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Facts to remember about lithium

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  1. 1. LITHIUM <ul><ul><li>IN PSYCHIATRY </li></ul></ul>
  2. 2. Class This drug is a member of the following class: Mood stabilizer (?) Antimanic Hematopoietic
  3. 3. DOSAGE
  4. 4. Dosing Information a)  Lithium Carbonate <ul><li>Adult Bipolar disorder, </li></ul><ul><li>manic episode 1)  acute, 1800 mg/day ORALLY in 2-3 divided doses; desired serum lithium level ranging between 1-1.5 mEq/L 2)  maintenance, 900-1200 mg/day ORALLY in 2-3 divided doses; desired serum lithium levels ranging between 0.6-1.2 mEq/L </li></ul>
  5. 5. Dosing Information a)  Lithium Carbonate <ul><li>Cluster headache 300-900 mg/day ORALLY (divided doses); keep serum concentration below 1.2 mEq/L </li></ul>
  6. 6. Dosing Information a)  Lithium Carbonate <ul><li>Graves' disease; Adjunct 900 mg/day ORALLY for 6 days beginning on the day of radioiodine administration </li></ul>
  7. 7. Pediatric <ul><li>Safety and effectiveness in pediatric patients below the age of 12 have not been established </li></ul><ul><li>Conduct disorder, adolescent-onset type: dose </li></ul><ul><li>300-2100 mg/day ORALLY (divided doses); desired serum lithium level ranging between 0.8-1.2 mEq/L </li></ul>
  9. 9. Clinical Applications <ul><li>Lithium Carbonate </li></ul><ul><li>FDA Approved Indications a)  Bipolar disorder, manic episode </li></ul><ul><li>Non-FDA Approved Indications a)  Cluster headache b)  Conduct disorder, adolescent-onset type c)  Graves' disease; Adjunct </li></ul>
  11. 12. MANIA - MAINTENANCE DOSE <ul><li>When manic symptoms subside, the dose of lithium should be reduced to maintain a serum concentration of 0.6 to 1.2 millimole/liter </li></ul><ul><li>Usual maintenance doses are 900 to 1200 milligrams/day; dosage will vary between individuals. </li></ul><ul><li>Serum lithium concentrations should be monitored at least every 2 months. </li></ul><ul><li>Patients with lithium levels of 0.8 to 1 millimole/liter had fewer relapses than patients with lithium levels of 0.4 to 0.6 millimole/liter </li></ul><ul><li>MOST CLINICIANS RECOMMEND AN INITIAL DOSE OF 900 TO 1200 MILLIGRAMS DAILY. SINGLE DAILY DOSING HAS BEEN SHOWN TO BE AS TOLERABLE AS DIVIDED DOSING IN OUTPATIENTS ON MAINTENANCE LITHIUM </li></ul>
  12. 13. IMPORTANT NOTE <ul><li>Immediate release tablets are usually given 3 or 4 times daily while controlled release tablets are usually given twice daily. </li></ul><ul><li>Lithium tolerance is greater during the acute manic phase and decreases when manic symptoms subside </li></ul>
  13. 14. Dosage in Renal Failure <ul><li>The following dosage reduction has been recommended in patients with renal failure: glomerular filtration rate (GFR) greater than 50 milliliters/minute, no dosage reduction; GFR 10 to 50 milliliters/minute, 50 to 75% of the usual dose; GFR less than 10 milliliters/minute, 25 to 50% of the usual dose given at the normal dosage interval. </li></ul><ul><li>  Lithium clearance in patients with chronic renal disease decreased by a mean of 25 </li></ul>
  14. 15. Dosage in Geriatric Patients <ul><li>It may be necessary to decrease lithium dosage by as much as 50% in elderly patients to compensate for reduced clearance </li></ul><ul><li>Geriatric patients should be treated with initial lower doses of lithium and titrated to the desired therapeutic response. Some reports have indicated that elderly patients may develop symptoms of lithium toxicity at therapeutic serum levels </li></ul>
  15. 16. Dosage Adjustment During Dialysis <ul><li>maintenance dose should be given following hemodialysis Serum lithium concentrations following dialysis are useful as a dosing guideline </li></ul>
