Lavoro svolto da Federica Fassio e Francesca Di Nunno
DESCRIPTION
Lithium is a ion (Li+) that can be used as a drug (Wikipedia Lithium pharmacology).
A number of chemical salt are used medically as a mood stabilizing drug. Lithium carbonate (Li2CO3), sold under several trade names, is the most commonly prescribed, while the citrate salt lithium citrate (Li3C6H5O7), the sulfate salt lithium sulfate (Li2SO4), lithium aspartate and the orotate salt lithium orotate are alternatives.
CLASSIFICATION
Lithium carbonate is often referred to as an “antimanic” drug, but in many parts of the world it is considered a “mood-stabilizing” agent because of its primary action of preventing mood swings in patients with bipolar affective (manic-depressive) disorder.
INDICATIONS
1. Bipolar Affective Disorder
Stephen Soreff; Feb 9 2010
2. Recurrent endogenous depression
3. Schizoaffective disorder
4. Schizophrenia
PHARMACOKINETICS
- Absorption: virtually complete within 6–8 hours; peak plasma levels in 30 minutes to 2 hours
- Distribution: in total body water; slow entry into intracellular compartment. Initial volume of distribution is 0.5 L/kg, rising to 0.7–0.9 L/kg; some sequestration in bone. No protein binding.
- Excretion: virtually entirely in urine. Lithium clearance about 20% of creatinine. Plasma half-life about 20 hours
- Target plasma concentration: 0.6–1.4 mEq/L
- Dosage: 0.5 mEq/kg/d in divided doses
Monitoring Treatment
Clinicians rely on measurements of serum lithium concentrations for assessing both the dosage required for treatment of acute mania and for prophylactic maintenance.
MOLECULAR MECHANISM
Despite considerable investigation, the mode of action of lithium remains unclear. The major possibilities being investigated include:
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. It inhibits the latter process, ie, Li+-Na+ exchange is gradually slowed after lithium is introduced into the body. At therapeutic concentrations (around 1 mmol/L), it does not significantly affect the Na+/Ca2+ exchange process or the Na+/K+ ATPase sodium pump.
EFFECTS ON NEUROTRANSMITTERS
Lithium appears to enhance some of the actions of serotonin, though findings have been contradictory. Its effects on norepinephrine are variable. The drug may decrease norepinephrine and dopamine turnover, and these effects, if confirmed, might be relevant to its antimanic action. Lithium also appears to block the development of dopamine receptor supersensitivity that may accompany chronic therapy with antipsychotic agents. Finally, lithium may augment the synthesis of acetylcholine, perhaps by increasing choline uptake into nerve terminals.
EFFECTS ON SECOND MESSENGERS
One of the best-defined effects of, lithium is its action on inositol phosphates. Early studies of lithium demonstrated changes in brain inositol phosphate levels, but the significance of these changes was not appreciated until the second-messenger roles of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) were discovered. IP3 and DAG are important second messengers for both -adrenergic and muscarinic transmission. Lithium inhibits several important enzymes in the normal recycling of membrane phosphoinositides, including conversion of IP2 to IP1 (inositol monophosphate) and the conversion of IP1 to inositol. This block leads to a depletion of phosphatidylinositol-4,5-bisphosphate (PIP2), the membrane precursor of IP3 and DAG. Over time, the effects of transmitters on the cell diminish in proportion to the amount of activity in the PIP2-dependent pathways. Before therapy, such activity might be greatly increased in mania; thus, lithium could cause a selective depression of the overactive circuits.
Comment
- If Bipolar disorder (BP) depends on impairment of inositol metabolism and and in alcoholism we have lower liver inositol synthesis we can expect an increased prevalence of BP in alcoholism
- Classic Kraepelian observations and contemporary epidemiological studies have noted a high prevalence rate between bipolar disorder and alcoholism. The extent to which these two illnesses are comorbid (i.e., two distinct disease processes each with an independent course of illness), genetically linked, or different phenotypic expressions of bipolar illness itself continues to be investigated. It is increasingly clear that co-occurring alcohol abuse or dependence in bipolar disorder phenomenologically changes the illness presentation with higher rates of mixed or dysphoric mania, rapid cycling, increased symptom severity, and higher levels of novelty seeking, suicidality, aggressivity, and impulsivity. It is very encouraging that interest and efforts at evaluating pharmacotherapeutic compounds has substantially increased over the past few years in this difficult-to-treat patient population. This article will review the clinical studies that have evaluated the effectiveness of conventional mood stabilizers (lithium, carbamazepine, divalproex, and atypical antipsychotics) in the treatment of alcohol withdrawal and relapse prevention in patients with alcoholism and in the treatment of bipolar disorder with comorbid alcoholism. A number of add-on, adjunctive medications, such as naltrexone, acamprosate, topiramate, and the atypical antipsychotics quetiapine and clozapine, may be candidates for further testing.
