Antipsychotics, Neuroleptics


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Antipsychotics, Neuroleptics

  1. 1. 11/28/2015 1 Hiwa K. Saaed, PhD Pharmacology & Toxicology Antipsychotics “neuroleptics or major tranquilizers” 2015-2016 FIRST-GENERATION (low potency) Chlorpromazine Thioridazine FIRST-GENERATION (high potency) Fluphenazine Haloperidol Loxapine Perphenazine Pimozide Prochlorperazine Thiothixene Triuoperazine SECOND-GENERATION Aripiprazole Asenapine Clozapine Iloperidone Lurasidone Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone
  2. 2. Learning objectives Pharmacy students should: – be familiar with the symptoms & health consequences of schizophrenia – be able to describe the mechanism(s) of action and adverse effects of antipsychotics 11/28/2015 2 ANTIPSYCHOTICS
  3. 3. ANTIPSYCHOTICS 11/28/2015 3
  4. 4. A. Phenothiazine derivatives (tricyclic+S+side chain) Divided depending on side chain: • Aliphatic group: chlorpromazine oldest • Piperazine group: trifluperazine, fluphenazine, terphenazine, prochlorperazine, thiethylperazine • Piperidin group: thioridazine, mesoridazine B. Thioxanthene derivatives: (thiothixene, flupenthixole) less potent than phenothiazine group. C. Butyrophenone derivatives: (haloperidol) highly potent like piperazine phenothiazine D. Miscellaneous structures: pimozide, molindone, loxapine, clozapine, quetiapine,Risperidone sertindole, olanzapine, and zeprasidone. 11/28/2015 4 ANTIPSYCHOTICS Chemical classification
  5. 5. The Greek translation is schizein “split” and phren “mind” which refers to a split from reality. • Schizophrenia is a type of chronic psychosis characterized by delusions, hallucinations (often in the form of voices), and thinking or speech disturbances. • The onset of illness is often during late adolescence or early adulthood. • It occurs in about 1% of the population and is a chronic and disabling disorder. 11/28/2015 5 SCHIZOPHRENIA
  6. 6. Schizophrenia has a strong genetic component and probably reflects some fundamental biochemical abnormality, possibly a dysfunction of the mesolimbic or mesocortical dopaminergic neuronal pathways. It is characterized by: 1. Positive symptoms; are those that can be regarded as an abnormality or exaggeration of normal function. 2. Negative symptoms; are those that indicate a loss or decrease in function 11/28/2015 6 SCHIZOPHRENIA
  7. 7. Symptoms of Schizophrenia +ve symptoms: the presence of inappropriate behaviors Delusions (false belief) Hallucinations (false perception) often in the form of voices thinking or speech disturbances bizarre behavior -ve symptoms: the absence of appropriate behaviors  Lack of motivation  social withdrawal  blunted affect  poverty of speech  anhedonia (lack of interest in pleasurable activities) 11/28/2015 7 SCHIZOPHRENIA
  8. 8. • Used primarily to treat schizophrenia, • also effective in other psychotic disorders, such as manic states with psychotic symptoms such as grandiosity or paranoia and hallucinations, and delirium. • Neuroleptic drugs are not curative and do not eliminate the fundamental thinking disorder, but they often: 1. Decrease the intensity of hallucinations and delusions. 2. Permit the psychotic patient to function in a supportive environment. 11/28/2015 8 ANTIPSYCHOTICS
  9. 9. ANTIPSYCHOTICS MECHANISM OF ACTION • 1. Dopamine antagonism: ALL of the first-generation and MOST of the second- generation block D2 dopamine receptors in the brain and the periphery. • 2. Serotonin receptor–blocking activity: MOST of the second generation agents appear to exert part of their unique action through inhibition of serotonin receptors (5-HT), particularly 5-HT2A receptors. 11/28/2015 9
  10. 10. DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA This hypothesis is suggests that excessive dopaminergic activity plays a role in the disorder: 1. many antipsychotic drugs strongly block D2 receptors in the CNS, especially in the mesolimbic-frontal system. 2. Dopamine precursor or agonist, either aggravate schizophrenia or produce psychosis de novo in some patients; such as  levodopa (a precursor),  amphetamines (releasers of dopamine),  apomorphine (a direct dopamine receptor agonist), 3. Increase in brain dopamine receptor density 11/28/2015 10
