+
PHM142 Fall 2011
Instructor: Henderson
Biochemistry of Lithium
Lauren Filice (lauren.filice@mail.utoronto.ca)
Jennifer Jin (jennifer.jin@utoronto.ca) Course: PHM142
Marina Mikhail (marina_mikhail@hotmail.com) Instructor: Dr. Jeffrey Henderson
Clarisse Nyirazuba (clarisse.nyirazuba@utoronto.com) Sign-up date: Nov. 28, 2011
+
Outline
Lithium ion
Pharmacological use
Psychiatric disorders
Mechanisms of action
Toxicity
Drug interactions
Summary
+
What is lithium?
Lithium (Li+) is a monovalent cation
Soft, low density alkali metal
Lithium salts have been used as medication for over 60 years
Pharmacological effects were discovered in 1949 by John Cade
Mood-stabilizing drug used in a variety of neuropsychiatric
disorders
Modifys intracellular signal transduction pathways in the CNS
+
Pharmacological use
Drugs: lithium carbonate (Li2CO3), lithium citrate (Li3C6H5O7 - shown)
Brand names: Carbolith, Duralith, Lithane, Lithmax
Treatment of bipolar disorder, depression, chronic cluster headache
Anti-suicidal and neuro-protective effects
Well-absorbed, widely distributed in most tissues, crosses blood-
brain barrier
Exhibits narrow therapeutic window with serious toxic side effects
Numerous drug and food interactions
Controversial, but still generally considered effective as a
psychiatric drug Image from Wikipedia
+
Psychiatric disorders
Bipolar disorder (manic depressive illness)
characterized by recurrent mood swings, from euphoric to depressive
fairly high morbidity and mortality, affects 1-3% of the population
associated with many other illnesses and substance abuse
due to changes in the phosphatidylinositol second messenger system
Acute manic episodes
elated mood
hyperactivity
decreased sleep, attention span
irritability
Depression
feeling of hopeless, helpless, or worthless
loss of interest or pleasure
decreased energy, concentration
changes in appetite, sleep
+
Mechanisms of lithium
in bipolar disorder
Possible mechanisms which have previously been proposed:
Inositol depletion
Decreased GSK-3 activity
Stabilization of cAMP levels
Monoamine Hypothesis on Neurotransmitter Signaling
+
Inositol depletion
Li+ enters cells as Na+ channel mimic
Phosphatidylinositol Signaling Cascade:
inhibits 2 enzymes : Inositol phosphatase converting inositol-2
phosphate to inositol 1 phosphate (IP1), and Inositol phosphatase
converting IP1 to inositol.
Lithium is thought to inhibit these enzymes by mimicking Mg2+.
Reduced PIP2 levels while enhancing PIP3
Downstream, low levels of IP3 and DAG (Diacylglycerol) result in
lowered PKC (Protein Kinase C) activity and Ca2+ release
Schloesser & Huang et al, 2007
+
Decreased glycogen synthase
kinase-3 activity
Glycogen synthase kinase (GSK-3) is a major brain enzyme involved
in:
stabilizing synaptic connections
modulating critical neuronal circuits in brain
Lithium directly inhibits GSK3 by competitive binding N-terminal
active site for Mg2+
not effective on its own
GSK-3 activity is also inhibited INDIRECTLY by Li+
Li+ upregulates the PI3/Akt pathway
Serine phosphorylation levels of 3(beta) Ser-9 and 3(Alpha) Ser-21
The PP-1/I-2 path inhibition enhances GSK-3 inhibition
+
Inhibition of GSK-3
by lithium
Schloesser & Huang et al, 2007
+
Lithium toxicity
Lithium toxicity relates to serum concentrations in excess of 1.5
mmol/L which are often very close to therapeutic concentrations
of the drug
Acute lithium overdose may lead to symptoms of nausea,
vomiting, diarrhea
Chronic lithium intoxication may lead to symptoms of drowsiness,
muscle twitches, altered mental status, seizures or coma
To treat lithium toxicity, can reduce dosage, maintain
fluid/electrolyte balance, can use hemodialysis if renal failure
occurs
`
http://www.davita.com/kidney-
disease/dialysis/treatment/what-is-
+
Hypothyroidism
In this state the thyroid gland does not make enough
thyroid hormone
Lithium is a goitrogen and may cause goitre by inhibition of
TSH receptor
Chance of occurence is as high as 15% of patients on long-
term lithium therapy
http://www.webmd.com/a-to-z-guides/thyroid-gland
+
Mechanism of hypothyroidism
caused by lithium Li+
Li+
Li+
Principles of Human Physiology, 2009
+
Drug interactions
Decreases serum Increases serum
concentration of Lithium concentration of Lithium
Calcitonin ACE Inhibitors
Calcium Polystyrene Sulfonate Angiotensin II Receptor Blockers
Carbonic Anhydrase Inhibitors Nonsteroidal Anti-Inflammatory
Sodium Polystyrene Sulfonate Sodium Bicarbonate
Theophylline Derivatives Sodium Chloride
Thiazide Diuretics Topiramate
Sodium Bicarbonate Desmopressin
Sodium Chloride Loop Diuretics*
Antipsychotics Calcium Channel Blockers*
Loop Diuretics* Abrupt withdrawal of caffeine (24%)
Calcium Channel Blockers
+
Drugs that enhance the adverse
or toxic effects of lithium
CarBAMazepine
Calcium Channel Blockers
Drug Adverse
Fosphenytoin Effects/
Lithium Side
MAO Inhibitors Effects
Methyldopa
Phenytoin
Potassium Iodide
Selective Serotonin Reuptake Inhibitors
+
Lithium enhances the adverse
or toxic effects of these drugs
Amphetamines
Antipsychotics
Lithium Adverse
Desmopressin Effects/
Drug Side
Sibutramine Effects
Serotonin Modulators
Neuromuscular-Blocking Agents
Tricyclic Antidepressants
+
Summary
Lithium is a mood-stabilizing drug with anti-suicidal properties used for treatment of bipolar disorder,
depression, and chronic cluster headache.
