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Detail explanation of mechanism of action of Lithium as a mood stabiliser



2. As we go along. History Introduction to mood disorders DSM 4 criteria & subtypes Pathogenesis Pharmacology of antimanic drugs Newer approaches Non pharmacological treatments Treatment in special populations Treatment of resistant mania 3. 400 B.C- Hippocrates 30 A.D- Roman physician described melancholiaAretaeus of Cappadocia 1899-Emil Kraepelin 1949, John Cade Works of Sigmund Freud 4. Mania & Hypomania Distinct period of an abnormally and persistently elevated expansive, or irritable mood lasting for at least 1 week, or less if a patient must be hospitalized Hypomanic episode At least 4 days Not sufficiently severe to cause impairment in social or occupational functioning, and No psychotic features are present Cyclothymia - one or more Hypomanic episodes Dysthymic (chronic depression) episodes 5. DSM-IV DIAGNOSIS OF MANIADSM-IV 6. Dopamine HypothesisStriatum, the nucleus accumbens, olfactorytubercle. Substantia nigra, VTA , hypothalamus, cortical areas 7. Mesolimbicmesocortical: Control behavior, cognitive funtion - D Receptor. Nigrostriatal: Control Voluntary Movement D and D receptor. Tuberoinfundibular: Control prolactin secretion D receptor.Vesicular monoamine transporter protein (VMAT2) 8. CHOLINERGIC SYSTEM Cholinergic monoaminergic interaction hypothesis Complex interrelations of cholinergic and monoaminergic neurotransmitter Play a role in the pathophysiology and treatment of affective disorders. Hypocholinergic or hyperadrenergic drive would cause mania. By stimulation of muscarinic M4 receptorsM4 receptors are found in high density in limbic and cortical, decrease cAMP Acetylcholine precursors, such as lecithin (phosphotidyl choline) or choline in combination with lithium, have been used to successfully treat manic patients. 9. Noradrenergic systemMHPG NE 10. GLUTAMATE HYPOTHESIS Major excitatory neurotransmitters in the CNS. Intergral for synaptic transmission in brain circuitry. Key regulator of synaptic strength and plasticity Bind to (NMDA) receptor, and an excess of glutamatergic stimulation High concentration of NMDA receptors exists in the hippocampus 11. Deleterious glutamate signaling 12. Second Messengers and Intracellular Cascades Increase in Gs levels in frontal, temporal and occipital cortices of BD subjects. Mononuclear leucocytes of manic patients PlateletsG PROTIENSMood states 13. A significant increase in the activity of basal and activated AC among maniac subjectsSignificant increase in PIP2 levels 14. Alter the conformation of the cytoskeleton through actin filaments.The PKC signaling pathway Regulation of neuronal excitability neurotransmitter release long-term synaptic eventsattenuation of PKC activity may play a role in the antimanic effects of mood stabilisers 15. `Modulation of proteins associated with cytoskeleton microtubules- tau, MAP-1B MAP-2, ApoptosisNEURONAL SURVIVALdestabilization of microtubules conformation 16. CALCIUM-SIGNALING ABNORMALITIES Abnormal Ca2+ homeostasis in bipolar disorder Elevated intracellular Ca2+ levels in platelets, lymphocytes and neutrophils of patients with BDMarked blunting of Gproteinactivated PI hydrolysis Altered mRNA expression ofIMPase type2a,proteins important roles in Ca2+TRPM2homeostasis 17. ALTERATIONS OF HORMONAL REGULATIONS 18. GeneticsStrongly genetic MZ concordance 40 -45% Heritability 80 85% Leading linked regions 6q, 8q, 13q, 22q Leading candidate genes BDNF DAOA DISC TPH2 SLC6A$ Genes implicated by GWAS DGKH CACNA1C ANK3Concordance in MZ twins of 50-70% Early-onset bipolar disorder may be even more genetic 19. DRUG INDUCED MANIA Levodopa Corticosteroids Tricyclic and monoamine oxidase inhibitor Thyroxine Isoniazid Sympathomimetic drugs Chloroquine, baclofen Alprazolam Captopril Amphetamine Phencyclidine. 20. CLASSIFICATION Mood StabiliserAnti epilepticsAnti PsychoticsAnti Adrenergic DrugsLithiumSodium valporateOlanzapineClonidineCarbamezapineQuatepinePropranalolLamotrigineApriprazoleGabapentinZisaperidoneToperamateRisperidoneBenzodiazepines Cholinomimetics Clonazepam LorazepamPhysostigmineCalcium Channel Blockers Verapramil Nifedipine Nimodipine 21. LITHIUM Introduction of Li+ in 1949 (Li+) is the lightest of the alkali metals Monoamines implicated in the pathophysiology of mood disorders Second-messenger and other intracellular molecular mechanisms involved in signal transduction Gene regulation and cell survival. 