Advantages and disadvantages using lithium-based drugs

Advantages and disadvantages using lithium-based drugs

The name ‘lithium’ stems from the Greek word ‘lithos’ which means stone. Lithium salts are well known for their use in batteries, metal alloys and glass manufacture. Nevertheless, Li also has a clinical application in the treatment of manic depression or BD. BD affects 1–2% of the population and severely reduces the quality of life for the patients and also increases the likelihood of patients committing suicide. Research has shown that lithium salts are very successful in the treatment of BD, and a broad research in this area has been stimulated. The main question addressed within this research is how the lithium ion (Li⁺) can be modified in order to improve its activity to patent their findings, which would result in income for the manufacturer. Unfortunately, the simple ion is the active ingredient and this makes it difficult to patent and secure any intellectual property.

Li is a member of group 1 alkali metals and is the lightest and smallest solid element. Li has an atomic number of 3 and contains a single valence electron, which determines its redox chemistry and reactivity. In nature, Li is found as ores, for example, spodumene [LiAl(SiO₃)₂], or at low concentrations as salts, for example, in rivers. The metal itself is soft and white in appearance; it has the lowest reactivity within the group of alkali metals. The Li⁺ ion has the smallest ionic radius of all known metals.

1. Isotopes of lithium and their medicinal application

Lithium occurs as mixture of two stable, naturally occurring isotopes, namely ⁶Li with an occurrence of 7.59% and the major isotope ⁷Li (92.41%). The nucleus of ⁶Li contains three protons and three neutrons, whilst ⁷Li contains three protons and four neutrons.

 ⁶Li and ⁷Li are both NMR (nuclear magnetic resonance) active nuclei, which means their presence can be monitored via NMR technology. Using this analytical tool, it is possible to differentiate between intra- and extracellular Li⁺ concentrations and therefore, the uptake of Li⁺ into different cells can be monitored. The use of ⁶Li results in sharper NMR spectra because of its properties, but it also has a lower intensity. ⁶Li salts can also be used to monitor the distribution of lithium in the tissue. A further application of ⁶Li is the production of tritium atoms (³₁H) and their use in atomic reactors. In this process, ⁶Li is bombarded with neutrons, which results in the production of tritium atoms and radioactive -particles (⁴₂He):

⁶₃Li+¹₀n→³₁H+⁴₂He

Equation 2.11 shows the activation of ⁶Li.

2. Historical developments in lithium-based drugs

The first medical use of Li⁺ was described in 1859 for the treatment of rheumatic conditions and gout. The theory at that time was based on the ability of lithium to dissolve nitrogen-containing compounds such as uric acid. Their build-up in the body was believed to cause many illnesses such as rheumatic conditions and gout problems. In 1880, Li⁺ was first reported as being used in the treatment of BD, and in 1885 lithium carbonate (Li₂CO₃) and lithium citrate [Li₃C₃H₅O(COO)₃] were included in the British Pharmacopoeia. It also became clear that there is a direct link between NaCl intake and heart diseases as well as hypertension. Therefore, LiCl was prescribed as replacement for NaCl in the diet of affected patients [3b].

The urea hypothesis and the connection of NaCl to heart diseases stimulated the use of lithium salts in common food. The prime example is the soft drink 7Up^©, which has been marketed in 1929 under the label Bib-Label Lithiated Lemon-Lime Soda. 7Up contained lithium citrate and was also marketed as a hang-over cure. The actual Li⁺ was subsequently removed in 1950 [3b].

John Cade’s experiments on guinea pigs in 1949 initiated the discovery of Li⁺ and its sedative and mood-control properties. Uric acid was known to have mood-controlling properties and Cade used lithium urate as a control solution. To his surprise, he discovered that lithium urate had tranquillising properties, and after further experiments he concluded that this was caused by the lithium ion .

Nevertheless, there were drawbacks, especially when the FDA banned Li⁺ salts following the death of four US patients. These patients had an average intake of 14 g of lithium chloride (LiCl) per day in order to replace NaCl. Another stumbling stone in the way of success of Li⁺ was the discovery of chlorpromazine, the first antipsychotic drug, which is still used for the treatment of BD. In the early 1970s, Li⁺ was re-approved by FDA and is now used in 50% of the treatment of BD .

