Presentation on theme: "Actions, uses and side effects"— Presentation transcript:
1Actions, uses and side effects AntipsychoticsActions, uses and side effects
2Aims Overview of dopamine physiology Antipsychotic classifications Movement disorders +neuroleptic malignant syndromeStroke and mortality riskPCF/NICE guidelines delirium + challenging behaviour in dementiaConclusionsNot going to cover some specifics or doses and side effects etc of each drug
3Dopamine PhysiologyNeurophysiology of dopamine underpins an understanding of the therapeutic uses and side effects of dopamine antagonistsMesolimbicmesocortical pathwayNigrostriatal pathwaytubero-infundibular pathway(chemoreceptor trigger zone)
4Mesolimbic + mesocortical pathways Mesolimbic (midbrain – limbic cortex)Pleasure, motivation and rewardIncrease in dopamine leads to ‘positive’ symptoms of psychosisMesocortical (midbrain to prefrontal cortex)Mood, cognitive function, concentrationDecrease in dopamine leads to ‘negative’ symptoms of psychosis’‘positive’ symptoms of psychosis(hallucinations, delusionsDecrease in dopamine leads to ‘negative’ symptoms of psychosis’ (apathy, anhedonia, cognitive blunting
5Thalamic Sensory Gating Arousal, motivation and attention regulated by a two way loop between mesolimbic/cortical systems and thalamusThalamus acts as a filter to allow relevant information through to cerebral cortexgate formed by GABAergic neurones which are switched off by dopamine to allow salient information throughDopamine excess leads to excessive throughput resulting in hallucinations and delusions
6Nigrostriatal Pathway Nigrostriatal (Substantia nigra – corpus striatum)as part of the extrapyramidal nervous system, controls movementsdegenerates in Parkinson’s diseaseBlockade of D2 receptors in this pathway causes the drug-induced movement disorders
7Tubero-infundibular pathway Tubero-infundibular pathway (hypothalamus – pituitary)Dopamine acts on the pituitary as an inhibitor of prolactin secretionBlockade of D2 receptors by typical antipsychotics and risperidone can cause hyperprolactinaemiaOther 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.
8Effect 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
10Typical Vs. Atypical Variation within and overlap between classes ALL D2 antagonists to varying degreesVariable effects on other receptors:Muscarinic (dry mouth, constipation etc)Adrenergic (postural hypotension)Histamine (drowsiness)Serotoninergic (weight gain)16 different receptors!
11Typical Vs. AtypicalAtypical generally have lower affinity and shorter duration of D2 antagonismAtypicals generally have greater seretonin receptor antagonism (5HT2) than D2 antagonismAtypicals have greater seretonin receptor antagonism than typicals
125HT2 AntagonismSerotonin regulates dopamine release in dopamine pathways apart from mesolimbicserotonin inhibits the release of dopamine in those pathwaysWhen 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 actionsOlanzapine + respiridone ? Improve negative symptoms
13Antipsychotic Receptor Affinities * Decreasing levels of movement disorders as you get lower down the listD25HT2a5HT2c5HT3H1α1α2AChmHaloperidol++++++Levomeprozinerisperidoneolanzapinequetiapine
14Antipsychotic 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. typical5 times lower risk of longer term extrapyramidal side effects with atypicals vs. haloperidolOverall discontinuation for undesirable side effects are comparable
15Movement Disorders Acute Dystonia (spasms) 10% of patients treated with antipsychotics (commoner in young adults)Starts abruptly within days accompanied by anxietyRetrocolis, torticolis, trismus, grimacing, tongue dysfunction, oculogyric crisis, abnormal positioning limbs or trunkDiazepam 5mg IV (benzo) or Procyclidine 5-10mg IV/IM (repeat after 30 min if needed)Continue oral antimuscarinic for 1 week (procyclidine or orophenadrine)
16Movement Disorders Acute Akathisia (motor restlessness) 20% when using typical antipsychoticsWithin days and resolves within week of stoppingRestless, pacing, rocking from foot to foot, fidgety movements, inability to sit or stand for a few minutesPropranolol 10mg tds +/- benzodiazepine
17Movement Disorders Parkinsonism 30-60% on long term antipsychotics Any point other than first week but more usually weeks to monthsCoarse resting tremor, muscular rigidity, shuffling gait, sialorrhoea, bradkinesia (face)procyclidine 2.5mg-5mg tdsMetoclopramide and all antipsychotics typical>atypicalLowest dose for shortest period timeDementia. Elderly, pre-existing extrapyramidal signs, genetics play factorMeto and antidep
