Drugs For Psyciatric Disorders

DRUGS FOR PSYCHIATRIC DISORDERS ANTIPSYCHOTIC DRUGS ANTI-ANXIETY DRUGS ANTIDEPRESSANT DRUGS LITHIUM

ANTIPSYCHOTC DRUGS The antipsychotic drugs also known as neuroleptic drugs are useful for the treatment of schizophrenia, agitated states & other psychosis. SCHIZOPHRENIA: It is a psychosis with clear sensorium but a marked thinking disturbance due to excessive dopaminergic activity at the D2 receptors in the mesolimbic frontal system. CLASSIFICATION (TYPICAL) 1. PHENOTHIZINE DERIVATIVES: Chlorpromazine, Thioridazine, Trifluoperazine, Perphenazine. 2. THIOXANTHINE DERIVATIVES: Thiothixine 3. BUTYROPHENONE DERIVATIVES: Haloperidol 4. MISCELLANEOUS: (ATYPICAL) Pimozide, Molindone, Clozapine, Ziprasidone, Aripiprazole, Risperidone.

MECHANISM OF ACTION: Chlorpromazine blocks the D2 receptors in the mesolimbic mesofrontal dopaminer-gic fibers to show antipsychotic effects. Receptors like alpha, muscarinic, histaminic(H1) and serotonin (5HT2) are also blocked to show non-antipsychotic effects. PHARMACOLOGICAL EFFECTS: (a) PSYCHOLOGICAL EFFECTS: Psychotic persons show improvement in their performance. The non-psychotic persons suffer from sleepiness, restless-ness, impaired performance & muscarinic effects. (b) NEUROPHYSIOLOGIC EFFECTS: Slowing of electroencephalographic frequencies and increase in their synchronization.

ENDOCRINE EFFECTS: Amenorrhea, galactorrhea, false +iv pregnancy tests & increased libido in women. In men decreased libido and gyneacomastia. CARDIOVASCULAR EFFECTS: Orthostatic hypotension, high resting pulse rate & increased heart rate. Decrease in the peripheral resistance, B.P. & stroke volume. Prolongation of QT interval, abnormal configurations of ST segment and T waves and arrhythmias. PHARMACOKINETICS: Orally readily but incompletely absorbed, undergo significant first-pass metabolism, highly lipid soluble, 92-99% plasma protein bound, longer duration of action. Mesoridazine is a more potent metabolite of thioridazine. The metabolites of chlorpromazine are excreted in the urine weeks after the

ADVERSE REACTIONS: (a) BEHAVIORAL: Akinesia, pseudodepression, toxic confusional states with prominent anti-muscarinic actions. (b) NEUROLOGIC : Extrapyramidal reactions (Parkison-ism) seen as akathesia (uncontrolable restlessness) and acute dystonic reactions (spastic retrocollis or torticollis). Tardive dyskinesia (late occurring syndrome of abnormal choreoathetoid movements) which is due to decreased cholinergic activity secondry to supersensitivity of dopamine receptors in the caudate-putamen, less seen with atypical anti-psychotics. Seizures with chlorpromazine and clozapine.

(c) AUTONOMIC: Antimuscarinic adverse effects. Adrenoceptor-blocking effects like orthostatic hypo-tension and impaired ejaculation seen with chlorpromazine & mesoridazine. (d) METABOLIC & ENDOCRINE: Weight gain, hyperglycemia, hyperprolactinemia in women leading to amenorrhea-galactorrhea syndrome. In men loss of libido, impotence and infertility. (e) TOXIC or ALLERGIC REACTIONS: Agranulocytosis (especially by clozapine), cholestatic jaundice and skin eruptions. (f) OCULAR: Chlorpromazine gets deposited in the lens and cornea. Thioridazine gets deposited in the retina to give “browning of vision.”

