’ symptoms of psychosis’ Decrease in dopamine leads to ‘negative’ symptoms of psychosis’

5 Thalamic Sensory Gating Arousal, motivation and attention regulated by a two way loop between mesolimbic/cortical systems and thalamus 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 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 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 Dopamine excess leads to excessive throughput resulting in hallucinations and delusions

6 Nigrostriatal Pathway Nigrostriatal (Substantia nigra – corpus striatum) Nigrostriatal (Substantia nigra – corpus striatum) as part of the extrapyramidal nervous system, controls movements as part of the extrapyramidal nervous system, controls movements degenerates in Parkinson’s disease degenerates in Parkinson’s disease Blockade of D2 receptors in this pathway causes the drug-induced movement disorders Blockade of D2 receptors in this pathway causes the drug-induced movement disorders

7 Tubero-infundibular pathway Tubero-infundibular pathway (hypothalamus – pituitary) Tubero-infundibular pathway (hypothalamus – pituitary) Dopamine acts on the pituitary as an inhibitor of prolactin secretion Dopamine acts on the pituitary as an inhibitor of prolactin secretion Blockade of D2 receptors by typical antipsychotics and risperidone can cause hyperprolactinaemia 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. Other atypical antipsychotics do not cause sustained hyperprolactinaemia because of their lower affinity for D2 receptors.

8 Effect of D 2 receptor antagonism

9 Classification of antipsychotics ‘ Typical’ ‘ Typical’ Phenothiazines – Levomepromazine, chlorpromazine, prochlorperazine Phenothiazines – Levomepromazine, chlorpromazine, prochlorperazine Butyrophenones – Haloperidol Butyrophenones – Haloperidol ‘atypical’ ‘atypical’ Aripripazole, clozapine, olanzapine, quetiapine, risperidone Aripripazole, clozapine, olanzapine, quetiapine, risperidone

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

11 Typical Vs. Atypical Atypical generally have lower affinity and shorter duration of D2 antagonism Atypical generally have lower affinity and shorter duration of D2 antagonism Atypicals generally have greater seretonin receptor antagonism (5HT2) than D2 antagonism Atypicals generally have greater seretonin receptor antagonism (5HT2) than D2 antagonism Atypicals have greater seretonin receptor antagonism than typicals Atypicals have greater seretonin receptor antagonism than typicals

12 5HT2 Antagonism Serotonin regulates dopamine release in dopamine pathways apart from mesolimbic Serotonin regulates dopamine release in dopamine pathways apart from mesolimbic serotonin inhibits the release of dopamine in those pathways serotonin inhibits the release of dopamine in those pathways When serotonin receptors are blocked dopamine levels increase. When serotonin receptors are blocked dopamine levels increase. naturally occurring dopamine then fills D2 receptors preventing blockade by the antipsychotic agent. 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) Less D2 blockade therefore no worsening of negative symptoms, less movement disorders and less hyperprolactanaemia (apart from risperidone)

13 Antipsychotic Receptor Affinities *Decreasing levels of movement disorders as you get lower down the list D25HT2a5HT2c5HT3H1 α1α1α1α1 α2α2α2α2AChm Haloperidol Levomeprozine risperidone olanzapine quetiapine

14 Antipsychotic Tolerability Movement disorders/ extrapyramidal; side effects. Worst haloperidol, best quetiapine. 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 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 5 times lower risk of longer term extrapyramidal side effects with atypicals vs. haloperidol Overall discontinuation for undesirable side effects are comparable Overall discontinuation for undesirable side effects are comparable

15 Movement Disorders Acute Dystonia (spasms) Acute Dystonia (spasms) 10% of patients treated with antipsychotics (commoner in young adults) 10% of patients treated with antipsychotics (commoner in young adults) Starts abruptly within days accompanied by anxiety Starts abruptly within days accompanied by anxiety Retrocolis, torticolis, trismus, grimacing, tongue dysfunction, oculogyric crisis, abnormal positioning limbs or trunk 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) Diazepam 5mg IV (benzo) or Procyclidine 5-10mg IV/IM (repeat after 30 min if needed)

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

17 Movement Disorders Parkinsonism Parkinsonism 30-60% on long term antipsychotics 30-60% on long term antipsychotics Any point other than first week but more usually weeks to months Any point other than first week but more usually weeks to months Coarse resting tremor, muscular rigidity, shuffling gait, sialorrhoea, bradkinesia (face) Coarse resting tremor, muscular rigidity, shuffling gait, sialorrhoea, bradkinesia (face) procyclidine 2.5mg-5mg tds procyclidine 2.5mg-5mg tds

