Lesson 15 - Antipsychotic Drugs (CEU 2024/25) PDF

Lesson 15 Antipsychotic drugs 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 SUMMARY 1. SCHIZOPHRENIA 2. ANTIPSYCHOTIC DRUGS – Clinical efficacy – Mechanism of action – Unwanted effects – Pharmacokinetics – Clinical uses....

Lesson 15 Antipsychotic drugs 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 SUMMARY 1. SCHIZOPHRENIA 2. ANTIPSYCHOTIC DRUGS – Clinical efficacy – Mechanism of action – Unwanted effects – Pharmacokinetics – Clinical uses. 2 1. SCHIZOPHRENIA Schizophrenia is a chronic and complex psychiatric disorder that profoundly affects how a person thinks, perceives reality, manages emotions, and interacts with others -Affects young people, it’s often chronic and disabling -Affects 1% of population 3 1. SCHIZOPHRENIA Symptoms: Delusions: False, irrational beliefs that are not shared by the surrounding cultural reality (e.g., beliefs of being persecuted or having special powers) Hallucinations: Sensory experiences without a real external stimulus, typically in the form of hearing voices speaking to or about the patient. Disorganized thinking: Confused, incoherent speech or difficulty organizing thoughts and ideas logically. Disorganized or catatonic behavior: Unpredictable, bizarre, or repetitive behaviors, ranging from lack of response to external stimuli to purposeless hyperactivity. Negative symptoms: Diminished emotional and social capabilities, such as apathy, flat affect, social withdrawal, and lack of motivation. 4  1. SCHIZOPHRENIA Other symptoms: Anxiety, guilt, depression and self punishment Suicide attempts: 50% of cases. «selective attention» Etiology: It is a multifactorial disorder due to: Genetics: A strong familial predisposition plays a significant role Environmental factors: Such as perinatal complications, viral infections during pregnancy, early psychological trauma Neurobiology: Dysregulation in the dopaminergic system and neurotransmitter imbalances are among the primary hypotheses. 5  1. SCHIZOPHRENIA Etiology: The neurochemical and neuroanatomical alterations in schizophrenia reflect a disruption in the balance of multiple neurotransmitter systems expecially: -Dopaminergic dysregulation -Glutamatergic and GABAergic dysfunctions 6  1. SCHIZOPHRENIA Etiology: Dopamine dysregulation: hyperactivity of dopamine transmission in the mesolimbic pathway is associated with positive symptoms (e.g., hallucinations, delusions). dopaminergic hypoactivity in the mesocortical pathway, particularly in the prefrontal cortex, is linked to negative symptoms (e.g., flat affect, anhedonia) and cognitive deficits. Glutamate, hypofunction of NMDA (N-methyl-D-aspartate) receptors : particularly in the prefrontal cortex and hippocampus. Reduced NMDA receptor activity could contribute to both positive and negative symptoms, as well as cognitive dysfunction. 7 1. SCHIZOPHRENIA DOPAMINERGIC PATHWAYS INVOLVED Several dopaminergic pathways are key to understanding the therapeutic effects and side effects of antipsychotics: ✓ Mesolimbic pathway: it is involved in emotional regulation and motivation. Hyperactivity of dopamine in this pathway is linked to positive symptoms of schizophrenia. Antipsychotics reduce this hyperactivity, alleviating hallucinations and delusions. ✓ Mesocortical pathway: Associated with cognitive and affective functions. Dopamine hypoactivity in this pathway is associated with negative symptoms and cognitive deficits. Atypical antipsychotics, through serotonergic modulation, may improve symptoms in this pathway. ✓ Nigrostriatal pathway: It controls motor function. D2 receptor blockade in this pathway by typical antipsychotics leads to extrapyramidal side effects. ✓ Tuberoinfundibular pathway: Regulates prolactin secretion. D2 receptor blockade here results in increased prolactin levels, causing hyperprolactinemia (menstrual disturbances, galactorrhea, sexual dysfunction). 8 INDEX 1. SCHIZOPHRENIA 2. ANTIPSYCHOTIC DRUGS – Clinical efficacy – Mechanism of action – Unwanted effects – Pharmacokinetics – Clinical uses. 9 2. ANTIPSYCHOTIC DRUGS Two groups of antipsychotic drugs: 1° generation (typical or conventional antipsychotic drugs) primarily act by blocking D2 receptors, reducing positive symptoms but often causing significant motor side effects Chlorpromazine, Haloperidol, Fluphenazine Flupentixol, Clopentixol 2°generation (atypical antipsychotic drugs) block both D2 and 5-HT2A receptors, offering a more balanced treatment of positive and negative symptoms with a lower risk of extrapyramidal side effects, though they carry a risk of metabolic issues. Clozapine, Risperidone, Sertindole, Quetiapine, Amisulpride, Aripiprazole, Zotepine, Ziprasidone 10  2. ANTIPSYCHOTIC DRUGS Clinical efficacy