<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Lorazepam and explain in detail? [/INST] Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety disorders, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and chemotherapy-induced nausea and vomiting. It is also used during surgery to interfere with memory formation and to sedate those who are being mechanically ventilated. It is also used, along with other treatments, for acute coronary syndrome due to cocaine use. It can be given by mouth or as an injection into a muscle or vein. When given by injection onset of effects is between one and thirty minutes and effects last for up to a day.Common side effects include weakness, sleepiness, low blood pressure, and a decreased effort to breathe. When given intravenously the person should be closely monitored. Among those who are depressed there may be an increased risk of suicide. With long-term use, larger doses may be required for the same effect. Physical dependence and psychological dependence may also occur. If stopped suddenly after long-term use, benzodiazepine withdrawal syndrome may occur. Older people more often develop adverse effects. In this age group lorazepam is associated with falls and hip fractures. Due to these concerns, lorazepam use is generally only recommended for up to two to four weeks.Lorazepam was initially patented in 1963 and went on sale in the United States in 1977. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 69th most commonly prescribed medication in the United States, with more than 10 million prescriptions.

Medical uses
Anxiety
Lorazepam is used in the short-term management of severe anxiety. In the US, the FDA advises against use of benzodiazepines such as lorazepam for longer than four weeks. It is fast acting, and useful in treating fast onset panic anxiety.Lorazepam can effectively reduce agitation and induce sleep, and the duration of effects from a single dose makes it an appropriate choice for the short-term treatment of insomnia, especially in the presence of severe anxiety or night terrors. It has a fairly short duration of action.Withdrawal symptoms, including rebound insomnia and rebound anxiety, may occur after seven days use of lorazepam.

Seizures
Intravenous diazepam or lorazepam are first-line treatments for convulsive status epilepticus. Lorazepam is more effective than diazepam and intravenous phenytoin in the treatment of status epilepticus and has a lower risk of continuing seizures that might require additional medication. However, phenobarbital has a superior success rate compared to lorazepam and other drugs, at least in the elderly.Lorazepams anticonvulsant properties and pharmacokinetic profile make intravenous use reliable for terminating acute seizures, but induce prolonged sedation. Oral benzodiazepines, including lorazepam, are occasionally used as long-term prophylactic treatment of resistant absence seizures; because of gradual tolerance to their anti-seizure effects, benzodiazepines such as lorazepam are not considered first-line therapies.Lorazepams anticonvulsant and CNS depressant properties are useful for the treatment and prevention of alcohol withdrawal syndrome. In this setting, impaired liver function is not a hazard with lorazepam, since lorazepam does not require oxidation, in the liver or otherwise, for its metabolism.

Sedation
Lorazepam is sometimes used for individuals receiving mechanical ventilation. However, in critically ill people, propofol has been found to be superior to lorazepam both in effectiveness and overall cost; as a result, the use of propofol for this indication is now encouraged, whereas the use of lorazepam is discouraged.Its relative effectiveness in preventing new memory formation, along with its ability to reduce agitation and anxiety, makes lorazepam useful as premedication. It is given before a general anesthetic to reduce the amount of anesthetic required, or before unpleasant awake procedures, such as in dentistry or endoscopies, to reduce anxiety, to increase compliance, and to induce amnesia for the procedure. Lorazepam by mouth is given 90 to 120 minutes before procedures, and intravenous lorazepam as late as 10 minutes before procedures. Lorazepam is sometimes used as an alternative to midazolam in palliative sedation. In intensive care units lorazepam is sometimes used to produce anxiolysis, hypnosis, and amnesia.

Agitation
Lorazepam is sometimes used as an alternative to haloperidol when there is the need for rapid sedation of violent or agitated individuals, but haloperidol plus promethazine is preferred due to better effectiveness and due to lorazepams adverse effects on respiratory function. However, adverse effects such as behavioral disinhibition may make benzodiazepines inappropriate for some people who are acutely psychotic . Acute delirium is sometimes treated with lorazepam, but as it can cause paradoxical effects, it is preferably given together with haloperidol. Lorazepam is absorbed relatively slowly if given intramuscularly, a common route in restraint situations.

Other
Catatonia with inability to speak is responsive to lorazepam. Symptoms may recur and treatment for some days may be necessary. Catatonia due to abrupt or overly rapid withdrawal from benzodiazepines, as part of the benzodiazepine withdrawal syndrome, should also respond to lorazepam treatment. As lorazepam can have paradoxical effects, haloperidol is sometimes given at the same time.It is sometimes used in chemotherapy in addition to medications used to treat nausea and vomiting, i.e. nausea and vomiting caused or worsened by psychological sensitization to the thought of being sick.

Adverse effects
Many beneficial effects of lorazepam (e.g., sedative, muscle relaxant, anti-anxiety, and amnesic effects) may become adverse effects when unwanted. Adverse effects can include sedation and low blood pressure; the effects of lorazepam are increased in combination with other CNS depressant drugs. Other adverse effects include confusion, ataxia, inhibiting the formation of new memories, pupil constriction and hangover effects. With long-term benzodiazepine use it is unclear whether cognitive impairments fully return to normal after stopping lorazepam use; cognitive deficits persist for at least six months after withdrawal, but longer than six months may be required for recovery of cognitive function. Lorazepam appears to have more profound adverse effects on memory than other benzodiazepines; it impairs both explicit and implicit memory. In the elderly, falls may occur as a result of benzodiazepines. Adverse effects are more common in the elderly, and they appear at lower doses than in younger people. Benzodiazepines can cause or worsen depression. Paradoxical effects can also occur, such as worsening of seizures, or paradoxical excitement; paradoxical excitement is more likely to occur in the elderly, children, those with a history of alcohol abuse, and in people with a history of aggression or anger problems. Lorazepams effects are dose-dependent, meaning the higher the dose, the stronger the effects (and side effects) will be. Using the smallest dose needed to achieve desired effects lessens the risk of adverse effects. Sedative drugs and sleeping pills, including lorazepam, have been associated with an increased risk of death.Sedation is the side effect people taking lorazepam most frequently report. In a group of around 3,500 people treated for anxiety, the most common side effects complained of from lorazepam were sedation (15.9%), dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%). Side effects such as sedation and unsteadiness increased with age. Cognitive impairment, behavioural disinhibition and respiratory depression as well as hypotension may also occur.
Paradoxical effects: In some cases, paradoxical effects can occur with benzodiazepines, such as increased hostility, aggression, angry outbursts, and psychomotor agitation. These effects are seen more commonly with lorazepam than with other benzodiazepines. Paradoxical effects are more likely to occur with higher doses, in people with pre-existing personality disorders and those with a psychiatric illness. Frustrating stimuli may trigger such reactions, though the drug may have been prescribed to help the person cope with such stress and frustration in the first place. As paradoxical effects appear to be dose-related, they usually subside on dose reduction or on complete withdrawal of lorazepam.
Suicidality: Benzodiazepines are associated with increased risk of suicide, possibly due to disinhibition. Higher dosages appear to confer greater risk.
Amnesic effects: Among benzodiazepines, lorazepam has relatively strong amnesic effects, but people soon develop tolerance to this with regular use. To avoid amnesia (or excess sedation) being a problem, the initial total daily lorazepam dose should not exceed 2 mg. This also applies to use for night sedation. Five participants in a sleep study were prescribed lorazepam 4 mg at night, and the next evening, three subjects unexpectedly volunteered memory gaps for parts of that day, an effect that subsided completely after two to three days use. Amnesic effects cannot be estimated from the degree of sedation present, since the two effects are unrelated.
High-dose or prolonged parenterally administered lorazepam with its associated solvent can cause propylene glycol intoxication and poisoning.In September 2020, the U.S. Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Contraindications
Lorazepam should be avoided in people with:

