ANTI MANIC DUGS
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cover pathophysiology and treatment of mania and bipolar disorder.

cover pathophysiology and treatment of mania and bipolar disorder.

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  • A manic episode is defined in the American Psychiatric Association's diagnostic manual as, or a medical illness (e.g., hyperthyroidism),
  • (41). Additional support is found from a study on the central cholinesterase inhibitor physostigmine (administered intravenously), in which transient modulation of symptoms in manic cases and induction of depression in euthymic bipolar patients stabilized with lithium were observed.
  • (41). Additional support is found from a study on the central cholinesterase inhibitor physostigmine (administered intravenously), in which transient modulation of symptoms in manic cases and induction of depression in euthymic bipolar patients stabilized with lithium were observed.
  • (41). Additional support is found from a study on the central cholinesterase inhibitor physostigmine (administered intravenously), in which transient modulation of symptoms in manic cases and induction of depression in euthymic bipolar patients stabilized with lithium were observed.
  • (41). Additional support is found from a study on the central cholinesterase inhibitor physostigmine (administered intravenously), in which transient modulation of symptoms in manic cases and induction of depression in euthymic bipolar patients stabilized with lithium were observed.
  • J Biol Rhythms. 2012 Oct;27(5):339-52.Cellular circadian clocks in mood disorders.McCarthy MJ, Welsh DK.SourceDepartment of Psychiatry, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.AbstractBipolar disorder (BD) and major depressive disorder (MDD) are heritable neuropsychiatric disorders associated with disrupted circadian rhythms. The hypothesis that circadian clock dysfunction plays a causal role in these disorders has endured for decades but has been difficult to test and remains controversial. In the meantime, the discovery of clock genes and cellular clocks has revolutionized our understanding of circadian timing. Cellular circadian clocks are located in the suprachiasmatic nucleus (SCN), the brain's primary circadian pacemaker, but also throughout the brain and peripheral tissues. In BD and MDD patients, defects have been found in SCN-dependent rhythms of body temperature and melatonin release. However, these are imperfect and indirect indicators of SCN function. Moreover, the SCN may not be particularly relevant to mood regulation, whereas the lateral habenula, ventral tegmentum, and hippocampus, which also contain cellular clocks, have established roles in this regard. Dysfunction in these non-SCN clocks could contribute directly to the pathophysiology of BD/MDD. We hypothesize that circadian clock dysfunction in non-SCN clocks is a trait marker of mood disorders, encoded by pathological genetic variants. Because network features of the SCN render it uniquely resistant to perturbation, previous studies of SCN outputs in mood disorders patients may have failed to detect genetic defects affecting non-SCN clocks, which include not only mood-regulating neurons in the brain but also peripheral cells accessible in human subjects. Therefore, reporters of rhythmic clock gene expression in cells from patients or mouse models could provide a direct assay of the molecular gears of the clock, in cellular clocks that are likely to be more representative than the SCN of mood-regulating neurons in patients. This approach, informed by the new insights and tools of modern chronobiology, will allow a more definitive test of the role of cellular circadian clocks in mood disorders.
  •  The study concluded that antipsychotic drugs were significantly more effective than mood stabilizers; olanzapine, risperidone, and quetiapine were better tolerated than haloperidol. Risperidone, olanza­pine, and haloperidol were particularly efficacious
  • Typical D2 receptor affinity,Atypical 5HT
  • Evidence suggests that lithium, unlike any other mood stabilizer, may have a antisucide.Hajek T, Kopecek M, Höschl C, Alda M. Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis. J Psychiatry Neurosci. Apr 16 2012;37(3):110143.