It generally effective, but its use is controversial due to its narrow therapeutic window, many serious toxic effects,
and numerous food and drug interactions.
Lithium directly and indirectly inhibits a major enzyme GSK-3 known to have long-term changes in stabilizing
synaptic connections and modulating critical neuronal circuits in brain.
Lithium mimics Mg2+ and disrupts the phosphatidylinositol signalling cascade by competitive inhibition of
inositol phosphatase enzymes, which depletes inositol levels and blocks the regeneration of PIP2.
Low levels of IP3 and DAG leads to low PKC activity and Ca2+ release in the cell.
Lithium toxicity may occur with overdose of the drug or occasionally even at therapeutic concentrations.
This leads to common symptoms for acute toxicity like nausea and vomiting, or symptoms of chronic toxicity such
as drowsiness and muscle spasms.
One adverse effect, hypothyroidism, is caused by inhibition in the thyroid hormone production pathway.
Abruptly decreasing the ingestion of caffeine will increase the serum concentration of lithium.
Multiple drugs have the capabilities to either increase or decrease the serum concentration of lithium, therefore,
lithium doses needs to be altered based on the effects of these drugs.
+
References
Borsotto M, et al (2007): PP2A-Bgamma subunit and KCNQ2 K+ channels in bipolar
disorder. Pharmacogenomics Journal (2):123-32.
Frost RE, Messiha FS. (1983) Clinical Uses of Lithium Salts. Brain Res. Bull. 11(2):219-231.
Livingstone, C., & Rampes, H. (2006). Lithium: a review of its metabolic adverse effects. J.
of Psychopharmacology, 20(3), 347-355. Retrieved from http://tinyurl.com/cke3g96
Marmol F. (2008) Lithium: Bipolar disorder and neurodegenerative diseases Possible
cellular mechanisms of the therapeutic effects of lithium. Progress in
Neuropsychopharmacology & Bio. Psy. 32(8):1761-1771.
Mester R, Toren P, Mizrachi I, Wolmer L, Karni N, Weizman A. (1995) Caffeine Withdrawal
Increases Lithium Blood Levels. Biol Psychiatry 37:348-350.
O'Brien W. T. and. Klein P. S. (2009) Validating GSK3 as an in vivo target of lithium action.
Biochem Soc Trans. Vol 37( 5): 1133–1138.
+
References
Repchinsky, C., Welbanks, L., Hutsul, J., Jovaisas, B., & Lewis, G. (Eds.) (2011). Cps 2011,
compendium pharmaceuticals and specialties. (46 ed.). Canadian Pharmacist
Association. Retrieved from https://www-e-therapeutics-
ca.myaccess.library.utoronto.ca/cps.showMonograph.action?newSearch=true&simpleI
ndex=BrandGeneric&simpleQuery=lithium
Rybakowski J. (2011) Lithium in neuropsychiatry: A 2010 update. World J. Biol.
Psychiatry. 12(5):340-348.
Savarese, D. M., and Zand, J. M. (2011) Lithium: Drug information. Retrieved
fromhttp://www.uptodate.com.proxy1.lib.uwo.ca:2048/contents/lithium-drug-
information?source=search_result&search=Lithium&selectedTitle=1~150
Schloesser R.J, Huang J, Klein P.S, and Manji H. K. (2007) Cellular Plasticity Cascades in
the Pathophysiology and Treatment of Bipolar Disorder. Neuropsychopharmacology.
(33): 110-133.
Stanfield, C. L., & Germann, W. J. (2009). Principles of human physiology. (3 ed.). San
Francisco: Benjamin-Cummings Pub Co.