Actions, uses and side effects Antipsychotics Actions, uses and side effects

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 Not going to cover some specifics or doses and side effects etc of each drug

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)

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’ ‘positive’ symptoms of psychosis(hallucinations, delusions Decrease in dopamine leads to ‘negative’ symptoms of psychosis’ (apathy, anhedonia, cognitive blunting

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

Nigrostriatal Pathway Nigrostriatal (Substantia nigra – corpus striatum) 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 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. Symptoms of hyperprolactinaemia include amenorrhoea, galactorrhoea, infertility, loss of libido and erectile dysfunction, gynaecomastia. Resulting hypogonadism may cause osteoporosis.

Effect of D2 receptor antagonism Meto and domperidone! Domperidone does not cross blood brain barrier therefore less movement disorders but still works on CTZ (outside blood brain barrier). METO????? Cholinergic system in wall GI tract – dopamine acts as a break on GI transit so blocking can act as prokinetic

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

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) 16 different receptors!

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

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) Mirtazapine increases dopamine release by 5ht2 antagonism and is one its antidepressant actions Olanzapine + respiridone ? Improve negative symptoms

Antipsychotic Receptor Affinities * Decreasing levels of movement disorders as you get lower down the list D2 5HT2a 5HT2c 5HT3 H1 α1 α2 AChm Haloperidol +++ + ++ Levomeprozine risperidone olanzapine quetiapine

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

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) Continue oral antimuscarinic for 1 week (procyclidine or orophenadrine)

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

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 Metoclopramide and all antipsychotics typical>atypical Lowest dose for shortest period time Dementia. Elderly, pre-existing extrapyramidal signs, genetics play factor Meto and antidep

Movement Disorders Tardive Dyskinesia 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%) 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) Tetrabenazine depletes presynaptic dopamine stores and blocks post synaptic dopamine receptors

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 Similar syndrome if parkinsons and stop levodopa or bromocriptine (dopamine agonsists)

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

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 Risperidone 1200 patients, 4 trials, 764/29 cerebrovascular events/4 deaths vs 466/7/1 = 4%vs 2 % (5-6 deaths vs 2-3) (40 vs 20) NNH =25 (1-3months) Olanzapine 1600 patients, 5 trials, 1178/15 (1.3%) vs 478/2 (0.4%) = (4 vs 13 out of 1000) absolute increased risk was 0.9 % RR 3 (CI 0.7-13.5) Fifteen trials (9 unpublished), generally 10 to 12 weeks in duration, contrasts of atypical antipsychotic drugs with placebo met criteria. 3353 patients drug and 1757 placebo. Death occurred more often among patients randomized to drugs (118 [3.5%] vs 40 [2.3%] retrospective cohort study involving 22,890 0ver 65 Conventional antipsychotic medications were associated with a significantly higher adjusted risk of death than were atypical antipsychotic medications at all intervals studied (≤180 days: relative risk, 1.37; <40 days:relative risk, 1.56; 40 to 79 days: relative risk, 1.37; 80 to 180 days: relative risk, 1.27; The greatest increases in risk occurred soon after therapy was initiated and with higher dosages of conventional antipsychotic medications.

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

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.

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. 175 patients, olanzapine (74) haloperidol (72) and a control group (29).They were prospectively observed and treated for a week, CGI SI scores of olanzapine, haloperidol and control group were reduced significantly 82.4%,87.5% and 31% respectively. The effective rate of treatment groups and control group had significant difference ( P 0.01) olanzapine was the earliest on response time,haloperidol was the second,and the control was the last The incidence rates of dry mouth and extrapyramidal symptoms in haloperidol group were higher than that in olanzapine,which had significant difference( P 0.01).Conclusion Olanzapine and haloperidol had similar effects on senile delirium.However,olanzapine effected more rapidly and had fewer side effects A total of 42 patients were randomized to quetiapine or a placebo group. The primary outcome measure was the Delirium Rating Scale Revised 98. The quetiapine group improved more rapidly than the placebo group. Specifically, the quetiapine group recovered 82.7% faster (S.E. 37.1%, P=.026) than the placebo group in terms of DRS-R-98 severity score: Quetiapine has the potential to more quickly reduce the severity of noncognitive aspects of delirium. This study was underpowered for treatment comparisons at specific points in time but nonetheless detected significant differences when analyzing the whole study period. While it is not possible to draw definitive conclusions, further larger studies exploring the use of quetiapine in other delirium populations seem justified. Larger increments in the dose of quetiapine may yield even stronger results. 36 adult intensive care unit patients with delirium. Patients were randomized to receive quetiapine 50 mg every 12 hrs or placebo. Quetiapine was increased every 24 hrs (50 to 100 to 150 to 200 mg every 12 hrs) if more than one dose of haloperidol was given in the previous 24 hrs. Quetiapine was associated with a shorter time to first resolution of delirium 1.0 vs. 4.5 days a reduced duration of delirium [36 vs.120 hrs), and less agitation 6 vs. 36 hrs. Whereas mortality (11% quetiapine vs. 17%) and intensive care unit length of stay (16 quetiapine vs. 16 days) were similar, subjects treated with quetiapine were more likely to be discharged home or to rehabilitation (89% quetiapine vs. 56%). Subjects treated with quetiapine required fewer days of as-needed haloperidol 3 vs.4

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 risk–benefit analysis start low and titrated upward treatment is time limited and regularly reviewed

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

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 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! 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 N+V in post op and gastroenterology not palliative care

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)

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 don’t 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