  • Katzung pharmacology
  • Uses for Lithium SaltsBipolar DisorderManagement of bipolar disorder, 410422 particularly acute manic or mixed episodes in patients with bipolar 1 or bipolar 2 disorder.401403404405406407409410411412421422A first-line agent in the initial treatment of depressive, manic, or mixed episodes in patients with bipolar disorder.401421aCombination therapy with an atypical antipsychotic, another mood stabilizing agent, and/or antidepressant may be required to adequately treat rapid cycling and more severe depressive, manic, or mixed episodes.401403411412420421422423Maintenance therapy has been shown to prevent or diminish the intensity of subsequent manic episodes in patients with bipolar disorder with a history of mania.403404405407410412421422424Major Depression†Should be used only in patients who fail to respond to other antidepressants.aSchizoaffective and Schizophrenic Disorders†Limited effectiveness when used alone; should be used only after antipsychotic agents have failed.439aMay be added to existing antipsychotic therapy, but efficacy of such combined therapy has varied in different clinical studies.439 Careful monitoring (e.g., serum lithium concentrations, adverse effects, possible adverse drug interactions) recommended.439aDisorders of Impulse Control†Has reduced temper outbursts, impulsive antisocial behavior, and the number of assaultive acts in a small number of adults with disorders of impulse control†.aPsychiatric Disorders in Children†Treatment of children with apparent mixed bipolar disorder symptomatology†, hyperactivity with psychotic or neurotic components†, or aggressive behavior† or aggressive outbursts† associated with attention-deficit hyperactivity disorder (ADHD); should be used only after more conservative therapies have failed.aNeutropenia and Anemia†Treatment of neutropenia† or anemia† secondary to antineoplasticdrugs.aRoutine use not recommended for congenital, idiopathic, or cyclic neutropenias†; Felty’s syndrome†; or aplasticanemia†.aHyperthyroidism†Treatment of hyperthyroidism†; other treatments (e.g., radioactive iodine, surgery, propylthiouracil, methimazole) currently are preferred.aSIADH†No longer considered one of the therapies of choice; generally has been replaced with other more effective and/or less toxic therapies (e.g., demeclocycline).a
  • Effects on Electrolytes and Ion TransportLithium is closely related to sodium in its properties. It can substitute for sodium in generatingaction potentials and in Na+-Na+ exchange across the membrane. It inhibits the latter process, ie,Li+-Na+ exchange is gradually slowed after lithium is introduced into the body. At therapeuticconcentrations (around 1 mmol/L), it does not significantly affect the Na+/Ca2+ exchange process orthe Na+/K+ ATPase sodium pump.Effects on NeurotransmittersLithium appears to enhance some of the actions of serotonin, though findings have beencontradictory. Its effects on norepinephrine are variable. The drug may decrease norepinephrine anddopamine turnover, and these effects, if confirmed, might be relevant to its antimanic action.Lithium also appears to block the development of dopamine receptor supersensitivity that mayaccompany chronic therapy with antipsychotic agents. Finally, lithium may augment the synthesisof acetylcholine, perhaps by increasing choline uptake into nerve terminals. Some clinical studieshave suggested that increasing cholinergic activity may mitigate mania. However, as noted below, asecond-messenger effect of lithium may obviate any effect of increased acetylcholine release
  • One of the best-defined effects of lithium is its action on inositol phosphates. Early studies oflithium demonstrated changes in brain inositol phosphate levels, but the significance of thesechanges was not appreciated until the second-messenger roles of inositol-1,4,5-trisphosphate (IP3)and diacylglycerol (DAG) were discovered. As described in Chapter 2: Drug Receptors &Pharmacodynamics, IP3 and DAG are important second messengers for both -adrenergic andmuscarinic transmission. Lithium inhibits several important enzymes in the normal recycling ofmembrane phosphoinositides, including conversion of IP2 to IP1 (inositolmonophosphate) and theconversion of IP to inositol (Figure 29–4). This block leads to a depletion of phosphatidylinositol-4,5-bisphosphate (PIP2), the membrane precursor of IP3 and DAG. Over time, the effects oftransmitters on the cell will diminish in proportion to the amount of activity in the PIP2-dependentpathways. Before therapy, such activity might be greatly increased in mania; thus, lithium couldcause a selective depression of the overactive circuits.Studies of noradrenergic effects in isolated brain tissue indicate that lithium can inhibitnorepinephrine-sensitive adenylylcyclase. Such an effect could relate to both its antidepressant andits antimanic effects. The relationship of these effects to lithium's actions on IP3 mechanisms iscurrently unknown.Since lithium affects second-messenger systems involving both activation of adenylylcyclase andphosphoinositol turnover, it is not surprising that G proteins are also found to be affected. Severalstudies suggest that lithium may uncouple receptors from their G proteins; indeed, two of lithium'smost common side effects, polyuria and subclinical hypothyroidism, may be due to uncoupling ofthe vasopressin and TSH receptors from their G proteins.The major current working hypothesis for lithium's therapeutic mechanism of action supposes thatits effects on phosphoinositol turnover, leading to an early relative reduction of myoinositol inhuman brain, are part of an initiating cascade of intracellular changes. Effects on specific isoformsof protein kinase C may be most relevant. Alterations of protein kinase C-mediated signaling altergene expression and the production of proteins implicated in long-term neuroplastic events thatcould underlie long-term mood stabilization.
