lithium

LITHIUMIN PSYCHIATRY

Class

This drug is a member of the following class:Mood stabilizer (?)

AntimanicHematopoietic

Dosing Informationa) Lithium Carbonate

Adult Bipolar disorder,

manic episode1) acute, 1800 mg/day ORALLY in 2-3 divided doses; desired serum lithium level ranging between 1-1.5 mEq/L2) maintenance, 900-1200 mg/day ORALLY in 2-3 divided doses; desired serum lithium levels ranging between 0.6-1.2 mEq/L


Cluster headache 300-900 mg/day ORALLY (divided doses); keep serum concentration below 1.2 mEq/L


Graves' disease; Adjunct 900 mg/day ORALLY for 6 days beginning on the day of radioiodine administration

Pediatric

Safety and effectiveness in pediatric patients below the age of 12 have not been established

Conduct disorder, adolescent-onset type: dose

300-2100 mg/day ORALLY (divided doses); desired serum lithium level ranging between 0.8-1.2 mEq/L

Clinical Applications Lithium Carbonate

FDA Approved Indicationsa) Bipolar disorder, manic episode

Non-FDA Approved Indicationsa) Cluster headacheb) Conduct disorder, adolescent-onset typec) Graves' disease; Adjunct

Bipolar disorder 1) ACUTE MANIA THE USUAL RECOMMENDED DOSE

FOR ACUTE MANIA IS 1800 MILLIGRAMS/DAY IN DIVIDED DOSES TO ACHIEVE THE DESIRED SERUM LEVEL OF 1 TO 1.5 MILLIMOLE/LITER

DOSES SHOULD BE INDIVIDUALIZED TO APPROPRIATE SERUM LEVEL AND PATIENT RESPONSE. UNTIL THE SERUM LEVEL AND THE PATIENT'S CLINICAL CONDITION ARE STABLE, LITHIUM CONCENTRATION SHOULD BE DETERMINED TWICE WEEKLY.

MANIA - MAINTENANCE DOSE When manic symptoms subside, the dose of lithium

should be reduced to maintain a serum concentration of 0.6 to 1.2 millimole/liter

Usual maintenance doses are 900 to 1200 milligrams/day; dosage will vary between individuals.

Serum lithium concentrations should be monitored at

least every 2 months.

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

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

IMPORTANT NOTE

Immediate release tablets are usually given 3 or 4 times daily while controlled release tablets are usually given twice daily.

Lithium tolerance is greater during the acute manic phase and decreases when manic symptoms subside

Dosage in Renal Failure 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.

Lithium clearance in patients with chronic renal disease decreased by a mean of 25

Dosage in Geriatric Patients It may be necessary to decrease

lithium dosage by as much as 50% in elderly patients to compensate for reduced clearance

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

Dosage Adjustment During Dialysis maintenance dose should be

given following hemodialysis Serum lithium concentrations following dialysis are useful as a dosing guideline

Pediatric Dosage Bipolar disorder Use in patients less than

12 years old is not recommended due to a lack of information regarding safety and effectiveness

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.

Pharmacoinetics

Onset and Duration Onset- Initial Response Mania, oral: 7 to 14 days

Drug Concentration Levels Therapeutic Drug Concentration ACUTE MANIA/HYPOMANIA

a) 1 to 1.5 millimol/liter

PROPHYLAXIS AND MAINTENANCE THERAPY OF MANIAa) 0.6 to 1.2 mmol/L

DEPRESSIONa) 0.3 to 0.6 millimol/liter

Time to Peak Concentration Oral: 0.5 to 2 hours Due to slow tissue distribution,

complete plasma-tissue equilibration and steady-state plasma levels usually require 5 to 10 days of therapy

Absorption A) Bioavailability 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

Distribution - Distribution Sites Protein Binding

a) None

Distribution - Distribution Sites OTHER DISTRIBUTION SITES

a) Fluids, good1) Lithium distributes throughout intracellular and extracellular fluids and is not protein bound (Baer, 1973).b) Placenta, good1) Lithium passes into breast milk and across the placental barrier (Prod Info Eskalith(R), 2002; Schou & Amdisen, 1973a).c) Tissues, good1) Lithium undergoes widespread tissue localization and is taken up rapidly by the liver and kidney, and more slowly by muscle, bone and brain

Distribution Kinetics1) Volume of Distribution

0.7 to 1.4 liters/kilogram

Distribution Kinetics Volume of Distribution

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

Metabolism Metabolism Sites and Kinetics

1) Urine, almost entirely

Excretion Kidney Renal Clearance (rate)

