Antipsychotics “Neuroleptics/ Major Tranquilizers” 2017-2018 Hiwa K. Saaed, PhD Pharmacology & Toxicology hiwa.saaed@univsul.edu.iq 9/19/2018

ANTIPSYCHOTICS 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 9/19/2018

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 and is a chronic and disabling disorder. 9/19/2018

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: Positive symptoms; are those that can be regarded as an abnormality or exaggeration of normal function. Negative symptoms; are those that indicate a loss or decrease in function 9/19/2018

Symptoms of Schizophrenia +ve symptoms: the presence of inappropriate behaviors -ve symptoms: the absence of appropriate behaviors Delusions (false belief) Hallucinations (false perception) often in the form of voices thinking or speech disturbances bizarre behavior Lack of motivation social withdrawal blunted affect poverty of speech anhedonia (lack of interest in pleasurable activities) 9/19/2018

ANTIPSYCHOTICS 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: Decrease the intensity of hallucinations and delusions. Permit the psychotic patient to function in a supportive environment. 9/19/2018

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. 9/19/2018

DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA This hypothesis is suggests that excessive dopaminergic activity plays a role in the disorder: many antipsychotic drugs strongly block D2 receptors in the CNS, especially in the mesolimbic-frontal system. 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), Increase in brain dopamine receptor density; postmortem 9/19/2018

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. 9/19/2018

DOPAMINERGIC & SEROTONERGIC SYSTEMS: 9/19/2018

CHEMICAL CLASSIFICATION ANTIPSYCHOTICS 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. 9/19/2018

PHARMACOLOGICAL CLASSIFICATION ANTIPSYCHOTICS PHARMACOLOGICAL CLASSIFICATION The antipsychotic drugs 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 D2 receptor, which, in turn, may influence the adverse effect profile of the drug. 9/19/2018

ANTIPSYCHOTICS 1ST-GENERATION (low potency) Thioridazine, Chlorpromazine 1ST-GENERATION (High potency) Fluphenazine Haloperidol Loxapine Perphenazine Pimozide Prochlorperazine Thiothixene Triuoperazine 2nd-GENERATION Aripiprazole Asenapine Clozapine Iloperidone Lurasidone Olanzapine Paliperidone Quetiapine Risperidone Ziprasidone 9/19/2018

ANTIPSYCHOTICS/ 1ST-GENERATION 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. Effective in controlling +ve symptoms 9/19/2018

ANTIPSYCHOTICS/ SECOND-GENERATION 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. Effective in controlling -ve symptoms, Much More costly, less EPS 9/19/2018

DOPAMINE RECEPTOR-BLOCKING ACTIVITY IN THE BRAIN: 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. Dopamine receptor Type: 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. 9/19/2018

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. 9/19/2018

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 Antipsychotic Extrapyramidal Antiemetic Antimuscarinic Blockade of α-adrenergic receptors: Other effects 9/19/2018

PHARMACOLOGICAL ACTIONS 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. 9/19/2018

PHARMACOLOGICAL ACTIONS 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 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 9/19/2018

ANTIPSYCHOTICS AUTONOMIC EFFECTS 9/19/2018

THERAPEUTIC USES Schizophrenia Rx 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 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). 9/19/2018

THERAPEUTIC USES As tranqulizers to manage agitated and disruptive behavior. Treatment of chronic pain with severe anxiety in combination with opiates. Hiccups: chlorpromazine Antipruritus and sedation: promethazine 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. Also, risperidone and aripiprazole are approved for the management of disruptive behavior and irritability secondary to autism. 9/19/2018

ANTIPSYCHOTICS 1.EXTRAPYRAMIDAL SIDE EFFECTS 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. 9/19/2018

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 9/19/2018

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. 9/19/2018

2. 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 discontinuation of the neuroleptic supportive therapy, administration of…may be helpful: dantrolene diazepam bromocriptine 9/19/2018

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 (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. 9/19/2018

CAUTIONS AND CONTAINDICATIONS acute agitation accompanying withdrawal from alcohol or other drugs may be aggravated by the neuroleptics (Tx; benzodiazepine). Chlorpromazine and clozapine are contraindicated in patients with seizure disorders, because these drugs can lower seizure threshold. The neuroleptics can also aggravate epilepsy. 9/19/2018

ANTIPSYCHOTICS Adverse pharmacologic effects antipsychotic drugs. 9/19/2018

ANTIPSYCHOTICS Relative receptor-blocking actions of neuroleptic drugs. 9/19/2018