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CLINICAL PHARMACOKINETICS OF LITHIUM

1. Uses:

- Mania.

- Bipolar manic/depressive disorder.

- Major depression.

 

2. Pharmacokinetic Overview:

(a) Absorption:

- Administered orally (conventional/sustained release tablets).

- Almost completely (85-100%) absorbed with peak levels within 1-3 hours with conventional tablets.

(b) Distribution:

- Distributes into total body water and is widely, but unevenly, distributed throughout the body’s organs.

- Vd : 0.5 - 1.2L/kg (decreases with advancing age).

- Not protein bound.

(c) Elimination:

- Not metabolised.

- Almost 100% excreted unchanged (saliva, sweat, faeces < 5%).

- Lithium clearance is GFR (Cl).

- Cl is ~ 20% of Cl (80% reabsorbed).

- Dosage must be reduced in renal disease (see later).

- Half-life : 7-20 hours with normal renal function.

3. Plasma level monitoring:

- Therapeutic range : 0.8 - 1.5nmol/L.

- Measure trough levels (post-absorption and distributed phases) for greater reproducibility in interpretation of levels, ie. morning level 12-14 hours after evening dose.

 

4. Adverse effects:

(a) GI symptoms:

- Nausea
- Vomiting.
- Persistent hand tremor (30-50% patients).
- Muscle weakness and fatigue.

These symptoms may indicate impending toxicity. Therefore, plasma levels should be measured.

(b) Toxicity:

Moderate: Sedation, lethargy, ataxia, nystagmus, coarse tremor.

Severe: Confusion, delirium, seizure, coma, renal failure, respiratory arrest.

Treatment: Physiological support (eg. rehydration, correct electrolyte imbalances), haemodialysis.

(c) ? Long term renal Toxicity:

GFR , polyuria.

(d) Thyroid dysfunction:

(~ 10% hypothyroidism).

TABLE: Adverse and Toxic Effects of Lithium
Transient Effects and Mild Toxicity (Li < 1.5mEq/litre)	Moderate Toxicity (Li > 1.5mEq/litre)
Fine tremor  Nausea, vomiting, diarrhoea, epigastric pain  Muscle weakness  Polyuria, polydipsia	Coarsening of tremor  Reappearance of GI symptoms Confusion (organicity)  Sedation, lethargy
Persistent Effects	Severe Toxicity (Li > 2.5mEq/litre)
Fine tremor  Polyuria, polydipsia  Hypothyroidism, nontoxic goiter Leukocytosis	Seizures  Hyper-reflexia  Cardiovascular collapse  Permanent neurologic sequelae

 

5. Drug interactions:

Drug Interactions
Antipsychotic drugs (Phenothiazines, butyrophenones)	Increase risk of neurotoxicity; mechanism uncertain
Diuretic drugs	Reduce all Lithium clearance; increase risk of toxicity
Non-steroidal anti-inflammatory drugs (NSAID’s)	Reduce renal Lithium clearance; increase risk of toxicity

- Reabsorption processes for Na and Li in the proximal tubule are nearly identical.

- Changes in sodium balance can lead to large changes in Lithium clearance.

Eg. Thiazide diuretics - reabsorption of Na from distal tubule compensatory Na (and Li) reabsorption from proximal tubule Lithium clearance and plasma levels.

 

6. Dosage and administration:

Dosages of Lithium required to produce therapeutic plasma levels vary from 1g/day to 3g/day, generally administered in 3 divided doses.

Particular care should be exercised in the elderly and in patients with renal impairment.

Estimation of dosage in renal impairment (refer also to renal failure lectures):

Fraction of normal MD = (1 - fe) + fe x (Cl/120

Where the normal MD is ~ 20mg/kg/day.

NB: TDM and clinical supervision should be used to more accurately individualise dosage.

 

7. Clinical Example:

A 35 year old male (70kg) was readmitted to the Psychiatric Hospital. His wife reported that he was not sleeping for 5 consecutive nights, claiming to be the Pope. He had purchased $5,000 of religious garments at a department store. On two previous admissions the patient was diagnosed as having a bipolar manic-depressive disorder. He also has a history of chronic glomerulonephritis (latest serum creatinine 0.22 mmol/L).

What dosage regimen of Lithium do you suggest?

 

 

TABLE 1: Recommendations for Lithium use to Minimise the Risk of Renal Toxicity
Pre-treatment	Investigate history for evidence of renal disorder or hypertension. Serum creatinine, electrolytes. (Creatinine clearance, urinary concentrating tests may be advisable if there is pre-existing renal disease).
Monitoring	Check plasma Lithium levels every 1-3 months - therapeutic range 0.5-1.0mmol.L. Repeat creatinine and electrolytes each 3 months. Avoid concurrent medications especially neuroleptics if possible. Question patient regularly regarding thirst, urine output - if polyuria exceeds 3 litres/day and is progressive, further assessment of renal function required.
Precautions	Avoid lithium intoxication - 95% of Lithium is eliminated via the kidney. Lithium elimination may be adversely affected by surgery or acute medical illness. Diuretics and some non-steroidal anti-inflammatory drugs may increase plasma levels.

 

TABLE 2: Factors Influencing Lithium Blood Levels
Raised blood levels of Lithium
1. Drug interactions	Neuroleptics: Haloperidol, Phenothiazines Anticonvulsants: Carbamazepine Thiazide diuretics Indomethacin
2. Physical illness	Renal disease Cardiac failure Dehydration from any cause Viral infections
3. Salt loss	Reduced intake Hot weather Excessive exercise Diarrhoea
Reduced blood levels of Lithium
1. Decreased absorption	Antacids
2. Increased excretion	Increased salt intake Decreased salt loss (cool weather) Alkalinisation of urine

 

TABLE 3: Adverse Effects of Lithium
Gastrointestinal	- Nausea, vomiting, diarrhoea
Neurological	- Fine tremor, muscle weakness
Dermatological	- Acne, eczema, psoriasis
Cardiovascular	- Nonspecific benign ECG changes, ventricular and nodal arrhythmias
Endocrine	- Hypothyroidism, diffuse goitre
Renal	- Polyuria, polydipsia
Haematological	- Reversible neutrophilia
Metabolic	- Weight gain

 

TABLE 4: Signs of Lithium Toxicity
Early signs
Increase in adverse effects	- Polyuria  - Nausea, vomiting, diarrhoea  - Increased tremor
Apathy, tiredness
Weakness of muscles (“heavy limbed”)
Difficulty concentrating and thinking
Coarse tremor including jaw
Unsteadiness in walking and tasks
Later signs
Dysarthria  Ataxia of gait  Hyper-reflexia  Confusional state	- Clouding of consciousness  - Disorientation

 

TABLE 5: Indications for Anticonvulsants in Manic-depressive Illness

1. In acute episodes (Clonazepam) - Severe manic excitement.  - Mania not responsive to neuroleptics and Lithium. - Contraindications to neuroleptics and Lithium.  - Rapid control of symptoms required.  - ? Severe excitement in schizophrenia.

2. In prophylaxis (Carbamazepine) - Severe bipolar illness unresponsive to Lithium.  - Rapid cycling bipolar illness poorly controlled with Lithium.  - Lithium contraindicated.