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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 - PowerPoint PPT Presentation

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  • Antipsychotic AgentsSchizophrenia is the most common psychosis having the following POSITIVE SYMPTOMS:Delusions: fixed constant beliefsHallucinations (auditory/visual): false perceptions in the absence of real external stimuliDisorganized thoughts, behavior & speechIn addition to psychotic symptomsNegative symptoms; apathy, low mood, blunted emotion, & social withdrawal mostly are presentCognitive difficulties; attention, concentration, & memorySchizophrenia/psychosis related to DAergic hyperactivity

  • Dopamine Receptor SubtypesFive types, all G-protein coupledD1 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

  • Dopamine Receptor Subtypes

  • Dopamine Receptor Subtypes

  • Dopaminergic Pathways

  • Schizophrenia Dopaminergic Biochemical Hypothesis Schizophrenia/psychosis related to DAergic hyperactivity in mesolimbic/mesocortical tractsNeuroleptics 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 effectsD2 blockade in hypothalamphseal pathway leads to hyperprolactinemiaNeuroleptic block histmainergic, -adrenergic, and cholinergic receptors

  • Classes of Neuroleptics

  • Antipsychotic Actions of NeurolepticsAntipsychotic effect rely upon D2 receptor blockade in limbic systemReduction of delusion-hallucinations-thoughts disorders (Positive symptoms)Negative symptoms & cognitive impairment are poorly affected by typical neurolepticsAtypical neuroleptics (clozapine) improve moderately the negative symptsomsNo effect on intellectual activity of the patient & minor motor incoordiantion (unlike other CNS depressants)Antipsychotic effect takes several weeks to develop

  • Atypical NeurolepticsClozapine & Resperidone are characterized by low extrapyrimdal side effects & lower TDNo hyperprolctinemiaThey improve negative symptoms of schizophrenia more than typical onesThey have higher affinity for D4 receptors when compared to D2 & block 5-HT2A receptors Nigrostriatal DA pathway is under inhibitory serotoninergic modulationClozapine can produce agranulocytosis; frequent WBCs monitoring

  • Antinausea & Antivomiting EffectsCTZ is a reticular formation part in the medulla oblangata outside the BBBNeuroleptic 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

  • EXTRAPYRIMADAL SIDE-EFFECTS1- Neuroleptic-induced ParkinsonismBlockade of D2 receptors in the nigrostriatal pathways by antipsychotics underlie the Parkinsonian disorder including:Akinesia: shorter steps, reduced arm swing, micrographia & difficulty in motion initiationRigidity: StiffnessTemor similar to Parkinsons disease

  • EXTRAPYRIMADAL SIDE-EFFECTS

    2- Neuroleptic Malignant SyndromeRare, severe, may be fatalCardinal signs: severe rigidity, fever, marked autonomic disturbance, & muscle destruction (increased creatine-PK)Can not be predicted, irregular dose-relationTreat hyperthermia, dantrolene (central muscle relaxant), bromocriptine

    3- Neuroleptic-Induced Dyskinesia/DystoniasOccurs 1-3 days consisting of involuntary motions of lips, jaw & tongue (speech difficulty)Acute dystonias: involuntary twisting of neck, pelvis, & eyes

  • 4- Neuroleptic Induced AkathisiaAkathisia is a motor restlessness, usually lower limb, accompanied by feeling of restlessnessRestlessness & anxiety usually accompany schizophrenia overshadowing the akathisiaOnset of akathisia coincides with initiation of treatment complaining of restless legsPatients report relief upon moving their legs

  • Treatment of Neuroleptic-Induced Parkinsonism, Dystonias, & AkathisiaStriatal GABAergic neural output is controlled by DAergic nigral & local cholinergic inputsDAergic blockade by neuroleptics renders cholinergic input to be dominating resulting in parkinsonism & dystoniasBezotropine/biperiden, by blocking cholinergic receptors, restore DA/Ach balanceL-DOPA restores DA but antagonize therapyNeuroleptic-anticholinergic combinations are routine for children & young menMajority of adults, first treated with neuroleptics, & anticholinergic added whenever needed

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

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

  • Unwanted SedationIt is mediated mainly via histaminergic & cholinergic receptor blockadeLow-potency agents are of highest sedation & high-potency the leastIt is presented as attention & concentration difficulties, daytime drowsiness & fatigueOrthostatic HypotensionSome neuroleptics have -adrenergic blockade &/or direct effect on vasomotor centre

  • Anticholinergic Side EffectsLow-potency neuroleptics are of potent cholinergic effects but not high-potency onesAnticholinergic effects include: dry mouth, constipation, urinary retention, in addition to dry eyes & blurred visionThere may be decreased aqueous humor outflow leading to increased IOP & glaucoma attacks in sensitive patientsThe intrinsic antimuscarinic activity of low-potency neuroleptics might be related to the low extrapyrimadal side effects

  • Other DA-Independent Side EffectsJaundicePhenothiazine-induced jaundice occurs in a very limited number of patientsPossibly hypersensitivity dose-independent reactionsDermatitis & PhotosensitivityMost frequent with low-potency agents in a limited no. of patientsPatients become sunlight-sensitive & may develop sunburnsPossible skin & corneal hyperpigmentaion

  • Other side Effects & ContraindicationsSignificant weight gain is common with atypical neurolepticsCPZ & clozapine are contraindicated in patients with seizure disorder, where they lower seizure thresholdClozapine-induced agranulocytosis limit its use to refractory schizopheniaTachycardiaSexual dysfunction

  • CaseW 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.

  • 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

  • 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.

  • Questions1) Relate different Dopamine Pathway to therapeutic and side effects;Mesolimbic/MesocorticalNigrostriatalHypothalamic/pituitary

    2) Advantage of atypical neuroleptics Vs Typical regarding; Receptors, Therapeutic effects and Side effects.

    3) Differentiate b

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