Antipsychotic Agents

1. Antipsychotic Agents • Schizophrenia is the most common psychosis having the following POSITIVE SYMPTOMS: • Delusions: fixed constant beliefs • Hallucinations (auditory/visual): false perceptions in the absence of real external stimuli • Disorganized thoughts, behavior & speech In addition to psychotic symptoms • Negative symptoms; apathy, low mood, blunted emotion, & social withdrawal mostly are present • Cognitive difficulties; attention, concentration, & memory • Schizophrenia/psychosis related to DAergic hyperactivity

2. Dopamine Receptor Subtypes • Five types, all G-protein coupled • D1 receptor subfamily - D1 and D5 receptor subtypes • D2 receptor subfamily - D2, D3 and D4 receptor subtypes • D1 receptors stimulate whereas D2 receptors reduce, or do not change, adenylyl cyclase activity mediating the postsynaptic response to dopamine

3. Dopamine Receptor Subtypes

4. Dopamine Receptor Subtypes

5. Dopaminergic Pathways

6. Schizophrenia Dopaminergic Biochemical Hypothesis • Schizophrenia/psychosis related to DAergic hyperactivity in mesolimbic/mesocortical tracts • Neuroleptics antipsychotic therapeutic effects (positive signs) are via blockade of DA-2 receptors in mesolimbic & mesocortical pathways • D2 blockade in nigrostriatal pathways results in parkinsonian side effects • D2 blockade in hypothalamphseal pathway leads to hyperprolactinemia • Neuroleptic block histmainergic, α-adrenergic, and cholinergic receptors

7. Classes of Neuroleptics

8. Antipsychotic Actions of Neuroleptics • Antipsychotic effect rely upon D2 receptor blockade in limbic system • Reduction of delusion-hallucinations-thoughts disorders (Positive symptoms) • Negative symptoms & cognitive impairment are poorly affected by typical neuroleptics • Atypical neuroleptics (clozapine) improve moderately the negative symptsoms • No effect on intellectual activity of the patient & minor motor incoordiantion (unlike other CNS depressants) • Antipsychotic effect takes several weeks to develop

9. Atypical Neuroleptics • Clozapine & Resperidone are characterized by low extrapyrimdal side effects & lower TD • No hyperprolctinemia • They improve negative symptoms of schizophrenia more than typical ones • They have higher affinity for D4 receptors when compared to D2 & block 5-HT2A receptors • Nigrostriatal DA pathway is under inhibitory serotoninergic modulation • Clozapine can produce agranulocytosis; frequent WBCs monitoring

10. Antinausea & Antivomiting Effects • CTZ is a reticular formation part in the medulla oblangata outside the BBB • Neuroleptic by D2 receptor blockade in the CTZ, can protect against nausea/vomiting induced by cancer chemotherapy, pregnancy, radiation sickness (domperidone, metoclopramide & prochloperazine) • Phenothiazines like promethazine, meclizine are effective in motion sickness

11. EXTRAPYRIMADAL SIDE-EFFECTS1- Neuroleptic-induced Parkinsonism • Blockade of D2 receptors in the nigrostriatal pathways by antipsychotics underlie the Parkinsonian disorder including: • Akinesia: shorter steps, reduced arm swing, micrographia & difficulty in motion initiation • Rigidity: Stiffness • Temor similar to Parkinson’s disease

12. 2- Neuroleptic Malignant Syndrome Rare, severe, may be fatal Cardinal signs: severe rigidity, fever, marked autonomic disturbance, & muscle destruction (increased creatine-PK) Can not be predicted, irregular dose-relation Treat hyperthermia, dantrolene (central muscle relaxant), bromocriptine 3- Neuroleptic-Induced Dyskinesia/Dystonias Occurs 1-3 days consisting of involuntary motions of lips, jaw & tongue (speech difficulty) Acute dystonias: involuntary twisting of neck, pelvis, & eyes EXTRAPYRIMADAL SIDE-EFFECTS

13. 4- Neuroleptic Induced Akathisia • Akathisia is a motor restlessness, usually lower limb, accompanied by feeling of restlessness • Restlessness & anxiety usually accompany schizophrenia overshadowing the akathisia • Onset of akathisia coincides with initiation of treatment complaining of “restless” legs • Patients report relief upon moving their legs

14. Treatment of Neuroleptic-Induced Parkinsonism, Dystonias, & Akathisia • Striatal GABAergic neural output is controlled by DAergic nigral & local cholinergic inputs • DAergic blockade by neuroleptics renders cholinergic input to be dominating resulting in parkinsonism & dystonias • Bezotropine/biperiden, by blocking cholinergic receptors, restore DA/Ach balance • L-DOPA restores DA but antagonize therapy • Neuroleptic-anticholinergic combinations are routine for children & young men • Majority of adults, first treated with neuroleptics, & anticholinergic added whenever needed