(g) CARDIAC: Thioridazine in high doses causes T-wave abnormalities, ventricular arrhythmias, cardiac conduction block and death. Ziprasidone causes QT prolonation. (h) PREGNANCY: These drugs carry the risk of teratogenesis. (i) NEUROLEPTIC MALIGNANT SYNDROME: It occurs due to excessively rapid blockade of postsynaptic dopamine receptors. Seen as muscle rigidity, high grade fever, stress leucocytosis followed by a severe type of extrapyramidal syndrome. CLINICAL USES: (A) PSYCHATRIC INDICATIONS: 1. Schizophrenia 2. Schizoaffective disorders 3. Manic episode (in bipolar affective disorder)

4. Tourette”s syndrome. 5. To control psychosis and agitation in depression. 6. Senile dementia of Alzheimer type. (II) NON-PSYCHIATRIC INDICATIONS: 1. Antiemetic 2. Antipruritic 3. Preoperative sedatives 4. Neuroleptanesthesia

ANTIANXIETY DRUGS The antianxiety drugs also known as anxiolytics are basically sedative-hypnotics. They are used for the relief of anxiety. In low doses they produce sedation and in high doses they will produce sleep. CLASSIFICATION (a) BENZODIAZEPINES: Diazepam, Chlordiazepxide, Flurazepam, Oxazepam, Lorazepam, Triazolam (b) BARBITURATES: Pentobarbital, Secobarbital, Phenobarbital, (c) MISCELLANEOUS: Buspirone, Zolpidem, Zaleplon Chloral hydrate

MECHANISM: The benzodiazepines enhance GABA-ergic inhibition at the GABA receptor. The barbiturates increase the duration of opening of chloride channel and inhibit the stimulation of glutamate receptor. ACTIONS: The anxiolytics produce relief of anxiety, sedation, hypnosis, anesthesia, anticonvulsant effects, muscle relaxation, respiratory depression in pulmonary disease, cardiovascular depression, psychologic and phsyiologic dependence. TOXICITY: Impaired judgement, diminished motor skills, delerium, agression, violence, behavioral disinhibition, hypersensitivity and teratogenecity. NEWER DRUGS: 1. Buspirone has selective anxiolytic effects without sedation or euphoria. It acts as a partial agonist at brain 5HT1A receptors. It does not interact with

GABA-ergic system and does not show anticonvulsant, hypnotic or muscle relaxant properties. It has also affinity for dopamine D2 receptors. It does not show rebound anxiety, has minimal abuse liability. Adverse effects are tachycardia, palpitations, nervousness, GIT distress and parasthesias. 2. Zolpidem binds to BDZ-subtype of receptor and facilitates GABA-mediated neuronal inhibition. Actions are antagonized by flumazenil. It can suppress REM sleep and causes rebound insomnia after abrupt discontinuation of the drug. Respiratory depression occurs when taken with alcohol. 3. Zaleplon facilitates inhibitory actions of GABA, produces rapid onset and short duration of sleep. Amnesia and next day impairment of psychomotor performance occurs. 4. Venlafaxine and paroxetine (antidepressants) are drugs of first choice in generalized anxiety disorders.

ANTIDEPRESSANT DRUGS Depression is a common psychiatric disorder classified into three groups:• Reactive or secondary depression occuring in response to real stimuli e.g., grief, illness. • Endogenous (Major) depression, a genetically determined biochemical disorder. (c) Manic-depressive (Bipolar-affective) disorder with alternate phases of mania and depression. PATHOPHYSIOLOGY: There is depletion of serotonin or norepinephrine (or both) in the vesicles of pre-synaptic nerve endings of the CNS.

CLASSIFICATION (a) TRICYCLIC ANTIDEPRESSANTS (TCAs): Imipramine, Amytryptyline, Doxepin, Desipramine. (b) HETEROCYCLICS: (second & third generation drugs) Amoxapine, Maprotiline, Trazodone, Bupropion, Venlafaxine, Mirtazipine. (c) SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIs): Fluoxetine, Paroxetine, Sertraline,Citalopram. (d) MONOAMINE OXIDASE INHIBITORS (MAOIs): Phenalzine, Isocarboxazid, Tranylcypromine. PHARMACOKINETICS: The effects of tranylcypromine persist for seven days and those of phenelzine last for 2-3 weeks after discontinuation of the drug.