22. Lithium increase the SE inhibitory input to VTA and SNc nuclei 23. AFTERLithium at conc of 1-10 mEq/L inhibits the Ca++dependent release of NE and DABEFORE 24. Influence G-protein function is by modulating the posttranslational modification of ADP-ribosylation of Gproteins 25. Interference with PIP2 PATHWAYActivated PLCINOSITOL MONOPHOSPHATE 26. AXONAL GROWTH HIPPOCAMPUS 27. Enhances the binding of tau to microtubules which promotes microtubule assemblyDEPHOSPHORYLATION 28. Decrease gene expression of PLA2 29. Bcl-2 AP-1, AMI-1, PEBP-2 30. PHARMACOKINETICS Completely absorbed in GIT within 68 hours; peak plasma levels in 30 minutes to 2 hours Distribution: Initial volume of distribution is 0.5 L/kg, rising to 0.7 0.9 L/kg; some sequestration in bone. No protein binding.Excretion: virtually entirely in urine. Lithium clearance about 20% of creatinine. Plasma half-life about 20 hoursTarget plasma concentration: 0.61.4 mEq/LDosage: 0.5 mEq/kg/d in divided doses Carbonate capsules slow release tablets citrate syrup (8 mmol/ 5 mL) 31. Thaizides Spironolactone Amiloride Furosemide Indomethacin Ibuprofen Naproxen COX-2 inhibitors Fosinopril Lisinopril 32. SERUM LEVEL MONITORING Acceptably safe are between 0.6 and 1.5 mEq/L. 1.0-1.5 mEq/L- acutely manic or hypomanic patients.0.6-1.0 mEq/L long-term prophylaxis. 0.8-1.0 mEq/L experience decreased relapse risk Trough from samples obtained 10-12 hours after the last oral dose of the day. Trough concentration:0.8-1mEq/lIndividualization of serum levels is often necessary to obtain a favorable risk-benefit relationship 33. Acute poisoning - Voluntary or accidental ingestion in a previously untreated patientAcute-on-chronic - Voluntary or accidental ingestion in a patient currently using lithiumChronic or therapeutic poisoning Progressive lithium toxicity, generally in a patient on lithium therapy 34. Acute Toxicity and Overdose Nausea, vomiting, abdominal pain, profuse diarrheaPolyuria,Coarse tremorAtaxia, coma, and convulsionsMental confusion, hyperreflexia, gross tremor, dysarthria, seizures, and cranial nerve and focal neurological signsComa and death.Cognitive and motor neurological damage irreversible, with persistent cerebellar tremor being the most common 35. SERUM PLASMA LEVELS Mmol/LEffects0.5None1Mild tremor1.5Coarse tremor2Hyperreflexia, dysarthria2.5Myoclonia, ataxia, confusion> 3.0Delirium, coma, seizures 36. LITHIUM TOXICITY 37. Role of sodium polystyrene sulfonate (Kayexalate)NO ANTIDOTE HEMODIALYSISAdmit patients with serum lithium levels higher than 2 mEq/L. Admit to an ICU patients with chronically elevated lithium levels higher than 4 mEq/L 38. Adverse effects Polyuria and compensatory polydipsia Benign, diffuse, non tender thyroditis Benign and reversible T-wave flattening in ~20% of patients , U wave enlargement Sinus bradycardia, AV blocks Dermatitis, folliculitis, and vasculitis can occur with Li+ administration Ebstein's malformation Floppy baby syndrome 39. Therapeutic uses Acute mania- 600-mg loading dose (150,300,600mg) Prophylactic treatment of bipolar disease Treatment-resistant major depression Monotherapy for unipolar depression Suicide reduction extends to unipolar mood disorder Alzheimer type, stroke, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, 40. ANTIEPILEPTICS CARBAMEZAPINE SODIUM VALPROATE LAMOTRIGINE TOPIRAMATE GABAPENTIN 41. CARBAMAZEPINE Iminostilbene derivative with a tricyclic structure Mechanism of actionInositol depletion as a mechanism underlying carbamazepine's mood stabilizing properties (Williams et al., 2002). 42. Pharmacokinetics Absorbed slowly and erratically after oral administration 75% to 90% is protein bound Undergoes extensive hepatic metabolism predominantly by conversion to a10,11-epoxide Substrate and inducer of CYP3A4 Induces CYP2C, CYP3A, and UGT, thus enhancing the metabolism of drugs degraded by these enzymes Half life 20 to 40hrsAnticonvulsants ,Hormonal contraceptives Neuroleptics Erythromycin,Cimetidine, Isoniazid,Fluoxetine Therapeutic plasma concentrations 6 to 12 g/mL 43. Therapeutic uses Acute bipolar mania- 400-1400mg/day Maintenance therapy- 4-12 ug/ml drawn at 12 hrs after last dose, minimum of 5 days after last dose change Partial seizuresGeneralized tonic-clonic seizures Absence seizures Trigeminal neuralgia. 44. Acute mania 400 mg/day- larger dose given at bedtime due to the sedating properties Titration proceeds by 200-mg increments every 24-48 hours based on clinical response and serum trough levels Extended-release form FDA 2005 Better tolerated compared to older preparations Effective as monotherapy with once-daily dosingImmediate release forms of carbamazepine cannot be loaded 45. Adverse effects Nausea, vomiting, diarrhoea and visual disturbances Hypersensitivity rash, photosensitivity, hepatitis, granulocyte suppression and aplastic anemia Lyells syndrome,Stevens-Johnson ADH action enhancement hyponatremia and water retention CBZ level, Teratogenicity CBC + Transient elevation of hepatic differential,reticulocyte transaminases count Aplastic anemia,AgranulocytosisSGPT every 3 months till stable. 46. Oxcarbazepine 10-keto analogue of carbamazepine. Metabolite: MHD- 10-monohydroxy derivative Half-life 8-10 h Therapeut