Sodium ions (Na+) are necessary in small amounts for some types of plants, but sodium as a nutrient is more generally needed in larger amounts by animals, due to their use of it for generation of nerve impulses and for maintenance of electrolyte balance and fluid balance. In animals, sodium ions are necessary for the aforementioned functions and for heart activity and certain metabolic functions. The health effects of salt reflect what happens when the body has too much or too little sodium.
Characteristic concentrations of sodium in model organisms are: 10 mM in E. coli, 30 mM in budding yeast, 10 mM in mammalian cell and 100 mM in blood plasma.
The
minimum physiological requirement for sodium is between 115 and 500 mg
per day depending on sweating due to physical activity, and whether the
person is adapted to the climate. Sodium chloride is the principal source of sodium in the diet, and is used as seasoning and preservative, such as for pickling and jerky; most of it comes from processed foods. The Adequate Intake for sodium is 1.2 to 1.5 g per day, but on average people in the United States consume 3.4 g per day, the minimum amount that promotes hypertension. Note that salt contains about 39.3% sodium by mass—the rest being chlorine and other trace chemicals; thus the Tolerable Upper Intake Level of 2.3 g sodium would be about 5.9 g of salt—about 1 teaspoon. The average daily excretion of sodium is between 40 and 220 mEq.
Normal serum sodium levels are between approximately 135 and 145 mEq/L (135 to 145 mmol/L). A serum sodium level of less than 135 mEq/L qualifies as hyponatremia, which is considered severe when the serum sodium level is below 125 mEq/L.
The renin–angiotensin system and the atrial natriuretic peptide indirectly regulate the amount of signal transduction in the human central nervous system, which depends on sodium ion motion across the nerve cell membrane, in all nerves. Sodium is thus important in neuron function and osmoregulation between cells and the extracellular fluid; the distribution of sodium ions are mediated in all animals by sodium–potassium pumps, which are active transporter solute pumps, pumping ions against the gradient, and sodium-potassium channels.
Sodium channels are known to be less selective in comparison to
potassium channels. Sodium is the most prominent cation in extracellular
fluid: in the 15 L of extracellular fluid in a 70 kg human there is around 50 grams of sodium, 90% of the body's total sodium content.
Some potent neurotoxins, such as batrachotoxin, increase the sodium ion permeability of the cell membranes in nerves and muscles, causing a massive and irreversible depolarization
of the membranes with potentially fatal consequences. However, drugs
with smaller effects on sodium ion motion in nerves may have diverse
pharmacological effects that range from anti-depressant to anti-seizure
actions.
Other animals
Since only some plants need sodium and those in small quantities, a completely plant-based diet will generally be very low in sodium. This requires some herbivores to obtain their sodium from salt licks and other mineral sources. The animal need for sodium is probably the reason for the highly conserved ability to taste
the sodium ion as "salty." Receptors for the pure salty taste respond
best to sodium; otherwise, the receptors respond only to a few other
small monovalent cations (Li+, NH+4 and somewhat to K+). The calcium ion (Ca2+) also tastes salty and sometimes bitter to some people but, like potassium, can trigger other tastes.
In C4 plants, sodium is a micronutrient that aids in metabolism, specifically in regeneration of phosphoenolpyruvate (involved in the biosynthesis of various aromatic compounds, and in carbon fixation) and synthesis of chlorophyll. In others, it substitutes for potassium in several roles, such as maintaining turgor pressure and aiding in the opening and closing of stomata. Excess sodium in the soil limits the uptake of water due to decreased water potential, which may result in wilting; similar concentrations in the cytoplasm can lead to enzyme inhibition, which in turn causes necrosis and chlorosis. To avoid these problems, plants developed mechanisms that limit sodium uptake by roots, store them in cell vacuoles, and control them over long distances;
excess sodium may also be stored in old plant tissue, limiting the
damage to new growth. Though much how excess sodium loading in the xylem
is yet to be determined. However, anti porter CHX21 can be attributed
to active loading of sodium into the xylem.
Function of sodium ions
Sodium is the primary cation
(positively charged ion) in extracellular fluids in animals and humans.
These fluids, such as blood plasma and extracellular fluids in other
tissues, bathe cells and carry out transport functions for nutrients and
wastes. Sodium is also the principal cation in seawater, although the
concentration there is about 3.8 times what it is normally in
extracellular body fluids.
Although the system for maintaining optimal salt and water balance in the body is a complex one, one of the primary ways in which the human body keeps track of loss of body water is that osmoreceptors in the hypothalamus
sense a balance of sodium and water concentration in extracellular
fluids. Relative loss of body water will cause sodium concentration to
rise higher than normal, a condition known as hypernatremia.