3. The biology of lithium and its medicinal application

Lithium salts are used in the prophylaxis and treatment of mania, and in the prophylaxis of BD and recur-rent depression. Lithium therapy is taken orally, usually as lithium carbonate (Li₂CO₃) or lithium citrate [Li₃C₃H₅O(COO)₃], with a total dose of up to 30 mmol/day. Li₂CO₃ is the preferred lithium salt used, as it causes the least irritation to the stomach. The treatment has to be closely monitored, and Li⁺ blood concentra-tions are measured 12 h after administration to achieve a serum lithium concentration of 0.4–1 mmol/l. The therapeutic index (concentration window from efficacy to toxicity) for Li⁺ is very narrow, and plasma Li⁺ concentrations above 2 mM require emergency treatment for poisoning (Figure 2.6) .

The administered Li⁺ is distributed uniformly in the body tissues and in the blood plasma, with the external cell Li⁺ concentration being below 2 mM. Experiments studying the lithium distribution in rats after admin-istration of a high dose of ⁶Li⁺ showed that there was no exceptional accumulation of ⁶Li⁺ in the brain. ⁶Li⁺ distributes fairly uniformly in the body, with bones and endocrine glands showing higher concentrations (Figure 2.7) .

Li⁺ ions are not soluble in lipids and therefore do not cross plasma membranes. The transport into cells occurs via exchange mechanism by lithium–sodium counter-transport, anion exchange (so-called Li⁺/CO₃²⁻ co-transport) and other unrelated transport molecules. The specific mode of action of the simple Li⁺ ion is currently unknown, but it is clear that a displacement of Mg²⁺ by Li⁺ is involved. Therefore, an alteration of the Mg²⁺ balance in the blood and the urine can be observed in patients treated with Li⁺ [3b]. This displace-ment is actually not surprising because the properties of Li⁺ and Mg²⁺ are similar, which can be explained by the concept of diagonal relationship.

4. Excursus: diagonal relationship and periodicity

Within the periodic table, the element pairs Li/Mg, Be/Al, B/Si and others form a so-called diagonal rela-tionship to each other. With this concept, similarities in biological activity can be explained as the element pairs have similar properties.

Diagonally adjacent elements of the second and third periods have similar properties – this concept is called diagonal relationship. These pairs (Li/Mg, Be/Al, B/Si, etc.) have similarities in ion size, atomic radius, reactive behaviour and other properties.

Diagonal relationship is a result of opposite effects, which crossing and descending within the periodic table has. The size of an atom decreases within the same period (from left to right). The reason is that a positive charge is added to the nucleus together with an extra electron orbital. Increasing the nucleus charge means that the electron orbitals are pulled closer to the nucleus. The atomic radius increases when descending within the same group, which is due to the fact that extra orbitals with electrons are added (Figure 2.8) .

Trends can be seen for the electronegativity and the ionisation energy; both increase when moving within the same period from left to right and decrease within the same group. Within a small atom, the electrons are located close to the nucleus and held tightly, which leads to a high ionisation energy. Therefore, the ionisation energy decreases within the group and increases within the period (from left to right) – showing the opposite trend compared to the atomic radius. A similar explanation can also be used for summarising the trends seen for the electronegativity: small atoms tend to attract electrons more strongly than larger ones. This means fluorine is the most electronegative element within the Periodic Tables of Elements (Figure 2.9).

This structure of trends is summarised under the term periodicity of the elements. This means that within the periodic table, all elements follow the above-mentioned trends in a repetitive way. This allows predicting trends for atomic and ionic radii, electronegativity and ionisation energy (Figure 2.10).

In relation to the diagonal relationship, it becomes clear by studying the described trends that these effects cancel each other when descending within the group and crossing by one element within the PSE. Therefore, elements diagonally positioned within the periodic table have similar properties, such as similar atomic size, electronegativity and ionisation energy (Figure 2.11).

The concept of the diagonal relationship is crucial for the biological activity of lithium drugs, which is mainly due to the properties of the Li⁺ ion being similar to the Mg²⁺ ion. In comparison, the size of the Li⁺ ion is similar to that of Mg²⁺ and therefore they compete for the same binding sites in proteins. Nevertheless, lithium has relatively specific effects, and so only proteins with a low affinity for Mg²⁺ are targeted. Li⁺ and Mg²⁺ salts have similar solubility, for example, CO₃²⁻, PO₄³⁻, F⁻ salts have a low water solubility, and halide and alkyl salts are soluble in organic solvents. Li⁺ and Mg²⁺ compounds are generally hydrated, for example, LiCl⋅3H₂O and MgCl₂⋅6H₂O. Similarities in ionic size, solubility, electronegativity and solubility result in similar biological activity and therefore pharmaceutical application [3b].

