Lithium is an alkali metal that has been used to treat bipolar disorder and other conditions. It has a narrow therapeutic window, and toxicity can occur with both acute and chronic overdoses. Symptoms of acute toxicity initially involve the GI system but then progress to the CNS, causing tremors, seizures, and potentially coma. Treatment involves fluid replacement and electrolyte monitoring, with dialysis for severe cases. Chronic toxicity poses the highest neurologic risk due to lithium accumulation in tissues over time.

1. Nisreen Sami Hassab
Higher Diploma in
Toxicology & Pharmacology
Supervised by:-
Dr. Ammar Ali Hussein
2019
LITHIUM TOXOICITY

2. Lithium (Li), chemical element of Group 1 (Ia) in the periodic table,
the alkali metal group, lightest of the solid elements. The metal itself—which
is soft, white, and lustrous—and several of its alloys and compounds are
produced on an industrial scale.
It has a single valence electron, which it readily loses to become the
positively charged cation.
"Lithia" water was first used in the late 1800s to treat mania and gout. Over
time, and likely due to low lithium content, "Lithia" water was ultimately
replaced by lithium tablets. With the higher concentrations in the tablets,
lithium's association with tremors and weakness became apparent and in
1898the first descriptions of lithium toxicity appeared.

3. About a half century later, the calming effects of lithium in 10 patients
with mania were described ; the drug's more toxic effects were
recognized when lithium chloride was used as a salt substitute in
patients with heart failure in 1949 .
Lithium's toxic effects limited its clinical use until appropriate serum
monitoring became more readily available. In the 1970s, Lithium
carbonate was approved in the United States for the treatment of acute
mania and bipolar disorder and it has been in use ever since( FDA)
banned the use it in 1940s because the fatalities but lifted the ban in
1970s.
In 2016, there were 6901 cases of lithium intoxication reported to the
American Association of Poison Control Centers .

5. What important elements share a similar valence with lithium?
Sodium and potassium.
Lithium is usually administered orally as a salt in combination with what anion?
Lithium carbonate (Li2CO3). Lithium citrate and lithium orotate are also used.

6. What is the mechanism of action of lithium?
While exact mechanisms are unknown, lithium appears to modulate the
release of serotonin and norepinephrine. lithium has been used as a mood
stabilizing agent, its mechanism of action remains elusive but may reflect
alterations in transduction pathways related to glutamate, inositol
monophosphate, and glycogen synthase kinase 3 in the central nervous
system (CNS). Lithium has been shown to decrease the release of
noradrenaline and dopamine from nerve terminals and may also transiently
increase the release of serotonin, which may account for its mood stabilizing
properties.
Lithium has a very narrow therapeutic index, and clinical features of toxicity
can be noted at plasma lithium concentrations .Patients with bipolar affective
disorder have diminished GABA neurotransmission. Thus, low GABA levels
can result in excitatory toxicity. Lithium increases the levels of GABA which in
turn reduces glutamate and down regulates the NMDA receptor. Lithium also
directly activates the GABA receptor .
.

7. Clinical Features of Lithium Toxicity:-
Influence of the Pattern of Exposure on Lithium Pharmacokinetics, and the Onset
and Offset of Toxicity Although lithium can eventually lead to multisystem toxicity,
lithium’s most important site of toxicity is the CNS.
The risk of development of neurotoxicity is directly related to the pattern of
exposure that led to the poisoning, which in turn reflects the pharmacokinetic
properties of lithium. There are 3 patterns of lithium poisoning: acute, acute-on-
chronic, and chronic .
The risk of neurotoxicity is lowest with acute poisoning and highest with chronic
poisoning, owing to the differences in the opportunity for lithium to distribute to the
intracellular space in the CNS, relative to the plasma concentration–time profile.
Over a number of hours post ingestion, lithium distributes into the whole body
water. The rate at which it distributes in, and then out of, intracellular spaces is
slow relative to the rate at which lithium is eliminated from the body.

8. The blood–brain barrier may additionally slow distribution into the
brain. Because the intracellular concentration in the brain is
considered the main site of toxicity of lithium, Chronic poisoning
occurs when lithium intake exceeds elimination on a chronic basis,
usually weeks, Finally, acute-on-chronic poisoning occurs when an
individual who is already taking lithium chronically takes an acute
overdose. Here, the risk of neurotoxicity depends on the steady-state
concentration prior to the overdose.