18Movement 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 movementsResolution 30% 3 months, further 40% 5 years, sometimes irreversible especially elderlySpecialist advice on treatments (tetrabenazine, levodopa, clonidine, baclofen, diazepam,valproate, pyridoxine)Tetrabenazine depletes presynaptic dopamine stores and blocks post synaptic dopamine receptors
19Neuroleptic Malignant Syndrome Caused by acute dopamine depletionUsually within two weeks of starting or dose increase of antipsychoticOccurs less than 1% of patients on antipsychoticsDeath occurs in 20% and bromocriptine halves mortalitySelf limiting and resolves in 1-2 weeks if causal drug stoppedSubsequent antipsychotic use has a 30-50% chance of causing a reoccuranceSimilar syndrome if parkinsons and stop levodopa or bromocriptine (dopamine agonsists)
20Neuroleptic Malignant Syndrome Bradykinesia – immobilisation – akinsesia – stupor accompanied by lead pipe rigidity, fever and autonomic instabilityEssential features – severe muscle rigidity, pyrexia +/- sweatingAdditional – muteness/stupor, tachycardia, labile BPManagement – stop causal drug, benzo +/- bromocriptine, may need IVIIf acidosis, hypoxia, renal failure may need acute management/ICU
21Other 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 determinedRisperidone 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 )Fifteen trials (9 unpublished), generally 10 to 12 weeks in duration, contrasts of atypical antipsychotic drugs with placebo met criteria 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 65Conventional antipsychotic medications were associated with a significantly higher adjustedrisk 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.
22Other considerations Parkinsons Try and avoid antipsychotics but if needed use queitiapine (could try trazadone or benzo)EpilepsyAll antipsychotics cause dose dependent reduction in seizure threshold. Lowest risk with Haloperidol
23NICE Guidelines Delirium Find and treat reversible causesUse environmental factors to help keep patient from distressIf 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.
24PCF4 – DeliriumDelirium is distressing and associated with higher mortality, reduced performance status and increased admissions to nursing homesAntipsychotics 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 effectsA 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
25Nice Guidelines Dementia Do not use for mild-to-moderate symptomsConsider for severe symptoms (psychosis and/or agitated behaviour causing significant distress) only if:risks and benefits have been fully discussedchanges in cognition are regularly assessed and recordedtarget symptoms identified and changes regularly assessed and recordedcomorbid conditions, such as depression, have been considereddrug is chosen after an individual risk–benefit analysisstart low and titrated upwardtreatment is time limited and regularly reviewed
26PCF4 – Agitation in Dementia Treat causes (inc infection/pain)Environmental factors firstDrugs as a last resort, evidence of benefit modest at best and risks are significantIf drugs needed lowest dose for shortest periodHaloperidol, olanzapine, queitapine, risperidone
27Individual Drug Properties bio-availabilityOnsetTime to peak plasma concentrationHalf life (Hr)Duration(Hr)Haloperidol45-75%1hr (PO)10-15 (SC)2-6hr (PO)10-20min (SC)13-3524+Levomepromazine20-40%30min1-3hr (PO)30-90min (SC)15-3012-24risperidone99%*1-2hr (PO)2412-48olanzapine60%5-8hr (PO)34-52quetiapine100%1.5hr (PO)7-1412h*hours to days in delirium, days to weeks in psychosisN.B all metabolised by various CP450 enzymes (liver)Reduce doses in elderly, renal and liver impairment (generally half of usual dose)
28Interesting facts! Haloperidol Bioavailability 45-75% orally and 60-70% SC? Should reduce dose by injectionLiquid is odourless, colourless and tastelessProlongs QT intervalPlasma concentration halved by carbamazepineEvidence for N+V in post op and gastroenterology not palliative care
29Interesting facts! Levomepromazine Licensed for pain! Olanzapine Evidence in phase 1 and phase 2 trial of efficacy for vomiting with moderately and highly emetogenic chemotherapyAdversely affects diabetic controlDrowsiness and wt. gain most common side effectsSmoking can decrease plasma levels (as can omeprazole, carbamazepine, rifampicin)
30ConclusionsBe 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 atypicalsUse 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