5. What are the pharmacological targets of lithium?

The precise mechanism of action of lithium ions as mood stabilisers is unknown. Current research shows that there are two main targets in the cell – the enzymes glycogen synthase kinase-3 (GSK-3) and the phospho-monoesterases family (PMEs) [3b].

GSK-3 is a serine/threonine protein kinase, which is known to play an important role in many biological processes. GSK-3 is an enzyme that mediates the addition of phosphate molecules onto the hydroxyl groups of certain serine and threonine amino acids, in particular cellular substrates. Li⁺ inhibits GSK-3 enzymes via competition for Mg²⁺ binding .

Phosphoric monoester hydrolases (PMEs) are enzymes that catalyse the hydrolysis of O—P bonds by nucleophilic attack of phosphorous by cysteine residues or coordinated metal ions. Inositol monophosphatase (InsP) is the best known member of this family. Li⁺ and Mg²⁺ both have a high affinity to bind to phos-phate groups. Li⁺ inhibits the enzymatic function of InsP and prevents phosphate release from the active site. Generally, inositol phosphatases are Mg²⁺-dependent, but Li⁺ binds to one of the catalytic Mg²⁺ sites. Binding Li⁺ to phosphate-containing messenger molecules could perturb the transcellular communication and thus be antipsychotic [3b].

Lithium inhibits GSK-3 and InsP, and both pathways have therefore been suggested to be involved in the treatment of BD and schizophrenia. The theory behind this hypothesis is that overactive InsP signalling in the brain of these patients potentially causes BD and this may be reduced by the inhibitory effect of lithium on such signalling .

GSK-3 alters structure of cerebella neurons, and lithium is a neuroprotective agent that can reduce the hypersensitivity to toxins as seen in cells that overexpress GSK-3. It is believed that lithium potentially can protect against disease-induced cell death. GSK-3 has been implicated in the origins of schizophrenia, but with the availability of many antipsychotic drugs on the market, lithium ions are not in common use for the treatment of schizophrenia .

There are also several direct roles of lithium in the treatment of Alzheimer’s disease. Alzheimer’s disease is a neurodegenerative brain disorder causing neuronal dysfunction and ultimately cell death. This leads ulti-mately to dementia, affecting in the United States around 10% of people aged over 65 and 48% aged over 85. Onset occurs with the accumulation of extracellular senile plaques composed of amyloid-β peptides and with the accumulation of intercellular neurofibrillary tangles. GSK-3 is necessary for the accumulation of tangles, and subsequently GSK-3 inhibition reduces the production of peptides – this is where the Li⁺ interaction comes into play [3b].

6. Adverse effects and toxicity

Lithium has a very narrow therapeutic window, which makes the monitoring of blood levels essential during the treatment. Blood plasma concentrations of more than 1.5 mmol/l Li⁺ may cause toxic effects, usually tremors in the fingers, renal impairment and convulsion. Also, memory problems are a very common side effect, and complaints about slowed mental ability and forgetfulness are commonly reported. Extreme doses of lithium can cause nausea and diarrhea, and doses above 2 mmol/l require emergency treat-ment, as these levels may be fatal. Weight gain and decreased thyroid levels are also commonly reported problems. The blood serum level of Li⁺ has to be monitored 12 h after administration, and health care pro-fessionals also have to be aware that the mood-stabilising effects of lithium take a couple of days to take effect .

Lithium salts have severe adverse effects on the renal system. Lithium therapy can damage the internal structures of the kidneys, which are the tubular structure of the nephrons, and can lead to diabetes insipidus. One out of five patients experience polyuria – excess production of urine, which is the number one symptom of diabetes insipidus. Therefore, the kidney function has to be closely monitored for patients undergoing long-term therapy, with a full test of the kidney function every 6–12 months for stabilised regimes [3a, 6].

Great care has to be taken when lithium is given with nonsteroidal anti-inflammatory drugs (NSAIDs) because up to 60% increase of Li⁺ concentration in blood has been observed. NSAIDs reduce the clearance of lithium through kidneys, and as a result lithium poisoning is possible. Furthermore, the concurrent use of diuretics, which can result in sodium depletion, can make lithium toxicity worse and can be hazardous [3a].