MECHANISM: Tricyclics block the amine (norepinephrine or serotonin) reuptake pumps, which terminate amine neurotransmission. This permits longer availability of neurotransmitters at the receptor site. The MAOIs block the metabolism of the amine neurotransmitters which permits more amines to accumulate in presynaptic stores and more to be released. The heterocyclics (second generation) have mechanism like tricyclics & MAOIs. They also antagonise subtypes of serotonin receptors (5HT2A or 5HT2C). Bupropion alters the output of norepinephrine and occupy 25% of dopamine reuptake pumps. Mirtazapine (third generation) also antagonises alpha-receptors. The SSRIs inhibit 80% of serotonin reuptake pumps and permit accumulation of serotonin in the synaptic cleft.

Moreover there is decrease in the intracellular cAMP, down-regulation of beta-receptors and phosphorylation of regulatory elements. EFFECTS OF SPECIFIC ANTIDEPRESSANTS: The first generation antidepressants (tricyclics) have varying degrees of selectivity for the reuptake pumps for norepinephrine and serotonin. They have also autonomic effects. The second generation drugs, like amoxipine shows both antipsychotic and antidepressant effects, but dopamine receptor blockade causes akathesia, parkinsonism etc. The third generation drugs, like venlafaxine is a potent inhibitor of serotonin pumps. Mirtazapine is a potent anti-histaminic with greater sedating effects and does not decrease libido or sexual function.

The SSRIs cause decrease in libido and sexual function. They cause serotonin syndrome when used in combination with MAOIs due to marked increase of serotonin in the synapses. The MAOIs which block irreversibly both A & B forms of MAOs are subject to very high risk of hypertensive crisis if tyramine containing foods are taken (because of the loss of first-pass hepatic metabolism of tyramine). Moclobemide is a short acting MAO inhibitor is free of the above effects. Selegeline is a selective MAO-B inhibitor so metabolism of dopamine is inhibited and its amount increases, which makes it useful for parkinsonism. ADVERSE EFFECTS TRICYCLICS: Sedation, tremor, insomnia, blurred vision, constipation, urinary hesitancy, confusion, hypotension,

conduction defects, arrhythmias, aggravation of psychosis, withdrawl syndrome, seizures, weight gain, sexual disturbances. MAOIs: Sleep disturbances, weight gain, postural hypotension, sexual disturbances ( by phenelzine) AMOXAPINE: Similar to tricyclics plus some of antipsychotics. MIRTAZAPINE: Somnolence, increased appetite, weight gain dizziness. TRAZODONE , NEFAZADONE: Drowsiness, dizziness, insomnia, nausea, agitation. VENLAFAXINE: Nausea, somnolence, sweating, dizziness, sexual disturbances, hypertension, anxiety. BUPROPION: Dizziness, dry mouth, sweating, tremor, agravation of psychosis, seizures (high doses). FLUOXETINE (other SSRIs): GIT symptoms, decreased libido,

sexual dysfunction, anxiety, insomnia, tremor. CLINICAL USES 1. Depression 2. Panic disorder 3. Obcessive-compulsive disorder 4. Enuresis 5. Chronic pain 6. Bulimia (eating disorder) 7. Attention Deficit Hyperkinetic Disorder (ADHD) 8. Social disorder 9. Generalized Anxiety Disorder

LITHIUM Lithium carbonate is known as antimanic drug, also known as “mood stabilizing” agent primarily used for bipolar affective (manic-depressive) disorders. Carbamazepine is also useful for manic-depressive patients. Valproate is useful for mania and is a mood stabilizer. The atypical antipsycho-tics are approved as antimanic agents and mood stbilizers. BIPOLAR AFFECTIVE DISORDER: