Antipsychotics. Neuroleptics/ Major Tranquilizers. Hiwa K. Saaed, PhD Pharmacology & Toxicology /5/18 1

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1 Antipsychotics Neuroleptics/ Major Tranquilizers Hiwa K. Saaed, PhD Pharmacology & Toxicology /5/18 1 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 12/5/18 2 1

2 SCHIZOPHRENIA Schizophrenia: the Greek translation is schizein split and phren mind which refers to a split from reality. 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 It is a chronic and disabling disorder. 12/5/18 3 SCHIZOPHRENIA 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 12/5/18 4 2

3 Symptoms of Schizophrenia +ve symptoms: the presence of inappropriate behaviors -ve symptoms: the absence of appropriate behaviors üdelusions (false belief) ühallucinations (false perception) often in the form of voices üthinking or speech disturbances übizarre behavior ülack of motivation üsocial withdrawal üblunted affect üpoverty of speech üanhedonia (lack of interest in pleasurable activities) 12/5/18 5 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. 12/5/18 6 3

4 MECHANISM OF ACTION 1. Dopamine antagonism: ALL of the first-generation and MOST of the second-generation block D 2 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-HT 2A receptors. 12/5/18 6 DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA This hypothesis is suggests that excessive dopaminergic activity plays a role in the disorder: 1. many antipsychotic drugs strongly block D 2 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; post-mortem 12/5/18 8 4

5 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. 12/5/18 9 DOPAMINERGIC & SEROTONERGIC SYSTEMS: 12/5/

6 CHEMICAL CLASSIFICATION 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. 12/5/18 11 PHARMACOLOGICAL CLASSIFICATION are divided into: First-generation (conventional, typical, or traditional) low potency high potency Second-generation ( atypical antipsychotics) This classification: does not indicate clinical effectiveness of the drugs, specifies affinity for the dopamine D 2 receptor, which, in turn, may influence the adverse effect profile of the drug. 1ST-GENERATION (low potency) Ø Thioridazine, Ø Chlorpromazine (High potency) Ø Fluphenazine Ø Haloperidol Ø Loxapine Ø Perphenazine Ø Pimozide Ø Prochlorperazine Ø Thiothixene Ø Triuoperazine 2 nd -GENERATION Ø Aripiprazole Ø Asenapine Ø Clozapine Ø Iloperidone Ø Lurasidone Ø Olanzapine Ø Paliperidone Ø Quetiapine Ø Risperidone Ø Ziprasidone 12/5/

7 / 1 ST -GENERATION are competitive inhibitors at a variety of receptors, but their antipsychotic effects reflect competitive blocking of dopamine D 2 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. Effective in controlling +ve symptoms 12/5/18 13 / SECOND-GENERATION have a lower incidence of EPS than the 1 ST -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. Effective in controlling -ve symptoms, Much More costly, less EPS 12/5/

8 DOPAMINE RECEPTOR-BLOCKING ACTIVITY IN THE BRAIN: the clinical efficacy of the typical neuroleptic drugs correlates closely with their relative ability to block D 2 receptors in the mesolimbic system of the brain. On the other hand, the atypical drug clozapine has a high affinity for the D 4 receptor and 5-HT 2, very low affinity to D 2 which may explain its minimal ability to cause extrapyramidal side effects. Dopamine receptor Type: D 1 and D 5 receptors: activate adenylyl cyclase. D 2, D 3, and D 4 receptors: inhibit adenylyl cyclase, or mediate membrane K + channel opening leading to neuronal hyperpolarization. 12/5/18 15 SEROTONIN RECEPTOR-BLOCKING ACTIVITY IN THE BRAIN: Clozapine: has high affinity for D 1, D 2, D 4, 5-HT 2A, muscarinic, and α-adrenergic receptors. Olanzapine, Risperidone and quetiapine: blocks 5-HT 2 receptors to a greater extent than it does D 2 receptors. Ziprasidone: an antagonist at the D 2, 5-HT 2A and 5-HT 1D an agonist at 5-HT 1A Aripiprazole: is a partial agonist at D 2 and 5-HT 1A receptors but strong antagonist at 5-HT 2A receptors. 12/5/

9 PHARMACOLOGICAL ACTIONS 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 12/5/18 17 PHARMACOLOGICAL ACTIONS 1. Antipsychotic actions: All antipsychotic drugs can reduce hallucinations and delusions (known as positive symptoms) by blocking D2 receptors in the mesolimbic system of the brain. The negative symptoms, such as blunted affect, apathy, and impaired attention, as well as cognitive impairment, are not as responsive to therapy, particularly with the first-generation antipsychotics. Many second-generation agents, such as clozapine, can ameliorate the negative symptoms to some extent. 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. 12/5/

10 2. Antiemetic effects Except thioridazine and aripiprazole, MOST of the neuroleptic drugs block D2- receptors of the chemoreceptor trigger zone (CTZ) of the medulla. 3. Antimuscarinic effects: SOME; particularly thioridazine, chlorpromazine, clozapine, and olanzapine produce anticholinergic effects. 4. Blockade of α-adrenergic receptors: causes orthostatic hypotension and light-headedness. Other effects PHARMACOLOGICAL ACTIONS 5. Alter temperature-regulating mechanisms and can produce poikilothermia (body temperature varies with the environment). 6. Increases in prolactin release (block D 2 receptor) 7. Sedation (H 1 blockade) all except haloperidol 12/5/18 19 AUTONOMIC EFFECTS 12/5/

11 THERAPEUTIC USES 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 Lurasidone and quetiapine are approved. as adjunctive agents with antidepressants for treatment of refractory depression: aripiprazole and quetiapine are used 3. Prevention of severe nausea and vomiting: Most commonly prochlorperazine are useful in the treatment of druginduced nausea, but NO nausea arising from motion sickness (scopolamine is the drug of choice). 12/5/18 21 THERAPEUTIC USES 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. However, risperidone and haloperidol are also commonly prescribed for this tic disorder. 9. Also, risperidone and aripiprazole are approved for the management of disruptive behavior and irritability secondary to autism. 12/5/

12 1. EXTRAPYRAMIDAL SIDE EFFECTS 1. It is appearance is time and dose 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. 12/5/18 23 TARDIVE DYSKINESIA, TD (D2 SUPERSENSITIVITY PHENOMENON): 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 12/5/

13 AVOIDING EP ADVERSE EFFECTS thioridazine, show few EP disturbances: strong anticholinergic activity. This contrasts with haloperidol and fluphenazine, which have low anticholinergic activity and produce EP effects. Clozapine and risperidone: a low potential for causing EP symptoms and lower risk of Tardive Dyskinesia. 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. 12/5/ NEUROLEPTIC MALIGNANT SYNDROME: Neuroleptic malignant syndrome: 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 1. supportive therapy, administration of may be helpful: dantrolene diazepam bromocriptine 12/5/

14 3. Other side effects: Anticholinergic; dry mouth, urinary retention, constipation, and loss of accommodation. Thioridazine-clozapine-haloperidol (high to less) Antiadrenergic; Lowering BP and orthostatic hypotension (αblocker), 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. 12/5/18 27 CAUTIONS AND CONTAINDICATIONS 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. 12/5/

15 Adverse pharmacologic effects antipsychotic drugs. 12/5/18 29 Relative receptor-blocking actions of neuroleptic drugs. 12/5/