This ordinarily results in thirst. Conversely, an excess of body water
caused by drinking will result in too little sodium in the blood (hyponatremia), a condition which is again sensed by the hypothalamus, causing a decrease in vasopressin hormone secretion from the posterior pituitary, and a consequent loss of water in the urine, which acts to restore blood sodium concentrations to normal.
Severely dehydrated persons, such as people rescued from ocean or
desert survival situations, usually have very high blood sodium
concentrations. These must be very carefully and slowly returned to
normal, since too-rapid correction of hypernatremia may result in brain
damage from cellular swelling, as water moves suddenly into cells with
high osmolar content.
In humans, a high-salt intake was demonstrated to attenuate nitric oxide
production. Nitric oxide (NO) contributes to vessel homeostasis by
inhibiting vascular smooth muscle contraction and growth, platelet
aggregation, and leukocyte adhesion to the endothelium.
Urinary sodium
Because the hypothalamus/osmoreceptor
system ordinarily works well to cause drinking or urination to restore
the body's sodium concentrations to normal, this system can be used in
medical treatment to regulate the body's total fluid content, by first
controlling the body's sodium content. Thus, when a powerful diuretic
drug is given which causes the kidneys to excrete sodium, the effect is
accompanied by an excretion of body water (water loss accompanies
sodium loss). This happens because the kidney is unable to efficiently
retain water while excreting large amounts of sodium. In addition, after
sodium excretion, the osmoreceptor
system may sense lowered sodium concentration in the blood and then
direct compensatory urinary water loss in order to correct the hyponatremic (low blood sodium) state.
Certain lithium compounds, also known as lithium salts, are used as psychiatric medications, primarily for bipolar disorder and for major depressive disorder. In lower doses, other salts such as lithium citrate are known as nutritional lithium and have occasionally been used to treat ADHD. Lithium is taken orally.
Common side effects include increased urination, shakiness of the hands, and increased thirst. Serious side effects include hypothyroidism, diabetes insipidus, and lithium toxicity. Blood level monitoring is recommended to decrease the risk of potential toxicity. If levels become too high, diarrhea, vomiting, poor coordination, sleepiness, and ringing in the ears may occur. Lithium is teratogenic
at high doses, especially during the first trimester of pregnancy. The
use of lithium while breastfeeding is controversial; however, many
international health authorities advise against it, and the long-term
outcomes of perinatal lithium exposure have not been studied. The American Academy of Pediatrics lists lithium as contraindicated for pregnancy and lactation. The United States Food and Drug Administration categorizes lithium as having positive evidence of risk for pregnancy and possible hazardous risk for lactation.
Lithium salts are classified as mood stabilizers. Lithium's mechanism of action is not known.
In the nineteenth century, lithium was used in people who had gout, epilepsy, and cancer. Its use in the treatment of mental disorders began with Carl Lange in Denmark and William Alexander Hammond in New York City,
who used lithium to treat mania from the 1870s onwards, based on
now-discredited theories involving its effect on uric acid. Use of
lithium for mental disorders was re-established (on a different
theoretical basis) in 1948 by John Cade in Australia. It is on the World Health Organization's List of Essential Medicines, and is available as a generic medication. In 2020, it was the 197th most commonly prescribed medication in the United States, with more than 2million prescriptions. It appears to be under-utilised in older people, though the reason for that is unclear.
Medical uses
A bottle of lithium medicine containing 300 mg capsules of lithium carbonate.
In 1970, lithium was approved by the United States Food and Drug Administration (FDA) for the treatment of bipolar disorder, which remains its primary use in the United States. It is sometimes used when other treatments are not effective in a number of other conditions, including major depression, schizophrenia, disorders of impulse control, and some psychiatric disorders in children. Because the FDA has not approved lithium for the treatment of other disorders, such use is off-label.
Bipolar disorder
Lithium is primarily used as a maintenance drug in the treatment of bipolar disorder to stabilize mood and prevent manic episodes, but it may also be helpful in the acute treatment of manic episodes. Lithium carbonate
treatment was previously considered to be unsuitable for children;
however, more recent studies show its effectiveness for treatment of
early-onset bipolar disorder in children as young as eight. The required
dosage is slightly less than the toxic level (representing a low therapeutic index), requiring close monitoring of blood levels of lithium carbonate during treatment.
A limited amount of evidence suggests lithium carbonate may contribute
to treatment of substance use disorders for some people with bipolar
disorder.
Schizophrenic disorders
Lithium
is recommended for the treatment of schizophrenic disorders only after
other antipsychotics have failed; it has limited effectiveness when used
alone.
The results of different clinical studies of the efficacy of combining
lithium with antipsychotic therapy for treating schizophrenic disorders
have varied.
