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65 Cards in this Set
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Reserpine |
Antipsychotic actions. Deplete brain dopamine and NE. |
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Amphetamine |
Induce psychosis in man and animal models. Releases DA from presynaptic terminals. Antipsychotics block its psychotomimetic actions. |
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DA receptor agonists |
Bromocriptine, L- dopa, apomorphine. |
Antipsychotics block the peripheral and central actions of the DA receptor agonists. |
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2 major families of DA RECEPTORS |
D1-like (D1, D5) D2-like (D2, D3, D4) |
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Nature of DA receptors |
GPCR localised both pre- and post-synaptically. |
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D1 |
Primarily post-synaptic |
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D2 and D3 |
Pre- and post-synaptic |
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Selective D2 Antipsychotics |
Good Antipsychotics |
Raclopride |
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Selective D1 blockers |
Not Antipsychotics |
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Spiroroperidol |
Most potent Antipsychotic. |
Low KD, low IC50. Low doses needed to control schizophrenia. |
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Promazine |
Least potent Antipsychotic. |
High KD, high IC50. High doses needed to control schizophrenia. |
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Examples of Antipsychotics |
Spiroroperidol, benperidol, trifluperidol, primozide, fluphenazine, haloperidol, thiothexene, Trifluperazine, moperone, prochlorperazine, molindone, thioridazine, clozapine, chlorpromazine trazodone, promizine. |
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Number of Dopaminergic pathways |
3 |
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Types of Dopaminergic pathways |
Substantia nigra Ventral tegmental area Hypothalamus |
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AMPAKINES |
Enhance glutamate receptor activity |
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CX516 |
An ampakine. CX516 enhance Antipsychotic-like effect in experimental animals CX516 improve memory in humans |
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Xanomeline |
Anti muscarinic. Effective in Tx psychiatric disturbance in alzheimer's |
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M1 and M4 receptors |
Linked to psychosis |
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Muscarinic agonists |
Block effect of apomorphine on prepulse inhibition of the startle reflex |
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N-desmethylclozapine |
Exhibits M1 agonist activity |
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ARIPIPRAZOLE effects |
May improve both+ and - symptoms of schizophrenia Relatively low side effect profile |
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ARIPIPRAZOLE MOA |
D2 partial agonist 5Ht1A receptor agonist 5HT2A antagonist |
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ARIPIPRAZOLE side effects |
Lower weight gain than other Antipsychotics Fewer EP side effects than other Antipsychotics |
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Adverse effects |
Headache Anxiety Insomnia |
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Toxic confusional state is produced by phenothiazines |
Due to central anticholinergic effects; especially troublesome in older patients |
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Nigrostraital pathway |
Function: modulates extrapyramidal system; movement. Antipsychotic effect: movement disorders example parkinson's disease |
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Mesolimbic pathway |
Function: Arousal, memory, motivation. Antipsychotic effect : relief of psychosis |
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Mesocortical pathway |
Function : cognition, communication, social function, response to stress Antipsychotic effect : increase in negative symptoms |
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Tubero-infundibular pathway |
Function : regulates prolactin release Antipsychotic effect : increase in prolactin concentrations |
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Glutamate and schizophrenia |
Glutamate is the major excitatory neurotransmitter in the brain |
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Phenycyclidine (PCP) |
PCP produces symptoms that mimic schizophrenia. PCP occupies receptors within calcium receptors of NMDA receptor complex. |
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Typical Antipsychotics |
PHENOTHIAZINES: chlorpromazine BUTYROPHENONES: haloperidol THIOXANTHENES: thiothixene DIBENZOTHIEPINE: zotepine DIBENZOXAZEPINE: loxapine DIHYDROINDOLONES: molindole DIPHENYLBUTYLPIPERIDINES: pimozide |
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Classes of phenothiazines |
3 classes: Aliphatic compounds Piperidines Piperazines |
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Aliphatic compounds |
Chlorpromazine-pronounced sedative effects. Moderate EP and autonomic effects. |
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Piperidines |
Thioridazine, mesoridazine Moderate sedative effects. Fewer EP but more autonomic effects. |
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Piperazines |
Trifluperazine, fluphenazine Fewer sedative effects. Pronounced EP but less autonomic effects |
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Piperidines |
Thioridazine, mesoridazine Moderate sedative effects. Fewer EP but more autonomic effects. |
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MOA of phenothiazines |