Allergy or hypersensitivity – Past hypersensitivity or allergy to lorazepam, to any benzodiazepine, or to any of the ingredients in lorazepam tablets or injections
Respiratory failure – Benzodiazepines, including lorazepam, may depress central nervous system respiratory drive and are contraindicated in severe respiratory failure. An example would be the inappropriate use to relieve anxiety associated with acute severe asthma. The anxiolytic effects may also be detrimental to a persons willingness and ability to fight for breath. However, if mechanical ventilation becomes necessary, lorazepam may be used to facilitate deep sedation.
Acute intoxication – Lorazepam may interact synergistically with the effects of alcohol, narcotics, or other psychoactive substances. It should, therefore, not be administered to a drunk or intoxicated person.
Ataxia – This is a neurological clinical sign, consisting of unsteady and clumsy motion of the limbs and torso, due to the failure of gross muscle movement coordination, most evident on standing and walking. It is the classic way in which acute alcohol intoxication may affect a person. Benzodiazepines should not be administered to people already-ataxic.
Acute narrow-angle glaucoma – Lorazepam has pupil-dilating effects, which may further interfere with the drainage of aqueous humor from the anterior chamber of the eye, thus worsening narrow-angle glaucoma.
Sleep apnea – Sleep apnea may be worsened by lorazepams central nervous system depressant effects. It may further reduce the persons ability to protect his or her airway during sleep.
Myasthenia gravis – This condition is characterized by muscle weakness, so a muscle relaxant such as lorazepam may exacerbate symptoms.
Pregnancy and breastfeeding – Lorazepam belongs to the Food and Drug Administration (FDA) pregnancy category D, which means it is likely to cause harm to the developing baby if taken during the first trimester of pregnancy. The evidence is inconclusive whether lorazepam if taken early in pregnancy results in reduced intelligence, neurodevelopmental problems, physical malformations in cardiac or facial structure, or other malformations in some newborns. Lorazepam given to pregnant women antenatally may cause floppy infant syndrome in the neonate, or respiratory depression necessitating ventilation. Regular lorazepam use during late pregnancy (the third trimester), carries a definite risk of benzodiazepine withdrawal syndrome in the neonate. Neonatal benzodiazepine withdrawal may include hypotonia, reluctance to suck, apneic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Lorazepam may also inhibit fetal liver bilirubin glucuronidation, leading to neonatal jaundice. Lorazepam is present in breast milk, so caution must be exercised about breastfeeding.

Specific groups
Children and the elderly – The safety and effectiveness of lorazepam is not well determined in children under 18 years of age, but it is used to treat acute seizures. Dose requirements have to be individualized, especially in people who are elderly and debilitated in whom the risk of oversedation is greater. Long-term therapy may lead to cognitive deficits, especially in the elderly, which may only be partially reversible. The elderly metabolize benzodiazepines more slowly than younger people and are more sensitive to the adverse effects of benzodiazepines compared to younger individuals even at similar plasma levels. Additionally, the elderly tend to take more drugs which may interact or enhance the effects of benzodiazepines. Benzodiazepines, including lorazepam, have been found to increase the risk of falls and fractures in the elderly. As a result, dosage recommendations for the elderly are about half of those used in younger individuals and used for no longer than two weeks. Lorazepam may also be slower to clear in the elderly, leading potentially to accumulation and enhanced effects. Lorazepam, similar to other benzodiazepines and nonbenzodiazepines, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete, tolerance develops to these impairments.
Liver or kidney failure – Lorazepam may be safer than most benzodiazepines in people with impaired liver function. Like oxazepam, it does not require liver oxidation, but only liver glucuronidation into lorazepam-glucuronide. Therefore, impaired liver function is unlikely to result in lorazepam accumulation to an extent causing adverse reactions. Similarly kidney disease has minimal effects on lorazepam levels.
Surgical premedication – Informed consent given only after receiving lorazepam premedication could have its validity challenged later. Staff must use chaperones to guard against allegations of abuse during treatment. Such allegations may arise because of incomplete amnesia, disinhibition, and impaired ability to process cues. Because of its relatively long duration of residual effects (sedation, ataxia, hypotension, and amnesia), lorazepam premedication is best suited for hospital inpatient use. People should not be discharged from the hospital within 24 hours of receiving lorazepam premedication unless accompanied by a caregiver. They should also not drive, operate machinery, or use alcohol within this period.
Drug and alcohol dependence – The risk of abuse of lorazepam is increased in dependent people.
Comorbid psychiatric disorders also increase the risk of dependence and paradoxical adverse effects.