  • Mechanism of action of lithium on the calcium-sensing receptor. The calcium sensing receptor is a membranal G-protein-coupled receptor (GPCR). Agonists of the CASR are mainly polyvalent cations. In parathyroid chief cells, the activation of the CASR (black arrow) leads to an interaction between the CASR and the membranalphospholipase C, leading to the production of inositoltriphosphate (IP3) and diacylglycerol (DAG). Finally, the elevation of intracellular calcium (Ca-i) seems to activate the phosphorylation of protein-kinase C and inhibits the release of PTH. Paradoxically, lithium, as a monovalentcation, capable to activate GPCR, might be thought to be a weak agonist of the CASR (thin dotted arrow), but rather acts as an inhibitor of the latter, probably by interfering with intracellular molecular pathways. Indeed, lithium inhibits specifically and strongly (transparent thick arrow) the enzyme inositolmonophosphatase (IMPase) and reduces the production of IP3 and Ca-i. Thus, lithium might have a dual effect on the CASR; the final effect of lithium on parathyroid chief cells might be the result of a balance between a weak activation at the level of the CASR and a stronger inhibition of intracellular pathways at the level of the IMPase.
  • 1-which can be very troublesome, is frequently observed. This tremor can be attenuated by reducing the day doses and increasing the evening dose. i.e. by giving a higher dose the evening than the morning. Beta-blockers can also decrease tremor.2-, because lithium inhibits the response of the kidney to the antidiuretic hormone on aquaporins 2. This polyuria can decrease during treatment, but when it persists and induces a diabetes insipidus, the treatment should be stopped.3-Inhibition of secretion of thyroid hormones, which generally induces a 4-with neutrophils reaching from 10 000 to 20 000 mm3 instead of 7 to 8 000 normally. This hyperleucocytosis is reversible with the discontinuation of the treatment. The symptoms announcing poisoning are muscular contractions, difficulties of writing, a difficult step, apathy and dysarthria.
  • The proposed mechanisms of action of valproic acid–induced AP are a direct toxic effect of free radicals on the pancreatic tissue and a depletion of superoxide dismutase, catalase, and glutathione peroxidase
  • Somnolence (or "drowsiness") is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periodsParkinsonism (also known as Parkinson's syndrome, atypical Parkinson's, or secondary Parkinson's) is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability
  • Somnolence (or "drowsiness") is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periodsParkinsonism (also known as Parkinson's syndrome, atypical Parkinson's, or secondary Parkinson's) is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability

ANTI MANIC DUGS Presentation Transcript

  • 1. ASADULLAH R.Ph, CRCP 2012-MPHIL-1795
  • 2. Mania Madness, frenzy “A Phase of Bipolar disorders characterized by expansiveness, elation, agitation, hyper excitability, hyperactivity, and increased speed of thought or speech(flight of ideas)”. A mood disorder, In a senses opposite to depression. “A period of seven or more days of unusually and continuously effusive and open elated or irritable mood, where the mood is not caused by drugs/medication or a medical illness and(a) is causing obvious difficulties at work or in social relationships and activities, or(b) requires admission to hospital to protect the person or others, or(c) the person is suffering psychosis.”