  11. 11. DOPAMINERGIC SYSTEMS: • Mesolimbic-mesocortical pathway: the one most closely related to behavior (mental and emotional) • Nigrostriatal pathway: it is involved in the coordination of posture and voluntary movement • Tuberoinfundibular pathway: inhibit prolactin secretion • Medullary-periventricular: eating behavior • Incertohypothalamic: It has a role in sexual behavior. 11/28/2015 11
  13. 13. The antipsychotic drugs are divided into: • FIRST-GENERATION (also called conventional, typical, or traditional antipsychotics) • low potency • high potency • SECOND-GENERATION AGENTS (also called “atypical” antipsychotics) This classification: • does not indicate clinical effectiveness of the drugs, • specifies affinity for the dopamine D2 receptor, which, in turn, may influence the adverse effect profile of the drug. 11/28/2015 13 ANTIPSYCHOTICS
  14. 14. • are competitive inhibitors at a variety of receptors, • but their antipsychotic effects reflect competitive blocking of dopamine D2 receptors. • are more likely to be associated with movement disorders known as extrapyramidal symptoms (EPS), • More likely with haloperidol. • Less likely with chlorpromazine. • No one drug is clinically more effective than another. 11/28/2015 14 ANTIPSYCHOTICS 1ST-GENERATION
  15. 15. • have a lower incidence of EPS than the 1ST-generation • but are associated with a higher risk of metabolic side effects, such as • diabetes, • hypercholesterolemia, • and weight gain. • The second-generation drugs appear to owe their unique activity to blockade of both serotonin and dopamine and, perhaps, other receptors. 11/28/2015 15 ANTIPSYCHOTICS 2ND-GENERATION
  16. 16. Decrease dopaminergic and/or serotonergic neurotransmission. Effective in controlling +ve symptoms Typical ‘Classic’ drugs (D2) • Chlorpromazine • Fluphenazine • Haloperidol • Thioridazine • trifluperazine Effective in controlling -ve symptoms, More costly, less EPS Atypical ‘Newer’ 5-HT2 • Clozapine • Quetiapine • Risperidione • Ziprasidone • aripiprazole 11/28/2015 16 ANTIPSYCHOTICS
  17. 17. DOPAMINE RECEPTOR-BLOCKING ACTIVITY IN THE BRAIN: D1 and D5 receptors: activate adenylyl cyclase. D2, D3, and D4 receptors: inhibit adenylyl cyclase , or mediate membrane K+ channel opening leading to neuronal hyperpolarization. the clinical efficacy of the typical neuroleptic drugs correlates closely with their relative ability to block D2 receptors in the mesolimbic system of the brain. On the other hand, the atypical drug clozapine has a high affinity for the D4 receptor and 5-HT2, very low affinity to D2 which may explain its minimal ability to cause extrapyramidal side effects. 11/28/2015 17
  18. 18. SEROTONIN RECEPTOR-BLOCKING ACTIVITY IN THE BRAIN: Clozapine: has high affinity for D1, D2, D4, 5-HT2A, muscarinic, and α-adrenergic receptors. Olanzapine, Risperidone and quetiapine: blocks 5-HT2 receptors to a greater extent than it does D2 receptors. Ziprasidone: an antagonist at the D2, 5-HT2A and 5-HT1D an agonist at 5-HT1A Aripiprazole: is a partial agonist at D2 and 5-HT1A receptors but strong antagonist at 5-HT2A receptors. 11/28/2015 18
  19. 19. The clinical effects of antipsychotic drugs appear to reflect a blockade at dopamine and/or serotonin receptors. However, many of these agents also block cholinergic, adrenergic, and histaminergic receptors. PHARMACOLOGICAL EFFECTS 1. Antipsychotic 2. Extrapyramidal 3. Antiemetic 4. Antimuscarinic 5. Blockade of α-adrenergic receptors: 6. Other effects 11/28/2015 19 ANTIPSYCHOTICS
  20. 20. 1. Antipsychotic actions: Neuroleptic stage ALL the drugs also have • a calming effect • reduce spontaneous physical movements, • produce emotional indifference to environment. The antipsychotic effects usually take several weeks to occur, suggesting that the therapeutic effects related to secondary changes in the corticostriatal pathways. 2. Antiemetic effects Except thioridazine, MOST of the neuroleptic drugs D2- receptors of the chemoreceptor trigger zone (CTZ) of the medulla. 11/28/2015 20 ANTIPSYCHOTICS pharmacological actions
  21. 21. 3. Antimuscarinic effects: SOME; particularly thioridazine, chlorpromazine, clozapine, and olanzapine 4. Blockade of α-adrenergic receptors: causes orthostatic hypotension and light-headedness. Other effects 5. Alter temperature-regulating mechanisms and can produce poikilothermia (body temperature varies with the environment). 6. Increases in prolactin release (block D2 receptor) 7. Sedation (H1 blockade) all except haloperidol 11/28/2015 21