Major depressive disorder
Lithium is widely prescribed as a treatment for depression.
Augmentation
If therapy with antidepressants does not fully treat the symptoms of major depressive disorder (MDD) then a second augmentation agent
is sometimes added to the therapy. Lithium is one of the few
augmentation agents for antidepressants to demonstrate efficacy in
treating MDD in multiple randomized controlled trials and it has been
prescribed (off-label) for this purpose since the 1980s.
Monotherapy
There are a few old studies indicating efficacy of lithium for acute depression with lithium having the same efficacy as tricyclic antidepressants.
A recent study concluded that lithium works best on chronic and
recurrent depression when compared to modern antidepressant (i.e.
citalopram) but not for patients with no history of depression.
Prevention of suicide
Lithium
is widely believed to prevent suicide, and often used in clinical
practice towards that end. However, meta-analyses, faced with
evidence-base limitations, have yielded differing results, and it
therefore remains unclear whether or not lithium is efficacious in the
prevention of suicide.
Alzheimer's disease
Alzheimer's disease affects forty-five million people and is the fifth leading cause of death in the 65 plus population. There is no complete cure for the disease, currently. However, lithium
is being evaluated for its effectiveness as a potential therapeutic
measure. One of the leading causes of Alzheimer's is the
hyperphosphorylation of the tau protein by the enzyme GSK-3, which leads
to the overproduction of amyloid peptides that cause cell death.
To combat this toxic amyloid aggregation, lithium upregulates the
production of neuroprotectors and neurotrophic factors, as well as it
inhibits the GSK-3 enzyme. Lithium also stimulates neurogenesis within the hippocampus, making it thicker. Yet another cause of Alzheimer's disease is the dysregulation of calcium ions within the brain. Too much or too little calcium within the brain can lead to cell death. Lithium is able to restore the intracellular calcium homeostasis through inhibiting the wrongful influx of calcium upstream.
It also promotes the redirection of the influx of the calcium ions into
the lumen of the endoplasmic reticulum of the cells to reduce the
oxidative stress within the mitochondria.
In 2009, a study was performed by Hampel and colleagues
that asked patients with Alzheimer's to take a low dose of lithium
daily for three months; it resulted in a significant slowing of
cognitive decline, benefitting patients being in the prodromal stage the
most.
Upon a secondary analysis, the brains of the Alzheimer's patients were
studied and shown to have an increase in BDNF markers, meaning they had
actually shown cognitive improvement. Another study, a population study this time by Kessing et al., showed a negative correlation between Alzheimer's disease deaths and the presence of lithium in drinking water. Areas with increased lithium in their drinking water showed less dementia overall in their population.
Monitoring
Those
who use lithium should receive regular serum level tests and should
monitor thyroid and kidney function for abnormalities, as it interferes
with the regulation of sodium and water levels in the body, and can cause dehydration.
Dehydration, which is compounded by heat, can result in increasing
lithium levels. The dehydration is due to lithium inhibition of the
action of antidiuretic hormone,
which normally enables the kidney to reabsorb water from urine. This
causes an inability to concentrate urine, leading to consequent loss of
body water and thirst.
Lithium concentrations in whole blood, plasma, serum or urine may
be measured using instrumental techniques as a guide to therapy, to
confirm the diagnosis in potential poisoning victims or to assist in the
forensic investigation in a case of fatal overdosage. Serum lithium
concentrations are usually in the range of 0.5–1.3 mmol/L (0.5–1.3 mEq/L)
in well-controlled people, but may increase to 1.8–2.5 mmol/L in those
who accumulate the drug over time and to 3–10 mmol/L in acute overdose.
Lithium salts have a narrow therapeutic/toxic ratio, so should not be prescribed unless facilities for monitoring plasma concentrations are available. Doses are adjusted to achieve plasma concentrations of 0.4 to 1.2 mmol Li+ /L on samples taken 12 hours after the preceding dose.
Given the rates of thyroid dysfunction, thyroid parameters should
be checked before lithium is instituted and monitored after 3–6 months
and then every 6–12 months.
Given the risks of kidney malfunction, serum creatinine and eGFR
should be checked before lithium is instituted and monitored after 3–6
months at regular interval. Patients who have a rise in creatinine on
three or more occasions, even if their eGFR is > 60 ml/min/
1.73m2 require further evaluation, including a urinalysis for
haematuria, proteinuria, a review of their medical history with
attention paid to cardiovascular, urological and medication history, and
blood pressure control and management. Overt proteinuria should be
further quantified with a urine protein to creatinine ratio.
Discontinuation
For
patients who have achieved long term remission, it is recommended to
discontinue lithium gradually and in a controlled fashion.