  • 3. Bipolar disorder Bipolar disorder, or manic-depressive illness (MDI), is one of the most common, severe, and persistent mental illnesses. Bipolar disorder is a serious lifelong struggle and challenge. Bipolar disorder is characterized by periods of deep, prolonged, and profound depression that alternate with periods of an excessively elevated or irritable mood known as mania.
  • 4.  Unipolar major depressive disorder and bipolar disorder share depressive symptoms, but bipolar disorder is defined by episodes of mania or hypomania. Bipolar disorder constitutes 1 pole of a spectrum of mood disorders that includes including bipolar I (BPI), bipolar II (BPII), cyclothymia (oscillating high and low moods), and major depression.
  • 5. Manic Episode characterized by at least 1 week of profound mood disturbance, characterized by elation, irritability, or expansiveness . At least 3 of the following symptoms must also be present: Grandiosity Diminished need for sleep Excessive talking or pressured speech Racing thoughts or flight of ideas Clear evidence of distractibility Increased level of goal-focused activity at home, at work, or sexually Excessive pleasurable activities, often with painful consequences
  • 6. Hypomanic Episode Hypomanic episodes are characterized by an elevated, expansive, or irritable mood of at least 4 days‟ duration. At least 3 of the following symptoms are also present: Grandiosity or inflated self-esteem Diminished need for sleep Pressured speech Racing thoughts or flight of ideas Clear evidence of distractibility Psychomotor agitation at home, at work, or sexually Engaging in activities with a high potential for painful consequences
  • 7. Neurobiology OF MANIA AND BIPOLAR DISORDER* Ambiguous till dateBiogenic amine neurotransmitters:Noradrenergic system:NE turnover increase in the cortical and thalamic areas of BD subjects where decrease in depression Serotogenic system:Reduced 5-hydroxytryptamine (5- HT)1A receptor binding potential in raphe and hippocampus- amygdala of brain in depressed patientsDopaminergic system DA agonists are effective antidepressants and are able to precipitate mania. D2 receptor found in caudate, putamen, nucleus accumbens, cerebral cortex and hypothalmus is negativly coupled to adenylyl cyclase. Older antipsychotics act through blockage of D2 receptors , which eventualy result in extrpyramidal system (muscle rigidty , involuntry movement, pseudoparkinsonism)
  • 8. Cholinergic system  cholinergic tone decrease during mania , pilocarpine elicit pupillary constriction ,  The response of pilocarpine enhance after lithium and VPA ,adding evidence on the effects of lithium perhaps potentiating brain cholinergic systems  relative inferiority of noradrenergic compared to cholinergic tone was associated with depression, while the reverse was associated with maniaReceptor Nature PathwayD2 Inhibitory Presynaptic: decr Ca+ conduct Postsynaptic:Gi, incr K+ conduct ,decr cAMPM3 Excitatory Gq ,incr IP3 & DAGAlpha 1 Excitatory Gq ,incr IP3 & DAG5 HT-2 Excitatory Gq ,incr IP3 & DAG
  • 9. Signal pathways abnormalities*cellular signaling pathways interact at various levels, allow the cell to receive, process, and respond to information signaling pathways represent major targets for a number of hormones, including glucocorticoids, thyroid hormones, and gonadal steroids , may explain mood disorder with alterd hormonal level. (e.g. the frequent onset of bipolar disorder in puberty, triggering of episodes in the postpartum period)G Protein abnormalities:Postmortem brain studies have reported increased levels of the stimulatory G protein (Gαs) accompanied by increases in post-receptor stimulated adenylyl cyclase (AC) activity in BD.