  16. 17. Pediatric Dosage <ul><li>Bipolar disorder Use in patients less than 12 years old is not recommended due to a lack of information regarding safety and effectiveness </li></ul><ul><li>Lithium carbonate monotherapy (32 to 63 milligrams/kilogram/day) was reported effective in the treatment of manic episodes with psychotic features in prepubertal children (6 to 12 years of age) in an open study (Varanka, 1988). All of 10 children treated improved after an average of 11 days of lithium therapy (range, 3 to 24 days). Therapeutic lithium levels (0.6 to 1.4 millimole/liter) were achieved within 3 to 5 days in all children. Controlled studies are required to further evaluate the efficacy of lithium in this patient population. </li></ul>
  17. 18. Pharmacoinetics
  18. 19. Onset and Duration <ul><li>Onset- Initial Response </li></ul><ul><li>  Mania, oral: 7 to 14 days </li></ul>
  19. 20. Drug Concentration Levels <ul><li>  Therapeutic Drug Concentration </li></ul><ul><li>ACUTE MANIA/HYPOMANIA a)  1 to 1.5 millimol/liter </li></ul><ul><li>PROPHYLAXIS AND MAINTENANCE THERAPY OF MANIA a)  0.6 to 1.2 mmol/L </li></ul><ul><li>DEPRESSION a)  0.3 to 0.6 millimol/liter </li></ul>
  20. 21. Time to Peak Concentration <ul><li>Oral: 0.5 to 2 hours </li></ul><ul><li>Due to slow tissue distribution, complete plasma-tissue equilibration and steady-state plasma levels usually require 5 to 10 days of therapy </li></ul>
  21. 22. Absorption A)  Bioavailability <ul><li>LIQUID VERSUS SOLID: No significant difference in bioavailability exists following oral administration of lithium carbonate capsules or lithium citrate liquid. Liquid lithium achieves higher peak levels and a faster time-to-peak than tablets SLOW-RELEASE VERSUS STANDARD FORMULATION: Standard lithium carbonate and the slow-release form provide equivalent steady-state lithium levels </li></ul>
  22. 23. Distribution - Distribution Sites <ul><li>  Protein Binding a)  None </li></ul>
  23. 24. Distribution - Distribution Sites <ul><li>OTHER DISTRIBUTION SITES a)  Fluids, good 1)  Lithium distributes throughout intracellular and extracellular fluids and is not protein bound (Baer, 1973). b)  Placenta, good 1)  Lithium passes into breast milk and across the placental barrier (Prod Info Eskalith(R), 2002; Schou & Amdisen, 1973a). c)  Tissues, good 1)  Lithium undergoes widespread tissue localization and is taken up rapidly by the liver and kidney, and more slowly by muscle, bone and brain </li></ul>
  24. 25. Distribution Kinetics 1)  Volume of Distribution <ul><li>0.7 to 1.4 liters/kilogram </li></ul>
  25. 26. Distribution Kinetics Volume of Distribution <ul><li>Relative volume of distribution of lithium was studied in young and elderly patients and patients with renal insufficiency. In young patients with normal renal function (age 23 to 28 years), the volume of distribution was 120.45% of body weight (ie, 0.8 to 0.9 L/kg). In elderly patients with normal renal function (age 52 to 65 years), the volume of distribution was 92.65% of body weight (ie, 0.7 to 0.8 L/kg). In patients with renal insufficiency (58 to 65 years), the volume of distribution was 81% of body weight). 2)  Lithium distribution may be related to sympathetic adrenal activity and sodium distribution in manic patients. Tissue lithium concentrations may continue to increase for hours after plasma lithium concentrations have peaked </li></ul>
  26. 27. Metabolism <ul><li>Metabolism Sites and Kinetics 1)  Urine, almost entirely </li></ul>
  27. 28. Excretion <ul><li>Kidney </li></ul><ul><li>Renal Clearance (rate) 10 to 37 milliliters/minute </li></ul><ul><li>  Renal Excretion (%) 89% to 98% </li></ul><ul><li>1)  Increases in lithium serum levels occur with sodium depletion or with a low salt diet secondary to enhanced proximal tubular reabsorption of the lithium ion. Renal excretion of lithium does not appear to be enhanced by increasing water intake or acidification of urine . 2)  Lean body weight and creatinine clearance are important predictors of lithium clearance </li></ul>
  28. 29. Excretion <ul><li>Total Body Clearance 1.13 mL/min/kg </li></ul>
  29. 30. Excretion <ul><li>Total Body Clearance 1.13 mL/min/kg </li></ul>
  30. 31. ddss
  31. 32. Excretion <ul><li>Other OTHER EXCRETION </li></ul><ul><li>  FECES, insignificant </li></ul>