Discontinuation symptoms may occur in patients stopping the
medication including irritability, restlessness and somatic symptoms
like vertigo, dizziness or lightheadedness. Symptoms occur within the
first week and are generally mild and self-limiting within weeks.
Hand tremor
(usually transient, but can persist in some) with an incidence of 27%.
If severe, psychiatrist may lower lithium dosage, change lithium salt
type or modify lithium preparation from long to short acting (despite
lacking evidence for these procedures) or use pharmacological help
Lithium carbonate can induce a 1–2 kg of weight gain.
In addition to tremors, lithium treatment appears to be a risk factor for development of parkinsonism-like symptoms, although the causal mechanism remains unknown.
Most side effects of lithium are dose-dependent. The lowest effective dose is used to limit the risk of side effects.
In a systematic literature review, the authors found 250 reports
containing 1100 individuals who developed lithium-related movement
disorders. The abnormal movements encountered were parkinsonism,
dyskinesia, myoclonus, dystonia, Creutzfeldt-Jakob-like syndrome,
akathisia, restless legs syndrome symptoms, tics, cerebellar syndromes,
and stuttering.
Hypothyroidism
The rate of hypothyroidism
is around six times higher in people who take lithium. Low thyroid
hormone levels in turn increase the likelihood of developing depression.
People taking lithium thus should routinely be assessed for
hypothyroidism and treated with synthetic thyroxine if necessary.
Because lithium competes with the antidiuretic hormone in the kidney, it increases water output into the urine, a condition called nephrogenic diabetes insipidus. Clearance of lithium by the kidneys is usually successful with certain diuretic medications, including amiloride and triamterene. It increases the appetite and thirst ("polydypsia") and reduces the activity of thyroid hormone (hypothyroidism). The latter can be corrected by treatment with thyroxine and does not require the lithium dose to be adjusted. Lithium is also believed to permanently affect renal function, although this does not appear to be common.
Pregnancy and breast feeding
Lithium is a teratogen, causing birth defects in a small number of newborn babies. Case reports and several retrospective studies have demonstrated possible increases in the rate of a congenital heart defect known as Ebstein's anomaly, if taken during a woman's pregnancy. As a consequence, fetal echocardiography is routinely performed in pregnant women taking lithium to exclude the possibility of cardiac anomalies. Lamotrigine seems to be a possible alternative to lithium in pregnant women for the treatment of acute bipolar depression or for the management of bipolar patients with normal mood. Gabapentin and clonazepam are also indicated as antipanic medications during the childbearing years and during pregnancy. Valproic acid and carbamazepine also tend to be associated with teratogenicity.
While it appears to be safe to use while breastfeeding a number of guidelines list it as a contraindication including the British National Formulary.
Kidney damage
Lithium has been associated with several forms of kidney injury.
It is estimated that impaired urinary concentrating ability is present
in at least half of individuals on chronic lithium therapy, a condition
called lithium-induced nephrogenic diabetes insipidus. Continued use of lithium can lead to more serious kidney damage in an aggravated form of diabetes insipidus. Chronic kidney disease caused by lithium has not been proven with various contradicting results presented by a 2018 review.
In rare cases, some forms of lithium-caused kidney damage may be
progressive and lead to end-stage kidney failure with a reported
incidence of 0.2% to 0.7%.
Lithium is primarily cleared from the body through glomerular filtration, but some is then reabsorbed together with sodium through the proximal tubule. Its levels are therefore sensitive to water and electrolyte balance.
Diuretics act by lowering water and sodium levels; this causes more
reabsorption of lithium in the proximal tubules so that the removal of
lithium from the body is less, leading to increased blood levels of
lithium.
ACE inhibitors have also been shown in a retrospective case-control
study to increase lithium concentrations. This is likely due to
constriction of the afferent arteriole of the glomerulus, resulting in
decreased glomerular filtration rate and clearance. Another possible
mechanism is that ACE inhibitors can lead to a decrease in sodium and
water. This will increase lithium reabsorption and its concentrations in
the body.
There are also drugs that can increase the clearance of lithium
from the body, which can result in decreased lithium levels in the
blood. These drugs include theophylline, caffeine, and acetazolamide. Additionally, increasing dietary sodium intake may also reduce lithium levels by prompting the kidneys to excrete more lithium.
High doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy has been reported.
Indeed, these and other antipsychotics have been associated with increased risk of lithium neurotoxicity, even with low therapeutic lithium doses.
Classical psychedelics such as psilocybin and LSD may cause seizures if taken while using lithium, although further research is needed.
Lithium toxicity, which is also called lithium overdose and lithium
poisoning, is the condition of having too much lithium in the blood.
