Lithium, Lithane®

• Lithane®

• Antimanic agent

• Capsules: 150 mg; 300 mg

• Acute manic episodes
• Manic- depressive disorders
• Maintenance therapy: preventing or diminishing the frequency of subsequent relapses in bipolar manic-depressive patients (with a strong history of mania).

Mechanism of action:

1. Lithium alters sodium transport in nerve and muscle cells,
2. Shift toward intraneuronal metabolism of catecholamines
3. Inhibitory action on the intracellular formation of cyclic AMP

Pharmacokinetics:

1. Absorption: from the gastrointestinal (GI) tract – Peak Plasma Concentration: 2-4 hours after consumption.
2. Distribution: Slowly Crosses the blood brain barrier.
3. Elimination and excretion: 99% Urine, 1% Feces
4. Lithium plasma Half life: 24 hours
5. Attention: concentration of sodium will increase lithium reabsorption and might result in retention or intoxication.

Acute Mania:

• Should be based primarily on the patient’s clinical condition
• Initially 600 and 900 mg/day, reaching a level of 1200 to 1800 mg in three divided doses on the second
• Serum Li-Carbonate level Between 1 and 1.5 mmol/L

Mania (Long term control):

• Between 600 and 1200 mg/day divided in three doses
• Serum levels between 0.6 and 1.2 mmol/L (Less than 1.5 mmol/L)
• No satisfactory response in 14 days = discontinue Li Carbonate therapy!

• Sodium Bicarbonate (NaHco3):
  • Decreased lithium effects
• Potassium Iodide:
  • Hypothyroidic and goitrogenic effects
• Haloperidol:
  • Combined therapy should be monitored closely for early evidence of neurologic toxicity (Encephalopathic syndrome) and discontinued promptly.
• Diuretics and Angiotensin Converting Enzyme (ACE) Inhibitors: (Na Loss)
  • If such combinations lithium dosage may need to be decreased
• Phenothiazines:
  • Increases in red cell uptake of lithium
• Chlorpromazine:
  • Increases in renal lithium excretion
• Non-Steroidal Anti-Inflammatory Drugs (NSAID)s:
  • Increase significantly, steady state plasma lithium levels
• Selective Serotonin Reuptake Inhibitors (SSRI) Drugs:
  • Enhance the serotonergic effects of SSRI drugs
  • Fluvoxamine: convulsions
  • Fluoxetine: Increased and decreased lithium levels
  • Sertraline: Tremors
• Carbamazepine:
  • Neurotoxicity (in the absence of toxic serum lithium concentrations)
• Neuromuscular Blocking Agents: (eg: Succinylcholine, Pancuronium)
  • In chronic lithium therapy: Long duration of action of these drugs
• Theophylline:
  • In chronic lithium therapy: Long duration of action of these drugs
  • Enhances renal clearance of lithium = Reduce serum lithium concentrations
  • Caution: Discontinuation of theophylline on chronic lithium therapy = Excessive lithium response (Toxicity)
• Calcium Channel Blockers (CCBs):
  •  Neurotoxicity
• Propranolol:
  • Increase lithium serum concentrations
  • Bradycardia
• Tricyclic Antidepressants:
  • Lower the seizure threshold
• Diazepam:
  • Serious hypothermia
• Sodium Chloride:
  • Developing symptoms of lithium toxicity.
• Urea:
  • Enhance renal excretion of lithium = Reduced lithium serum concentrations.

Most frequent side effects are the initial post-absorptive symptoms:

• Gastrointestinal discomfort (earliest): Anorexia, nausea, vomiting, diarrhea, abdominal pain, and weight loss.
• Nausea
• Vertigo
• Muscle weakness
• Dazed feeling
• Mostly associated with a rapid rise in serum lithium levels

More common and persistent adverse reactions:

• Fine tremor of the hands
• Fatigue
• Thirst
• Polyuria: Nephrogenic Diabetes Inspedius (polyuria-Polydipsia

Other side effects: (Less frequent)

• Metallic taste
• Fasciculation
• Twitching, especially of facial muscles and clonic movements of the limbs
• CNS & PNS& Autonom: Urinary and fecal incontinence, blurred vision, dry mouth
• Seizures
• Somnolence
• Cardiovascular: Arrhythmia, hypotension, reversible flattening isoelectricity or inversion of T-waves in ECG.
• Thyroid Abnormalities: Euthyroid goiter and/or hypothyroidism (including myxedema)
• Hypersensitivity
• Hematologic: Anemia, leukopenia and leukocytosis.

1. Significant cardiovascular or renal disease.
2. Severe debilitation state
3. Severe dehydration
4. Sodium depletion, brain damage, and in conditions requiring low sodium intake
5. Children < 12 years of age

Pregnancy: Increase significantly, steady state plasma lithium levels

Lactation: Nursing should not be undertaken

Screen initially & periodically:

1. BUN (Blood Urea Nitrogen)
2. Serum Cr (Creatinin)
3. 24 hour urine volume
4. Serum Na
5. Serum K
6. FBS (Fasting Blood sugar)
7. TSH (Thyroid stimulating hormone)
8. ECG (Electrocardiography)
9. Serum Calcium
10. Record of weight
11. Urine Specific gravity

Low therapeutic index:

• Therapeutic plasma level relatively close to toxic level (Geriatrics more susceptible)
• Li Plasma level: Max= 1.5-2 mmol/L
• Serum lithium levels in uncomplicated cases receiving maintenance therapy should be monitored at least every 2 months.
• Signs and symptoms of Li-Carbonate intoxication:
  1. Fatigue,
  2. Muscular weakness,
  3. Incoordination,
  4. Drowsiness,
  5. Coarse tremors,
  6. Diarrhea
  7. Vomiting
• Li-Carbonate is mainly excreted by kidneys, therefore Adequate renal function + Adequate salt and fluid intake (2500 to 3000 mL a day) are essential.

Frequent serum Li- Carbonate determinations are required especially during the initial period of treatment:

• First blood sample blood sample: Before the patient has had his/her first lithium dose.
• Second blood sample blood sample: 9 – 12 hours after his/her last dose of drug.
• If > 2mmol/L = Discontinue
• Three times weekly during the initial period of administration
• If >1.5- 2 mmol/L = Discontinue for 24 hours and recheck the Li-Carbonate plasma level, if normal, restart.
• Decrease tolerance: When the acute attack subsides, reduce the dose rapidly in order to produce serum lithium levels no higher than between 0.6 and 1.2 mmol/L

In case of nephrogenic diabetes insipidus, with polyuria and polydipsia:

• Avoid dehydration with resulting lithium retention and toxicity
• Mostly reversible

Lithium plus Haloperidol: Combined therapy should be monitored closely for early evidence of neurologic toxicity (Encephalopathic syndrome) and discontinued promptly:

• Encephalopathic syndrome characteristics:

1. Weakness
2. Lethargy
3. Fever
4. Tremulousness
5. Confusion
6. Extrapyramidal symptoms
7. Leukocytosis, elevated serum enzymes
8. Elevated BUN and FBS

Patients on Li- Carbonate with:

• Cardiovascular diseases:
  • Observed carefully for signs of arrhythmias.
  • Initial & Periodic ECG
• Thyroid Disorder:
  • Initially & periodically TSH
  • Exam thyroid before initial Li therapy for non-toxic nodular goiter

Discontinuation of therapy:

• No withdrawal symptoms/ Rebound phenomenon (almost)

Li Carbonate Overdose management general steps: (No antidote)

1. Lavage
2. Correction of fluid and electrolyte imbalance
3. Regulation of kidney function
4. Hemodialysis