DRUGS USED IN PSYCHIATRIC DISORDERSdr. IGA Artini, M.ScDepartment of PharmacologyFaculty of MedicineUdayana University

Able to describe the pharmacokinetic and pharmacodynamic of sedative-hypnotic drugsLearning outcomesAble to describe the pharmacokinetic and pharmacodynamic of antipsychotic drugsAble to describe the pharmacokinetic and pharmacodynamic of drugs used in mood disorders

1. SEDATIVE-HYPNOTIC AND ANXYOLITIC DRUGS 2. ANTIPSYCHOTIC DRUGS3. DRUGS USED IN MOOD DISORDERS (ANTIDEPRESSANT DRUGS AND LITHIUM)DRUGS USED IN PSYCHIATRIC DISORDERS

Types of ion channels and neurotransmitter receptors in the CNSGPCR which interact directly with ion channel

SEDATIVE-HYPNOTIC AND ANXYOLITIC DRUGS

Class of sedative-hypnotic drugs

Triazolam : fast absorption ( diazepam, chlorazepate)Diazepam, triazolam rapid onset (chlordiazepoxide, lorazepam)Form active metabolite long T1/2, cumulative effectEstazolam, oxazepam, lorazepam directly converted to inactive metabolite Pharmacokinetic of benzodiazepines and barbiturates- Chlordiazepoxide: 24 hrs- Diazepam: 72 hrs Flurazepam: 75 hrs- Lorazepam: 12 hrs - Nitrazepam: 24 hrs- Oxazepam: 12 hrs

Barbiturates : well absorbedThiopental : very rapid onsetSlow metabolized but inactive metabolite T1/2 longEnzyme inducer (>< BDZ)

Biotransformation of benzodiazepinesBoldface, drugs available for clinical use; *, active metabolite

GABAA receptor-chloride ion channel macromolecular complexAntagonized by flumazenilBinding of BDZ into BDZ binding site (between alpha 1 and gamma 2) facilitates the inhibitory actions of GABA increase the frequency of GABA-mediated chloride ion channel opening.

*Ngatidjan, ANTIPSIKOTICSr-GABAr-BDZBDZ not substitute GABA, only facilitate GABA activity but not directly interact.BDZ binding to r-BDZ increase probability of chloride channel opening Increase frequency of channel opening hyperpolarization reducce nerve cell activity

Ngatidjan, ANTIPSIKOTICS

Bind to GABAA receptor (different sites from BDZ)Not antagonized by flumazenilIncrease the duration of GABA-mediated chloride ion channel openingFacilitate the inhibitory effect of GABAAlso depress glutamic acid action

Pharmacodynamic of sedative-hypnotic drugs Sedation (relief of anxiety) Hypnosis (promote sleep onset and increase the duration of the sleep state) Anesthesia (loss of consciousness, amnesia and suppression of reflexes) Anticonvulsant Muscle relaxation Medullary depression (respiratory arrest, hypotension, cardiovascular collapse, death)

NREM phase 1, 2, 3 and 4 intercepted by REM 90'* sleeping onset * phase 2 NREM * phase 3 and 4 NREM * REM

For drug A, an increase in dose above that needed for hypnosis may lead to a state of general anesthesia. At still higher doses, sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma and death.Drug B, has greater safety margin (safer for clinical use)A : Older sedative hypnotics including barbiturates and alcoholsB : Newer sedative hypnotics including benzodiazepinesCNS effect depend on dose

Psychomotor dysfunction (cognitive impairment, decreased psychomotor skill, daytime sedation, amnesia), rebound insomnia, dependence, tolerance, CNS depression, allergy, abuse, CV and respiratory depression (if OD) Additive CNS depression (severe respiratory and cardiovascular depression) alcohol, antihistamine, antipsychotic, opioid, TCA, anticonvulsant Barbiturates induce formation of liver microsomal enzymes Barbiturates contraindicated in porrphyria disease

Buspirone not interact directly to GABA system, partial agonist for 5HT1A receptor, slow onset Zolpidem : bind BZ1 receptor selectively; antagonized by flumazenil; minimal tolerance and dependence; minimal psychomotor depression and amnesia; rapid onset; short duration

ANTIPSYCHOTIC DRUGS

Pharmacokinetic : Long half life, highly lipid soluble, bind protein, long duration

Site of action of neurolepticsOlder drugs have high affinity for D2 receptor in brain Most of newer drugs not a potent antagonist of D2 receptor Mesocortical mesolimbic (behavior) antipsychotic effect Nigrostriatal (coordinating voluntary movement) Tuberoinfundibular (inhibit prolactin secretion) Medullary periventricular (eating behavior) Incertohypotalamic (copullatory behavior in rats)

ButyrophenonesPhenothiazinesAtypical neuroleptics (Clozapine, Olanzapine, Risperidone)Pharmacodynamics : Autonomic effect, performance disorders, psychomotor disorder, sedation, endocrine effect, neurologic effect, cardiovascular effectClinical uses : Treatment of schizophrenia, schizoaffective, mania, bipolar disorders, non psychiatric indication (antiemetic)