This condition also happens in persons that are taking lithium in which
the lithium levels are affected by drug interactions in the body.
In acute toxicity, people have primarily gastrointestinal symptoms such as vomiting and diarrhea, which may result in volume depletion.
During acute toxicity, lithium distributes later into the central
nervous system resulting in mild neurological symptoms, such as
dizziness.
In chronic toxicity, people have primarily neurological symptoms which include nystagmus, tremor, hyperreflexia, ataxia, and change in mental status.
During chronic toxicity, the gastrointestinal symptoms seen in acute
toxicity are less prominent. The symptoms are often vague and
nonspecific.
If the lithium toxicity is mild or moderate, lithium dosage is
reduced or stopped entirely. If the toxicity is severe, lithium may need
to be removed from the body.
Mechanism of action
The specific biochemical mechanism of lithium action in stabilizing mood is unknown.
Unlike many other psychoactive drugs, Li+ typically produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations.
Lithium may also increase the release of serotonin by neurons in the brain. In vitro studies performed on serotonergic neurons from rat raphe nuclei have shown that when these neurons are treated with lithium, serotonin release is enhanced during a depolarization compared to no lithium treatment and the same depolarization.
Lithium both directly and indirectly inhibits GSK3β (glycogen synthase kinase 3β) which results in the activation of mTOR. This leads to an increase in neuroprotective mechanisms by facilitating the Akt signaling pathway. GSK-3β is a downstream target of monoamine systems. As such, it is directly implicated in cognition and mood regulation. During mania, GSK-3β is activated via dopamine overactivity. GSK-3β inhibits the transcription factors β-catenin
and cyclic AMP (cAMP) response element binding protein (CREB), by
phosphorylation. This results in a decrease in the transcription of
important genes encoding for neurotrophins. In addition, several authors proposed that pAp-phosphatase could be one of the therapeutic targets of lithium.
This hypothesis was supported by the low Ki of lithium for human
pAp-phosphatase compatible within the range of therapeutic
concentrations of lithium in the plasma of people (0.8–1 mM). The Ki of
human pAp-phosphatase is ten times lower than that of GSK3β (glycogen synthase kinase 3β).
Inhibition of pAp-phosphatase by lithium leads to increased levels of
pAp (3′-5′ phosphoadenosine phosphate), which was shown to inhibit PARP-1.
Another mechanism proposed in 2007 is that lithium may interact with nitric oxide
(NO) signalling pathway in the central nervous system, which plays a
crucial role in neural plasticity. The NO system could be involved in
the antidepressant effect of lithium in the Porsolt forced swimming test
in mice. It was also reported that NMDA receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test, indicating the possible involvement of NMDA receptor/NO signaling in the action of lithium in this animal model of learned helplessness.
Lithium possesses neuroprotective properties by preventing apoptosis and increasing cell longevity.
Although the search for a novel lithium-specific receptor is
ongoing, the high concentration of lithium compounds required to elicit a
significant pharmacological effect leads mainstream researchers to
believe that the existence of such a receptor is unlikely.
During mania, there is an increase in neurotransmission of dopamine that causes a secondary homeostatic down-regulation, resulting in decreased neurotransmission of dopamine, which can cause depression. Additionally, the post-synaptic actions of dopamine are mediated through G-protein coupled receptors.
Once dopamine is coupled to the G-protein receptors, it stimulates
other secondary messenger systems that modulate neurotransmission.
Studies found that in autopsies
(which do not necessarily reflect living people), people with bipolar
disorder had increased G-protein coupling compared to people without
bipolar disorder.
Lithium treatment alters the function of certain subunits of the
dopamine associated G-protein, which may be part of its mechanism of
action.
Glutamate and NMDA receptors
Glutamate levels are observed to be elevated during mania. Lithium is thought to provide long-term mood stabilization and have anti-manic properties by modulating glutamate levels. It is proposed that lithium competes with magnesium for binding to NMDA glutamate receptor, increasing the availability of glutamate in post-synapticneurons, leading to a homeostatic increase in glutamate re-uptake which reduces glutamatergic transmission.
The NMDA receptor is also affected by other neurotransmitters such as serotonin and dopamine. Effects observed appear exclusive to lithium and have not been observed by other monovalent ions such as rubidium and caesium.
GABA receptors
GABA is an inhibitory neurotransmitter that plays an important role in regulating dopamine and glutamateneurotransmission. It was found that patients with bipolar disorder had lower GABA levels, which results in excitotoxicity and can cause apoptosis (cell loss). Lithium has been shown to increase the level of GABA in plasma and cerebral spinal fluid. Lithium counteracts these degrading processes by decreasing pro-apoptotic proteins and stimulating release of neuroprotective proteins.
