Lithium Toxicity

By:
Radhika Dhital
• Lithium is an element which is the smallest alkali. It was first approved by the U.S. food
and Drug Administration (FDA) as a mood stabilizing medication for treatment of
mania in 1970s.

• Its mechanism of action is unknown but it is thought to work in the synapse to hasten the
destruction of catecholamine (dopamine, norepinephrine), inhibit neurotransmitter
release and decrease the sensitivity of postsynaptic receptors. Lithium is a very
powerful antimanic drug.
 Indications of lithium
• Acute mania
• Prophylaxis of bipolar and unipolar mood disorder.
• Schizo-affective disorder.
• Cyclothymia
• Impulsivity and aggression
• Chronic alcoholism and psychoactive substance use disorder.
• Other disorders – cluster headache, hyperthyroidism, borderline personality disorder,
cyclical vomiting, Huntington’s chorea, bulimia nervosa, trichotillomania, premenstrual
dysphoric disorder
 Mechanism of action

• The probable mechanism of action can be:

• Accelerates the presynaptic reuptake and destruction of catecholamines, like nor

epinephrine.

• Inhibits the release of the catecholamines at the synapse.

• Decrease the postsynaptic serotonin receptor sensitivity.

• All these actions result in decreased catecholamine activity, thus ameliorating mania.
Dosage Lithium carbonate: 300 mg tablets; 400 mg sustained release tablets. Lithium
citrate: 300 mg/5 ml liquid
• The usual range of dose per day in acute mania is 900-2100 mg given in 2-3
divided doses.

•Before starting, essential to ensure normal functioning of kidneys (most important),

thyroid, heart, and CNS

Pharmacokinetics

 Lithium is very rapidly absorbed from the gastrointestinal tract.

 Lithium is readily absorbed with peak plasma levels occurring 2-4hours after a
single oral dose of lithium carbonate.
 Lithium is distributed rapidly in liver and kidney and more slowly in muscle,
brain and bone. Crosses blood–brain barrier and placenta; distributed into breast
milk.

 Elimination is predominantly via kidneys. 95% excreted in urine, 1% in feces, 4–

5% in sweat.

 Lithium is reabsorbed in the proximal tubules and is influenced by sodium

balance. Depletion of sodium can precipitate lithium toxicity.
• Blood lithium levels
• Therapeutic levels= 0.6-1.2 mEq/L (for treatment of acute mania)
• Prophylactic level= 0.6-1.0 mEq/L (for prevention of relapse in bipolar disorder)
• Toxic lithium level > 2.0 mEq/L

Side effects
1. Neurological
• Tremors, muscular weakness, cogwheel rigidity, seizures
• Neurotoxicity: delirium, abnormal involuntary movements, coma
2. Renal
• Occurs in 10-50% of the patient
• Polyuria, polydipsia, nephrogenic diabetes insipidus, nephrotic syndrome
3. Cardiovascular
• The effect on the heart is similar to hypokalaemia.
The commonest ECG change is T-wave depression

4. Endocrine
• Goitre
• Hypothyroidism
• Abnormal thyroid function
• Weight gain (pedal edema is also common)
5. Gastrointestinal
• Nausea, vomiting, diarrhoea, metallic taste and abdominal pain

6. Dermatological
• Acneiform eruptions, papular eruptions and exacerbations of psoriasis

7. Pregnancy and lactation

• Teratogenic (possibly)
• Increased incidence of Ebstein’s anomaly, when taken in first trimester.
• Secreted in milk and can cause toxicity in the infant
 Contraindications

• Presence of clear evidence of cardiac, renal, thyroid or neurological dysfunction

• Presence of blood dyscrasias
• During the first trimester of pregnancy and lactation
• History of seizures
• Hypothyroidism
• Severe dehydration
 Nurse’s responsibilities for a patient receiving lithium
• The pre lithium work up
• A complete physical history
• ECG
• Blood studies (TC, DC, Hb, FBS, BUN, creatinine, electrolytes)
• Urine: Routine and microscopic examination
• Renal function test (blood urea, Cr, urine specific gravity.
• Thyroid function test
To achieve therapeutic effect and prevent lithium toxicity, the following precautions
should be taken:

• Lithium should be taken in regular basis, preferably at the same time.