Tolerance and dependence
Dependence typified by a withdrawal syndrome occurs in about one-third of individuals who are treated for longer than four weeks with a benzodiazepine. Higher doses and longer periods of use increase the risk of developing a benzodiazepine dependence. Potent benzodiazepines with a relatively short half life, such as lorazepam, alprazolam, and triazolam, have the highest risk of causing a dependence. Tolerance to benzodiazepine effects develops with regular use. This is desirable with amnesic and sedative effects but undesirable with anxiolytic, hypnotic, and anticonvulsant effects. People initially experience drastic relief from anxiety and sleeplessness, but symptoms gradually return, relatively soon in the case of insomnia, but more slowly in the case of anxiety symptoms. After four to six months of regular benzodiazepine use, evidence of continued efficacy declines.If regular treatment is continued for longer than four to six months, dose increases may be necessary to maintain effects, but treatment-resistant symptoms may in fact be benzodiazepine withdrawal symptoms. Due to the development of tolerance to the anticonvulsant effects, benzodiazepines are generally not recommended for long-term use for the management of epilepsy. Increasing the dose may overcome tolerance, but tolerance may then develop to the higher dose and adverse effects may persist and worsen. The mechanism of tolerance to benzodiazepines is complex and involves GABAA receptor downregulation, alterations to subunit configuration of GABAA receptors, uncoupling and internalisation of the benzodiazepine binding site from the GABAA receptor complex as well as changes in gene expression.The likelihood of dependence is relatively high with lorazepam compared to other benzodiazepines. Lorazepams relatively short serum half-life, its confinement mainly to blood, and its inactive metabolite can result in interdose withdrawal phenomena and next-dose cravings, that may reinforce psychological dependence. Because of its high potency, the smallest lorazepam tablet strength of 0.5 mg is also a significant dose. To minimise the risk of physical/psychological dependence, lorazepam is best used only short-term, at the smallest effective dose. If any benzodiazepine has been used long-term, the recommendation is a gradual dose taper over a period of weeks, months or longer, according to dose and duration of use, the degree of dependence and the individual.
Coming off long-term lorazepam use may be more realistically achieved by a gradual switch to an equivalent dose of diazepam and a period of stabilization on this, and only then initiating dose reductions. The advantage of switching to diazepam is that dose reductions are felt less acutely, because of the longer half-lives (20–200 hours) of diazepam and its active metabolites.

Withdrawal
On abrupt or overly rapid discontinuation of lorazepam, anxiety, and signs of physical withdrawal have been observed, similar to those seen on withdrawal from alcohol and barbiturates. Lorazepam, as with other benzodiazepine drugs, can cause physical dependence, addiction, and benzodiazepine withdrawal syndrome. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can, however, occur from standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regimen. Rebound effects often resemble the condition being treated, but typically at a more intense level and may be difficult to diagnose. Withdrawal symptoms can range from mild anxiety and insomnia to more severe symptoms such as seizures and psychosis. The risk and severity of withdrawal are increased with long-term use, use of high doses, abrupt or over-rapid reduction, among other factors. Short-acting benzodiazepines such as lorazepam are more likely to cause a more severe withdrawal syndrome compared to longer-acting benzodiazepines.Withdrawal symptoms can occur after taking therapeutic doses of lorazepam for as little as one week. Withdrawal symptoms include headaches, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, dysphoria, dizziness, derealization, depersonalization, numbness/tingling of extremities, hypersensitivity to light, sound, and smell, perceptual distortions, nausea, vomiting, diarrhea, appetite loss, hallucinations, delirium, seizures, tremor, stomach cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, short-term memory loss, and hyperthermia. It takes about 18–36 hours for the benzodiazepine to be removed from the body. The ease of physical dependence to lorazepam, (Ativan brand was particularly cited), and its withdrawal were brought to the attention of the British public during the early 1980s in Esther Rantzens BBC TV series Thats Life!, in a feature on the drug over a number of episodes.

Interactions
Lorazepam is not usually fatal in overdose, but may cause respiratory depression if taken in overdose with alcohol. The combination also causes greater enhancement of the disinhibitory and amnesic effects of both drugs, with potentially embarrassing or criminal consequences. Some experts advise that people should be warned against drinking alcohol while on lorazepam treatment, but such clear warnings are not universal.Greater adverse effects may also occur when lorazepam is used with other drugs, such as opioids or other hypnotics. Lorazepam may also interact with rifabutin. Valproate inhibits the metabolism of lorazepam, whereas carbamazepine, lamotrigine, phenobarbital, phenytoin, and rifampin increase its rate of metabolism. Some antidepressants, antiepileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opiates, antipsychotics and alcohol, when taken with lorazepam may result in enhanced sedative effects.

