Lithium Clinical Considerations in Internal Medicine

Question: Discuss about the Lithium Clinical Considerations in Internal Medicine. Answer: Introduction Lithium is the third element of the periodic table which shares certain properties with elements such as sodium and potassium (1, 2, 14). Lithium is majorly used in the hospital for treatment of mental disorders specifically as the mood stabilizer in treatment and maintained of bipolar diseases (1, 2, 3, 4, 12, 14, 16). The effectiveness of therapy of bipolar disease was discovered in 1949. In addition, lithium has remained as a drug of choice in bipolar treatment as it is said to reduce the risk of suicide in such patients (4, 6, 9). Furthermore, lithium is used in the treatment of depression, schizophrenia, schizoaffective disorder and other mental illnesses (1, 2, 3, 6, 7, 8). This drug profile seeks to demonstrate the mechanism of action, side effects and toxicity, clinical uses, drug formulation, chemical structure, pharmacokinetics, requirements for therapeutic drug monitoring and consideration when using lithium in special population. Mechanism of Action The specific mechanism of action of lithium is not well known especially as a mood stabilizer (2, 4, 7, 9, 12,). Lithium can alter the sodium transport across the cell membranes of the nerves; it can also alter serotonin and catecholamine metabolism and intracellular signaling using the second messengers (9). Lithium can also reduce proteins kinase C activity which can affect genome expression associated with neurotransmission (12). Lithium may increase cytoprotective proteins activating a cascade of growth factors that might increase the gray matter and in that matter enhancing neurogenesis activation and trophic actions that usually maintains synapse (12). Mediated by monoamine neurotransmitters, lithium can change synaptic transmission and in that case increasing the time of the presynaptic destruction of catecholamines thus inhibiting transmitters release at the synapse and reducing postsynaptic receptor sensitivity (9, 12). Various studies have shown that lithium has a tendency of increasing the release of serotonins by brain neurons. By inhibiting 5-HT1A and 5HT1B receptors, lithium has demonstrated to enhance the release of serotonin to the synapse making it have an antidepressant effect (6). Lithium has also be seen to interact with Nitric Oxide which in turns signals the pathway in the neural system that plays a significant role in neural plasticity (12, 13). Through modulation of glutamate levels, lithium is also believed to provide long-term mood stabilization. This is due to its competing actions with magnesium towards glutamate receptors. During the manic episodes, there is a rise in dopamine transmission that when regulated using hemostasis can lead to depression (12, 16). The G-proteins receptors are typically responsible for postsynaptic actions of dopamine. In that case, lithium is believed to alter some G-proteins sub-units that are associated with dopamine as part of the mechanism of actio n (12). Adverse effects/ Toxicity The most common adverse effects of Lithium with occurs in more than ten percent of all treated patients include headaches, hyperreflexia which involve a patient having highly responsive reflexes, muscle weakness, increase in number of white blood cells, nausea, muscle twitching, increase thirst and urination , weight gain, vertigo, confusion, low memory, constipation, diarrhea, and hand tremors ( 1, 2, 8, 11, 15,). Other adverse effects occur between 1-10 % of patients treated with lithium which includes hypothyroidism, acne, hair loss, extrapyramidal side effects like muscle rigidity and parkinsonism and goiter (1 2, 3, 4 , 5 8, 9, 14, ). There are others side effects that are very rare and mostly occur below 1 % of all patients treated with lithium which include seizures, edema, renal toxicity, sinus node dysfunction, coma, Brugada syndrome which is a heart conduction abnormality, elevated levels of magnesium, calcium, thyroid and parathyroid hormones and rise in intracranial press ure (1, 3, 13, 15, ). Clinical Uses The primary and most common clinical uses of lithium are in bipolar disorders where it is used as a mood stabilizer( 1, 2, 3, 4, 5, ). Lithium is normally used in acute manic episodes, bipolar prophylaxis, and treatment of acute bipolar depression. In acute manic episodes, lithium can be used to stabilize the mood of patients without combining with other adjunctive treatments like the use of benzodiazepines or antipsychotics (13). In acute bipolar depression, Lithium can be utilized as a first line treatment as a mood stabilizer without even using antidepressants. Antidepressants are only combined with lithium when a fast effect is required ( 8). When acute episodes of bipolar disorders dissolve, lithium is continued as a prophylaxis drug of choice. In addition, Lithium can be used for the treatment of resistant depression as an augmentation of antidepressants ( 14). Other than that, lithium uses has demonstrated to reduce suicidal attempts in bipolar disease. Dosage and Available Formulation The usual form of Lithium medicine in tablet form which are in different milligrams. Some of the common milligrams include 300mg, 150mg, 450mg and 600mg. Lithium can also be in a vial of 5 milliliters which contains 300mg of lithium (4, 5,). The dosage of Lithium is prescribed according to the condition and the age of the patient. Adults or anybody above 12 years receive a full dose as compared to children below 12 years (4, 5). The usual adult dose for patients suffering from acute mania is 1800mg per day with regular doses of 600mg orally divided into three times a day and an extended dose of 900mg orally twice a day. The long-term control of mania includes a maintenance dose of 900mg per day and a conventional formulation of 300mg orally four times a day( 4, 5) . The usual treatments for adulthood in bipolar disease are similar to that of acute mania. However, dosing must be given in accordance to response to treatment and lithium serum levels (5). In addition, there is an alternative treatment dose in the extended formulation of 600mg four times a day for long-term control (5). The dosage for pediatrics over 12 years is also similar to that of an adult ( 4). The only difference is on alternative extended formulation where the dosage is reduced to 300mg four times a day in