  • 10. The protein kinase C signaling pathway:PKC is one of the major intracellular mediators of signals generated upon external stimulation of cells via a variety of neurotransmitter receptors M1, M3, M5 α1 5-HT2A . PKC induce the hydrolysis of various membrane phospholipids.increased PKC activity and translocation found in different experiments of BD brains moreover attenuation of PKC activity may play a role in the antimanic effects of lithium and VPA.Novel selective PKC inhibitors if devolped may have very useful action against mania. Tamoxifen is underinvestigation.Abnormalities of calcium signaling Calcium ions play a critical role in regulating the synthesis and release of neurotransmitters, neuronal excitability, elevations in both resting and stimulated intracellular Ca2+ levels in platelets, lymphocytes and neutrophils of patients with BD.*The underlying neurobiology of bipolar disorder, world psychiatryHUSSEINI K MANJI,1 JORGE A QUIROZ,1 JENNIFER L PAYNE,1 JASKARAN SINGH,1 BARBARA P LOPES,1 JENILEE S VIEGAS,1 and
  • 11. Genetic abnormalities*Genes associated with mania and BP include:Glycogen synthase kinase 3 (GSK-3):GSK3β is a central regulator of the circadian clock. Negative mutation in the CLOCK gene normally contributing to circadian periodicity in humans results in behavior mimicking mania.ANK3(ANKYRIN G):ANK3 is an adaptor protein found at axon initial segments that regulates the assembly of voltage- gated sodium channels. CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel)ANK3 and subunits of the calcium channel are down-regulated in mouse brain in response to lithium, which indicates a possible therapeutic mechanism of action
  • 12. Genetic abnormalities*Diacylglycerol kinase eta (DGKH) gene: GWAS published by 2011 pointed first intron of diacylglycerol kinase eta (DGKH) gene, a key protein in the lithium-sensitive phosphatidyl inositol pathway. Lithium-mediated inhibition of GSK3β is thought to result in downregulation of molecules involved in cell death and upregulation of neuroprotective factors.
  • 13. 1:Stephen Soreff, MD President of Education Initiatives, Nottingham, NH; Faculty, Boston University, Boston, MA and Daniel Webster College, Nashua, NH
  • 14. Differential Diagnosis∂ Acute intoxication with recreational drugs, such CLINICAL FEATURES OF MANIA as amfetamines, amfetamine derivatives (MDMA:Characteristicand cocaine appearance mania. Ecstasy), Clinical can mimicMood Elevated or irritableTalk Chronic use of cannabis can of ideas ∂ Fast, pressurized, flight induce manic like features.Energy Excessive ∂ Cushings syndrome had a secondarywealth, power, influence orIdeas Grandiose, self-confident, delusions of manic illness of religious significance, sometimes persecutory ∂ corticosteroids can induce mania ∂ Dopamine agonists (e.g. bromocriptine) are alsoCognition Disturbance of registration of memories known to sometimes induce secondary mania.Physical Insomnia, mild to moderate weight loss, increased libido ∂ The excited phase of catatonic schizophrenia can sometimes be mistaken for mania. excessive drinking orBehaviour Disinhibition, increased sexual activity, spendingHallucinations Fleeting auditory or, more rarely, visual
  • 15. TreatmentPharmacotherapyDrug Mania Mixed Maintenance DepressionLithium X XValporate XR XCarbamazepine X XLamotrigine XArippiprazole X X XZiprasidone X XResperidone X XAsenapine X XQuetiapine X XChlorpromazine XOlanzapine X X XTable. FDA-Approved Bipolar Treatment Regimens
  • 16. • Lorazepam, ClonazepamAnixloytic Mood • Lithium carbonateStabilizer • Carbamazepine, valporate sodium, DivalporateAnticonv sodium,Lamotrigine, ulsant • Risperidone,Olanzapine,Quetiapine Atypicalantipsycho ,Airpiprazole,Asenapine tics Typical • Loxapine.Chlorpromazine, FluphenazineAntipsychoti cs
  • 17. Acute treatment of mania: an update on new medications.Case School of Medicine, Mood Disorders Program, University Hospitals Case Medical Center, 11400 Euclid Avenue, Suite 200, Cleveland, OH 44106, USA. Prashant.Gajwani@uhhs.com
  • 18. Mood Stabilizer LITHIUM: In use since the 1870s. Initially used to treat depression, gout, and neutropenia, and for cluster headache prophylaxis, In 1940s FDA banned the use of lithium because of fatalities but lifted in 1970. Narrow therapeutic index that predisposes poisoning with relatively minor changes in medications or health status. May protect and preserve the hippocampal volumes, also claimed neuroprotective.