Lithium's regulation of both excitatory dopaminergic and glutamatergic
systems through GABA may play a role in its mood stabilizing effects.
Cyclic AMP secondary messengers
Lithium's
therapeutic effects are thought to be partially attributable to its
interactions with several signal transduction mechanisms. The cyclic AMP
secondary messenger system is shown to be modulated by lithium. Lithium
was found to increase the basal levels of cyclic AMP but impair
receptor coupled stimulation of cyclic AMP production. It is hypothesized that the dual effects of lithium are due to the inhibition of G-proteins that mediate cyclic AMP production. Over a long period of lithium treatment, cyclic AMP and adenylate cyclase levels are further changed by gene transcription factors.
Inositol depletion hypothesis
Lithium treatment has been found to inhibit the enzyme inositol monophosphatase, involved in degrading inositol monophosphate to inositol required in PIP2 synthesis. This leads to lower levels of inositol triphosphate, created by decomposition of PIP2. This effect has been suggested to be further enhanced with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression. It is known with good certainty that signals from the receptors coupled to the phosphoinositidesignal transduction are affected by lithium. myo-inositol is also regulated by the high affinity sodium mI transport system (SMIT). Lithium is hypothesized to inhibit mI entering the cells and mitigating the function of SMIT. Reductions of cellular levels of myo-inositol results in the inhibition of the phosphoinositide cycle.
Neurotrophic Factors
Various
neurotrophic factors such as BDNF and mesencephalic astrocyte-derived
neurotrophic factor have been shown to be modulated by various mood
stabilizers.
History
Lithium was first used in the 19th century as a treatment for gout after scientists discovered that, at least in the laboratory, lithium could dissolve uric acid crystals isolated from the kidneys. The levels of lithium needed to dissolve urate in the body, however, were toxic. Because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders, Carl Lange in Denmark and William Alexander Hammond in New York City used lithium to treat mania from the 1870s onwards.
By the turn of the 20th century, as theory regarding mood
disorders evolved and so-called "brain gout" disappeared as a medical
entity, the use of lithium in psychiatry was largely abandoned; however,
a number of lithium preparations were still produced for the control of
renal calculi and uric acid diathesis. As accumulating knowledge indicated a role for excess sodium intake in hypertension and heart disease, lithium salts were prescribed to patients for use as a replacement for dietary table salt (sodium chloride).
This practice and the sale of lithium itself were both banned in the
United States in February 1949, following publication of reports
detailing side effects and deaths.
Also in 1949, the Australian psychiatrist John Cade and Australian biochemistShirley Andrews rediscovered the usefulness of lithium salts in treating mania while working at the Royal Park Psychiatric Hospital in Victoria.
They were injecting rodents with urine extracts taken from manic
patients in an attempt to isolate a metabolic compound which might be
causing mental symptoms. Since uric acid in gout was known to be
psychoactive, (adenosine receptors on neurons are stimulated by it; caffeine
blocks them), they needed soluble urate for a control. They used
lithium urate, already known to be the most soluble urate compound, and
observed that it caused the rodents to become tranquil. Cade and Andrews
traced the effect to the lithium ion itself, and after Cade ingested
lithium himself to ensure its safety in humans, he proposed lithium
salts as tranquilizers.
He soon succeeded in controlling mania in chronically hospitalized
patients with them. This was one of the first successful applications of
a drug to treat mental illness, and it opened the door for the
development of medicines for other mental problems in the next decades.
The rest of the world was slow to adopt this treatment, largely
because of deaths which resulted from even relatively minor overdosing,
including those reported from use of lithium chloride as a substitute for table salt. Largely through the research and other efforts of Denmark's Mogens Schou and Paul Baastrup in Europe, and Samuel Gershon and Baron Shopsin in the U.S., this resistance was slowly overcome. Following the recommendation of the APA Lithium Task Force (William Bunney, Irvin Cohen (Chair), Jonathan Cole, Ronald R. Fieve, Samuel Gershon, Robert Prien, and Joseph Tupin), the application of lithium in manic illness was approved by the United States Food and Drug Administration in 1970, becoming the 50th nation to do so. In 1974, this application was extended to its use as a preventive agent for manic-depressive illness.
Fieve, who had opened the first lithium clinic in North America
in 1966, helped popularize the psychiatric use of lithium through his
national TV appearances and his bestselling book, Moodswing. In
addition, Fieve and David L. Dunner developed the concept of "rapid cycling" bipolar disorder based on non-response to lithium.