long-term control (5). In severe renal impaired patients, only the extended release formulations can be given. It is important to avoid lithium in pregnancy where possible (5). Chemical Structures Related to Pharmacokinetic Parameters Li+ b) Li2CO3 Above a) is the chemical structure of Lithium which commonly occurs as Lithium carbonate with a chemical structure shown at b) (6) Lithium ion is absorbed completely in the gastrointestinal tract. The complete absorption takes place in about first 8 hours where the peak concentration in the serum starts at about 2 to 4 hours on an oral dose (7). Due to slow release preparations of lithium carbonate, there is a much slower rate of absorption which readily decreases the early plasma serum peak. Lithium ions are first distributed to extracellular fluids before it enters into the tissues (7). Other structures of lithium salts that can be used as drugs include Lithium lactate and lithium salicylate as shown in the below figures respectively (7). Lithium Lactate and Lithium salicylate The lithium lactate when absorbed in the gastrointestinal tract reach in the plasma levels at 2 hours but the peak is usually at 24 hours, and it is later eliminated rapidly (8). Lithium salicylate, on the other hand, reaches the peak by 48 hours and it is eliminated slowly(8). A study was done by Smith et al. showed that lithium carbonate normally has a larger bioavailability as compared to the high other Lithium salts( 8). Interesting pharmacokinetic parameters and clinical implications In slow and controlled release forms of lithium, the serum pick period after absorption in the gastrointestinal tract is about 4 to 5 hours(13,15). However, Lithium is rapidly absorbed in regular preparation with serum levels peaking at around 2 hours. Since the drug is not metabolized in the liver, it is not highly affected by the first past effect in the alimentary canal (14). Different from other antipsychotic agents, Lithium has no metabolites or clinically crucial binding properties to proteins (9). The renal clearance of the drug is about 20% of the creatinine clearance since most of the Lithium is reabsorbed in proximal convoluted tubules. Lithium is almost entirely excreted by the kidney but there some small traces excreted through feces and sweat(2,3,). The elimination half-life of lithium is about 24 hours. The half-life in elderly patients is a bit longer due to a decrease infiltration rate at Bowmans capsule and shorter in youths (3). The drug has no protein bound charact eristic, and around 80% is reabsorbed in proximal convoluted tubules( 1). The levels of Lithium in serum usually increase when the sodium levels decrease in serum which is accelerated during dehydration(1,3). Requirement for Therapeutic Drug Monitoring (TDM) A report was written by Ratanajamit et al. in 2008 indicated there was appropriateness for therapeutic drug monitoring of lithium between 2004 and 2005 lithium treatment of psychotic disorders (3). The study showed that of all the participants 41.8 % had suspected toxicity, there were about 27% who required various tests without specific indications, serum lithium levels were reported in 91. 2% of all patients who had not taken lithium drug for about five days during the treatment period(3). In addition, 44. 6% of these required dosage alterations (3). Before giving the Lithium treatment, certain parameters such complete blood count, electrocardiograph, baseline creatinine levels and thyroxin stimulating hormones should be checked. Lithium used if the first term of pregnancy has been associated with Ebstein anomaly where 1 out of 1000 is affected and therefore should be monitored during pregnancy(1, 14). The patients under treatment using lithium should receive regular serum levels test, kidney function test, and thyroid hormones levels as they interfere with water and sodium regulations in the body(9,16). This is the major and underlying cause of dehydration in patients under lithium treatment. The dehydration in the body normally increases the lithium levels(8). This dehydration is primarily brought by inhibition of antidiuretic hormone by increase in lithium levels thus inhibiting water reuptake in the kidney(11,13). This in turn led to the loss of water exhibited by thirst. The monitoring of lithium can be performed by measurin g lithium concentration in serum, blood, and urine and use the results as a guide to therapy. The standard serum concentration of Lithium is usually between 0.5 to 1.4 mmol/l (4). When it accumulates over a certain duration of time, mostly after five days, the level increases up to between 1.8 to 2.5mmol/l. During an overdose, the levels can go up to 3 to 10 mmol/l (4). At this time, the dosage required should be adjusted, and the patient monitored in facilities where plasma ratio can be easily be seen (5). Dosages are adjusted to achieve the normal values which are usually to lower in aged patients and to increase in young patients (5). Factors that indicate that lithium is in accordance with the correct therapy and normal values include the absence of adverse effects, no psychosis, and classic mania (16). Consideration of Lithium in Special Population In renal dose adjustments, mild and moderate renal problems do not need any adjustments to the dosage. However, severe renal problems require only the extended release formulation where small doses are started slowly with close monitoring of toxicity (4, 5). The immediate release formulations are contraindicated in severe renal dysfunction. The serum levels should be checked prior to the next dose (4). This is commonly done between 10 to 12 hours from the previous dose. The acute episodes of increase in lithium levels are determined, and dose changed after three days. The long term dose adjustment can be changed after two months (5). Caution should be taken and doses adjusted in patients suffering from cardiovascular disorders (4,5). Lithium should be avoided in pregnancy as it causes cardiovascular problems, especially in the first trimester (1). In infants, lithium should be avoided as it causes drowsiness, cardiac and other permanent side effects to a child(2). Weight gain is a ma jor adverse effect of lithium since it has some metabolic effects on carbohydrates (2, 9). In that case, caution should be taken in obese patients as lithium will normally increase weight. 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