Lithium

A 29-year-old man is brought to the emergency center in a drunken stupor. He is accompanied by his wife, who states that he hasn’t been himself at all for the past few months. According to his wife, he was evaluated for depression by his personal physician about 3 months ago and started on an SSRI. He responded quite well to this therapy over the subsequent 2 months. He started feeling so good and so energetic that he stopped taking his medication.

He found that he needed less and less sleep, to the point where he is now only sleeping 2-3 hours a day. He has been showering his wife with very expensive gifts and has hit the maximum limit on all of their credit cards. He has been extremely romantic and more interested in sexual relations than at any time before. He has also started drinking heavily and has passed out drunk more than once. His work has suffered, and his boss said that he is in danger of being fired if things don’t straighten out. Other than being drunk, his physical examination and blood tests are normal. He is admitted to the psychiatric unit with a diagnosis of bipolar disorder and started on lithium.

What is the mechanism of action of lithium?

What are the common side effects of lithium?

What is the mechanism of lithium-induced polyuria?

Answers to case: Lithium

Summary: A 29-year-old man is diagnosed with bipolar disorder and is started on lithium.

Mechanism of action of lithium:

Not entirely known but may be related to inhibition of membrane phospholipid turnover with a reduction in key second messengers, important in the overactivity of catecholamines thought to be related to mood swings characteristic of bipolar disorder.

Common side effects of lithium:

Nausea, vomiting, diarrhea, tremor, edema, weight gain, polydipsia, and polyuria.

Mechanism of lithium-induced polyuria:

Renal collecting tubule becomes resistant to antidiuretic hormone.

Clinical correlation

Lithium (Li⁺) is an effective treatment for bipolar disorder. It is administered orally as lithium carbonate and eliminated almost entirely through the kidney. Lithium has a narrow therapeutic window. Even at therapeutic levels (0.5-1.4 mM/L), there are frequent side effects. These include GI side effects, tremor, edema, polydipsia, and polyuria, as well as diabetes insipidus and weight gain. It can cause a benign thyroid enlargement and even overt hypothyroidism (5%). It has been associated with congenital malformations when used during pregnancy. Frequent monitoring of blood levels is critical.

There are potentially serious adverse effects at somewhat higher levels (above 2 mM/L). These include confusion, dizziness, ataxia, and vomiting at even higher blood levels (above 2.5 mM/L) progress to seizures, circulatory collapse, and coma. Lithium also has significant drug interactions that may increase its blood levels. Increased sodium clearance or depletion, such as caused by thiazide diuretics, some nonsteroidal anti-inflammatory drugs (NSAIDs; but not aspirin or acetaminophen), or severe vomiting and diarrhea, can lead to the increased renal reabsorption of lithium, thus causing toxicity.

Approach to pharmacology of lithium

Objectives

1. Describe the mechanism of action of lithium.
2. List other pharmacologic agents used to treat bipolar disease.

Definitions

Bipolar affective (manic-depressive) disorder: Bipolar disorder is characterized by paranoid thoughts, hyperactivity, and grandiosity, alternating in a cyclic fashion with symptoms of depression that often requires concomitant use of antidepressant agents.

Lithium: Class

In addition to Li⁺, the antiepileptic drugs valproic acid and carbamazepine, and the antipsychotic agent quetiapine are also first-line drugs that are effective for the treatment of the manic component of bipolar disease, often in patients unresponsive to lithium. These agents are referred to as mood stabilizers. Their adverse effect profiles when used to treat manic-depression are generally milder than for lithium.

Structure

Lithium is a small, monovalent cation that is similar in its properties to sodium and that enters cells through Na⁺ channels.

Mechanism of Action

Lithium has a number of actions that may have some relationship to its therapeutic activity, including its effects on the synthesis and release of the neuro-transmitters norepinephrine, serotonin, and dopamine. Lithium’s most common and best-studied effect is on the membrane recycling of phospho-inositides. It inhibits the key inositol phosphatase enzyme, inositol monophos-phatase, with depletion of free inositol that is necessary for the activity of the second messengers inositol trisphosphate (IP₃) and diacylglycerol (DAG), which mediate the cellular actions of G-protein-coupled muscarinic choli-noreceptors, α-adrenoceptors, and serotonin 5-HT₂ receptors.

Administration

Lithium, as lithium carbonate, carbamazepine, and valproic acid are administered orally.

Pharmacokinetics

Lithium has a relatively slow onset of therapeutic action (valproic acid’s effects can be achieved in a few days).

More than 90 percent of Li⁺ is excreted into the urine, but only 20 percent is cleared. Lithium is actively reabsorbed in the proximal tubule in competition with and at the same sites as Na⁺. Sodium depletion as a result of a low-Na⁺ diet, as well as diarrhea, concomitant use of diuretics, or even sweating, can lead to increased Li⁺ retention and toxicity.

Because the renal clearance of lithium increases during pregnancy and then decreases following delivery, careful monitoring of lithium concentrations is necessary to avoid toxicity.

Questions

[1] The therapeutic action of Li⁺ is thought to be caused by direct inhibition of which of the following?

A. Inositol monophosphatase

B. Inositol trisphosphate (IP₃)

C. Diacylglycerol (DAG)

D. Muscarinic cholinoreceptors

[2] The renal clearance of Li⁺ may increase with which of the following?

A. Diarrhea

B. Diuretics

C. NSAIDs

D. Pregnancy

[3] Which of the following is the most likely adverse effect of Li⁺ at therapeutic doses?

A. GI dysfunction

B. Hyperthyroidism

C. Oliguria

D. Thrombocytopenia

Answers

[1] A. The therapeutic action of Li⁺ is thought to be caused by direct inhibition of inositol monophosphatase. Its effects on IP₃, DAG, and muscarinic cholinoceptor activities are an indirect consequence of this inhibition.

[2] D. The renal clearance of Li⁺ may increase with pregnancy, which may lead to a reduction in its therapeutic effect. Diarrhea, certain NSAIDs, and diuretics that result in hyponatremia decrease the renal clearance of Li⁺, which may result in more severe adverse effects.

[3] A. GI dysfunction, polydipsia (and polyuria), and hypothyroidism are adverse effects of Li⁺ that may occur at therapeutic doses.

Pharmacology pearls

Measurement of serum lithium concentrations are used routinely to carefully monitor treatment and to evaluate the likelihood of toxicity.

Lithium is associated with thyroid enlargement; hypothyroidism; diabetes insipidus; diarrhea, nausea, and vomiting; and weight gain. It has been associated with congenital malformations when used in pregnancy.

Lithium has a relatively slow onset of therapeutic action, and therefore antipsychotic drugs, such as olanzepine, or benzodiazepines are used acutely to calm seriously agitated patients with bipolar affective disorder.

Antidepressant agents may precipitate mania and induce more rapid cycling in some patients.