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Antipsychotic/Neuroleptic Agents and Lithium Schizophrenia Definition 1. It is a mental disorder characterized by a. disintegration of thought processes b. disintegration of emotional responsiveness. 2. It most commonly manifests itself as a. Auditory hallucinations b. Paranoid c. Bizarre delusions d. Disorganized speech and thinking e. Accompanied by significant social or occupational dysfunction Types of Schizophrenia 1. Positive Symptoms/Florid Schizophrenia a. It is manifested as having one of the following abnormal behaviours which is absent in a normal human being i. Delusion ii. Hallucination iii. Disorganized behaviour 2. Negative Symptoms/Deficit Schizophrenia a. It is manifested as NOT having one of the normal behaviours which is present in a normal human being i. Social withdrawal ii. Mood disturbance (Anhedomia) iii. Reduced motivation Types of Antipsychotic Drugs 1. Typical Antipsychotics – use in the Tx of Florid Schizophrenia a. High potency i. Haloperidol b. Low potency i. Chlorpromazine 2. Atypical Antipsychotics p – use in the Tx of Deficit Schizophrenia a. Clozapine Hypothesis of Schizophrenia’s Pathogenesis 1. Dopamine hypothesis a. Overactivity of Dopamine in the Mesolimbic pathway of the brain i. Mesolimbic pathway is important in the integration of human’s behaviour ii. All humans have irrational thought, but it doesn’t take into serious matter as it is easily swept away iii. But in the increase in the activity of the Mesolimbic pathway, the irrational is somehow taken seriously and lead to delutions b. After administering a Dopamine enhancing drug, subject appeared to develop Psychosis c. By administering the Antipsychotic drug to subject, the potency of the drug is directly propotional to the binding of Dopamine receptors, specifically the D2 receptors 2. Serotonin Hypothesis a. 5-HT2A receptors are receptors that modulate the release of Dopamine from i. Cortex ii. Limbic region iii. Striatum b. Stimulation of these receptors also can cause the depolarization of Glutamate neurons, by which may modulate behaviour of a human being Typical Antipsychotic Drugs Haloperidol Pharmacokinetic Absorption Readily absorp orally Udergoes extensive 1st pass metabolism, **lower compared to that of Chlorpromazine Distribution Is it highly lipophilic drug; therefore it can easily distributed to all compartments of the body, particularly and importantly the BBB Highly protein bound Metabolism Undergoes hepatic metabolism Excretion Excreted via urine Mechanism of Action Competitively inhibits the D2 receptors at o Mesolimbic area (desirable effect) Inhibition of this area will reduce the activity of the Dopamine in the integration of behaviour Hence, lead to the reduce in hyperactivity of the Mesolimbic pathway (antipsychosis effect) o Nigrostriatal Tract (undesirable effect) This area involve in the extrapyramidal motor tract, controlling the involuntary movement of the body Inhibition of this will lead to Extrapyramidal Symptoms (EPS) which include Dystonia Parkinsonism Akathasia Tardive dyskinesia o Tuberinfundibular area (undesirable effect) This area regulate the release of Prolactin through inhibitory pathway of Dopamine Inhibition of this pathway will lead to uncontrol release of Prolactin presented with Galactorrhea Adverse Effects Extrapyramidal Symptoms o Acute dystonia (characteristic side effect of Haloperidol) Sustained muscular contraction of Neck Eyes Throat Occurs immediately after treatment o Akathasia Continuous restless movement Occurs within the 1st week of treatment o Parkinsonism Neurological syndrome characterized by Tremor Hypokinesia, Rigidity Postural instability Occurs after one week of treatment o Tardive dyskinesia Spastic facial distortion with tongue movement Occurs after 6 months of treatment Orthostatic hypotension Dry mouth Histaminic side effects o Sedation o Due to inhibition of central H1 receptors SERIOUS SIDE EFFECT Narcoleptic Malignant Syndrome o Life threatening neurological disorder, manifested with Muscle rigidity High grade fever Cognitive changes (Detorium) Increased level of Creatine Kinase indicating muscle damage o Treated with Dantrolene – muscle relaxant Bromocriptine – Dopamine receptor agonist Comparison Haloperidol High Extrapyramidal symptoms High potency Less Histaminic side effects Chlorpromazine Less Extrapyramidal symptoms Low potency More Histaminic side effects Atypical Antipsychotic Drugs Clozapine Pharmacokinetic Absorption Complete absorption after oral admin Nevertheless, bioavailibility is 65% due to 1st pass metabolism Distribution Readily distributed across body compartments Metabolism Extensively metabolized by CYP450 into few active metabolites o Norclozapine This enzyme can be either o Inhibited by Theophylline Ciprofloxacin Fluvosamine o Induced by Cigarette smoke Excretion Excreted via urine and bile Mechanism of Action Preferentially inhibit D4 receptors compared to that of Typical Antipsychotic o Collectively, it has more activity towards D4 receptors of the Mesolimbic system compared to other part of the brain This explains why Clozapine has less Extrapyramidal Symptoms Clozapine is also a partial agonist at the 5-HT1A and 5-HT2A receptors, putatively improving o Depression o Anxiety o Negative cognitive symptoms It is also a strong antagonist of o Adrenergic receptors o Histaminic receptors o Cholinergic receptors Adverse Effects Common Extreme constipation Night-time drooling Muscle stiffness Sedation Tremors Orthostasis Hyperglycemia Weight gain Severe Side Effects Agranulocytosis o Due to unstable intermediary metabolite that produces oxidative stress in white cells and leads to cell death Cardiac toxicity Diabetic Ketoacidosis Mania Definition The presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable o Mood o Euphoria o Racing thought o Talkativeness o Arousal, and/ or o Energy levels It is the opposite of depression Mood Stabilizer Drugs Lithium Pharmacokinetic Absorption Readily absorp orally Distribution Has a very narrow therapeutic index; requires close monitoring of plasma level Excretion Excreted via urine Mechanism of Action Attenuate the signalling via Phosphotidyl Biphosphate (PIP2) 2nd messenger coupled receptors o It inhibits the resynthesis of of PIP2 Nevertheless, the MOA is still remain uncertain Adverse Effects Tremor Ataxia Confusion Diabetes insipidus o Though inhibition of Adenylyl Cyclase in the Principal cells at the Collecting Duct Thyroid dysfunction o Litium reduces the production of Thyroxine (T4) o It also reduced de-iodination of T4 to T3