Pharmacology of Antipsychotic drugs

Antipsychotic drugs, neuroleptic or anti-schizophrenic drugs are used mainly to manage psychosis (including delusions or hallucinations and disordered thought ) particularly in schizophrenia and bipolar depression

Schizophrenia

There is some evidence for involvement of 5-HT It is a chronic disabling disorder which affects people during late adolescence or early adulthood Schizophrenia has a strong genetic component and is probably due to biochemical abnormality (dysfunction of D-ergic neurons) There is some evidence for involvement of 5-HT

Patients with schizophrenia have problems with seeing things, hearing voices, imagining things, having terrifying thoughts (positive symptoms) Apathy , blunted emotions, anhedonia and reduced ability to react with people ‘social withdrawal’ (Negative symptoms)

Schizophrenia: Symptoms Positive Symptoms Hallucinations Delusions Thought disturbances Negative Symptoms Blunted emotions Social withdrawal Loss of motivation impaired personal hygiene

“Dopamine hypothesis” Schizophrenia has a strong genetic component and probably reflects too much dopamine activity in the mesolimbic system which is the part of brain that controls seeing, hearing, imaging etc…..

“Dopamine hypothesis” - Evidences Drugs that increase dopamine may produce positive psychotic symptoms (e.g. Cocaine, amphetamine) All known antipsychotics drugs capable of treating positive psychotic symptoms block the dopamine receptors (D2)

Antipsychotic Drugs

Atypical drugs are preferred as a first line treatment because they: Antipsychotics are broadly divided into two groups: The typical = 1st generation and the atypical = 2nd generation antipsychotics Atypical drugs are preferred as a first line treatment because they: 1- have fewer side effects 2- have additional benefits for the “ -ve symptoms”of schizophrenia

Mechanism of Action

All antipsychotic drugs block D2 receptors in the brain & periphery Atypical antipsychotics exert part of their action through blocking of 5-HT2A receptors Antipsychotics take days or weeks to work, suggesting that secondary effects (e.g. increase in number of D2-receptors in limbic structure) may be more important than direct effect of D2-receptor block.

Many antipsychotics block other receptors e. g Many antipsychotics block other receptors e.g. acetylcholine (M), noradrenaline (α ) and histamine (H1) receptors

Typical antipsychotic Drugs 1- Phenothiazine derivatives: Chlorpromazine, promethazine, Fluphenazine 2- Butyrophenone derivatives: Haloperidol, droperidol Atypical antipsychotic drugs Risperidone , Clozapine , Olanzapine Aripiprazole

Pharmacological Actions

1- Antipsychotic effects Though blocking D2 receptors in the mesolimbic system, antipsychotic drugs relieve hallucination, improve thoughts. The additional blocking effects of atypical antipsychotics on 5-HT2 receptors can treat the negative symptoms of schizophrenia 2- Autonomic effects: Anticholinergic effects , dry mouth, constipation and blurred vision Blocking of α–adrenergic receptors hypotension

3- Exrapyramidal effects Blocking of D2 receptors in the nigrostriatal pathway causes unwanted parkinsonian-like symptoms; rigidity and tremors. Clozapine and risperidone exhibit a low incidence of these symptoms ( block D4) 4- Antiemetic effect Blocking D2 receptors both centrally in the CTZ in the medulla and peripherally in the stomach

6-Antipsychotics block H1 receptors causing sedation and confusion 5- Endocrine effects: Amenorrhea-galactorrhea, false–positive pregnancy tests in women and decreased libido and gynecomastia in men (due to blockade of D2 in the pituitary leading to an increase in prolactin release) 6-Antipsychotics block H1 receptors causing sedation and confusion 7- Antipsychotic depress the hypothalamus affecting thermo-regulation (hypothermia)

Therapeutic Uses

1- Treatment of schizophrenia Typical antipsychotics are most effective in treating positive symptoms Atypical antipsychotics with serotonin blocking activity are effective in many patients resistant to the traditional agents, especially in treating negative symptoms

2- Treatment of other psychotic disorders e. g 2- Treatment of other psychotic disorders e.g. mania and mood (bipolar) disorders 3- Prevention of severe nausea and vomiting (drug-induced nausea) 4- Droperidol is used in combination with fentanyl in neuroleptanalgesia

6- To induce hypothermia in certain major operations (Chlorpromazine) 5- Due to its antihistaminic effects, promethazine is used in cases of pruritus and as a preoperative sedative 6- To induce hypothermia in certain major operations (Chlorpromazine) 7- Chlorpromazine is used to treat intractable hicough حازوقه

Adverse Effects

Extrapyramidal Symptoms (EPS) Dopamine Vs Acetylcholine Dopamine (inhibitory) and ACh (excitatory) have a reciprocal relationship in the Nigrostriatal pathway A delicate balance allows for normal movement Dopamine blockade by antipsychotic drugs results in relative increase in cholinergic activity causing EPS When high potency antipsychotics are chosen, we often prescribe anticholinergic medication like benztropine