- Studies of noradrenergic effects in isolated brain tissue indicate that lithium can inhibit norepinephrine-sensitive adenylyl cyclase. Such an effect could relate to both its antidepressant and its antimanic effects. The relationship of these effects to lithium’s actions on IP3 mechanisms is currently unknown.
Because lithium affects second-messenger systems involving both activation of adenylyl cyclase and phosphoinositol turnover, it is not surprising that G proteins are also found to be affected. Several studies suggest that, lithium may uncouple receptors from their G proteins; indeed, two of lithium’s most common side effects, polyuria and subclinical hypothyroidism, may be due to uncoupling of the vasopressin and thyroid-stimulating hormone (TSH) receptors from their G proteins.
The major current working hypothesis for lithium’s therapeutic mechanism of action supposes that its effects on phosphoinositol turnover, leading to an early relative reduction of myoinositol in human brain, are part of an initiating cascade of intracellular changes. Effects on specific isoforms of protein kinase C may be most relevant. Alterations of protein kinase C-mediated signaling alter gene expression and the production of proteins implicated in long-term neuroplastic events that could underlie long-term mood stabilization.
Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks
Drug Interactions
Renal clearance of lithium is reduced about 25% by diuretics (eg, thiazides), and doses may need to be reduced by a similar amount. A similar reduction in lithium clearance has been noted with several of the newer nonsteroidal anti-inflammatory drugs that block synthesis of prostaglandins. This interaction has not been reported for either aspirin or acetaminophen. All neuroleptics tested to date, with the possible exception of clozapine and the newer antipsychotics, may produce more severe extrapyramidal syndromes when combined with lithium.
PHARMACOGENOMICS
Genetic control of lithium sensitivity and regulation of inositol biosynthetic genes
King J, Keim M, Teo R, Weening KE, Kapur M, McQuillan K, Ryves J, Rogers B, Dalton E, Williams RS, Harwood AJ; 17 Jun 2010
Predicting response to lithium in bipolar disorder: a critical review of pharmacogenetic studies
Smith DJ, Evans R, Craddock N; 19 April 2010
Lithium: a key to the genetics of bipolar disorder
Cristiana Cruceanu, Martin Alda, Gustavo Turecki; 19 August 2009
SIDE EFFECTS
NEUROLOGIC AND PSYCHIATRIC ADVERSE EFFECTS
- Tremor
- Choreoathetosis
- Motor hyperactivity
- Ataxia
- Dysarthria
- Aphasia
- Mental confusion
- Withdrawal
DECREASED THYROID FUNCTION
- Decreases thyroid function
- Frank thyroid enlargement
- Hypothyroidism
(Obtaining a serum TSH concentration every 6–12 months, however, is prudent.)
NEPHROGENIC DIABETES INSIPIDUS AND OTHER RENAL ADVERSE EFFECTS
- Polydipsia
- Polyuria
- Nephrogenic diabetes insipidus
- Cronic interstitial nephritis
- Minimal-change glomerulopathy with nephrotic syndrome
EDEMA
CARDIAC ADVERSE EFFECTS
- The bradycardia-tachycardia (“sick sinus”) syndrome
- T-wave flattening
MISCELLANEOUS ADVERSE EFFECTS
- Transient acneiform eruptions
- Folliculitis
- Leukocytosis
TOXICITY
Therapeutic overdoses of lithium are more common than those due to deliberate or accidental ingestion of the drug. Therapeutic overdoses are usually due to accumulation of lithium resulting from some change in the patient’s status, such as diminished serum sodium, use of diuretics, or fluctuating renal function. Since the tissues will have already equilibrated with the blood, the plasma concentrations of lithium may not be excessively high in proportion to the degree of toxicity; any value over 2 mEq/L must be considered as indicating likely toxicity. Because lithium is a small ion, it is dialyzed readily.
MORE ABOUT MECHANISM...
Psychiatry Res. 2010 Jan 30;175(1-2):78-81. Epub 2009 Dec 6.
Cholesterol and affective morbidity
Fiedorowicz JG, Palagummi NM, Behrendtsen O, Coryell WH.
Psychiatry Investig. 2009 Jun;6(2):78-84. Epub 2009 Jun 30.
Correlates of metabolic abnormalities in bipolar I disorder at initiation of acute phase treatment
Kim B, Kim S, McIntyre RS, Park HJ, Kim SY, Joo YH.
Nephrol Dial Transplant. 2010 Jun 4. [Epub ahead of print]
Carbamazepine can induce kidney water absorption by increasing aquaporin 2 expression
de Bragança AC, Moyses ZP, Magaldi AJ.