• When lithium therapy is initiated, mild side effects such as fine hand tremors, increased
thirst and urination, nausea, anorexia, etc may develop. Most of them are transient and
do not represent lithium toxicity.

• Serious side effects of lithium that necessitate its discontinuation include vomiting,
extreme hand tremors, sedation, muscle weakness and vertigo.
 Contd…
• Since polyuria can lead to dehydration with the risk of lithium intoxication, pt should be
advised to drink enough water to compensate the fluid loss.

• People involved in heavy outdoor labor are prone to excessive sodium loss through
sweating. They must be advised to consume large amount of water with salt to
prevent lithium toxicity due to decreased sodium level.

• If severe vomiting or gastroenteritis develops, the pt should be told to report immediately

to the doctor.
• During the treatment, it is essential to estimate blood lithium levels at regular intervals. The
blood sample for estimation is taken approx. 12 -14 hrs after the last lithium dose.

• If any changes are made in the lithium dose, the next blood level is estimated after at least 7 days
of the last change.

• The pt should be told about the importance of regular follow up. In every six months, blood
sample should be taken for the estimation of electrolytes, urea, creatinine, TFT.

If a dose is missed, can be taken if < 2 hours has been elapsed; if longer than 2 hours, the next
dose be given as scheduled; never double up the doses.
Lithium toxicity
• Lithium toxicity is another term for a lithium overdose. It occurs when one take
too much lithium. A safe blood level of lithium is 0.6 and 1.2 milliequivalents per
liter (mEq/L).
• Lithium toxicity can happen when this level reaches 1.5 mEq/L or higher.
• Severe lithium toxicity happens at a level of 2.0 mEq/L and above, which can be
life-threatening in rare cases.
• Levels of 3.0 mEq/L and higher are considered a medical emergency.
 Causes and sign/symptoms of lithium toxicity

• Lithium toxicity is usually caused by taking more than prescribed dose of lithium, either at once or
slowly over a long period of time. There are three main types of lithium toxicity, each with different
causes:

• Acute toxicity. This happens when one take too much lithium at once, either accidentally or on purpose.

Common symptoms of acute toxicity include:

• Diarrhea

• Dizziness

• Nausea

• Stomach pains
Contd…

• Vomiting

• Weakness

Nervous system symptoms that may develop later, once the drug has been absorbed, can include

• Hand tremors

• Drowsiness

• Confusion or agitation

• Inability to fully control your arms and legs (ataxia)

• Muscle twitches

• Slurred speech

• Eye movements that you can't control (nystagmus)

• In severe cases, there may be symptoms such as:

• Seizures

• Coma

• Brain injury

• In rare cases, there may be heart problems

Chronic toxicity. This happens when one take a little too much lithium daily over a long period of time.
Dehydration, other medications, and other conditions including kidney problems, can affect how one's body
handles lithium. Over time, these factors can cause lithium to slowly build up in the body.
• Unlike in acute lithium poisoning, people with chronic lithium toxicity are much less likely to have stomach
and intestinal problems and instead usually present with neurologic symptoms first, such as:

• Slurred speech

• Drowsiness

• Ataxia

• Confusion or agitation

• Tremors

• Increased reflexes
• Severe cases of chronic toxicity may result in symptoms like:

• Memory problems and other cognitive impairment

• Significant movement problems

• Psychosis

• Kidney failure

• Seizures

• Coma

• If severe symptoms occur, they may persist long-term even after successful treatment in a
small number of people.
• Acute-on-chronic toxicity. This can happen if one take lithium every day for a
long period of time, but then suddenly take an extra pill one day, either
accidentally or on purpose.

• Symptoms of this condition typically include both the common gastrointestinal

symptoms of acute toxicity and some of the severe symptoms of chronic toxicity.
• The margin between the therapeutic and toxic levels of lithium is very narrow. The
usual range of therapeutic serum concentrations are:

• For acute mania: 1.0 to 1.5 meq/L

• For maintenance: 0.6 to 1.2 meq/L

• Symptoms of lithium toxicity begin to appear at blood levels greater than 1.5
meq/L.