10. What are four medical indications for lithium use?
1. Bipolar disorder
2. Depression (often in combination with antidepressants)
3. Prevention of migraine and cluster headaches
4. Treatment of thyroid storm in patients with iodine allergy.
What are four nonmedical uses of lithium?
1. Batteries
2. Mixed with alloys of aluminum, cadmium, and copper to make aircraft parts
3. Lithium chloride (LiCl) is a dessicant.
4. Lithium hydroxide (LiOH) is used to scavenge carbon dioxide in submarines
and spacecraft, forming lithium carbonate.
What are the clinical findings of acute lithium toxicity?
Initial findings manifest as GI symptoms, including nausea, vomiting, and
diarrhea. This is followed by CNS symptoms, including tremor, nystagmus,
fasciculations, ataxia, hyperreflexia, lethargy, seizures, and coma.
What ECG findings occur with lithium toxicity?
1. Flattened or inverted T-waves
2. ST depression

12. •Box 1. Drug Interactions That Can Increase Plasma Lithium
Concentrations:-
Nonsteroidal anti-inflammatory
drugs (NSAIDS), Renin-
angiotensin system inhibitors
Reduce glomerular filtration rate
(GFR)
Thiazide diuretics,
Spironolactone
5 Promote renal tubular
reabsorption
Calcium channel blockers
(diltiazem, verapamil).
Nifedipine has been shown to
reduce lithium clearance when
administered chronically
Uncertain mechanism

13. •Box 2. Clinical Manifestations of Lithium
Poisoning.
Manifestation:Organ system:
Wandering atrial pacemaker , sinus bradycardia, ST-
segment elevation, unmasking Brugada syndrome,
prolonged QT interval Uncommonly, life-threatening
arrhythmias
Cardiovascular
Lethargy, ataxia, confusion, agitation, neuromuscular
excitability (irregular coarse tremors, fasciculations,
myoclonic jerks, hyperreflexia) Severe lithium
toxicity can manifests as seizures, including
nonconvulsive status epilepticus
Neurological
Nausea, vomiting, diarrhoea, ileusGastrointestinal

14. •Box 3. Relationship Between Severity of Chronic Lithium
Toxicity and Plasma Concentrations.
Severity:Plasma Lithium
Concentration (mmol/L):
nausea, vomiting, tremor,
hyperreflexia, agitation, ataxia, muscle
weakness
(mild) 1.5-2.5
stupor, rigidity, hypertonia,
hypotension
(moderate ) 2.5-3.5
coma, convulsions, myoclonia,
collapse
(severe ) >3.5

15. •Box 4. Persistent Manifestations of Lithium
Toxicity:-
ataxia, dysarthria, dysphagiaCerebellar:
impaired memory, attention, executive
control, visuospatial deficits
Cognitive:
Tubulointerstitial nephropathy, nephrogenic
diabetes insipidus
Renal:

16. •Acute poisoning:
• It is generally stated that ingestion of >7.5 mg/kg of elemental lithium
(approximately 40 mg/kg of lithium carbonate) is associated with an increased
risk of toxicity. This dose corresponds to a concentration of 1.4 mmol/L elemental
lithium in the body water phase. However, acute overdoses generally confer a
better prognosis due to the lower risk of neurotoxicity because lithium will not
have had sufficient time to accumulate in the brain or other tissues, relative to
the shorter time required for distribution to less toxic sites (eg, erythrocytes,
muscle) and excretion.
•Acute-on-chronic poisoning:
• Here, the risk of neurotoxicity is higher than in acute poisoning because
some lithium has already distributed to the intracellular space in the CNS prior to
poisoning , patient who did not receive dialysis despite very high plasma lithium
concentrations (10.6 mmol/L at 13 hours after ingestion)
• with acute-on-chronic poisoning .

17. •Chronic poisoning:
•This mode of poisoning confers the highest risk of
neurotoxicity for 2 reasons,first, the time course (usually
weeks) maximizes the opportunity for lithium to distribute
to the CNS compartment and to accumulate in neural tissue
and induce toxicity , Second, the half-life of lithium is
prolonged in chronic poisoning compared to acute29 which
reflects both the redistribution of lithium from the
intracellular compartment to the vascular compartment and
possibly changes in renal handling of lithium such as seen
in nephrogenic diabetes insipidus.

18. Pregnancy and breast feeding:-
• Lithium is a teratogen, causing birth defects in a small number of newborn
babies. and several retrospective studies have demonstrated possible increases in
the rate of a congenital heart defect known as , if taken during a woman's
pregnancy. As a consequence, fetal echocardiography is routinely performed in
pregnant women taking lithium to exclude the possibility of cardiac
anomalies. Lamotrigine seems to be a possible alternative to lithium in pregnant
women for the treatment of acute bipolar depression or for the management of
bipolar patients with normal mood. Gabapentin and clonazepam are also
indicated as antipanic medications during the childbearing years and
during pregnancy. Valproic acid and carbamazepine also tend to be associated
with teratogenicity.
• While it appears to be safe to use while breastfeeding a number of guidelines
list it as a contraindication .