As with cocaine in Coca-Cola, lithium was widely marketed as one of a number of patent medicine products popular in the late-19th and early-20th centuries, and was the medicinal ingredient of a refreshment beverage. Charles Leiper Grigg, who launched his St. Louis-based company The Howdy Corporation, invented a formula for a lemon-limesoft drink in 1920. The product, originally named "Bib-Label Lithiated Lemon-Lime Soda", was launched two weeks before the Wall Street Crash of 1929. It contained the mood stabilizerlithium citrate, and was one of a number of patent medicine products popular in the late-19th and early-20th centuries. Its name was soon changed to 7 Up. All American beverage makers were forced to remove lithium in 1948. Despite the 1948 ban, in 1950 the Painesville Telegraph still carried an advertisement for a lithiated lemon beverage.
Lithium carbonate (Li 2CO 3), sold under several trade names, is the most commonly prescribed, while lithium citrate (Li 3C 6H 5O 7) is also used in conventional pharmacological treatments. Lithium orotate (C 5H 3LiN 2O 4), has been presented as an alternative. Lithium bromide and lithium chloride have been used in the past as table salt; however, they fell out of use in the 1940s, when it was discovered they were toxic in those large doses. Many other lithium salts and compounds exist, such as lithium fluoride and lithium iodide, but they are presumed to be as toxic or more so than the chloride and have never been evaluated for pharmacological effects.
Tentative evidence in Alzheimer's disease showed that lithium may slow progression. It has been studied for its potential use in the treatment of amyotrophic lateral sclerosis (ALS), but a study showed lithium had no effect on ALS outcomes.
Joint replacement is a procedure of orthopedic surgery known also as arthroplasty, in which an arthritic or dysfunctional joint surface is replaced with an orthopedic prosthesis.
Joint replacement is considered as a treatment when severe joint pain
or dysfunction is not alleviated by less-invasive therapies. Joint
replacement surgery is often indicated from various joint diseases, including osteoarthritis and rheumatoid arthritis.
Joint replacement has become more common, mostly with knee and hip replacements. About 773,000 Americans had a hip or knee replaced in 2009.
For shoulder replacement,
there are a few major approaches to access the shoulder joint. The
first is the deltopectoral approach, which saves the deltoid, but
requires the supraspinatus to be cut.
The second is the transdeltoid approach, which provides a straight on
approach at the glenoid. However, during this approach the deltoid is
put at risk for potential damage. Both techniques are used, depending on the surgeon's preferences.
The number of shoulder replacements carried out each year is
increasing, but research looking into global records suggests that nine
out of ten shoulder replacements last for at least a decade.
Hip replacement can be performed as a total replacement or a hemi (half) replacement. A total hip replacement consists of replacing both the acetabulum and the femoral head while hemiarthroplasty
generally only replaces the femoral head. Hip replacement is currently
the most common orthopaedic operation, though patient satisfaction
short- and long-term varies widely.
It is unclear whether the use of assistive equipment would help in post-operative care.
The operation typically involves substantial postoperative pain,
and includes vigorous physical rehabilitation. The recovery period may
be 6 weeks or longer and may involve the use of mobility aids (e.g.
walking frames, canes, crutches) to enable the person's return to
preoperative mobility.
Ankle replacement has become a treatment of choice for people requiring arthroplasty, replacing the conventional use of arthrodesis,
i.e. fusion of the bones. The restoration of range of motion is the key
feature in favor of ankle replacement with respect to arthrodesis.
However, clinical evidence of the superiority of the former has only
been demonstrated for particular isolated implant designs.
Finger joint replacement is a relatively quick procedure of about 30 minutes, but requires several months of subsequent therapy. Post-operative therapy may consist of wearing a hand splint or performing exercises to improve function and pain.
Risks and complications
Medical risks
The stress of the operation may result in medical problems of varying incidence and severity.
Loosening of the components: the bond between the bone and the components or the cement may break down or fatigue.
As a result, the component moves inside the bone, causing pain.
Fragments of wear debris may cause an inflammatory reaction with bone
absorption which can cause loosening. This phenomenon is known as osteolysis.
Polyethylene synovitis - Wear of the weight-bearing surfaces: polyethylene is thought to wear in weight-bearing joints such as the hip at a rate of 0.3mm per year.
This may be a problem in itself since the bearing surfaces are often
less than 10 mm thick and may deform as they get thinner. The wear may
also cause problems, as inflammation can be caused by increased
quantities of polyethylene wear particles in the synovial fluid.
There are many controversies. Much of the research effort of the
orthopedic-community is directed to studying and improving joint
replacement. The main controversies are
the best or most appropriate bearing surface - metal/polyethylene, metal-metal, ceramic-ceramic;
cemented vs uncemented fixation of the components;
Before
major surgery is performed, a complete pre-anaesthetic work-up is
required. In elderly people this usually would include ECG, urine tests,
hematology and blood tests. Cross match of blood is routine also, as a
high percentage of people receive a blood transfusion.