•The severity of lithium toxicity is often divided into the following three grades:
mild, moderate, and severe.
•Mild intoxication: (Serum lithium concentration between 1.5-2.5 mEq/L).

• Nausea

• Vomiting

• Severe diarrhea

• Tinnitus

• Lethargy

• Tremor

• fatigue

• Blurred vision

• Ataxia
Moderate intoxication: (serum lithium concentration between 2.5-3.5 mEq/L)

• Confusion

• Agitation

• Tachycardia

• Increasing tremor

• Muscular irritability

• Psychomotor retardation

• Excessive output of dilute urine

 Severe intoxication: (serum lithium concentration (more than 3.5 mEq/L)

• Impaired consciousness

• Coma

• seizures

• Hyperthermia

• hypotension

• Nystagmus

• Oliguria/ anuria

• Arrhythmias

• Myocardial infarction

• Cardiovascular collapse
Sensitivities and interactions with lithium

• Some people are more sensitive to lithium and may experience symptoms of
lithium toxicity at lower levels than others.

• This is especially true in people who are older or dehydrated. It’s also more likely
in people with cardiovascular and kidney problems.

• Certain foods or drinks may also affect lithium concentrations in the body

• Salt intake. Less salt can make lithium levels rise, while increasing salt intake
can cause it to fall.
• Caffeine intake. Caffeine found in coffee, tea, and soft drinks may have an effect
on lithium levels. Less caffeine can cause lithium levels to rise, while more can
cause it to lower.

• Avoid alcohol. Alcoholic beverages can have a negative effect on many

medications.

• Drug Interactions

• A. The most common cause of drug interactions is a change in the renal clearance
of lithium.
• B. Medications that decrease lithium levels include:

• 1. Xanthines (theophylline, aminophylline, caffeine).

• 2. Increased dietary sodium and sodium bicarbonate (antacids).

• 3. Carbonic anhydrase inhibitors (acetazolamide).

• 4. Osmotic diuretics (mannitol).

• C. Medications that increase lithium levels and increase the risk of toxicity include the following:

• 1. Potassium sparing diuretics (spironolactone), loop diuretics (furosemide), NSAIDS.

• D. Neurotoxicity is a frequent consequence of lithium toxicity, and a number of medications will
enhance the risk of lithium neurotoxicity. These medication include methyldopa, typical
antipsychotics, carbamazepine, phenytoin, calcium channel blockers.

• Close monitoring for symptoms of neurotoxicity is recommended. These symptoms include

tremor, disorientation, confusion, ataxia, and headaches.

• E. The action of neuromuscular-blocking agents, especially succinylcholine, will be prolonged by

lithium. Prolonged recovery from electroconvulsive therapy, often requiring ventilatory assistance,
may occur. Lithium should be discontinued prior to electroconvulsive therapy.
• Management of Lithium Toxicity

• Discontinue the drug immediately.

• For significant short-term ingestions, residual gastric content should be removed by induction of emesis,
gastric lavage and absorption with activated charcoal.

• If possible instruct the patient to ingest fluids.

• Assess serum lithium levels, serum electrolytes, renal functions, ECG as soon as possible.

• Maintenance of fluid and electrolyte balance.

• In a patient with serious manifestations of lithium toxicity, hemodialysis should be initiated.

• Nursing Implications

The pre-lithium work up:

• A complete physical history, ECG, blood studies (TC, DC, FBS, BUN, creatinine,
electrolytes) urine examination (routine and microscopic) must be carried out.

• It is important to assess renal function as renal side effects are common and the drug
can be dangerous in an individual with compromised kidney function.

• Thyroid functions should also be assessed, as the drug is known to depress the
thyroid gland.
• Assessment & Drug Effects

• Monitor response to drug. Usual lag of 1–2 wk precedes response to lithium

therapy. Keep physician informed of progress.

