1. Basic pharmacology of lithium
Domina Petric, MD

2. Pharmacokinetics I.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

3. Pharmacokinetics Lithium is a small monovalent cation.
Absorption virtually completes within 6-8 hours.
Peak plasma levels are reached in 30 minutes to 2 hours.
Distribution: in total body water, slow entry into intracellular compartment.
Initial volume of distribution is 0,5 L7kg, rising to 0,7-0,9 L/kg.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

4. Pharmacokinetics Lithium shows some sequestration in bone.
It is not bind to proteins.
There is no metabolism.
Excretion is virtually entierly in urine.
Lithium clearance is about 20% of creatinine.
Plasma half-life is about 20 hours.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

5. Pharmacokinetics Target plasma concentration is 0,6-1,4 mEq/L.
Dosage is 0,5 mEq/kg/day in divided doses.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

6. Target plasma concentration
Pharmacokinetics
Dosage
0,6-1,4 mEq/L
Target plasma concentration
0,6-1,4 mEq/L
Metabolism
None
Katzung, Masters, Trevor. Basic and clinical pharmacology.

7. Pharmacodynamics
II.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

8. Pharmacodynamics
Lithium directly inhibits two signal transduction pathways.
It suppresses inositol signaling through depletion of intracellular inositol.
It inhibits glycogen synthase kinase-3 (GSK-3).
GSK-3 is a multifunctional protein kinase and it is a component of diverse intracellular signaling pathways.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

9. Pharmacodynamics
GSK-3 is a component of diverse intracellular signaling pathways:
insulin/insulin-like growth factor
brain-derived neurotrophic factor (BDNF)
Wnt pathway
GSK-3 phosphorylates β-catenin, resulting in interaction with transcription factors.
Modulation of energy metabolism, neuroprotection and increase of neuroplasticity.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

10. Effects on electrolytes and ion transport
Lithium is closely related to sodium in its properties.
It can substitute for sodium in generating action potentials and in Na+-Na+ exchange across the membrane.
Li+-Na+ exchange is gradually slowed after lithium is introduced into the body.
At therapeutic concentrations (1 mmol/L) lithium does not significantly affect the Na+-Ca2+ exchanger nor the Na+/K+-ATPase pump.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

11. Enyzmes affected by lithium at therapeutic concentrations
Enzyme
Enzyme function, action of lithium
Inositol monophosphatase
The rate-limiting enyzme in inositol recycling. Inhibited by lithium: depletion of substrate for IP3 production.
Inositol polyphosphate
1-phosphatase
Inositol recycling. Inhibited by Li: depletion of substrate for IP3 production.
Bisphosphate nucleotidase
Involved in AMP production. Inhibited by Li: lithium-induced nephrogenic diabetes insipidus.
Fructose 1,6-biphosphatase
Gluconeogenesis. Inhibited by Li.
GSK-3
(glycogen synthase kinase-3)
Constitutively active enzyme that limits neurotrophic and neuroprotective processes. Inhibited by Li.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

12. Effects on second messengers
Inositol trisphosphate (IP3) and diacylglycerol (DAG) are important second messengers for both α-adrenergic and muscarinic transmission.
Lithium inhibits inositol monophosphatase (IMPase) and other important enyzmes in the normal recycling of membrane phosphoinositides:
conversion of IP2 (inositol diphosphate) to IP1 (inositol monophosphate)
conversion of IP1 to inositol
Katzung, Masters, Trevor. Basic and clinical pharmacology.

13. Effects on second messengers
This block leads to a depletion of free inositol and ultimately of phosphatidylinositol-4,5-bisphosphate (PIP2).
PIP2 is the membrane precursor of IP3 and DAG.
The effects of transmitters on the cell diminish over the time in proportion to the amount of activity in the PIP2-dependent pathways.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

14. Effects on second messengers
Blockade
Conversion of IP2 to IP1 Li
Blockade
Conversion of IP1 to inositol Li
Final result Li
Depletion of free inositol and PIP2
Katzung, Masters, Trevor. Basic and clinical pharmacology.

15. Effects on second messengers
The activity of described pathways is postulated to be markedly increased during a manic episode.
Treatment with lithium would be expected to diminish the activity in these circuits.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

16. Effects on second messengers
Lithium can inhibit norepinephrine-sensitive adenylyl cyclase.
Such an effect could relate to both its antidepressant and its antimanic effects.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

17. Effects on second messengers
Lithium affects second-messenger systems involving both activation of adenylyl cyclase and phosphoinositol turnover.
Lithium may uncouple receptors from their G proteins.
Polyuria and subclinical hypothyroidism (adverse effects of Li) may be due to uncoupling vasopressin and thyroid-stimulating hormone receptors from their G proteins.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

18. Effects on second messengers
Effects of lithium on phosphoinositol turnover leads to an early relative reduction of myoinositol in human brain.
Alterations of protein kinase C-mediated signaling alter gene expression and the production of proteins implicated in long-term neuroplastic events: long-term mood stabilization.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

19. Literature Katzung, Masters, Trevor. Basic and clinical pharmacology.