CNS Drugs - Antipsychotic Agents (AQA 2013) PDF

CNS – Drugs ANTIPSYCHOTIC AGENTS Dr. Qawasmeh Abdel Qader Faculty of Pharmacy Hebron University  ANTIPSYCHOYIC AGENTS Psychotic illness is compilation of multiple disorders Schizophrenia Maniac phase of bipolar syndrome Acute idiopathic psychosis Schizophrenia...

CNS – Drugs ANTIPSYCHOTIC AGENTS Dr. Qawasmeh Abdel Qader Faculty of Pharmacy Hebron University  ANTIPSYCHOYIC AGENTS Psychotic illness is compilation of multiple disorders Schizophrenia Maniac phase of bipolar syndrome Acute idiopathic psychosis Schizophrenia Delusion Hallucination Disordered thoughts Loss of normal emotions, ability and motivation Signs and symptoms  ANTIPSYCHOYIC AGENTS Classes Typical antipsychotic Known as first generation or conventional antipsychotic Atypical antipsychotic Known as second generation  Typical antipsychotic agents Examples Phenothiazines and Thioxanthenes Butyrophenones Diphenylbutylpiperidines Dihydroindolones Classification based on affinity to D2-receptors High potency agents (e.g., Haloperidol, Fluphenazine) Low potency agents (e.g., Chloropromazine)  Typical antipsychotic agents Mechanism of action – Binds to D2-receptors and block dopamine action Side effects – Low potency agents – High potency agents Little acute dystonia Acute dystonias (involuntary Sedation movements) Adrenergic activity Little sedation Anticholinergic activity Little adrenergic activity Little anticholinergic  Phenothiazines and Thioxanthenes Examples 1. Promazine 2. Chloropromazine 3. Perphenazine 4. Prochlorperazine 5. Fluphenazine 6. Trifluperazine 7. Chlorprothixene 8. Thiothixene Phenothiazines and Thioxanthenes Phenothiazine nucleus Thioxanthenes nucleus Structural differences 1. Isosteric replacement of N with C 2. R1 attached to the cyclic system by double bond 3. R1 can be cis or trans to R2 4. Cis isomer is the active form  Phenothiazines Chlorpromazine Phenothiazine nucleus Prototype Low potency typical antipsychotic Dopamine antagonist Anticholinergic, antihistaminic, antiadrenergic, antiserotonergic The Cl atom is critical for activity Poor bioavailability Metabolism?  Phenothiazines Prephenazine Thioridazine Thioridazine contain piperidine group Thioridazine has better bioavailability than chlorpromazine with longer duration of action Prephenazine contains a piperazine group Side effects: same as chlorpromazine  Phenothiazines Fluphenazine Prochlorperazine Typical antipsychotic drug Can be used to treat dementia (Alzeihymer) Have a piperazine ring Prochlorperazine is 10-20X > potent than chlorpromazine  Thioxanthenes Chlorprothixene Thiothixene Recommended in patients show resistance to other medication Antagonize D2 receptors  SAR – Phenothiazines Only position 2 in ring A and side chain give active antipsychotic agents Side chain tailing towards position 2 is critical – Superimpose with dopamine Substitution at position 1 instead of 2 hinders tailing no superimposition Substitution at position 3 instead of 2 is too far no superimposition -CF3 compounds more potent than Cl due to more VDW bonds with the side chain The basic amino group must be separated by 3-carbon atoms Piperazine affords more VDW contact with substituents at 2-position  SAR – Thioxanthenes The cis form shows better approximation to dopamine If there is no substitution at position 2 active compounds The cis and trans of the un-substituted thioxanthenes are equally active as antipsychotic  Butyrophenones Conformational similarity with phenothiazines – Three carbons – The t-amino group Examples Piperidine – Haloperidol – Droperidol – Pimozide Pharmacophore 1 4 Butyrophenone  Butyrophenones Haloperidol – Prototype – Recommended for long term use – R = OH Haloperidol – R = -OCO(CH2)8CH3 Haloperidol decanoate – Well absorbed from GIT – Metabolism reduces bioavailability (60%) – Mechanism: unclear 4 1 4 4 4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4-fluorobutyrophenone  Butyrophenones Haloperidol Metabolism  Butyrophenones Haloperidol – The behavior profile similar to chlorpromazine – The dose is 50 X < chlorpromazine 4 1 4 4 4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4-fluorobutyrophenone  Butyrophenones SAR Essentials Droperidol and Pimozide The t-amino group The p-substitution (F) ring A Phenyl ring at position 1 is required for D2 affinity Droperidol Carbon bridging modification Reduces activity Replacing piperidine ring by larger or smaller rings or by noncyclic amines Reduces activity Pimozide Replacing ketone with  ANTIPSYCHOYIC AGENTS Classes Typical antipsychotic Known as first generation or conventional antipsychotic Atypical antipsychotic Known as second generation  Atypical antipsychotic drugs Known as second generation Examples – Clozapine – Olanzapine – Quetiapine – Risperidone – Aripiprazole – Ziprasidone Show a greater reduction in positive and negative symptoms Enhance cognitive functions first line of treatment Recent drugs have affinity to 5-HT2A receptors  Atypical antipsychotic drugs Clozapine – No drug-food interaction – Metabolism N-oxidation Clozapine-N-Oxide N-demethylation N-desmethylclozapine – High affinity to 5-HT2A – High affinity to M1 and M4 muscarinic receptors – Several side effects Agranulocytosis nitrenium ion formed during metabolism  Atypical antipsychotic drugs Olanzapine – Disintegrates in saliva good for elderly – No drug-food interaction – Metabolism N-oxidation N-demethylation – High affinity to 5-HT2A, 2C, 6, α1 – Binds to H1 receptors – Several side effects Dyslipidemia Type-2-diabetes  Atypical antipsychotic drugs Quetiapine – Disintegrates in saliva good for elderly – No drug-food interaction – Metabolism S-oxidation major metabolite O-delakylation Aromatic hydroxilation – Drug-Drug interaction Carbamazepine induces CYTP Ketoconazole inhibit CYTP – Binds to α1, α2, H1 receptors – Several side effects Orthostatic hypotension α1-receptor mediated Somnolence H1-mediated  Atypical antipsychotic drugs Pyridine Pyrimidine Resperidone – No drug-food interaction – Metabolism Alicyclic C-oxidation 9-hydroxyresperidone – Not recommended for elderly Benzisoxazol – Drug-Drug interaction Rifampin induces CYTP Ketoconazole inhibit CYTP – Several side effects Orthostatic hypotension α1-receptor mediated Hyperprolactinemia  Atypical antipsychotic drugs Quinolone Aripiprazole – Disintegrate orally 2 1 5 – No drug-food interaction – Metabolism Oxidation Dehydroaripiprazole – Not recommended for elderly  Atypical antipsychotic drugs ziprasidone – Food enhances absorption – Metabolism S-oxidation Ziprasidone sulfoxide Aldehyde oxidase Dihydroziprasidone (major 2 metabolite) 1 N-delakylation Indolone – Low sedation Benzisothiazol – No weight gain – No hyperglycemia – Increase QTc-intervals End