• Lab test: Usually after 5 days. Periodic lithium levels (draw blood sample prior
to next dose or 8–12 h after last dose); periodic thyroid function tests.
• Monitor for signs and symptoms of lithium toxicity (e.g., vomiting, diarrhea, lack
of coordination, drowsiness, muscular weakness, slurred speech when level is
1.5–2.0 mEq/L; ataxia, blurred vision, giddiness, tinnitus, muscle twitching,
coarse tremors,
Cont…
• Polyuria when >2.0 mEq/L). Withhold one dose and call physician. Drug should
not be stopped abruptly.

• Monitor older adults carefully to prevent toxicity, which may occur at serum levels
ordinarily tolerated by other patients.

• Be alert to and report symptoms of hypothyroidism.

• Weigh patient daily; check ankles, tibiae, and wrists for edema. Report changes in
Intake & Output ratio, sudden weight gain, or edema.

• Report early signs of extrapyramidal reactions promptly to physician.

• Patient & Family Education

 Be alert to increased output of dilute urine and persistent thirst. Dose reduction may
be indicated.

 Contact physician if diarrhea or fever develops. Avoid practices that may encourage
dehydration: hot environment, excessive caffeine beverages (diuresis).

 Drink plenty of liquids (2–3 L/d) during stabilization period and at least 1–1½ L/d
during ongoing therapy.

 Avoid self-prescribed low-salt regimen, self-dosing with antacids containing

sodium, and high-sodium foods (e.g., prepared meats and diet soda).
Contd…
 Do not drive or engage in other potentially hazardous activities until response to
drug is known. Lithium may impair both physical and mental ability.

 Use effective contraceptive measures during lithium therapy. If therapy is

continued during pregnancy, serum lithium levels must be closely monitored to
prevent toxicity.

 Do not breast feed while taking this drug.

Neuroleptic Malignant Syndrome (NMS)
Neuroleptic Malignant Syndrome
• Introduction : NMS is a rare but potentially fatal side-effect of antipsychotics.
The onset is often, but not invariably in the first 10 days of treatment. The
syndrome lasts for one to two weeks after stopping the drug. It is essentially a
syndrome of sympathetic over-activity due to antagonizing dopaminergic activity.

• NMS can also be seen with other drugs such as antidepressants (selective
serotonin reuptake inhibitors may contribute to NMS as they are also indirect
dopamine antagonists) and lithium. The syndrome can also occur in people taking
anti-parkinsonism drugs known as dopaminergic if those drugs are discontinued
abruptly.
• Epidemiology:

1. Incidence 0.07–0.2%; M:F = 2:1(Oxford Handbook of Psychiatry,2013)

2. One large randomized trial conducted in China showed an incidence of 0.12% in patients taking
neuroleptics. (Deng, Chen, Phillips.1990)
3. A retrospective study conducted in India showed an incidence of 0.14%. (Chopra, Prakash, Raguram.1999)

Risk factors

 Using high-potency antipsychotics. For eg. Haloperidol, fluphenazine

 Recent or rapid dose increase
 Sudden withdrawal of anticholinergics
 Organic brain disease
 Parkinson’s disease
 Dehydration
 Hyperthyroidism

• Drugs reported to cause symptoms characteristic of NMS (Oxford Handbook of Psychiatry,3 rd

ed,2013)

1. Antipsychotics: aripiprazole, chlorpromazine, clozapine (rarely), fluphenazine, haloperidol, olanzapine,

promazine, quetiapine (rarely), risperidone, thioridazine.
2. Anti-Parkinsonian agents: amantadine (+ withdrawal), anticholinergics (withdrawal), levodopa (+
withdrawal).
3. Antidepressants: amoxapine, clomipramine, desipramine, trimipramine, venlafaxine.
4. Other: carbamazepine (+withdrawal), lithium, methylphenidate.
• Clinical features

1. Rapid onset (usually over 24-72 hours) of severe motor, mental and autonomic disorders.
2. The prominent motor symptom is generalized muscular hypertonicity; Dysphagia and
dyspnea due to stiffness of the muscles in the throat and chest.
3. Mental symptoms; akinetic mutism, stupor or impaired consciousness.
4. Autonomic disturbances symptoms; hyperpyrexia (>380C), unstable blood pressure,
tachycardia, excessive sweating, salivation and urinary incontinence.
5. In the blood, creatinine phosphokinase (CPK) levels may be raised to very high levels and
the white cell count may be increased.
6. Secondary features: pneumonia, thromboembolism, cardiovascular collapse and renal
failure.
• Pathophysiology