Overdose
In cases of a suspected lorazepam overdose, it is important to establish whether the person is a regular user of lorazepam or other benzodiazepines since regular use causes tolerance to develop. Also, one must ascertain whether other substances were also ingested.
Signs of overdose range through mental confusion, dysarthria, paradoxical reactions, drowsiness, hypotonia, ataxia, hypotension, hypnotic state, coma, cardiovascular depression, respiratory depression, and death. However, fatal overdoses on benzodiazepines alone are rare and less common than with barbiturates. Such a difference is largely due to benzodiazepine activity as a neuroreceptor modulator, and not as an activator per se. Lorazepam and similar medication do however act in synergy with alcohol, which increases the risk of overdose.
Early management of  people under alert includes emetics, gastric lavage, and activated charcoal. Otherwise, management is by observation, including of vital signs, support and, only if necessary, considering the hazards of doing so, giving intravenous flumazenil.
People are ideally nursed in a kind, frustration-free environment, since, when given or taken in high doses, benzodiazepines are more likely to cause paradoxical reactions. If shown sympathy, even quite crudely feigned, people may respond solicitously, but they may respond with disproportionate aggression to frustrating cues. Opportunistic counseling has limited value here, as the person is unlikely to recall this later, owing to drug-induced anterograde amnesia.

Detection in body fluids
Lorazepam may be quantitated in blood or plasma to confirm poisoning in hospitalized people, provide evidence of an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma concentrations are usually in a range of 10–300 μg/L in persons either receiving the drug therapeutically or in those arrested for impaired driving. Approximately 300–1000 μg/L is found in people after acute overdosage. Lorazepam may not be detected by commonly used urine drug screenings for benzodiazepines.

Pharmacology
Lorazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant, and muscle relaxant properties. It is a high-potency and an intermediate-acting benzodiazepine, and its uniqueness, advantages, and disadvantages are largely explained by its pharmacokinetic properties (poor water and lipid solubility, high protein binding and anoxidative metabolism to a pharmacologically inactive glucuronide form) and by its high relative potency (lorazepam 1 mg is equal in effect to diazepam 10 mg). The biological half-life of lorazepam is 10–20 hours.

Pharmacokinetics
Lorazepam is highly protein bound and is extensively metabolized into pharmacologically inactive metabolites. Due to its poor lipid solubility, lorazepam is absorbed relatively slowly by mouth and is unsuitable for rectal administration. However, its poor lipid solubility and high degree of protein binding (85–90%) mean its volume of distribution is mainly the vascular compartment, causing relatively prolonged peak effects. This contrasts with the highly lipid-soluble diazepam, which, although rapidly absorbed orally or rectally, soon redistributes from the serum to other parts of the body, in particular, body fat. This explains why one lorazepam dose, despite its shorter serum half-life, has more prolonged peak effects than an equivalent diazepam dose. Lorazepam is rapidly conjugated at its 3-hydroxy group into lorazepam glucuronide which is then excreted in the urine. Lorazepam glucuronide has no demonstrable CNS activity in animals. The plasma levels of lorazepam are proportional to the dose given. There is no evidence of accumulation of lorazepam on administration up to six months. On regular administration, diazepam will accumulate, since it has a longer half-life and active metabolites, these metabolites also have long half-lives.
Clinical example: Diazepam has long been a drug of choice for status epilepticus; its high lipid solubility means it gets absorbed with equal speed whether given orally, or rectally (nonintravenous routes are convenient in outside hospital settings), but diazepams high lipid solubility also means it does not remain in the vascular space, but soon redistributes into other body tissues. So, it may be necessary to repeat diazepam doses to maintain peak anticonvulsant effects, resulting in excess body accumulation. Lorazepam is a different case; its low lipid solubility makes it relatively slowly absorbed by any route other than intravenously, but once injected, it will not get significantly redistributed beyond the vascular space. Therefore, lorazepams anticonvulsant effects are more durable, thus reducing the need for repeated doses. If a person is known to usually stop convulsing after only one or two diazepam doses, it may be preferable because sedative after effects will be less than if a single dose of lorazepam is given (diazepam anticonvulsant/sedative effects wear off after 15–30 minutes, but lorazepam effects last 12–24 hours). The prolonged sedation from lorazepam may, however, be an acceptable trade-off for its reliable duration of effects, particularly if the person needs to be transferred to another facility. Although lorazepam is not necessarily better than diazepam at initially terminating seizures, lorazepam is, nevertheless, replacing diazepam as the intravenous agent of choice in status epilepticus.Lorazepam serum levels are proportional to the dose administered. Giving 2 mg oral lorazepam will result in a peak total serum level of around 20 ng/mL around two hours later, half of which is lorazepam, half its inactive metabolite, lorazepam-glucuronide. A similar lorazepam dose given intravenously will result in an earlier and higher peak serum level, with a higher relative proportion of unmetabolised (active) lorazepam. On regular administration, maximum serum levels are attained after three days. Longer-term use, up to six months, does not result in further accumulation. On discontinuation, lorazepam serum levels become negligible after three days and undetectable after about a week. Lorazepam is metabolized in the liver by conjugation into inactive lorazepam-glucuronide. This metabolism does not involve liver oxidation, so is relatively unaffected by reduced liver function. Lorazepam-glucuronide is more water-soluble than its precursor, so gets more widely distributed in the body, leading to a longer half-life than lorazepam. Lorazepam-glucuronide is eventually excreted by the kidneys, and, because of its tissue accumulation, it remains detectable, particularly in the urine, for substantially longer than lorazepam.