  • 19. Pharmacokinetics
  • 20. Indications & Uses Acute manic or mixed episodes in patients with BPI and BPII. Major Depression Schizoaffective and Schizophrenic Disorders Disorders of Impulse Control Psychiatric Disorders in Children Neutropenia and Anemiasecondary to antineoplastic drugs Hyperthyroidismradioactive iodine, surgery, propylthiouracil are preferred.a SIADHDemeclocycline is preferred for syndrome of inappropriate ADH secretion.
  • 21. Contraindication Renal or cardiovascular disease, Severe debilitation, dehydration, sodium depletion, Concomitant therapy with diuretics; very high risk of lithium toxicity under such conditions. History of Leukemia
  • 22. Mechanism of Action:Effects on Electrolytes and Ion Transport Lithium is closely related to sodium in properties. It can substitute for sodium in generating action potentials and in Na+-Na+ exchange across the membrane. It inhibits the latter process, but does not significantly affect the Na+/Ca2+ exchange or Na+/K+ ATPase .Effects on Neurotransmitters Lithium appears to enhance some of the actions of serotonin, though findings have been contradictory. Its effects on norepinephrine are variable. The drug may decrease norepinephrine and dopamine turnover, and these effects. Lithium also appears to block the development of dopamine receptor supersensitivity that may accompany chronic therapy with antipsychotic agents. Finally, lithium may augment the synthesis of acetylcholine, perhaps by increasing choline uptake into nerve terminals.
  • 23. Mechanism of Action:Effects on Second messenger: One of the best-defined effects of lithium is its action on inositol phosphates. IP3 and DAG are important 2nd messengers for both -adrenergic and muscarinic transmission. Lithium inhibits several important enzymes in the normal recycling of membrane phosphoinositides, including conversion of IP2 to IP1 (inositol monophosphate) and the conversion of IP to inositol.This block leads to a depletion of phosphatidylinositol-4,5- bisphosphate (PIP2), the membrane precursor of IP3 and DAG. Over time, the effects of transmitters on the cell will diminish in proportion to the amount of activity in the PIP2-dependent pathways.Iisolated brain tissue study indicate that lithium can inhibit norepinephrine-sensitive adenylyl cyclase. Such an effect could relate to both its antidepressant and its antimanic effects
  • 24.  Lithium may uncouple receptors from their G proteins; indeed, two of lithium„s most common side effects, polyuria and subclinical hypothyroidism, may be due to uncoupling of the vasopressin and TSH receptors from their G proteins.
  • 25. Dosage: May start with lower dose to minimize adverse drug reactions 900-2400 mg/day divided q6-8hr (immediate release tabs) OR 900-1800 mg divided q12hr PO if using extended release tabs Desirable serum lithium concentrations are 0.6- 1.2 mEq/L; although higher serum concentration may be needed not to exceed 1.5 mEq/L Administration: Take preferably with foodMonitor Serum lithium 12 hr after dose; 2 times/week until serum concentration and clinical condition stabilizes; thereafter q2month
  • 26. Interaction:Drug Severity Possible interactionSibutramine Contraindicated Increase toxicity by Pharmacodynamics synergismCandesarttan Use Alternative Increase Li levelLinezolid Use Alternative Increase serotonin level by inhibiting MAOLocaserin Use Alternative Both Increase serotonin levelFurazolidone Use Alternative Increase serotonin levelTranylcypromine Use Alternative Increase serotonin levelVilazodone Use Alternative Serotonin syndromeAspirin Monitor closely Decrease renal clearence of LiCarbamazepine Monitor closely Risk of neurotoxicityCitalopram Monitor closely Enhance serotonergic effectHaloperidol Monitor closely Risk of neurotoxicity
