Antipsychotics Lecture 6 PDF

Antipsychotics Lecture 6 By Matin A. Mahmood M.Sc. Pharmacology & Toxicology Ph.D. Pharmacology  Dopamine receptor in brain D1 : Inhibitory (presynaptic) D2 : Inhibitory (postsynaptic) D2: the predominant subtype in the brain: Regulates mood...

Antipsychotics Lecture 6 By Matin A. Mahmood M.Sc. Pharmacology & Toxicology Ph.D. Pharmacology  Dopamine receptor in brain D1 : Inhibitory (presynaptic) D2 : Inhibitory (postsynaptic) D2: the predominant subtype in the brain: Regulates mood, emotional stability in the limbic system and movement control in the basal ganglia.  Psychosis The term "psychosis" denotes a variety of mental disorders. mi Schizophrenia is a particular kind of psychosis characterized by abnormal social behavior and loss of contact with reality. Mi Common "positive" symptoms include false beliefs (delusions), unclear or confused thinking, and auditory hallucinations. Fo → - "Negative" symptoms include reduced social engagement, blunted emotions, and inactivity. It is suggested that central dopamine overactivity and 5HT2A receptors play important role in the pathogenesis. Schizophrenia 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. Schizophrenia has a strong genetic component and probably reflects some fundamental developmental and biochemical abnormality, possibly a dysfunction of the mesolimbic or mesocortical dopaminergic neuronal pathways.  The Dopamine Hypothesis 1. Blockade of the D2 dopamine receptor by all clinically effective antipsychotics correlates with antipsychotic potency 2. Drugs that increase dopaminergic activity produce or exacerbate schizophrenia (L-dopa, amphetamine) 3. Dopamine receptor density is increased in schizophrenia patients 4. Successful treatment of schizophrenia changes HVA in CSF, plasma, urine of patients (homovanillic acid -a Dopamine metabolite- decreased as the patient improved)  Evidence against Dopamine Hypothesis 1. Antipsychotics are only partially effective in most (70%) and ineffective for some patients. 2. Phencyclidine, an NMDA receptor antagonist, produces more schizophrenia-like symptoms in non-schizophrenic subjects than Dopamine agonists. 3. Atypical antipsychotics have low affinity for D2 receptors. First-generation antipsychotics The first-generation antipsychotic drugs (also called conventional) are competitive inhibitors at a variety of receptors, but their antipsychotic effects reflect competitive blockade of dopamine D2 receptors. First-generation antipsychotics are more likely to be associated with movement disorders known as extrapyramidal symptoms (EPS), particularly drugs that bind tightly to dopaminergic neuroreceptors, such as haloperidol. Movement disorders are somewhat less likely with medications that bind less potently, such as chlorpromazine. No one drug is clinically more effective than another. Second-generation antipsychotic drugs Called “atypical” antipsychotics Unique activity to blockade of both serotonin and dopamine receptors. Have a lower incidence of EPS than the first-generation agents but are associated with a higher risk of metabolic adverse effects, such as diabetes, hypercholesterolemia, and weight gain. Drug selection Second-generation agents are generally used as first-line therapy for schizophrenia to minimize the risk of debilitating EPS associated with the first-generation drugs that act primarily at the dopamine D2 receptor. The second-generation antipsychotics exhibit an efficacy that is equivalent to, and occasionally exceeds, that of the first generation antipsychotic agents. Differences in therapeutic efficacy among the second-generation drugs have not been established, and individual patient response and comorbid conditions must often be used to guide drug selection. Mechanism of action 1. Dopamine antagonism All of the first-generation and most of the second-generation antipsychotic drugs block D2 dopamine receptors in the brain and the periphery.  2. Serotonin receptor–blocking activity Most of the second-generation agents exert part of their action through inhibition of serotonin receptors (5-HT), particularly 5-HT2A receptors. Clozapine high affinity for D1, D4, 5-HT2, muscarinic, & α- adrenergic receptors weak dopamine D2 receptor antagonist. Risperidone blocks 5-HT2A > D2 receptors, as does olanzapine.  Aripiprazole : partial agonists at D2 and 5-HT1A receptors antagonists of 5-HT2A receptor Quetiapine weak blockade of D2 and 5-HT2A receptors. Its low risk for EPS may also be related to the relatively short period of time it binds to the D2 receptor. Actions The clinical effects of antipsychotic drugs reflect a blockade at dopamine and/or serotonin receptors. However, many antipsychotic agents also block cholinergic, adrenergic, and histaminergic receptors It is unknown what role, if any, these actions have in alleviating the symptoms of psychosis. However, the undesirable adverse effects of antipsychotic drugs often result from pharmacological actions at these other receptors  1. Antipsychotic effects All antipsychotic drugs can reduce hallucinations and delusions associated with schizophrenia (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.  2. Extrapyramidal effects Dystonias (sustained contraction of muscles leading to twisting, distorted postures), Parkinson-like symptoms, akathisia (motor restlessness), and tardive dyskinesia (involuntary movements, usually of the tongue, lips, neck, trunk, and limbs) can occur with both acute and chronic treatment. Blockade of dopamine receptors in the nigrostriatal pathway is believed to cause these unwanted movement symptoms. The second-generation antipsychotics exhibit a lower incidence of EPS. Dystonia Akathisia TD  3. Antiemetic effects The antipsychotic drugs have antiemetic effects that are mediated by blocking D2 receptors of the chemoreceptor trigger zone of the medulla  4. Anticholinergic effects (TCCO) Some of the antipsychotics, particularly thioridazine, chlorpromazine, clozapine, and olanzapine, produce anticholinergic effects. These effects include blurred vision, dry mouth (the exception is clozapine, which increases salivation), confusion, and inhibition of gastrointestinal and urinary tract smooth muscle, leading to constipation and urinary retention. The anticholinergic effects may actually assist in reducing the risk of EPS with these agents.  