Pre-operative planning requires accurate Xrays of the affected joint,
implant design selecting and size-matching to the xray images (a process
known as templating).
A few days' hospitalization is followed by several weeks of
protected function, healing and rehabilitation. This may then be
followed by several months of slow improvement in strength and
endurance.
Early mobilisation of the person is thought to be the key to reducing the chances of complications such as venous thromboembolism and Pneumonia. Modern practice is to mobilize people as soon as possible and ambulate
with walking aids when tolerated. Depending on the joint involved and
the pre-op status of the person, the time of hospitalization varies from
1 day to 2 weeks, with the average being 4–7 days in most regions.
Physiotherapy
is used extensively to help people recover function after joint
replacement surgery. A graded exercise programme is needed initially, as
the person's muscles take time to heal after the surgery; exercises for
range of motion of the joints and ambulation should not be strenuous.
Later when the muscles have healed, the aim of exercise expands to
include strengthening and recovery of function.
Materials
Some ceramic materials commonly used in joint replacement are alumina (Al2O3), zirconia (ZrO2), silica (SiO2), hydroxyapatite (Ca10(PO4)6(OH)2), titanium nitride (TiN), silicon nitride (Si3N4).
A combination of titanium and titanium carbide is a very hard ceramic
material often used in components of arthroplasties due to the
impressive degree of strength and toughness it presents, as well as its
compatibility with medical imaging.
Titanium carbide has proved to be possible to use combined with
sintered polycrystalline diamond surface (PCD), a superhard ceramic
which promises to provide an improved, strong, long-wearing material for
artificial joints. PCD is formed from polycrystalline diamond compact
(PDC) through a process involving high pressures and temperatures. When
compared with other ceramic materials such as cubic boron nitride,
silicon nitride, and aluminum oxide, PCD shows many better
characteristics, including a high level of hardness and a relatively low
coefficient of friction. For the application of artificial joints it
will likely be combined with certain metals and metal alloys like
cobalt, chrome, titanium, vanadium, stainless steel, aluminum, nickel,
hafnium, silicon, cobalt-chrome, tungsten, zirconium, etc. This means that people with nickel allergy or sensitivities to other metals are at risk for complications due to the chemicals in the device.
In knee replacements
there are two parts that are ceramic and they can be made of either the
same ceramic or different ones. If they are made of the same ceramic,
however, they have different weight ratios. These ceramic parts are
configured so that should shards break off of the implant, the particles
are benign and not sharp. They are also made so that if a shard were to
break off of one of the two ceramic components, they would be
noticeable through x-rays during a check-up or inspection of the
implant. With implants such as hip implants, the ball of the implant
could be made of ceramic, and between the ceramic layer and where it
attaches to the rest of the implant, there is usually a membrane to help
hold the ceramic. The membrane can help prevent cracks, but if cracks
should occur at two points which create a separate piece, the membrane
can hold the shard in place so that it doesn't leave the implant and
cause further injury. Because these cracks and separations can occur,
the material of the membrane is a bio-compatible polymer that has a high
fracture toughness and a high shear toughness.
Prosthesis replacement
The
prosthesis may need to be replaced due to complications such as
infection or prosthetic fracture. Replacement may be done in one single
surgical session. Alternatively, an initial surgery may be performed to
remove previous prosthetic material, and the new prosthesis is then
inserted in a separate surgery at a later time. In such cases,
especially when complicated by infection, a spacer may be used,
which is a sturdy mass to provide some basic joint stability and
mobility until a more permanent prosthesis is inserted. It can contain antibiotics to help treating any infection.
Two previously popular forms of arthroplasty were: (1) interpositional arthroplasty', with interposition of some other tissue like skin, muscle or tendon to keep inflammatory surfaces apart and (2) excisional arthroplasty in which the joint surface and bone were removed leaving scar tissue to fill in the gap. Other forms of arthroplasty include resection(al) arthroplasty, resurfacing arthroplasty, mold arthroplasty, cup arthroplasty, and silicone replacement arthroplasty. Osteotomy to restore or modify joint congruity is also a form of arthroplasty.
In recent decades, the most successful and common form of
arthroplasty is the surgical replacement of a joint or joint surface
with a prosthesis. For example, a hip joint that is affected by osteoarthritis may be replaced entirely (total hip arthroplasty) with a prosthetic hip. This procedure involves replacing both the acetabulum (hip socket) and the head and neck of the femur.
The purpose of doing this surgery is to relieve pain, to restore range
of motion and to improve walking ability, leading to the improvement of
muscle strength.