  • 27. Side Effect:COMMON SE: GI distress ,Upper LiCo3,Lower SR Hand tremor, poor coordination Sedation/lethargy Weight gain Polyuria / polydipsia Cognitive (memory ,concentrationSerious AE Renal:Nephrogenic Diabetes insipidus ,Tubular interstitialnephritis(treatment thiazide diuretic/amiloride) compensatory goiter without true hypothyroidism Neurological disorders ataxia, mental confusion, delusion, hallucinations Teratogenic (Pregnancy Category D)
  • 28. Over Dose/Poisoning:The likelihood of toxicity increases with increasing serum Lithium levels.Threshold level:1.5mEq/l Serum Signs of toxicity: Below 2.0mEq/l Diarrhea, vomiting, drowsiness, muscular weakness and lack of coordination Higher Level 2.0/3.0mEq/l giddiness, ataxia, blurred vision, tinnitus and a large output of dilute urine Treatment: No Specific Antidote, discontinue drug, Eliminate ion Follow protocol as for Barbiturate poisoning, Correct fluid /Electrolyte
  • 29. Anticonvulsants: VALPROIC ACIDFDA Seizure/Epilepsy 78, BiPolar disorder „961st marketed AED, Effective ant manic, BP depressionTherapeutic effect level 50-125 mg/lFetal Hepatotoxic ,pancreatitis (free radical effect)Not to used for Posttraumatic seizureBest for rapid-cycling and acute-mania
  • 30. Pharmacokinetics: Bioavailability: 81-89% of delayed-release Peak Plasma Concentration: 115-145 mcg/mL (IV) Protein Bound: 10-19% Volume of distribution: 92 L Metabolism: Liver, Excretion: Liver Metabolites: 2-propyl-3-ketopentanoic acid Half-Life: 6-16 hr; 10-67 hr (neonates)
  • 31. •Indication& Dosage: Bipolar ManiaInitial 25 mg/kg/day POIncrease rapidly to achieve lowest therapeutically effective dose,Maximum: 60 mg/kg/day Partial SeizuresPO: 10-15 mg/kg/day PO initially, THEN up to 30- 60 mg/kg/day Migraine, Prophylaxis250 mg PO q12hr Status Epilepticus SchizophreniaMaximum dose for an adult is 60mg/kg daily except 1g/kg/daily for migraine*Dose adjustment require in hepatic impairement.*Abbott Laboratories. Depakene (valproic acid) solution and liquid-filled capsules prescribing information. North Chicago, IL; 2009 Nov.
  • 32. •Mechanism Of Action: GABA level in the brain facilitate glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, An inhibitory effect on the GABA transporter GAT-1b thus blocking degradation of GABA. hyperpolarize membrane potentials by increasing membrane k conductance. 1(katzung pharmacology)
  • 33. Drug interaction: Doripenum, eratopenum, imipenem, meropenem,vorinostat, have serious interaction ,increase hepatic metabolism1 . Protein bounded drugs increase free VPA level e.g. Aspirin, carbamazepine,warfarin,digoxin etc VPA decrease level of liver metabolized drugs(cytochrome p450) e.g. carbamazepine, phenytoin,TCA,lamotrigine P450 inducers decrease VPA level. Mechanism of the drug interaction between valproic acid and carbapenem antibiotics in monkeys and rats journal of health sciences 2007
  • 34. Teratogenic potential : Pregnancy Category: D; known to cause neural tube defects in fetus Lactation: excreted in milk
  • 35. Carbamazepine :An anticonvulsant and specific analgesic for trigeminal neuralgia,psychomotor, seizure. Stabilizes inactivated state of sodium channels, thereby making neurons less excitable May reduce activity of necleus ventralis of the thalamus or decrease synaptic transimisssion or summation of temporal stimulation dose range: 800-1200 mg/day PO in divided doses Therapeutic range: 4-12 mg/L [16.9-50.8 micromoles/L] Maximum dose of 1600 mg/day Pregnency category D, enter in breast milk.