  32. 33. Elimination Half-life <ul><li>Parent Compound 1)  ELIMINATION HALF-LIFE a)  14 to 24 hours </li></ul><ul><li>1)  Duration of lithium treatment had a direct effect on prolonging the elimination half-life. Plasma half-life in patients on lithium therapy for less than 1 year was 1.65 days compared with 2.43 days in patients on lithium for more than 1 year continuously 2)  Creatinine clearance, sodium clearance, and potassium clearance show significant correlation with lithium clearance 3)  The half-life of lithium in elderly patients may be as long as 36 hours. The reduction in lithium clearance correlates with decreased creatinine clearance. 4)  The elimination half-life of lithium in children 9 to 12 years of age was 17.9 hours after a single 300-milligram oral dose 5)  Significantly longer lithium elimination half-lives were reported in bipolar patients compared with unipolar patients using plasma and red blood cell-level monitoring. Half-life values using plasma were: Bipolar I: 2.4 days, Bipolar II: 1.5, Unipolar: 1.1; for RBC: Bipolar I: 2.0, Bipolar II: 1.5, Unipolar: 0.8 </li></ul>
  33. 34. Effects vs. Adverse Drug Effects
  34. 35. Serious Adverse Effects <ul><li>  Papillary thyroid carcinoma </li></ul>
  35. 36. Serious Adverse Effects <ul><li>1)  Ataxia 2)  Blurred vision 3)  Bradyarrhythmia (Severe) 4)  Cardiac dysrhythmia 5)  Coma 6)  Giddiness 7)  Hypotension 8)  Polyuria, Dilute, may be a sign of serious toxicity 9)  Pseudotumor cerebri, Increased intracranial pressure and papilledema 10)  Seizure, Epileptiform 11)  Sinus node dysfunction 12)  Tinnitus, May be signs of serious toxicity </li></ul>
  36. 37. Adverse Reactions <ul><li>Cardiovascular Effects Dermatologic Effects Endocrine/Metabolic Effects Gastrointestinal Effects Hematologic Effects Hepatic Effects Immunologic Effects Musculoskeletal Effects Neurologic Effects Ophthalmic Effects Otic Effects Psychiatric Effects Renal Effects Reproductive Effects Other </li></ul>
  37. 38. Cardiovascular Effects <ul><li>Cardiovascular finding Edema Heart block Hypertension Myocarditis Sinus node dysfunction </li></ul>
  38. 39. Cardiovascular finding <ul><li>a)  In therapeutic doses, lithium produces reversible T WAVE FLATTENING,and rarely, VENTRICULAR ARRHYTHMIAS An estimated 28% to 40% of patients may experience atrioventricular block or other cardiac conduction abnormalities while receiving lithium. The changes are relatively benign, require no treatment, and do not require discontinuation of lithium.Lithium can be used safely in most patients with cardiac disease if the dose is adjusted to the rate of lithium excretion and lithium levels are monitored. Frequent electrocardiographic monitoring is recommended HYPERTENSION has been reported in 1 case </li></ul><ul><li>2)  Cardiac arrhythmias, hypotension, hypertension, peripheral circulatory collapse, bradycardia, myocarditis and sinus node dysfunction have occurred with lithium use and appear to be related to serum lithium levels. </li></ul>
  39. 40. Edema <ul><li>Edema has occurred during lithium therapy and disappears upon reduction of the dose or discontinuation of the drug. This may be attributable to tubular reabsorption of sodium </li></ul>
  40. 41. Heart block <ul><li>An estimated 28% to 40% of patients may experience AV block or other CARDIAC CONDUCTION ABNORMALITIES while receiving lithium . The changes are relatively benign, require no treatment, and do not require discontinuation of the lithium therapy </li></ul>
  41. 42. Sinus node dysfunction <ul><li>Reversible and irreversible sinus node dysfunction have been reported with long- term lithium therapy </li></ul>
  42. 43. Dermatologic Effects <ul><li>Alopecia Dermatological finding Folliculitis Nail damage Psoriasis Scaly skin </li></ul>
  43. 44. Endocrine/Metabolic Effects <ul><li>Autoimmune thyroiditis Body temperature above normal Body temperature finding Diabetes insipidus Disorder of fluid AND/OR electrolyte Endocrine finding Hypercalcemia Hyperglycemia Hyperkalemia Hyperosmolality, Serum Hyperparathyroidism Hyperthyroidism Hypoglycemia Hypokalemia Hypothermia Hypothyroidism Metabolic finding Papillary thyroid carcinoma Weight gain </li></ul>