  23. 23. 1. Schizophrenia Rx 2. Mania (bipolar disorder): initial Rx of Mania. Atypical antipsychotic drugs are often used with Lithium. maintenance Rx of bipolar disorder Olanzapine and aripiprazole are approved. 3. Prevention of severe nausea and vomiting: Most commonly prochlorperazine are useful in the treatment of drug-induced nausea, but NO nausea arising from motion sickness (scopolamine is the drug of choice). 11/28/2015 23 ANTIPSYCHOTICS THERAPEUTIC USES
  24. 24. 4. As tranqulizers to manage agitated and disruptive behavior. 5. Treatment of chronic pain with severe anxiety in combination with opiates. 6. Hiccups: chlorpromazine 7. Antipruritus and sedation: promethazine 8. Pimozide is primarily indicated for treatment of the motor and phonic tics of tourette disorder 11/28/2015 24 ANTIPSYCHOTICS THERAPEUTIC USES
  25. 25. ANTIPSYCHOTICS 1.EXTRAPYRAMIDAL SIDE EFFECTS 1. It is appearance is time dependent, -Early phase (reversible) • Acute dystonias “sustained contraction of muscles leading to twisting, distorted postures”* occurring within few days, (*Rx by Trihexphenidyl, orphenadrine, procyclidine, or diazepam), • followed by **akathisias (the inability to remain seated due to motor restlessness). • #Parkinson symptoms occur a bit later on. (**&# Rx by propranolol, or antimuscarinic), -Late phase (irreversible) • Tardive Dyskinesia: inappropriate postures of the neck, trunk, and limbs, which is irreversible, occurs with chronic treatment after months or years of treatment. 11/28/2015 25
  26. 26. • Patients display rhythmical involuntary movements, including lateral jaw movements, and “fly-catching” motions of tongue. • TD is postulated to result from an increased number of dopamine receptors • This makes the neuron supersensitive to the actions of dopamine, and it allows the dopaminergic input to this structure to overpower the cholinergic input, causing excess movement in the patient. • NB: antimuscarinic increase the severity of TD • Increase the dose of neuroleptic! Attenuate temporarily 11/28/2015 26 TARDIVE DYSKINESIA, TD (D2 SUPERSENSITIVITY PHENOMENON):
  27. 27. • Using Those drugs that exhibit strong anticholinergic activity, such as thioridazine, show few EP disturbances. • This contrasts with haloperidol and fluphenazine, which have low anticholinergic activity and produce EP effects. • Clozapine and risperidone: these drugs have a low potential for causing EP symptoms and lower risk of Tardive Dyskinesia. 11/28/2015 27 ANTIPSYCHOTICS AVOIDING EP ADVERSE EFFECTS
  28. 28. • Risperidone should be included among the first-line antipsychotic drugs, • Clozapine should be reserved for severely schizophrenic patients who are refractory to traditional therapy. • Clozapine can produce bone marrow suppression and CV side effects. The risk of severe agranulocytosis necessitates frequent monitoring of WBC count. 11/28/2015 28 ANTIPSYCHOTICS AVOIDING EP ADVERSE EFFECTS
  29. 29. this potentially fatal reaction to neuroleptic drugs is characterized by muscle rigidity, fever, stupor, unstable BP, and myoglobinemia. Treatment necessitates 1. discontinuation of the neuroleptic 2. supportive therapy, administration of: • Dantrolene • diazepam • or bromocriptine may be helpful. 11/28/2015 29 ANTIPSYCHOTICS 2. NEUROLEPTIC MALIGNANT SYNDROME:
  30. 30. • Anticholinergic; dry mouth, urinary retention, constipation, and loss of accommodation. Thioridazine, clozapine, haloperidol (high to less) • Antiadrenergic; Lowering BP and orthostatic hypotension (α-blocker), ex, phaenothiazine • Endocrine alteration: The neuroleptics depress the hypothalamus, causing amenorrhea, galactorrhea, infertility, and impotence. • Significant weight gain & hyperglycemia due to a diabetogenic with atypical clozapine & olanzapine. 11/28/2015 30 ANTIPSYCHOTICS 3. Other effects:
  31. 31. 1. acute agitation accompanying withdrawal from alcohol or other drugs may be aggravated by the neuroleptics (Tx; benzodiazepine). 2. Chlorpromazine and clozapine are contraindicated in patients with seizure disorders, because these drugs can lower seizure threshold. The neuroleptics can also aggravate epilepsy. 11/28/2015 31 ANTIPSYCHOTICS CAUTIONS AND CONTAINDICATIONS
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