Pharmacodynamics
Relative to other benzodiazepines, lorazepam is thought to have high affinity for GABA receptors, which may also explain its marked amnesic effects. Its main pharmacological effects are the enhancement of the effects of the neurotransmitter GABA at the GABAA receptor. Benzodiazepines, such as lorazepam, enhance the effects of GABA at the GABAA receptor via increasing the frequency of opening of the chloride ion channel on the GABAA receptors; which results in the therapeutic actions of benzodiazepines. They, however, do not on their own activate the GABAA receptors, but require the neurotransmitter GABA to be present. Thus, the effect of benzodiazepines is to enhance the effects of the neurotransmitter GABA.The magnitude and duration of lorazepam effects are dose-related, meaning larger doses have stronger and longer-lasting effects, because the brain has spare benzodiazepine drug receptor capacity, with single, clinical doses leading only to an occupancy of some 3% of the available receptors.The anticonvulsant properties of lorazepam and other benzodiazepines may be, in part or entirely, due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to get limited, by the benzodiazepine effect of slowing recovery of sodium channels from inactivation to deactivation in mouse spinal cord cell cultures, hence prolonging the refractory period.

Physical properties and formulations
Pure lorazepam is an almost white powder that is nearly insoluble in water and oil. In medicinal form, it is mainly available as tablets and a solution for injection, but, in some locations, it is also available as a skin patch, an oral solution, and a sublingual tablet.
Lorazepam tablets and syrups are administered by mouth only. Lorazepam tablets of the Ativan brand also contain lactose, microcrystalline cellulose, polacrilin, magnesium stearate, and coloring agents (indigo carmine in blue tablets and tartrazine in yellow tablets). Lorazepam for injection formulated with polyethylene glycol 400 in propylene glycol with 2.0% benzyl alcohol as preservative.
Lorazepam injectable solution is administered either by deep intramuscular injection or by intravenous injection. The injectable solution comes in 1 mL ampoules containing 2 or 4 mg of lorazepam. The solvents used are polyethylene glycol 400 and propylene glycol. As a preservative, the injectable solution contains benzyl alcohol. Toxicity from propylene glycol has been reported in the case of a person receiving a continuous lorazepam infusion. Intravenous injections should be given slowly and they should be closely monitored for side effects, such as respiratory depression, hypotension, or loss of airway control.
Peak effects roughly coincide with peak serum levels, which occur 10 minutes after intravenous injection, up to 60 minutes after intramuscular injection, and 90 to 120 minutes after oral administration, but initial effects will be noted before this. A clinically relevant lorazepam dose will normally be effective for six to 12 hours, making it unsuitable for regular once-daily administration, so it is usually prescribed as two to four daily doses when taken regularly, but this may be extended to five or six, especially in the case of elderly people who could not handle large doses at once.
Topical formulations of lorazepam, while used as treatment for nausea especially in people in hospice, ought not be used in this form and for this purpose as they have not been proven effective.

History
Historically, lorazepam is one of the "classical" benzodiazepines. Others include diazepam, clonazepam, oxazepam, nitrazepam, flurazepam, bromazepam, and clorazepate. Lorazepam was first introduced by Wyeth Pharmaceuticals in 1977 under the brand names Ativan and Temesta. The drug was developed by D.J. Richards, president of research. Wyeths original patent on lorazepam is expired in the United States.