SEVERE DRAWBACKS OF CURRENT TREATMENT – Not all schizophrenic patients respond (30% do not ) – Most are ineffective in relieving the negative and cognitive impairment. – Wide variety of side effects: extrapyramidal motor, endocrine and sedative effects – They may shorten survival through cardiac (pro-arrhythmic) effects – Abrupt cessation of antipsychotic drug: psychotic episode 12 2. ANTIPSYCHOTIC DRUGS 1° Generation Mechanism of action Typical antipsychotics block D2 receptors in the dopaminergic system, reducing positive symptoms of schizophrenia (hallucinations, delusions) -Blocking D2 receptors in other pathways, such as the nigrostriatal pathway, can lead to motor side effects (extrapyramidal symptoms, or EPS) similar to Parkinson's disease (rigidity, bradykinesia, tremors). -Blocking D2 receptors in the tuberoinfundibular pathway can cause hyperprolactinemia (increased prolactin levels, leading to galactorrhea and sexual dysfunction). 14 2. ANTIPSYCHOTIC DRUGS 1° Generation ADRs: Typical antipsychotics are associated with severe extrapyramidal side effects (EPS), including acute dystonia, akathisia, tardive dyskinesia, and parkinsonism. Sedation Weight gain Galactorrhea and sexual dysfunction Hypotension, due to blocking other receptors (e.g., H1 for histamine, α1 for NA, and M1 for Ach). 15  2. ANTIPSYCHOTIC DRUGS 2° Generation Mechanism of action Atypical antipsychotics act on a wider range of receptors and are less likely to cause extrapyramidal side effects Atypical antipsychotics block both dopamine D2 receptors and serotonin 5-HT2A receptors. The 5-HT2A receptor blockade in the prefrontal cortex is thought to help reduce negative symptoms (e.g., apathy, social withdrawal) and cognitive deficits. - It also modulates dopamine activity in other pathways, thereby reducing the risk of extrapyramidal side effects. The partial D2 receptor blockade, helps reduce positive symptoms while minimizing dopamine blockade in other pathways. 16 2. ANTIPSYCHOTIC DRUGS 2° Generation Advantages: cause fewer extrapyramidal side effects and have a lower risk of tardive dyskinesia. -They are also more effective in treating negative symptoms and cognitive impairments than first-generation drugs. ADRs: Metabolic syndrome (weight gain, hyperglycemia, dyslipidemia) anticholinergic effects (dry mouth, constipation, blurred vision) risk of QT prolongation (an alteration in cardiac electrical activity). 17  2. ANTIPSYCHOTIC DRUGS EFFECT ON MUSCARINIC RECEPTORS Some antipsychotic drugs are also muscarinic antagonists and have fewer side effects than others: Blocking D2 receptors enhances overproduction of Ach and muscarinic activation So combining antipsychotic drugs with antimuscarinic ones may improve de side effect profile. Side effect: constipation, dry mouth and blurred vision. 21  2. ANTIPSYCHOTIC DRUGS Other side effects: Jaundice Antipsychotic malignant syndrome: – Muscle rigidity. rapid rise in body temperature and mental confusion. – It is usually reversible, but death from renal or cardiovascular failure occurs in 10–20% of cases. 31 28  2. ANTIPSYCHOTIC DRUGS Pharmacokinetic Aspects – least 40% of schizophrenic patients fail to take drugs as prescribed. – acute toxicity of antipsychotic drugs is slight. – The plasma half-life: is 15–30 h, can be given orally or in urgent situations by IM injection. Slow-release (depot) preparations available. IM injection, the drug acts for 2–4 weeks. 29 2. ANTIPSYCHOTIC DRUGS Clinical uses: Behavioural emergencies – violent patients with a range of psychopathologies: To control hyperactive psychotic states: chlorpromazine, haloperidol, olanzapine, risperidone. IM dose is lower than oral dose 30  2. ANTIPSYCHOTIC DRUGS Clinical uses: Schizophrenia: first-generation antipsychotic drugs. – Depot injections (e.g. flupentixol decanoate): for better compliance – newer antipsychotic drugs – clozapine can cause agranulocytosis: effective against ‘negative’ features of schizophrenia. It is reserved for patients whose condition remains inadequately controlled despite previous use of two or more antipsychotic drugs, of which at least one is a second-generation drug. Blood count is monitored weekly for the first 18 weeks, and less frequently thereafter. 38  Other clinical uses: – Bipolar disorder, mania and depression – Short-term treatment of psychomotor agitation and severe anxiety chlorpromazine and haloperidol – Agitation and restlessness in the elderly – Restlessness and pain in palliative care levomepromazine – Nausea and vomiting chlorpromazine and haloperidol – Motor tics and intractable hiccup chlorpromazine and haloperidol – Antisocial sexual behavior benperidol – The treatment of involuntary movements caused by Huntington’s disease (mainly haloperidol) 39 34