Mechanism of effect
The precise mechanism of action of Lithium as a mood-stabilizing agent is currently unknown. It is possible that Lithium produces its effects by interacting with the transport of monovalent or divalent cations in neurons. An increasing number of scientists have come to the conclusion that the excitatory neurotransmitter glutamate is the key factor in understanding how lithium works.
Lithium has been shown to change the inward and outward currents of glutamate receptors (especially GluR3), without a shift in reversal potential. Lithium has been found to exert a dual effect on glutamate receptors, acting to keep the amount of glutamate active between cells at a stable, healthy level, neither too much nor too little. It is postulated that too much glutamate in the space between neurons causes mania, and too little, depression.
Another mechanism by which lithium might help to regulate mood include the non-competitive inhibition of an enzyme called inositol monophosphatase. Alternately lithium's action may be enhanced through the deactivation of the GSK-3B enzyme. The regulation of GSK-3B by lithium may affect the circadian clock.Pharmacodynamic
Inhibits postsynaptic D2 receptor supersensitivity. Alters cation transport in nerve and muscle cells and influences reuptake of serotonin or norepinephrine. nhibits phosphatidylinositol cycle second messenger systems.
Pharmacokinetics
Absorption
Bioavailability: Immediate release, 95-100%; extended release, 60-90%
Onset: Initial antimanic effect, 5-7 days; full effect, 10-21 days
Peak serum time: Immediate release, 0.5-2 hr; extended release, 4-12 hr
Peak plasma concentration: 0.4-0.9 mEq/L
Steady-state therapeutic plasma concentration: 0.5-1.3 mEq/L
Distribution
Vd: Approximates total body water (0.7-1 L/kg)
Elimination
Half-life: 18-24 hr; up to 36 hr with advanced age or renal impairment
Dialyzable: Yes (hemodialysis, 50-90 mL/min; peritoneal dialysis, 13-15 mL/min)
Renal clearance: 20-40 mL/min
Excretion: Urine (95-99%)
Drug indications
FDA-Labelled Indications
• Bipolar disorder, maintenance therapy
• Bipolar disorder, manic episode
Dosage
Extended-Release Tablet, 300 mg
Adults:
- Bipolar disorder, maintenance therapy: slow-release tablets, maintenance, 900 to 1200 mg/day ORALLY in 2 to 3 divided doses; desired serum lithium levels ranging between 0.6 to 1.2 mEq/L
- Bipolar disorder, maintenance therapy: immediate-release formulations, maintenance, 300 mg ORALLY 3 to 4 times daily; desired serum lithium levels ranging between 0.6 to 1.2 mEq/L
- Bipolar disorder, manic episode: slow-release tablets, acute mania, 1800 mg/day ORALLY in 2 to 3 divided doses; desired serum lithium levels ranging between 1.0 to 1.5 mEq/L
- Bipolar disorder, manic episode: immediate-release formulations, acute mania, 600 mg ORALLY 3 times daily; desired serum lithium levels ranging between 1.0 to 1.5 mEq/L
Dosing - FDA Labelled
- Bipolar disorder, maintenance therapy: Adult: yes
- Bipolar disorder, maintenance therapy: Pediatric: yes (12 y and older)
- Bipolar disorder, manic episode: Adult: yes
- Bipolar disorder, manic episode: Pediatric: yes (12 y and older)
Pediatrics:
- Safety and effectiveness in pediatric patients below the age of 12 have not been established
- Bipolar disorder, maintenance therapy: 12 y and older, slow-release tablets, maintenance, 900 to 1200 mg/day ORALLY in 2 to 3 divided doses; desired serum lithium levels ranging between 0.6 to 1.2 mEq/L
- Bipolar disorder, maintenance therapy: 12 y and older, immediate-release formulations, maintenance, 300 mg ORALLY 3 to 4 times daily; desired serum lithium levels ranging between 0.6 to 1.2 mEq/L
- Bipolar disorder, manic episode: 12 y and older, slow-release tablets, acute mania, 1800 mg/day ORALLY in 2 to 3 divided doses; desired serum lithium levels ranging between 1.0 to 1.5 mEq/L
- Bipolar disorder, manic episode: 12 y and older, immediate-release formulations, acute mania, 600 mg ORALLY 3 times daily; desired serum lithium levels ranging between 1.0 to 1.5 mEq/L
Drug contraindications
cardiovascular conditions• Cardiovascular disease, significant; high risk of lithium toxicity; if treatment is required, monitoring in a hospital setting is necessary(immediate release formulation).
• Concomitant use of diuretics; if treatment is required, monitoring in a hospital required(immediate release formulation).
• Debilitation, server; high risk of lithium toxicity, if treatment is required, monitoring in a hospital required(immediate release formulation).
• Dehydration,server; high risk of lithium toxicity, if treatment is required, monitoring in a hospital required(immediate release formulation).
• Renal disease, significant; high risk of lithium toxicity, if treatment is required, monitoring in a hospital required(immediate release formulation).
• Sodium depletion; high risk of lithium toxicity, if treatment is required, monitoring in a hospital required(immediate release formulation).
Side effects
Diarrhea , nausea , dry mouth , vomiting• Cardiovascular: Abnormal ECG, Reversible flattening, isoelectricity or inversion of T-waves
• Gastrointestinal: Diarrhea, Nausea (Mild), Vomiting, May be signs of toxicity, Xerostomia
• Musculoskeletal: Muscle irritability, Muscle weakness
• Neurologic: EEG abnormality, Diffuse slowing, widening of frequency spectrum, potentiation and disorganization of background rhythm, Fine tremor, Hyperreflexia, Deep tendon, Somnolence
• Ophthalmic: Visual field scotoma, Transient
• Renal: Albuminuria, Glycosuria, Oliguria, Polyuria
• Other: Little thirst
Interactions
Amitriptyline , Ergotamine-C , Enalapril , Ibuprofen , Piroxicam , Trazodone , Tranylcypromine , Topiramate , Fluticasone propinate , Fluvoxamine , Fluoxetine , Granisetron , Losartan , Metolazone , Mefenamic acid , Meloxicam , Nilotinib , Hydrochlorothiazide , Verapamil , Venlafaxine , Captopril , Clozapine , Insulin glargine , escitalopram , Filgrastim , Mefloquine , Spectinomycin , Lorcaserin , Telmisartan , Sacubitril and valsartan , Sodium Chloride serum , phenmetrazine , tropisetron , Blonanserin , cyclopenthiazideAlerts
Toxicity is closely related to serum lithium concentrations and may occur at dosages close to therapeutic levels; monitor therapy by measuring serum lithium
Equipped facilities should be identified before initiation of therapy to provide prompt and accurate serum lithium concentration data
Points of recommendation
- Patient should avoid activities requiring mental alertness or coordination until drug effects are realized.
- This drug may cause diarrhea, nausea, ataxia, muscle irritability or weakness, polyuria, oliguria, bradyarrhythmia, cardiac arrhythmia, hypotension, pseudotumor cerebri (nausea, vomiting, headache, pulsating intracranial sounds), dizziness, seizures, blurred vision, or drying and thinning of hair.
- Instruct patient to report signs/symptoms of toxicity, which may vary depending on degree of toxicity. These may include diarrhea, vomiting, tremor, ataxia, drowsiness, muscle weakness, lack of coordination, giddiness, blurred vision, tinnitus, or large volumes of dilute urine.
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