  • 36. Atypical Antipsychotics QUETIAPINEA 2nd genration psychotropic agent, convenience evidence formania treatment AbsorptionBioavailability: 100%,Peak Plasma Time:1.5 hr;6 hr XR DistributionProtein Bound: 83%,Vd: 6-14 L/kg Metabolism Hepatic CYP3A4 EliminationHalf-life elimination: 6 hr Excretion: Urine 73%; feces 20%
  • 37. Indications & Dosage: Bipolar I Disorder, ManiaMonotherapy or as an adjunct to lithium or divalproexDose :400-800 mg/day Bipolar I Disorder, MaintenanceImmediate-release: 400-800 mg/day PO q12hr Insomnia (Off-label)Usually start 25 mg PO qHS Major Depressive DisorderDosage range: 150-300 mg/day Alcohol Dependence (Off-label)25-50 mg PO qHS; not to exceed 300 mg
  • 38. Mechanism of Action: interact with serotonin (5HT2) and dopamine D1 and D2 receptors. higher selectivity for 5HT2 relative to D2 to low EPS high affinity at histaminergic and adrenergic alpha1 receptors, with a lower affinity at adrenergic alpha2 receptors.
  • 39. Drug Interaction: Increased risk of drowsiness and postural hypotension when used with alcohol. CYP3A4 inducers Phenytoin,CBZ decrease level CYP3A4 inhibitors Ketoconazole ,erythromycin increase level.Pregnancy Category: C Neonates exposed in 3rd trimester are at risk for EPS or withdrawal symptoms Lactation: excreted in breast milk, breast feeding is not recommended
  • 40. Tardive dyskinesia : Tardive dyskinesias are involuntary movements of the tongue, lips, face, trunk, and extremities. TD can be caused by long-term treatment with dopamine antagonists. Neuroleptics, Amisulpride, antiemetic metoclopramide, a potent D2 dopamine receptor antagonist, may cause TD, particularly in elderly patients. antihistamines, fluoxetine, Atypical antipsychotics particularly Quetiapine and clonazapine are used to reduced the tardive dyskinesia.* * A single-blind, randomized trial comparing quetiapine and haloperidol in the treatment of tardive dyskinesia Emsley R, Turner HJ, Schronen J, Botha K, Smit R, Oosthuizen PP.Department of Psychiatry, University of Stellenbosch, Cape Town, South Africa
  • 41. Ziprasidone : 2nd generation antipsychotic Used for bipolar I, schizophrenia, Acute agitation MOA:Antagonist at dopamine (D2), serotonin (5HT1D, 5HT2A) receptorsAgonist at serotonin 5HT1A receptorModerately inhibits reuptake of norepinephrine and serotoninAlso has alpha-blocking & antihistaminic activity Risk of QT prolongation. Less chance of hyperglycemia or diabetes and EPS.
  • 42. Loxapine : 1st generation antipsychotics Dibenzoxazepine antipsychotic; blocks mesolimbic D1 and D2 receptors in the brain; also has anti-serotonin 5HT2 activity extrapyramidal disease, parkinsonian, somnolence, tardive dyskinesia 10—20 mg PO q 24hr Inhaled preparation is in pipeline ,10mg Od, but FDA has Pulmonary saftey concerns1 Loxapine, as with all other antipsychotics has label warning “Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death”2 European medicine agency recmnded loxapine for the rapid control of agitation in adult with BP or schizophernia.(2012) 1 . Inhaled loxapine for agitation revisited: focus on effect sizes from 2 Phase III randomised controlled trials in persons with schizophrenia or bipolar disorder. Citrome L. New York Medical College, Valhalla 2. Antipsychotic drugs: sudden cardiac death among elderly patients. Narang P, El-Refai M, Parlapalli R, Danilov L, Manda S, Kaur G, Lippmann S.2010
  • 43. Prospective antimanic drugs: Tamoxifena nonsteroidal antiestrogen used to treat breast cancer, is a potent and selective PKC inhibitor that crosses the blood-brain barrier. AsenapineIncrease level of dopamine, NE and acetylcholine in cortical and limbic brain areas. also prevent from depression and protect cognitive function.
  • 44. GRATULATE FOR ATTENTION