10 to 37 milliliters/minute Renal Excretion (%)

89% to 98% 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

Excretion Total Body Clearance

1.13 mL/min/kg

Excretion Other

OTHER EXCRETION FECES, insignificant

Elimination Half-life Parent Compound

1) ELIMINATION HALF-LIFEa) 14 to 24 hours

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

Effects vs. Adverse Drug Effects

Serious Adverse Effects Papillary thyroid carcinoma

Serious Adverse Effects 1) Ataxia

2) Blurred vision3) Bradyarrhythmia (Severe)4) Cardiac dysrhythmia5) Coma6) Giddiness7) Hypotension8) Polyuria, Dilute, may be a sign of serious toxicity9) Pseudotumor cerebri, Increased intracranial pressure and papilledema10) Seizure, Epileptiform11) Sinus node dysfunction12) Tinnitus, May be signs of serious toxicity

Adverse Reactions Cardiovascular Effects

Dermatologic EffectsEndocrine/Metabolic EffectsGastrointestinal EffectsHematologic EffectsHepatic EffectsImmunologic EffectsMusculoskeletal EffectsNeurologic EffectsOphthalmic EffectsOtic EffectsPsychiatric EffectsRenal EffectsReproductive EffectsOther

Cardiovascular Effects Cardiovascular finding

EdemaHeart blockHypertensionMyocarditisSinus node dysfunction

Cardiovascular finding 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

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.

Edema 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

Heart block 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

Sinus node dysfunction Reversible and irreversible sinus

node dysfunction have been reported with long- term lithium therapy

Dermatologic Effects Alopecia

Dermatological findingFolliculitisNail damagePsoriasisScaly skin

Endocrine/Metabolic Effects Autoimmune thyroiditis

Body temperature above normalBody temperature findingDiabetes insipidusDisorder of fluid AND/OR electrolyteEndocrine findingHypercalcemiaHyperglycemiaHyperkalemiaHyperosmolality, SerumHyperparathyroidismHyperthyroidismHypoglycemiaHypokalemiaHypothermiaHypothyroidismMetabolic findingPapillary thyroid carcinomaWeight gain

Autoimmune thyroiditis 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.

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

Diabetes insipidus 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

Hyperthyroidism Thyrotoxicosis is also a

complication of lithium carbonate therapy

Hypothyroidism -common 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

Weight gain 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

Gastrointestinal Effects Aversion to food or drink

Excessive salivationGastrointestinal tract findingHyposecretion of salivary gland

Hematologic Effects Leukocytosis, thrombocytosis

and thrombosis have been reported with lithium therapy

Hepatic Effects Ascites

Hyperbilirubinemia

Immunologic Effects Myasthenia gravis and systemic

lupus erythematosus have been reported with lithium therapy

Neurologic Effects Cerebellar disorder

Cognitive function findingDeliriumExtrapyramidal signHeadacheMovement disorderNeurological findingNystagmusPeripheral neuropathyPseudotumor cerebriSeizureTremor

Delirium Organic brain syndrome and

DELIRIUM has occurred with lithium carbonate.

When combined with a neuroleptic, encephalopathy occurred.

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

Extrapyramidal sign Extrapyramidal side effects occur

rarely with lithium therapy. Reported effects include Parkinsonian-

like symptoms, rigidity, and choreoathetosis that have occurred at both toxic and therapeutic serum concentrations.

Lithium in combination with haloperidol therapy has resulted in rare cases of extrapyramidal toxicity, some of which have resulted in prolonged or permanent sequelae

Headache Lithium treatment has been

associated with the development of generalized headache, worsening of cluster headache, and exacerbation of migraine headache

Movement disorder Neurological movement

disorders associated with lithium use include ASTERIXIS, MYOCLONUS, and CHOREA

Neurological finding Cerebellar disorders, cognitive

findings, extrapyramidal symptoms, headaches, movement disorders, pseudotumor cerebri, seizures, sleep disorders and peripheral nerve impairment are associated with lithium use

Peripheral neuropathy 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

Seizure 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

Tremor 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

Ophthalmic Effects Degenerative disorder of macula

Eye / vision findingOculogyric crisisOphthalmoplegia

Otic Effects Tinnitus

Psychiatric Effects Mania

Psychiatric sign or symptomPsychotic disorderSleep disorder

Mania Lithium toxicity has been

reported to mimic manic states

Psychiatric sign or symptom 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.