Antipsychotics have a wide range of side effects 1- Sedation (drowsiness) is a common side effect of antipsychotics (?) This can be dealt with by taking medication at night just before going to bed 2- Movement disorders; Extrapyramidal side effects are common with the typical antipsychotics ; include dystonia, akathisia parkinsonian- like syndrome Treatment: anticholinergic drugs (benztropine)

Tardive dyskinesia It is the most important adverse effect of long-treatment with typical antipsychotic drugs and is characterized by excessive movement of the lips, tongue and jaw, limbs Tardive dyskinesia may be irreversible and is postulated to result from increased number of dopamine receptors that are synthesized in response to long-term dopamine receptor blockade, which leads to neuronal supersensitivity to dopamine

Atypical drugs have lower incidence of EPS & tardive dyskinesia as they block 5-HT2A receptors and have less D2 receptor blocking effect

3-Autonomic effects:Orthostatic hypotension 3-Autonomic effects:Orthostatic hypotension !!!!, (α-adrenoceptor blockade) and anticholinergic adverse effects (urinary retention, constipation, ppt of glaucoma,…..) 4- Endocrine and metabolic effects: hyperprolactinemia in the form of galactorrhea, amenorrhea in women, gynecomastia and changes in libido & impotence in men

5- Allergic reactions: Agranulocytosis (common with clozapine), cholestatic jaundice and skin eruptions 6-Occular complications: may cause retinal pigmentation, corneal and lens opacities (Chlorpromazine) 7- Clozapine and chlorpromazine tend to lower an individual’s seizure threshold

Neuroleptic Malignant Syndrome An idiosyncratic, life-threatening neurological disorder associated with antipsychotic therapy Idiosyncracy: An unusual or unexpected sensitivity exhibited by an individual to a particular food or drug. Idiosyncrasy is usually determined genetically and it may be due to a biological deficiency (e.g. an inability to metabolize a drug).

Neuroleptic Malignant Syndrome Clinical manifestations include: Encephalopathy, Hyperpyrexia, delirium Autonomic instability (BP) Rigidity of muscles Elevated creatine phosphokinse (CPK) due to increased muscular activity and rhabdomyolysis (destruction of muscle tissue)

Pathophysiology The mechanism is thought to depend on dopamine activity due to: Dopamine receptor blockade Genetically reduced function of dopamine receptor  There is an increased calcium release from the sarcoplasmic reticulum of muscle cells which can result in rigidity and cell breakdown

Treatment involves: Immediate discontinuation of antipsychotic drug Treat hyperthermia  Hydration, maintain vital functions Dantrolene sodium: a muscle relaxant that acts by abolishing excitation contraction coupling in muscle cell

Typical antipsychotics

Chlorpromazine Phenothiazine class Increased prolactin (gynaecomastia) Hypothermia Anticholinergic effects Hypersensitivity reactions Obstructive jaundice Ocular complications EPS

Fluphenazine Phenothiazine class but: does not cause jaundice causes less hypotension causes more EPS

Halopirodol Butyrophenone class As chlorpromazine but does not cause jaundice Fewer anticholinergic side effects Strong EPS tendency

Atypical Drugs

Differences between typical and atypical groups receptor profile Serotonin receptors (5-HT2A) are involved incidence of extrapyramidal side effects (less in atypical group) efficacy (specifically of Clozapine in treatment of resistant group of patients efficacy against negative symptoms

Clozapine Dibenzodiazepine class Potent antagonist at D4-receptors Selectively blocks 5-HT2A receptors Sedation Extrapyramidal side effects are minimal Low incidence of Tardive dyskinesia Increased risk for seizures (2-3%)

Clozapine Agranulocytosis in 1% (regular granulocyte counts weekly is required) Agranulocytosis risks increase when co-administered with carbamazepine Anticholinergic side effects Weigh gain Shows efficacy in 'treatment-resistant' patients Effective against negative and positive symptoms

Risperidone Largely replacing clozapine. No risk of agranulocytosis Low incidence of EPS and minimal sedation Weight gain Resperidone is approved for the treatment of autism and bipolar depression

Aripiprazole Recently approved drug Long acting (plasma half-life ∼3 days) No effect on prolactin secretion No weight gain Less incidence of dystonias and Tardive dyskinesia D2 partial agonist profile may account for paucity of side effects

Advantages & disadvantages of Clozapine Effective in the treatment of negative and positive symptoms of schizophrenia More effective than classical agents for resistant cases Clozapine has the risk of inducing agranulocytosis Clozapine tends to lower an individual seizure threshold

Advantages Disadvantages Incidence of extrapyramidal symptoms is lowest Tardive dyskinesia is extremely rare with clozapine Atypical drugs cause weigh gain Atypical drugs may exacerbate DM & hyperlipidemia Are more expensive than typical antipsychotics