Lithium (move to Drugs)
Lithium SAMPLE

Author: Federica Fassio
Date: 04/07/2010

Description

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

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.

Metabolism: none

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.

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

Predicting response to lithium in bipolar disorder: a critical review of pharmacogenetic studies

Lithium: a key to the genetics of bipolar disorder

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

  • sodium retention

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.

Comments
2010-07-05T09:23:15 - Gianpiero Pescarmona

Psychiatry Res. 2010 Jan 30;175(1-2):78-81. Epub 2009 Dec 6.
Cholesterol and affective morbidity. 2010
Fiedorowicz JG, Palagummi NM, Behrendtsen O, Coryell WH.

Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA. jess-fiedorowicz@uiowa.edu
Abstract
Depression and mania have been linked with low cholesterol though there has been limited prospective study of cholesterol and subsequent course of affective illness. We studied the relationship between fasting total cholesterol and subsequent depressive and manic symptoms. A total of 131 participants from a prospective cohort study were identified as having had a fasting total cholesterol evaluation at intake. Participants were predominantly inpatients at index visit and were followed for a median of 20 and up to 25 years. Cholesterol was modeled with age, gender, and index use of a mood stabilizer in linear regression to assess its influence on subsequent depressive symptom burden in participants with unipolar disorder as well as depressive and manic symptom burden in participants with bipolar disorder. Among bipolar participants (N=65), low cholesterol predicted a higher proportion of follow-up weeks with manic, but not depressive symptoms. Cholesterol did not appear to predict depressive symptom burden among participants with unipolar depression (N=66). Lower cholesterol levels may predispose individuals with bipolar disorder to a greater burden of manic symptomatology and may provide some insight into the underlying neurobiology.

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. 2009
Kim B, Kim S, McIntyre RS, Park HJ, Kim SY, Joo YH.

Department of Psychiatry and Health Promotion Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Abstract
OBJECTIVE: Treatment of bipolar patients is often complicated by metabolic abnormalities such as obesity, diabetes, and dyslipidemia. We therefore evaluated the prevalence of these abnormalities and their correlates, in bipolar I patients, at the time of commencement of pharmacological treatment for acute mood episodes. METHODS: The study cohort consisted of 184 bipolar I patients hospitalized for treatment of acute mood episodes. Socio-demographic and clinical variables were noted and metabolic parameters, including body mass index, fasting plasma glucose, fasting total cholesterol, and current treatment(s) for diabetes and/or dyslipidemia were measured before initiating medication(s). RESULTS: Fifty-six (30.4%) subjects met our criteria for obesity; 80 (43.5%) had hyperglycemia, with 8 (4.3%) receiving anti-diabetic medication; and 38 (20.7%) had hypercholesterolemia, with 2 (1.1%) receiving cholesterol-lowering agents. We found that male sex (chi(2)=5.359, p=0.021), depressed or mixed state versus manic state (chi(2)=4.302, p=0.038), and duration of illness (t=2.756, p=0.006) were significantly associated with obesity. Older age (t=3.668, p<0.001), later age of disease onset (t=2.271, p=0.024), and lower level of educational attainment (beta=-0.531, p=0.001) were associated with hyperglycemia. CONCLUSION: Our finding that metabolic abnormalities are prevalent when initiating acute pharmacological treatment in bipolar I patients indicates that these factors should be integrated into treatment plans at the onset of disease management.

Nephrol Dial Transplant. 2010 Jun 4. [Epub ahead of print]
Carbamazepine can induce kidney water absorption by increasing aquaporin 2 expression. 2010
de Bragança AC, Moyses ZP, Magaldi AJ.

Universidade de Sao Paulo, Hospital das Clínicas da Faculdade de Medicina da USP, Sao Paulo, Brazil.
Abstract
BACKGROUND: Carbamazepine (Carba) is an anticonvulsant and psychotropic drug used widely for the treatment of intellectual disability and severe pains, but the incidence of hyponatremia is a common related occurrence. This hyponatremia is frequently attributed to a SIADH induced by this drug. It is also known that Carba is used to decrease the urinary volume in Diabetes Insipidus (DI) because it has an antidiuretic effect. Lithium (Li) is one of the most important drugs used to treat bipolar mood disorders. However Li has the undesirable capacity to induce DI. Nowadays, the association of these drugs is used in the treatment of patients with psychiatric and neurological problems. METHODS: In vivo and in vitro (microperfusion) experiments were developed to investigate the effect of Carba in the rat Inner Medullary Collecting Duct (IMCD). RESULTS: The results revealed that Carba was able to stimulate the V2 vasopressin receptor-Protein G complex increasing the (Pf) and water absorption. In vivo studies showed that in rats with lithium-induced DI, Carba decreased the urinary volume and increased the urinary osmolality. AQP2 expression was increased both in normal IMCD incubated with Carba and in IMCD from lithium-induced DI after Carba addition to the diet, when compared with the control. CONCLUSION: These results showed that the hyponatremia observed in patients using this anticonvulsant drug, at least in part, is due to the Carba capacity to increase IMCD's Pf and that the Lithium-Carbamazepine association is beneficial to the patient.

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