The Capgras Syndrome denotes the delusional misidentification of familiar individuals as impostors or doubles

Sleep disorder SLEEPWALKING and

RESTLESS LEG SYNDROME have been reported with lithium use

Renal Effects Diabetes insipidus, nephrotic

syndrome, nephrotoxicity, elevated BUN and serum creatinine, glycosuria, albuminuria, and oliguria have been reported with lithium

Effects in Pregnancy

U.S. Food and Drug Administration's Pregnancy Category: Category D

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

Breastfeeding

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

Adverse effects due to breastfeeding

(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)

Adverse effects due to breastfeeding

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

Drug-Drug Interactions

Drug Interactions-major

Acetophenazine Azosemide Bemetizide Bendroflumethiazide Benzthiazide Bromperidol Bumetanide Buthiazide

Candesartan Cilexetil Canrenoate Chlorothiazide Chlorpromazine Chlorprothixene Chlorthalidone Clozapine Cyclothiazide

Drug Interactions-major Domperidone

Droperidol Flupenthixol Fluphenazine Furosemide

Haloperidol Hydrochlorothiazide Hydroflumethiazide Indapamide

Losartan

Drug Interactions-major Melperone

Mesoridazine Methotrimeprazine Methyclothiazide Metolazone Molindone Olanzapine

Penfluridol Periciazine Perphenazine Phenelzine Pimozide Pipamperone Pipotiazine Piretanide Polythiazide Prochlorperazine Promazine Promethazine

Drug Interactions-major Quinethazone

Remoxipride Risperidone Sertindole Sibutramine Spironolactone Sulpiride

Thiopropazate Thioproperazine Thioridazine Thiothixene Tiapride Torsemide Trichlormethiazide Trifluoperazine Triflupromazine Trimeprazine Valsartan Xipamide

Drug Interactions-Diuretics

Caution should be used when lithium and diuretics areused concomitantly because diuretic-induced sodiumloss may reduce the renal clearance of lithium andincrease serum lithium levels with risk of lithiumtoxicity. Patients receiving such combined therapyshould have serum lithium levels monitored closely andthe lithium dosage adjusted if necessary.

Drug Interactions-NSAID

Lithium levels should be monitored when patientsinitiate or discontinue NSAID use. In some cases,lithium toxicity has resulted from interactions betweenan NSAID and lithium. Indomethacin and piroxicamhave been reported to increase significantly, steady stateplasma lithium concentrations.

Drug Interactions-ACE inhibitors

There is evidence that angiotensin-converting enzymeinhibitors, such as enalapril and captopril, maysubstantially increase steady-state plasma lithium levels,sometimes resulting in lithium toxicity. When suchcombinations are used, lithium dosage may need to bedecreased, and plasma lithium levels should bemeasured more often.

Drug Interactions-Calcium Channel Blockers

Concurrent use of calcium channel blocking agents withlithium may increase the risk of neurotoxicity in theform of ataxia, tremors, nausea, vomiting, diarrheaand/or tinnitus. Caution is recommended

Drug Interactions-metronidazoles Concurrent use of

metronidazole with lithium may provoke lithium toxicity due to reduced renal clearance. Patients receiving such combined therapy should be monitored closely

Drug Interactions- SSRIs

The concomitant administration of lithium withselective serotonin reuptake inhibitors should beundertaken with caution as this combination has beenreported to result in symptoms such as diarrhea,confusion, tremor, dizziness, and agitation

Drug Intoxications

Lithium Intoxications-clinical effects MILD: N/V, tremors,

hyperreflexia, agitation, ataxia. MODERATE: CNS depression,

rigidity, hypertonia, fasciculation SEVERE: Seizures, myoclonus,

coma, and hypotension. Permanent neurologic injury (cerebellar or cognitive defects) possible. Neuroleptic malignant syndrome possible.

Lithium Intoxications-clinical effects Patients with chronic toxicity can

develop severe symptoms even with mildly elevated serum levels

Concomitant medications, concurrent illness, and increased age may precipitate toxicity.

Lithium Intoxications-treatment 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)

Hypotensive episode: IV 0.9% NaCl, dopamine, norepinephrine

Lithium Intoxications-treatment Enhanced elimination: 0.9%

NaCl 10-20 ml/kg bolus followed by twice maintenance fluid rates. Hemodialysis for moderate/severe exposure or rapidly rising levelsMonitoring of patient: Vital signs, electrolytes, serial lithium levels, urinalysis, serum creatinine.

Range Of Toxicity

Effects more severe with chronic intoxication.

Levels correlate poorly with toxicity

Levels as high as 3 to 6 mEq/L have been noted in asymptomatic patients.

lithium

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