Chemistry of the Drug Lithium - Essay Example

Chemistry of the Drug Lithium Lithium is a naturally occurring, readily commercially available alkali metal with atomic number of 3, designated bysymbol Li, and atomic weight of 6.941. This is a silvery white or gray metal that is solid at 298 K. Looking at the periodic table, lithium is assigned group number 1 and period number 2. Therefore, it is group 1 (IA) element containing just a single valence electron (1S22S1). Lithium, as medically significant, is most commonly available as the carbonate or the citrate salt. These are used as drugs for various medical conditions, especially psychiatric disorders. Commercial synthesis of this drug requires addition of an electron to the poorly electronegative lithium ion (Li+). As a result, the synthesis requires an electrolytic step. The commercial ore spodumene, Li Al (SiO3)2 is widely used to produce this product. This is the α form. This is converted to β form by heating the ore to 1100 degrees centigrade. This renders the ore softer. Careful mixing with hot sulfuric acid and extraction in water generate a lithium sulfate (Li2SO4) solution. The sulfate is washed with sodium carbonate, Na2CO3. This results in a relatively stable precipitate of insoluble lithium carbonate, Li2CO3. The chemical reaction would be represented as Li2SO4 + Na2CO3 Na2SO4 +Li2CO3 Administered in this form, lithium in the body acts as a monovalent cation. This was used as a treatment for manic depressive psychosis despite its array of side effects since no other medications for this condition were available at that time. However, the mechanism by which lithium controls manic episodes and possibly influences affective disorders are not yet known for sure. It has been postulated that lithium may substitute for cellular cations, namely, sodium (Na+) and potassium (K+). Any cell, like brain cells, have extracellular fluid and intracellular fluid. The extracellular fluid is rich with sodium, and the intracellular fluid is rich with potassium. Whenever there is a signal transfer through the cell membrane, there is exchange of sodium and potassium from and into the cells. Due to reasons that, lithium belongs to the same alkali metal group as sodium and potassium, lithium too shares some of its properties with sodium and potassium. Apart from that, electron transfer during sodium and potassium transmembrane exchange creates the ideal environment of addition of an electron to Li+. Thus, if available in the cellular environment, lithium may enter the cells through the electron channels dedicated for transfer of sodium and potassium. Once available within the cell, lithium can exert its pharmacological action. Preclinical studies have shown that lithium alters sodium transport in nerve and muscle cells effecting a shift toward intraneuronal catecholamine metabolism. To answer this question that how does it do so, it has been proposed that lithium affects sodium-potassium stimulated adenosine triphosphatase (Na+, K+ ATPase) and interferes with adenylate cyclase activation. This, in turn, inhibits neurotransmitter (norepinephrine) release. Since this affects cyclic adenosine monophosphate (cAMP) concentration by adenylate cyclase inhibition, as expected, lithium also blocks inositol metabolism leading to depletion of cellular reserves of inositol. This, in turn, inhibits phospholipase-C mediated neural signal transduction. This might have effects in mood stabilization in mania and other related psychotic or neuropsychiatric disorders where lithium is being used, but yet, the exact cellular mechanism exerted by lithium carbonate needs to be established. Most other antimanic agents have sedative properties, while lithium is not sedative. Along with perceived alteration in nerve conduction mechanism, due to its effects of sodium and potassium transport, it is conceivable that lithium can also influence fluid and electrolyte balance in the homeostasis of the neural cells. It has long been proposed that there is a factor of fluid-electrolyte imbalance in affective disorders, and the therapeutic action of lithium may be related to this. By enhancing norepinephrine and serotonin uptake in the neural synaptosomes, lithium reduces their actions. We already know that it reduces cyclic AMP synthesis and reduces release of norepinephrine release from the synaptic vesicles, thus maybe retarding the manic thought neural signals. Lithium can replace sodium in ECF, and during the rapid intracellular influx phase when neural depolarization occurs, enters into the cell. Normally this mimics a sodium ion, but the sodium pump cannot effectively remove it. As a result, the cellular re-entry of potassium effected by the sodium pump is prevented. All these surmount to effect interference with electrolyte distribution across the neuronal cell membrane. The result is fall in transmembrane potential, interruption of conduction of signals, and decreased neuronal excitability. Cortically evoked potentials have demonstrated lithium-induced alteration of cerebral excitability. Lithium has shown to produce diuresis with increase in urinary sodium and potassium excretion. It has been demonstrated that a period of equilibrium or slight retention may follow. Some patients may develop persistent polyuria. Therapeutic dosage of 600 to 900 mg/day in 3 divided doses, increased to 1,200 to 1,800 mg/day in 3 divided doses to achieve a serum lithium level of 0.8 to 1.2 mmol/L would decrease the 24-hour exchangeable sodium. In fact, use of lithium carbonate for manic depressive illness has been associated with polyuria and polydyspsia caused by tubulointerstitial disease in the kidney. Renal functions require to be monitored in patients taking this drug, and great caution should be exercised if lithium is administered in patients with preexisting renal disease. There is some evidence that lithium may affect the metabolism of potassium, calcium, and magnesium. Lithium used in the management of bipolar disorder causes hypercalcemia in approximately 10% of patients. The parathyroids are involved in mediation of this hypercalcemia when continuous lithium therapy is undertaken, and parathromone (PTH) levels may be elevated. This drug is rapidly absorbed from the gastrointestinal tract and reaches a peak level within 2 to 4 hours of ingestion. It has negligible plasma protein binding and a volume distribution of about 0.6 L/kg body weight. About 95% of the drug load is excreted from the body by glomerular filtration with 80% of the active drug being reabsorbed by proximal tubules. Thus hyponatraemia and hypovolemia decreases its clearance, and alkalinization of urine increases it. Therapeutic levels of 0.6 to 1.2 mmol/L can be predicted by a serum half-life of 18 to 36 hours. As a result, there is a chance of cumulative rise of serum lithium leading to toxic effects that have a varied range of potentially dangerous effects leading to discontinuation of therapy. It has a very narrow therapeutic/toxic ratio dictating serial serum lithium concentration measurement regularly for the patients who are undergoing therapy with this drug. It is advisable that lithium therapy should be maintained in patients under careful clinical and laboratory control throughout the period of management with regular and periodic monitoring of kidney, cardiovascular, and thyroid functions. Conclusion: Many drugs have interactions with lithium, and lithium has potential side and adverse effects. The good news is that with advances of pharmacotherapeutics, there are many upcoming agents for treatment of manic depressive psychosis or bipolar disorders that may replace lithium, but not yet. [ Since this is a question-answer, I have not added any in-text citation and reference page, moreover due to the fact that, there was only one source necessary; please let me know if you need them, but that will make the sources to about 15] Read More