19. • Patient factor:-
• Nephrogenic diabetes insipidus:
the most common renal side effect of lithium, which predisposes the individual
to volume depletion, in particular free water, with consequent activation of the
renin–angiotensin aldosterone system which promotes lithium reabsorption.
Age older than 50 years: It may reflect age-related reduction in physical
reserve and/or increased prevalence of polypharmacy associated with this age-
group that predisposes to lithium poisoning.
• Renal impairment:
Lithium excretion is almost exclusively dependent on glomerular filtration rate
(GFR), Estimated GFR < 45 mL/min/1.73 m2,
Kidney Disease, In adults without a baseline serum creatinine, serum
creatinine > 176 mmol/L in adults, or > 132 mmol/L in the elderly patients or those
with low muscle mass Serum creatinine greater than 2 times the upper limit of
normal for age and weight in children without a baseline serum creatinine
concentration The presence of oligo/anuria .

20. •Thyroid dysfunction:
The prevalence of clinical hypothyroidism is increased in patients
taking lithium therapy, hyperthyroidism can increase lithium
reabsorption thereby reducing lithium excretionm therapy and may
lead to volume depletion secondary to the osmotic effects of
hypercalcemia.
The role of activated charcoal in the treatment of lithium toxicity?
It is a poor binder of lithium and is not useful in isolated lithium
ingestion; it should be given if there is a possibility of a recent co-
ingestion.

21. Describe the treatment for acute lithium toxicity:-
1. Optimize fluid and electrolyte (especially sodium) status to
increase renal excretion of lithium.
2. Whole bowel irrigation may be used to limit absorption.
3. Dialysis may be considered for severe neurotoxicity, but
forced diuresis plays no role in treatment.
The treatment for chronic lithium toxicity:-
Similar to that of acute toxicity; however, since CNS tissue
concentrations arelikely to be higher and neurologic symptoms
are likely to be more prominent, hemodialysis should play a
greater role in treatment.

22. Treatment:-
Stomach pumping. This procedure may be an option if you’ve taken lithium
within the last hour.
Whole bowel irrigation. You’ll swallow a solution or be given one through a tube
to help flush the extra lithium out of your intestines.
IV fluids. You may need these to restore your electrolyte balance.
Hemodialysis. This procedure uses an artificial kidney, called a hemodialyzer, to
remove waste from your blood.
Medication. If you start to have seizures, your doctor might prescribe an
anticonvulsant medication.
Vital sign monitoring. Your doctor may choose to keep you under supervision
while they monitor your vital signs, including your blood pressure and heart rate,
for any unusual signs.
Lithium toxicity can have lasting effects, so it’s important to seek medical
attention immediately if you think you may have it. Avoid home remedies, such
as activated charcoal, which doesn’t bind to lithium.
Sodium Polystyrene Sulfonate. Sodium polystyrene sulfonate is an ion exchange
resin that can be used as an adjunctive treatment for the management of
hyperkalemia.

23. Diuretics:-
The addition of amiloride and/or furosemide may
theoretically enhance lithium elimination by blocking
reabsorption in the renal tubules. Also, amiloride is a
proposed treatment for lithium-induced nephrogenic
diabetes insipidus. Amiloride blocks the epithelial sodium
channel located at the apical membrane of the principal
cells in the distal convoluted tubules and collection
system, which may reduce reabsorption.

24. Conclusion :-
Despite the diverse presentation of lithium toxicity, it remains a
common drug to treat a multitude of psychiatric disorders. Given its
prevalence in the community, it is important to recognize the initial
presentation of lithium toxicity as further progression can cause
development of permanent neurologic disorders and severe renal
dysfunction. Finally, always consider drug interactions, especially
with other antipsychotic medications as well as nephrotoxic agents,
particularly since the combination of these drugs with lithium
increases the risk of toxicity.

26.  References:-
1_Toxicology recall / editors, Christopher P. Holstege, Matthew P.
Borloz, John P. Benner ; associate
editors, David T. Lawrence, Nathan P. Charlton.2009
2_Journal of Intensive Care Medicine
The Author(s) 2016
Reprints and permission:
sagepub.com/journalsPermissions.nav
3-Medically reviewed by Dena Westphalen, PharmD on January 24,
2018 — Written by Jacquelyn Cafasso.
4-Altschul E, Grossman C, Doughtery R, et al. Lithium Toxicity: A
Review of Pathophysiology, Treatment, and Prognosis. Practical
Neurology. March 2016:42–45.