  44. 45. Autoimmune thyroiditis <ul><li>Thyroiditis is thought to occur in combination with an autoimmune response with lithium playing a contributory role. Lithium induced thyroid dysfunction may involve worsening of an underlying autoimmune thyroiditis possibly caused by shifts in T lymphocyte subpopulations. </li></ul><ul><li>However, the results of one controlled study suggest that long-term lithium therapy is not associated with an increased incidence of thyroid autoimmunity in patients receiving lithium for the treatment of affective disorders </li></ul>
  45. 46. Diabetes insipidus <ul><li>Symptoms of NEPHROGENIC DIABETES INSIPIDUS (POLYURIA, POLYDIPSIA, NOCTURIA) have been reported with lithium use and may be related to serum lithium levels. (In addition, chronic renal failure may predispose a patient to develop persistent nephrogenic diabetes insipidus. While occurrence is uncommon and may disappear within weeks of drug discontinuation, serious and fatal complications have rarely developed. Chlorthalidone, hydrochlorothiazide, or amiloride have been used to manage symptoms, and lithium dosing schedules that produce therapeutic response with minimum trough levels (ie, once daily regimens) may reduce the risk for developing lithium-induced polyuria </li></ul>
  46. 47. Hyperthyroidism <ul><li>Thyrotoxicosis is also a complication of lithium carbonate therapy </li></ul>
  47. 48. Hypothyroidism -common <ul><li>Lithium has been reported to suppress thyroid function, in 42% of patients , cause subclinical hypothyroidism in up to 23%, and cause overt hypothyroidism in between 8% to 19% of patients. The prevalence appears to be higher in women at 14% as compared to men at only 4.5% These effects occur 3 to 6 weeks after starting treatment and can be controlled with thyroid medication, although thyroid function tests may normalize over 6 months to 2 years with continuous lithium treatment </li></ul>
  48. 49. Weight gain <ul><li>Lithium maintenance treatment has been associated with weight gain, however, there are conflicting reports when chronic psychotic patients were studied. In a study regarding weight gain in conjunction with compliance, weight gain was stated to be a disturbing finding by patients </li></ul>
  49. 50. Gastrointestinal Effects <ul><li>Aversion to food or drink Excessive salivation Gastrointestinal tract finding Hyposecretion of salivary gland </li></ul>
  50. 51. Hematologic Effects <ul><li>Leukocytosis, thrombocytosis and thrombosis have been reported with lithium therapy </li></ul>
  51. 52. Hepatic Effects <ul><li>Ascites Hyperbilirubinemia </li></ul>
  52. 53. Immunologic Effects <ul><li>Myasthenia gravis and systemic lupus erythematosus have been reported with lithium therapy </li></ul>
  53. 54. Neurologic Effects <ul><li>Cerebellar disorder Cognitive function finding Delirium Extrapyramidal sign Headache Movement disorder Neurological finding Nystagmus Peripheral neuropathy Pseudotumor cerebri Seizure Tremor </li></ul>
  54. 55. Delirium <ul><li>Organic brain syndrome and DELIRIUM has occurred with lithium carbonate. </li></ul><ul><li>When combined with a neuroleptic, encephalopathy occurred. </li></ul><ul><li>Lithium has also been associated with neurotoxicity when used in treatment of a manic episode and should be discontinued prior to electroconvulsive for the organic brain syndrome patient </li></ul>
  55. 56. Extrapyramidal sign <ul><li>Extrapyramidal side effects occur rarely with lithium therapy. </li></ul><ul><li>Reported effects include Parkinsonian-like symptoms, rigidity, and choreoathetosis that have occurred at both toxic and therapeutic serum concentrations. </li></ul><ul><li>Lithium in combination with haloperidol therapy has resulted in rare cases of extrapyramidal toxicity, some of which have resulted in prolonged or permanent sequelae </li></ul>