Antagonists at various dopamine receptors (D1, D2) and at adrenergic and muscarinic receptors. They may also have lesser degree of activity at serotonin receptors. |
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Behavioural actions of phenothiazines |
Antipsychotic actions Quieting of agitated patients Sedation Decreased spontaneous activity |
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Extrapyramidal symptoms( Parkinsonism, akinesia, tremor, rigidity, etc.) produced by phenothiazines |
MOA: Antipsychotic antagonism of D2 receptors in the nigrostraital system Tx: reduce dose Change drugs to atypical or clozapine if severe Anticholinergic anti parkinson's drugs or amantadine
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EPS-Acute dystonia |
Spasms involving head, neck, trunk, extremities MOA: DA receptor blokade by Antipsychotic drugs Tx: benztropine, diphenhydramine |
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EPS-Akathisia |
State of extreme motor restlessness and drive to move MOA: uncertain Tx: reduce dose Switch to low potency or atypical Propranolol Benzodiazepines Amantadine Sometimes resistant to anticholinergic anti parkinson agent |
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EPS-tardive dyskinesia |
Stereotyped, repetitive, involuntary movements of the mouth, lips, tongue and choreiform movements of the limbs and body MOA : development of super sensitivity of DA receptors as a consequence of long term blockade. Tx: reduce dose Avoid anticholinergic drugs Switch to atypical |
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EPS-perioral tremor |
=Rabbit syndrome. Late appearing MOA: uncertain; DA receptor blockade Tx : respods to anticholinergic anti parkinson's drugs Reduce dose of Antipsychotic agent |
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Anti-emetic effect of phenothiazines |
Block emesis induced by morphine, apomorphine, etc acting on CTZ including chemotherapy agents MOA: antiemetic effect on CTZ is related to dopamine and or serotonin receptor blockade. |
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Piperazine substituted phenothiazines |
Are more potent antiemetics than others |
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ANS effects of phenothiazines |
Alpha receptor blockade leading to orthostayic hypotension and epinephrine reversal Muscarinic receptor blockade Antihistaminic activity Antiserotogernic activity |
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Cardiac effect of phenothiazines |
Local anestheyic Anticholinergic Quinidine- like (especially thioridazine) effects on the heart: depressed T wave, prolonged Qt interval. Reversible on discontinuation of the drug |
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Endocrine effects of phenothiazines |
Increased prolactin secretion Decreased secretion of gonadotropin, growth hormone and ACTH |
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Temperature regulation effect of phenothiazines |
Poikilothermic effect. |
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Side effects of phenothiazines |
Parkinsonism Neuroleptic malignant syndrome Akathisia Tardive dyskinesia Pseudo pregnancy Seizures at high doses |
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NMS |
Occurs in 0.2% of patients on Neuroleptic drugs esp potent Dopaminergic antagonists like haloperidol Symptoms: hyperthermia muscle rigidity Autonomic instability Fluctuating level of consciousness
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NMS Tx |
Bromocriptine Dantrolene Ģeneral management including temperature reduction Stop drug |
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Atypical Antipsychotics |
Diabenzodiazepine-clozapine Benzisoxazole-risperidone Thienobenzodiazepine-olanzapine Dibenzothiazepine-quetiapine Imidazolidinone-sertindole Benzamide-amisulpride |
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Clozapine MOA |
Serotonergic, alpha adrenergic, histaminergic blocking activity |
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Clozapine effects |
Minimal central dopaminergic activity Effectively relieves +and - symptoms in schizophrenia patients refractory to classical Antipsychotics |
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Clozapine risk |
Patient should be monitored for agranulocytosis |
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Risperidone MOA |
Antagonistic activity at 5HT2 and D2 receptors |
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Risperidone effects |
Produces fewer extrapyramidal effects Reduces both + and - symptoms of schizophrenia |
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Olanzepine MOA |
Antagonistic activity at 5HT2, D1, D2, H1, Alpha adrenergic, muscarinic receptors. |
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Olanzepine effects |
Improves + and - symptoms and affective component of schizophrenia Low potential to cause EP effects |
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Quetiapine MOA |
Exhibits HIGH affinity for 5HT2 THAN D1, D2. Also high affinity for histaminergic and alpha1 adrenergic receptors |
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Quetiapine effects |
Reduces both the+ and - symptoms of schizophrenia without EP effects, weight gain, agranulocytosis, or affecting prolactin levels |
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Amisulpride MOA |
Dual. At low doses block presynaptic D2 and D3 receptors to increase release of DA to Tx negative symptoms. At high doses, blocks postsynaptic D2, D3 receptors to improve + symptoms. |
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Schizophrenia therapy- new drug development |
5HT2A inverse agonists example LSD AMPAKINES example CX516 MUSCARINIC AGONISTS ARIPIPRAZOLE |
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