Receptor affinity profile of neurolepticsThe receptor affinities of each drug are compared in relation to its D2-receptor affinity, arbitrarily set at (++); antagonistic effects, except for ziprasidone (5-HT1A agonism)

Common side effects of antipsychotics and the mechanisms

Toxicity of antipsychotics

Toxicity of antipsychotics (contd)

Drug interaction involving antipsychotics Anticholinergic : additive of atropine-like effects CNS depressant (alcohol, barbiturates, benzodiazepines, antihstamines, TCA, opioid) : additive CNS depression Alpha adrenoceptor blocker : additive of alpha blocker effect

ANTIDEPRESSANT DRUGS

Monoamine-deficiency hypothesis of depressive disorders

Antidepressant Profile TCA well absorbed, large Vd, T1/2 8-36 h, structure related to phenothiazine SSRI require hepatic metabolism, other than fluoxetine not form long acting metabolite MAOI structure resemble amphetamine,inhibit both MAO A and B ireversibly, enzyme inhibitor, prolong duration

Mechanism of action of antidepressantTCA and heterocyclics inhibit reuptake of NE and 5-HT in brain (inhibit transporter); SSRI selectively inhibit reuptake of 5-HT in brain (inhibit transporter); MAOI inhibit metabolism of amine amine accumulation Other effects of antidepressant include amine (NE) uptake blockade in ANS, sedation, CNS stimulation, muscarinic receptor blockade, cardiovascular effects, seizure

Targets of Antidepressant Action on Noradrenergic and Serotonergic Neurons

Clinical Uses Major depressive disorders SSRI is preferred (more tolerable SE and safety, even though not more effective) TCA for psychomotor retardation, sleep disturbances, poor appetite, weight loss Bipolar disorders, acute panic attacks, phobic disorders, ADHD, enuresis SSRI cause lose weight, for OCD, generalized anxiety disorders, panic attacks, social phobia, bulimia MAOI anxiety, phobia

Common side effect of antidepressant Anticholinergic manifest as atropine-like effects (dry mouth, blurred vision, urinary retenton, reduce sweating, constipation) Orthostatic hypotension due to alpha adrenoceptor blockade

Overdosage of TCA lethal, 3Cs (coma, convulsion, cardiotoxicity), respiratory depression, circulatory collapse, hyperpyrexia, severe arrhythmia Overdosage of Heterocyclics seizure and cardiotoxicity Amoxapine dopamine receptor blocker akathisia, parkinsonism, amenorrhea-galactorrhea syndrome Overdosage of SSRI seizure Serotonin syndrome interaction fluoxetine and MAOI, life threatening, severe muscle rigidity, hyperthermia, myoclonus, cardiovascular instability, CNS stimulation (seizure) Overdosage of MAOI hyperthermia, seizure

Drug Interactions involving Antidepressants

AntidepressantInteract withEffectFluoxetineFluvoxamine

MAOI

NefazodoneParoxetine

SertralineTCALithium, TCA, warfarinAlprazolam, theophylline, TCA, warfarinSympathomimetics, tyramine, SSRIAlprazolam, triazolamProcyclidine, theophylline, TCA, warfarinTCA, warfarinCNS Depressant (ethanol, sedative), clonidine, metyldopaIncrease other drug levelIncrease other drug level

Hypertension crisis, serotonin syndromeIncrease other drug levelIncrease other drug level

Increase its effectAdditive CNS depressant, decrease antihypertensive effect

Serotonin biosynthesis and metabolism Spectrum of Clinical Findings

LITHIUM

LITHIUM PROFILE Absorbed rapidly, half life 20 h, slow onset, therapeutic plasma concentration 0.6 1.4 mEq/L Diuretic may increase lithium blood levelTheophylline increase renal clearance of lithium Treatment of bipolar disorder Neurologic effect (tremor, sedation, aphasia, ataxia), thyroid enlargement, reversible nephrogenic DI, edema, leukocytosis, congenital cardiac anomalies

Effect of lithium on the IP3 and DAG second-messengerPIP2, phosphatidylinositol-4,5-bisphosphate; PLC, phospholipase-C; G, coupling protein; EFFECTS, activation of protein kinase C, mobilization of intracellular Ca2+, etc

The actions of Li+ on postsynaptic receptor-mediated second-messenger signaling systems

TERIMA KASIH

*PHARMACOLECTURE08/03/2010Ngatidjan, AGONISTANTAG-2010*PHARMACOLECTURE08/03/2010Ngatidjan, AGONISTANTAG-2010*******PHARMACOLECTURE08/03/2010Ngatidjan, AGONISTANTAG-2010*LECTURE*Ngatidjan, ANTIPSYCHOTICS*PHARMACOLECTURE08/03/2010Ngatidjan, AGONISTANTAG-2010***PHARMACOLECTURE08/03/2010Ngatidjan, AGONISTANTAG-2010*****PHARMACOLECTURE08/03/2010Ngatidjan, AGONISTANTAG-2010*********PHARMACOLECTURE08/03/2010Ngatidjan, AGONISTANTAG-2010***********PHARMACOLECTURE08/03/2010Ngatidjan, AGONISTANTAG-2010*PHARMACOLECTURE08/03/2010Ngatidjan, AGONISTANTAG-2010**