Antipsychotic Drugs PDF 2021

Antipsychotic Drugs Dr Sarah Trinder [email protected] Courtauld Institute Galleries, London wiki Outline What is schizophrenia? Pathways involved Dopamine theory Glutamate Glu/GABA Side effects How receptor properties of antipsychotics ameliorate side effects? Schizophrenia ‘Is a disorder of t...

Antipsychotic Drugs Dr Sarah Trinder [email protected] Courtauld Institute Galleries, London wiki Outline What is schizophrenia? Pathways involved Dopamine theory Glutamate Glu/GABA Side effects How receptor properties of antipsychotics ameliorate side effects? Schizophrenia ‘Is a disorder of the mind that affects how you think, feel and behave.’ RCPsych ‘Positive’ clinical features Delusions – ideas of reference Hallucinations – voices Thought disorder – disconnected/wanders Abnormal, disorganised behaviour – disorientation, aggression Catatonia – immobility, purposeless activity ‘Negative’ clinical features Withdrawal Emotional flattening Anhedonia – loss of experiencing pleasure Cognitive defects (resistant to antipsychotics) Premature dementia Depression & anxiety Illustration Works/Corbis Schizophrenia 1% of population 1:10 with schizophrenia have a parent who suffers ♀=♂, common onset 15-35yrs old Up to 50% attempt suicide Genetic causes ˃100 susceptibility genes reported Most robust associations control neuronal development, synaptic connectivity & Glu-ergic transmission Neuregulin, NOTCH-4, TCF-4 Environmental causes Maternal viral infections Cannabis use stahlonline.cambridge.org PATHOPHYSIOLOGY OF SCHIZOPHRENIA Tuberoinfundibular Endocrine control Motor control Negative symptoms Blunted DA activity mainly D1 Positive symptoms Over activity of DA on D2 Adapted from Rang and Dale’s Pharmacology Dopamine theory Amphetamine-induced DA release (Carlson, 2000) Amphetamine behaviour akin to acute schizophrenic episode L-tyrosine L-dopa & DA agonists – Parkinson’s disease TH hallucinations L-dopa DAergic neuron metabolites DA antagonists control positive symptoms block amphetamine-induced effects DA Gi/o D2 MAO DAT Glutamate – negative symptoms ↓ vesicular glutamate transporter (VGluT) ↓ Glu = ↓ NMDA activation ↓ DAergic activity mesocorticol ↓ ↓[DA] in PFC = negative symptoms ↓ NMDA Na+/Ca2+ DAergic neuron Glutamate – positive symptoms Glu Glu GABA GABAergic neuron VTA DAergic neuron Mesolimbic pathway Glu/GABA – Sensory filtering Pre-frontal cortex Glu Glu VTA DA NcA GABA Thalamus Sensory input Neurodegeneration No symptoms in childhood Positive symptoms Negative symptoms Worsening & ↓ response to drugs Development of dementia http://www.rcslt.org/ ANTIPSYCHOTICS – MECHANISM OF ACTION Antipsychotics ˃40 different antipsychotics Typical/1st generation Chloromazine Cause unwanted motor effects Atypical/2nd generation Risperidone ↓ unwanted motor effects 20-30% patients treatment resistant – receptor polymorphisms? Antipsychotics - mechanism Dopamine receptor antagonists 1st gen show some D2 selectivity 2nd gen highly D2 selective D2 antagonism in mesolimbic – relieves +ive symptoms But D2 antagonism on other pathways! Nigrostriatal – motor effects (extrapyramidal) Tuberoinfundibular - ↑ prolactin secretion Mesolimbic (reward compartment) - ↓ pleasure Mesocorticol (PFC) – worsen negative symptoms Also interact with 5-HTR and mACh – but beneficial! Antipsychotics – 5-HTR LSD partial 5-HT agonist – produces hallucinations 5-HT2A (antagonist) & 5-HT1A (agonist/partial agonist) – ameliorate unwanted D2 antagonist effects 5-HT2A – Gi/o activation = inhibitory - ↓ neuronal excitability - ↓ NT release 5-HT2A DAergic neuron Antipsychotics are 5-HT2A antagonists Antipsychotics – 5-HTR Antipsychotics 5-HT1A (agonist/partial agonist) – autoreceptor Activation of 5-HT1A = ↓5-HT release = ↓5-HT2A activation = ↑DA release In striatum and PFC can improve motor effects and negative symptoms Antipsychotics - mACh D2 antagonist DAergic neuron ACh-ergic neuron D2 - inhibitory In striatum DA has inhibitory effects (via D2) on cholinergic neurons = ↓ACh If D2 is antagonised – ↑ACh = extrapyramidal motor unwanted effects BUT some 2nd generation antipsychotics = mACh antagonists Extrapyramidal effects Extrapyramidal motor effects Acute dystonias – involuntary movements (spasms) Occur early in treatment, decline with time or cessation D2 block nigrostriatal 5-HT2A/mACh block ameliorate pinterest.com Tardive dyskinesia – involuntary movements (face, tongue, trunk, limbs) Occurs after months/years 20-40% of patients treated with 1st gen Disabling & irreversible ↑D2 – chronic block D2 = ↑[Glu] or [amines] = excitotoxic neurodegeneration www.healthtap.com Endocrine & other effects Gallactorrhea – breast swelling, pain, lactation D2 activation ↓prolactin release – median eminence Tuberoinfidibular/tuberohypophyseal pathway Antipsychotics D2 antagonists = ↑[prolactin]plasma Breast swelling, pain, lactation Other effects Sexual dysfunction – D1/2, mACh, α1 Drowsiness, sedation – H1 – can be beneficial in aggressive patients Weight gain, ↑ risk diabetes, CV disease – H1, 5-HTR, mACh mACh antagonism H1 antagonism Antipsychotic drugs α1/2 antagonism Postural hypotension 5-HTR ↑ [DA] in PFC ↓ negative symptoms ↑ [DA] in NigS ↓ motor Weight gain Antipsychotic effects ↓positive effects Prefrontal cortex ↓ reward Limbic system/Cortex D2 antagonism Tuberoinfundibular Sedative Negative symptoms Mesocorticol pathway Dry mouth ↓ extrapyramidal motor Nigrostriatal pathway Pituitary gland Endocrine effects Breast swelling Lactation Impotence Striatum Basal ganglia Extrapyramidal motor effects Parkinsonism Dystonia Tardive dyskinesia Pharmakokinetics [antipsychotic]plasma & clinical effect – highly variable Adjust dosage – trial & error basis!!! Compliance – 40% patients fail to take drugs as prescribed Oral Intramuscular depot preparations – lasts 2-4 weeks Future developments What would be the properties of a silver bullet D2 antagonist? Drugs that ↑NDMA activity or act through mGlu Learning outcomes To describe schizophrenia To discuss the pathways involved in schizophrenia Dopamine theory Glutamate Glu/GABA Discuss antipsychotics How receptor properties of antipsychotics ameliorate side effects