• NMS is usually secondary to Dopamine activity in the CNS—i.e. striatum

(rigidity), hypothalamus (thermoregulation)—by blockade of D2-receptors or
decreased dopamine availability; impaired Ca++ mobilization in muscle cells leads
to rigidity (like malignant hyperthermia ); sympathetic nervous system activation or
dysfunction.

• Diagnosis

 Clinical presentation: ill patient, fever, diaphoresis, rigidity, disturbed conscious

level, fluctuating blood pressure, and tachycardia
 Laboratory tests: elevated creatine kinase (usually more than 1000 IU/L),
leukocytosis, and altered liver function tests
Complications

 Metabolic: dehydration and electrolyte imbalance

 Renal: acute renal failure (due to rhabdomyolysis)
 Cardiac: arrhythmias, cardiac arrest, myocardial infarction and cardiomyopathy
 Respiratory: respiratory failure from chest wall rigidity, aspiration pneumonia,
pulmonary embolism
 Vascular: deep venous thrombosis, thrombocytopenia, and disseminated
intravascular coagulation
 Seizures from hyperthermia and metabolic derangements
 Hepatic failure
Treatment

The following treatment procedure should be followed:

 Early recognition is extremely important to reduce mortality.

 Upon suspicion, stop antipsychotics immediately (also stop lithium and antidepressants if
used).
 Monitor vital signs.
 If diagnosed in a psychiatric setting, transfer patient to acute medical services where intensive
monitoring and treatment are available.
 Transfer to a medical unit immediately, to start treatment:

 Immediately stop any agents thought to be causative (esp. antipsychotics), or restart anti-
Parkinsonian agents.
  Supportive measures: oxygen, correct volume depletion/hypotension with
IV fluids, reduce the temperature (e.g. cooling blankets, antipyretics, cooled
IV fluids, ice packs, evaporative cooling).
 Benzodiazepines for acute behavioral disturbance (Note: use of restraint and
IM injection may complicate the interpretation of serum CK.)
 Rhabdomyolysis; vigorous hydration and alkalinization of the urine using
IV sodium bicarbonate to prevent renal failure.
 Pharmacotherapy to reduce rigidity; dantrolene (IV 0.8–2.5mg/kg qds; PO
50–100mg bd), lorazepam (up to 5mg); 2nd line: bromocriptine (PO 2.5–
10mg tds, increase to max 60mg/day), amantidine (PO 100–200mg bd); 3rd
line: nifedipine;
• Consider ECT (Note: increases risk of fatal arrhythmias)
• Nursing management

 Early identification of NMS is very important to reduce the mortality. So, nurses should have the
knowledge of side effects of antipsychotics, symptoms of NMS and the indications of the laboratory
values of the psychiatric patients on medicatopn.
 Immediate information to the doctors and immediate transfer to the intensive care settings.
 Monitoring vital signs
 Oxygenation.
 Ensure adequate hydration with IV fluids.
 Measures to reduce the temperature (e.g. cooling blankets, antipyretics, cooled IV fluids, ice packs,
evaporative cooling etc.).
 Medications as prescribed.
 Close observation of the patient.
 Providing patient and family education regarding side effects of antipsychotics and NMS symptoms.
• Course

 May last 7–10 days after stopping oral antipsychotics and up to 21 days after depot
antipsychotics (e.g. fluphenazine).

• Prognosis

 In the absence of rhabdomyolysis, renal failure, or aspiration pneumonia, and with good
supportive care, prognosis is good.

• Follow-up

 Monitor closely for residual symptoms. Once symptoms have settled allow 2+wks (if
possible) before restarting medication (use low-dose, low-potency, or atypical agents).
 Consider prophylaxis (bromocriptine).
 Inform patient about risk of recurrence if given antipsychotic medication.
 Ensure this is recorded prominently in their medical notes.