18 Movement Disorders Tardive Dyskinesia Tardive Dyskinesia 20% when using typical antipsychotics long term (> 3 months or > 1month in elderly) 20% when using typical antipsychotics long term (> 3 months or > 1month in elderly) Involuntary stereotyped chewing movements tongue and orofascial muscles reduced by sleep, torticollis, lordosis, akathesia (25%) 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 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 Resolution 30% 3 months, further 40% 5 years, sometimes irreversible especially elderly Specialist advice on treatments (tetrabenazine, levodopa, clonidine, baclofen, diazepam,valproate, pyridoxine) Specialist advice on treatments (tetrabenazine, levodopa, clonidine, baclofen, diazepam,valproate, pyridoxine)

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

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

21 Other considerations Stroke/All cause mortality risk 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) 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) 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 Relative risk with individual drugs has yet to be determined

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

23 NICE Guidelines Delirium Find and treat reversible causes Find and treat reversible causes Use environmental factors to help keep patient from distress 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. 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. 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. 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.

24 PCF4 – Delirium Delirium is distressing and associated with higher mortality, reduced performance status and increased admissions to nursing homes 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) 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) 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. When antipsychotics alone insufficient or sedation needed for hyperactive/frightened patients benzos or trazadone can be added.

25 Nice Guidelines Dementia Do not use for mild-to-moderate symptoms Do not use for mild-to-moderate symptoms Consider for severe symptoms (psychosis and/or agitated behaviour causing significant distress) only if: Consider for severe symptoms (psychosis and/or agitated behaviour causing significant distress) only if: risks and benefits have been fully discussed risks and benefits have been fully discussed changes in cognition are regularly assessed and recorded changes in cognition are regularly assessed and recorded target symptoms identified and changes regularly assessed and recorded target symptoms identified and changes regularly assessed and recorded comorbid conditions, such as depression, have been considered comorbid conditions, such as depression, have been considered drug is chosen after an individual risk–benefit analysis drug is chosen after an individual risk–benefit analysis start low and titrated upward start low and titrated upward treatment is time limited and regularly reviewed treatment is time limited and regularly reviewed

26 PCF4 – Agitation in Dementia Treat causes (inc infection/pain) Treat causes (inc infection/pain) Environmental factors first Environmental factors first Drugs as a last resort, evidence of benefit modest at best and risks are significant Drugs as a last resort, evidence of benefit modest at best and risks are significant If drugs needed lowest dose for shortest period If drugs needed lowest dose for shortest period Haloperidol, olanzapine, queitapine, risperidone Haloperidol, olanzapine, queitapine, risperidone

27 Individual Drug Properties bio- availability Onset Time to peak plasma concentration Half life (Hr) Duration (Hr) Haloperidol45-75% 1hr (PO) (SC) 2-6hr (PO) 10-20min (SC) Levomepromazine20-40%30min 1-3hr (PO) 30-90min (SC) risperidone99%*1-2hr (PO) olanzapine60%*5-8hr (PO) quetiapine100%*1.5hr (PO)7-1412h *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)

28 Interesting facts! Haloperidol Haloperidol Bioavailability 45-75% orally and 60-70% SC Bioavailability 45-75% orally and 60-70% SC ? Should reduce dose by injection ? Should reduce dose by injection Liquid is odourless, colourless and tasteless Liquid is odourless, colourless and tasteless Prolongs QT interval Prolongs QT interval Plasma concentration halved by carbamazepine Plasma concentration halved by carbamazepine Evidence for N+V in post op and gastroenterology not palliative care Evidence for N+V in post op and gastroenterology not palliative care

29 Interesting facts! Levomepromazine Levomepromazine Licensed for pain! Licensed for pain! Olanzapine Olanzapine Evidence in phase 1 and phase 2 trial of efficacy for vomiting with moderately and highly emetogenic chemotherapy Evidence in phase 1 and phase 2 trial of efficacy for vomiting with moderately and highly emetogenic chemotherapy Adversely affects diabetic control Adversely affects diabetic control Drowsiness and wt. gain most common side effects Drowsiness and wt. gain most common side effects Smoking can decrease plasma levels (as can omeprazole, carbamazepine, rifampicin) Smoking can decrease plasma levels (as can omeprazole, carbamazepine, rifampicin)

30 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) 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 don’t miss NMS! Look out for movement disorders and don’t miss NMS! Be aware of different profiles of typicals vs atypicals Be aware of different profiles of typicals vs atypicals Use antipsychotics in agitated delirium, jury still out about hypoactive delirium (? Use 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 Be cautious in dementia but not to cautious and if using anything use low doses and review regularly


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