5. Other effects Blockade of α-adrenergic receptors causes orthostatic hypotension and light-headedness. The antipsychotics also alter temperature-regulating mechanisms and can produce poikilothermia (condition in which body temperature varies with the environment). In the pituitary, antipsychotics that block D2 receptors may cause an increase in prolactin release.  5. Other effects Sedation occurs with those drugs that are potent antagonists of the H1- histamine receptor, including chlorpromazine, clozapine, olanzapine and quetiapine (CCOQ) Sexual dysfunction may also occur with the antipsychotics due to various receptor-binding characteristics. Weight gain is also a common adverse effect of antipsychotics and is more significant with the second-generation agents. Therapeutic uses 1. Treatment of schizophrenia The antipsychotics are the only efficacious pharmacological treatment for schizophrenia. The first-generation antipsychotics are generally most effective in treating the positive symptoms of schizophrenia. The atypical antipsychotics with 5-HT2A receptor–blocking activity may be effective in many patients who are resistant to the traditional agents, especially in treating the negative symptoms of schizophrenia.  2. Prevention of nausea and vomiting The older antipsychotics (most commonly, prochlorperazine ) are useful in the treatment of drug-induced nausea.  3. Other uses Chlorpromazine is used to treat intractable hiccups. Risperidone and aripiprazole are approved for the management of disruptive behavior and irritability secondary to autism. Some antipsychotics (aripiprazole and quetiapine) are used as adjunctive agents with antidepressants for treatment-refractory depression Absorption and metabolism After oral administration, the antipsychotics show variable absorption that is unaffected by food These agents readily pass into the brain and have a large volume of distribution. They are metabolized to many different metabolites, usually by the cytochrome P-450 system in the liver. Fluphenazine decanoate, haloperidol decanoate, risperidone microspheres, aripiprazole monohydrate, aripiprazole lauroxil, and olanzapine pamoate are long-acting injectable (LAI) formulations of antipsychotics. These formulations usually have a therapeutic duration of action of 2 to 4 weeks, with some having a duration of 6 to 12 weeks. Therefore, these LAI formulations are often used to treat outpatients and  individuals who are nonadherent with oral medications. Extrapyramidal effects The inhibitory effects of dopaminergic neurons are normally balanced by the excitatory actions of cholinergic neurons in the striatum. Blocking dopamine receptors alters this balance, causing a relative excess of cholinergic influence, which results in extrapyramidal motor effects. The appearance of the movement disorders is generally time- and dose dependent, with dystonias occurring within a few hours to days of treatment, followed by akathisias occurring within days to weeks. Extrapyramidal effects Parkinson-like symptoms of bradykinesia, rigidity, and tremor usually occur within weeks to months of initiating treatment. Tardive dyskinesia, which can be irreversible, may occur after months or years of treatment. If cholinergic activity is also blocked, a new, more nearly normal balance is restored, and extrapyramidal effects are minimized. This can be achieved by administration of an anticholinergic drug, such as benztropine. The therapeutic trade-off is a lower incidence of EPS in exchange for the adverse effect of muscarinic receptor blockade. Akathisia may respond better to β-blockers (for example, propranolol) or benzodiazepines, rather than anticholinergic medications. 2. Tardive dyskinesia Long-term treatment with antipsychotics can cause this motor disorder. Patients display involuntary movements, including bilateral and facial jaw movements and “fly-catching” motions of the tongue. A prolonged holiday from antipsychotics may cause the symptoms to diminish or disappear within a few months. However, in many individuals, tardive dyskinesia is irreversible and persists after discontinuation of therapy. Tardive dyskinesia is postulated to result from an increased number of dopamine receptors that are synthesized as a compensatory response to long-term dopamine receptor blockade. 2. Tardive dyskinesia 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. Traditional anti-EPS medications may actually worsen this condition. Valbenazine and deutetrabenazine are inhibitors of the vesicular monoamine transporter, and they are indicated for the management of tardive dyskinesia. These agents cause a decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores, ideally focused on dopamine, to address the symptoms of tardive dyskinesia. 3. Neuroleptic malignant syndrome This potentially fatal reaction to antipsychotic drugs is characterized by muscle rigidity, fever, altered mental status and stupor, unstable blood pressure, and myoglobinemia. Treatment necessitates discontinuation of the antipsychotic agent and supportive therapy. Administration of dantrolene or bromocriptine may be helpful. 4. Other effects Antipsychotics with potent antimuscarinic activity (dry mouth, urinary retention, constipation, and loss of visual accommodation). Others may block α-adrenergic receptors, resulting in lowered blood pressure and orthostatic hypotension. The antipsychotics depress the hypothalamus, thereby affecting thermoregulation and causing amenorrhea, galactorrhea, gynecomastia, infertility, and erectile dysfunction. Significant weight gain is often a reason for nonadherence. 4. Other effects Glucose and lipid profiles should be monitored in patients taking antipsychotics, as the second-generation agents may increase these laboratory parameters and possibly exacerbate preexisting diabetes or hyperlipidemia. Some antipsychotics have been associated with mild to significant QT prolongation. Thioridazine has the highest risk, also have cautions with their use due to this effect. Other antipsychotics have a general precaution regarding QT prolongation, even if the risk is relatively low. AE