  56. 57. Headache <ul><li>Lithium treatment has been associated with the development of generalized headache, worsening of cluster headache, and exacerbation of migraine headache </li></ul>
  57. 58. Movement disorder <ul><li>Neurological movement disorders associated with lithium use include ASTERIXIS, MYOCLONUS, and CHOREA </li></ul>
  58. 59. Neurological finding <ul><li>Cerebellar disorders, cognitive findings, extrapyramidal symptoms, headaches, movement disorders, pseudotumor cerebri, seizures, sleep disorders and peripheral nerve impairment are associated with lithium use </li></ul>
  59. 60. Peripheral neuropathy <ul><li>Lithium appeared to impair peripheral nerve function as measured by electroneurographic parameters including motor nerve conduction velocity (NCV) of peroneal and median nerves, sensory nerve conduction velocity of sural and median nerves, amplitude of motor potential of peroneal and median nerves, and amplitude of sensory action potential of the median nerve at the wrist and the sural nerve. Patients receiving lithium (n=34) were compared to affective controls (n=20), healthy controls (n=54), and pretreatment values (n=12). Significant differences were seen in the lithium treated patients as compared to controls in the motor NCV (peroneal nerve)(p less than 0.05), the motor action potential amplitude (peroneal nerve)(p less than 0.05), and the sensory action potential amplitude (sural and median nerve)(p less than 0.001). Significant differences were also seen in lithium-treated patients as compared to pretreatment values for peroneal motor NCV (p less than 0.01), sural and median sensory NCV (p less than 0.001, p less than 0.02, respectively), motor action potential amplitude of the peroneal nerve (p less than 0.05), and sensory action potential amplitude of the sural and median nerve </li></ul>
  60. 61. Seizure <ul><li>Major motor seizures with associated neurological disturbances have occurred in patients receiving therapeutic doses of lithium carbonate with or without toxic serum levels. No mechanism of action has been elucidated for lithium induced seizures. Patients at risk of seizure should be given lithium with caution </li></ul>
  61. 62. Tremor <ul><li>Persistent fine, rapid tremors occur in 30 to 50% of patients with therapeutic plasma levels. The tremor is a fast-frequency action tremor, which is exacerbated by tension, anxiety, fatigue, caffeine, and adrenergic stimulation, and is characterized by fine, jerky movements, especially in the fingers . Lithium tremor may persist at rest in some patients. Beta-blockers have been effective in the treatment of lithium-induced tremors </li></ul>
  62. 63. Ophthalmic Effects <ul><li>Degenerative disorder of macula Eye / vision finding Oculogyric crisis Ophthalmoplegia </li></ul>
  63. 64. Otic Effects <ul><li>Tinnitus </li></ul>
  64. 65. Psychiatric Effects <ul><li>Mania Psychiatric sign or symptom Psychotic disorder Sleep disorder </li></ul>
  65. 66. Mania <ul><li>Lithium toxicity has been reported to mimic manic states </li></ul>
  66. 67. Psychiatric sign or symptom <ul><li>Mania, psychosis (as seen in Capgras Syndrome and visual hallucinations) as well as worsening of organic brain syndromes have occurred with lithium use. These effects appear to be related to serum lithium levels. Patients with severe psychosis and anxiety may be at greater risk to develop lithium toxicity at therapeutic blood levels. </li></ul><ul><li>The Capgras Syndrome denotes the delusional misidentification of familiar individuals as impostors or doubles </li></ul>
  67. 68. Sleep disorder <ul><li>SLEEPWALKING and RESTLESS LEG SYNDROME have been reported with lithium use </li></ul>
  68. 69. Renal Effects <ul><li>Diabetes insipidus, nephrotic syndrome, nephrotoxicity, elevated BUN and serum creatinine, glycosuria, albuminuria, and oliguria have been reported with lithium </li></ul>
  69. 70. Effects in Pregnancy <ul><li>U.S. Food and Drug Administration's Pregnancy Category: Category D </li></ul><ul><li>There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective </li></ul>