15. Tardive Dyskinesia (TD) • After few months-years: Involuntary oral & lingual gum chewing-like movements, in addition to dystonic neck, & trunk motions • DA receptor up-regulation from chronic blockade is not mediating TD?: fast upregulation & slow TD • Neuroleptic dose increment may improve TD • Anticholinergics may worsen TD, though improving parkinsonian side effects • Neuroleptic stop is essential whenever psychotic status is improved • Atypical neuroleptic clozapine is alternative, suppressing TD or no further worsening

16. Hyperprolactinemia & Galactorrhea • Neuroleptics interact with hypothalamo-hypophyseal DA system (hypothalmus-pituitary axis) • Neuroleptics antagonize D2 receptors in mammotrophs of the pituitary gland, resulting in increased prolactin • Breast swelling & galactorrhea • Infertility & impotence may occur • They may block FSH & LH leading to failure of ovulation in women on antipsychotics leading to pseudopregnancy

17. Unwanted Sedation • It is mediated mainly via histaminergic & cholinergic receptor blockade • Low-potency agents are of highest sedation & high-potency the least • It is presented as attention & concentration difficulties, daytime drowsiness & fatigue Orthostatic Hypotension Some neuroleptics have α-adrenergic blockade &/or direct effect on vasomotor centre

18. Anticholinergic Side Effects • Low-potency neuroleptics are of potent cholinergic effects but not high-potency ones • Anticholinergic effects include: dry mouth, constipation, urinary retention, in addition to dry eyes & blurred vision • There may be decreased aqueous humor outflow leading to increased IOP & glaucoma attacks in sensitive patients • The intrinsic antimuscarinic activity of low-potency neuroleptics might be related to the low extrapyrimadal side effects

19. Jaundice Phenothiazine-induced jaundice occurs in a very limited number of patients Possibly hypersensitivity dose-independent reactions Dermatitis & Photosensitivity Most frequent with low-potency agents in a limited no. of patients Patients become sunlight-sensitive & may develop sunburns Possible skin & corneal hyperpigmentaion Other DA-Independent Side Effects

20. Other side Effects & Contraindications • Significant weight gain is common with atypical neuroleptics • CPZ & clozapine are contraindicated in patients with seizure disorder, where they lower seizure threshold • Clozapine-induced agranulocytosis limit its use to refractory schizophenia • Tachycardia • Sexual dysfunction

21. Case • W G., 19 years old when he was enrolled in university. His academic record was good, he won a place on the university sports team. When he returned to school for his second year, his roommate observed that W G. was staying by himself, avoiding the company of friends, and skipping school and athletic training, things he had never done before. • Some time later, he was heard speaking to himself as he sat isolated in his room, mumbling and smiling. Soon after, he confided to his roommate that he had uncovered a ‘grand conspiracy” to rob him of his athletic abilities and that he could hear the conspirators’ voices as they made plans to destroy him. • Finally; he accused his roommate of being a part of the conspiracy.

22. At this point, his friends called his parents and was taken to see a psychiatrist. The psychiatrist diagnosed him as showing early symptoms of schizophrenia, and he was admitted to the hospital. Blood and-urine tests were negative for signs of any general medical condition or the presence of any street drugs. • He was therefore treated with haloperidol at a starting dose of 10 mg per day. On the second day of his treatment, while a medical student was interviewing him, he seemed to develop a “seizure.” His neck strained backward with his face turned upward toward the ceiling. He was having difficulty speaking, But was quite conscious of his surroundings. The attending physician recognized this as an acute dystonic reaction to the medication rather than a seizure

23. The doctor immediately ordered an injection of benztropine, which resolved the situation in a matter of minutes. Following this experience, W.G. refused to have anything more to do with haloperidol. • However, he agreed to take loxapine instead after it was explained to him that he was less likely to have the dystonic reaction with this drug, especially if it was accompanied by benztropine. • The dose of loxapine was gradually increased to 40 mg/day He experienced sedation, blurred vision, drying of his eyes that made it difficult for him to wear contact lenses, and dry mouth. However, over the next 3 weeks his delusions and hallucinations disappeared. He developed insight into his problems, and the sedation, the dry mouth, and the dry eyes became much more bearable. He left the hospital a month later, went back to his dormitory; and resumed his academic life.

24. Questions 1) Relate different Dopamine Pathway to therapeutic and side effects; • Mesolimbic/Mesocortical • Nigrostriatal • Hypothalamic/pituitary 2) Advantage of atypical neuroleptics Vs Typical regarding; Receptors, Therapeutic effects and Side effects. 3) Differentiate between: Neuroleptic-induced Parkinsonism and Neuroleptic-induced tardive dyskinesia regarding the following points • Symptoms • Onset • Treatment

26. Biochemical Basis for Parkinson’s Disease • Connections of substantia nigra to striatum & back are the nigrostriatal pathways • Striatum output is GABAergic • Its activity modulated by the balance between cholinergic striatal interneurons (+) & substantia nigral DA (-) • Degeneration of nigrostriatal pathway (mainly DA cells in SN) is crucial for parkinson’s • The DA/ACh imbalance leads to the ACh (no-go) predominance & immobility