  70. 71. Breastfeeding <ul><li>American Academy of Pediatrics Rating: Drugs that have been associated with significant effects on some nursing infants and should be given to nursing mothers with caution </li></ul>
  71. 72. Adverse effects due to breastfeeding <ul><li>( floppiness, cyanosis, heart murmur, T-wave changes on electrocardiography, lethargy, hypothermia ) have been reported in breastfeeding infants in association with maternal use of lithium ( dose of 600 mg to 1200 mg per day ) </li></ul>
  72. 73. Adverse effects due to breastfeeding <ul><li>It has been suggested that mothers on lithium therapy wishing to breast feed their infants should be either partially or completely discontinued from the drug because of the immature metabolizing systems of the infant </li></ul>
  73. 74. Drug-Drug Interactions
  74. 75. Drug Interactions-major <ul><li>Acetophenazine Azosemide Bemetizide Bendroflumethiazide Benzthiazide Bromperidol Bumetanide Buthiazide </li></ul><ul><li>Candesartan Cilexetil Canrenoate Chlorothiazide Chlorpromazine Chlorprothixene Chlorthalidone Clozapine Cyclothiazide </li></ul>
  75. 76. Drug Interactions-major <ul><li>Domperidone Droperidol Flupenthixol Fluphenazine Furosemide </li></ul><ul><li>Haloperidol Hydrochlorothiazide Hydroflumethiazide Indapamide </li></ul><ul><li>Losartan </li></ul>
  76. 77. Drug Interactions-major <ul><li>Melperone Mesoridazine Methotrimeprazine Methyclothiazide Metolazone Molindone Olanzapine </li></ul><ul><li>Penfluridol Periciazine Perphenazine Phenelzine Pimozide Pipamperone Pipotiazine Piretanide Polythiazide Prochlorperazine Promazine Promethazine </li></ul>
  77. 78. Drug Interactions-major <ul><li>Quinethazone Remoxipride Risperidone Sertindole Sibutramine Spironolactone Sulpiride </li></ul><ul><li>Thiopropazate Thioproperazine Thioridazine Thiothixene Tiapride Torsemide Trichlormethiazide Trifluoperazine Triflupromazine Trimeprazine Valsartan Xipamide </li></ul>
  78. 79. Drug Interactions-Diuretics
  79. 80. Drug Interactions-NSAID
  80. 81. Drug Interactions-ACE inhibitors
  81. 82. Drug Interactions-Calcium Channel Blockers
  82. 83. Drug Interactions-metronidazoles <ul><li>Concurrent use of metronidazole with lithium may provoke lithium toxicity due to reduced renal clearance . Patients receiving such combined therapy should be monitored closely </li></ul>
  83. 84. Drug Interactions- SSRIs
  84. 85. Drug Intoxications
  85. 86. Lithium Intoxications-clinical effects <ul><li>MILD: N/V, tremors, hyperreflexia, agitation, ataxia. </li></ul><ul><li>MODERATE: CNS depression, rigidity, hypertonia, fasciculation </li></ul><ul><li>SEVERE: Seizures, myoclonus, coma, and hypotension. Permanent neurologic injury (cerebellar or cognitive defects) possible. Neuroleptic malignant syndrome possible. </li></ul>
  86. 87. Lithium Intoxications-clinical effects <ul><li>Patients with chronic toxicity can develop severe symptoms even with mildly elevated serum levels </li></ul><ul><li>Concomitant medications, concurrent illness, and increased age may precipitate toxicity. </li></ul>
  87. 88. Lithium Intoxications-treatment <ul><li>Decontamination: Gastric lavage. Activated charcoal minimal adsorption. WHOLE BOWEL IRRIGATION - Used for a large or sustained release ingestion. Polyethylene glycol (orally or by NG tube) </li></ul><ul><li>Hypotensive episode: IV 0.9% NaCl, dopamine, norepinephrine </li></ul>
  88. 89. Lithium Intoxications-treatment <ul><li>Enhanced elimination: 0.9% NaCl 10-20 ml/kg bolus followed by twice maintenance fluid rates. Hemodialysis for moderate/severe exposure or rapidly rising levels Monitoring of patient: Vital signs, electrolytes, serial lithium levels, urinalysis, serum creatinine. </li></ul>
  89. 90. Range Of Toxicity <ul><li>Effects more severe with chronic intoxication. </li></ul><ul><li>Levels correlate poorly with toxicity </li></ul><ul><li>Levels as high as 3 to 6 mEq/L have been noted in asymptomatic patients . </li></ul>
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