Society and culture
Recreational use
Lorazepam is also used for other purposes, such as recreational use, wherein the drug is taken to achieve a high, or when the drug is continued long-term against medical advice.A large-scale, nationwide, U.S. government study of pharmaceutical-related emergency department visits by SAMHSA found sedative-hypnotics are the pharmaceuticals most frequently used outside of their prescribed medical purpose in the United States, with 35% of drug-related emergency department visits involving sedative-hypnotics. In this category, benzodiazepines are most commonly used. Males and females use benzodiazepines for nonmedical purposes equally. Of drugs used in attempted suicide, benzodiazepines are the most commonly used pharmaceutical drugs, with 26% of attempted suicides involving them </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Dorzolamide/timolol and explain in detail? [/INST] Dorzolamide/timolol, sold under the brand name Cosopt among others, is a medication used to treat high pressure inside the eye including glaucoma. It is a combination of dorzolamide hydrochloride and timolol maleate. It may be used when a beta blocker, like timolol, is not sufficient alone. It is used as an eye drop.Common side effects include eye discomfort, eye redness, taste changes, and blurry vision. Serious side effects may include allergic reactions and heart failure. Use is not recommended in those with asthma, a sulfonamide allergy, or a slow heart rate. Dorzolamide is a carbonic anhydrase inhibitor and timolol is a beta blocker. Both work by decreasing the amount of aqueous humor made by the eye.The combination was approved for medical use in the United States in 1998. It is available as a generic medication. In 2019, it was the 207th most commonly prescribed medication in the United States, with more than 2 million prescriptions.

Adverse effects
Common adverse effects include temporarily blurred vision, cloudy vision, double vision, temporary burning/stinging/itching of the eye, watery eyes, feeling as if something is in the eye, drooping eyelid, sensitivity to light, cough, flu symptoms, nausea, and stomach pain.More serious adverse effects include dizziness, slow or irregular heartbeat, muscle weakness, mental/mood changes, and coldness/numbness/pain in the hands or feet.

Pharmacology
Dorzolamide is a human carboanydrase II inhibitor.  Inhibition of carboanhydrase in the ciliary processes of the eye decreases aqueous humor secretion supposedly by decreasing the formation rate of bicarbonate ions. This results in reduction in both sodium and fluid transport.
Timolol is a non-selective beta-adrenergic antagonist.

Comparison to other products
Despite each of the active ingredients being availed in their own respective formulations, combination formulations are typically more convenient for the patient without sacrificing any quality in therapy.  In the case of Cosopt, the combination formulation dosed twice daily provides equivalent treatment to both dorzolamide 2% dosed two times daily and timolol 0.5% dosed three times daily.  Specifically, the mean reduction in intraocular pressure was 27.4% for the combination product, 15.5% for dorzolamide 2%, and 22.2% for timolol 0.5%.
Compared to other products such as latanoprost, both are equally efficacious with regard to lowering intraocular pressure and getting patients to reach their target intraocular pressure.  Cosopt, though, is typically less well tolerated than other treatments due to a well documented feeling of ocular burning upon administration.

History
Cosopt gained Food and Drug Administration (FDA) approval in April 1998 and was supplied initially by Merck. In 2016, Merck & Co. had $95.3 billion in total assets, $40.3 billion in total equity, $24.3 billion in long term debt, and $13.4 billion in working capital. This same year Merck & Co spent $20 billion total split virtually evenly between research and development (R&D) and marketing efforts.  Cosopt had annual sales of $342 million during the 12 months before June 2008.  In September 2013,  Merck & Co </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Drospirenone and explain in detail? [/INST] Drospirenone is a progestin medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses. It is available both alone under the brand name Slynd and in combination with an estrogen under the brand name Yasmin among others. The medication is taken by mouth.Common side effects include acne, headache, breast tenderness, weight increase, and menstrual changes. Rare side effects may include high potassium levels and blood clots, among others. Drospirenone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has additional antimineralocorticoid and antiandrogenic activity and no other important hormonal activity. Because of its antimineralocorticoid activity and lack of undesirable off-target activity, drospirenone is said to more closely resemble bioidentical progesterone than other progestins.Drospirenone was patented in 1976 and introduced for medical use in 2000. It is available widely throughout the world. The medication is sometimes referred to as a "fourth-generation" progestin. It is available as a generic medication. In 2018, a formulation of drospirenone with ethinylestradiol was the 167th most commonly prescribed medication in the United States, with more than 3 million prescriptions.

Medical uses
Drospirenone (DRSP) is used by itself as a progestogen-only birth control pill, in combination with the estrogens ethinylestradiol (EE) or estetrol (E4), with or without supplemental folic acid (vitamin B9), as a combined birth control pill, and in combination with the estrogen estradiol (E2) for use in menopausal hormone therapy. A birth control pill with low-dose ethinylestradiol is also indicated for the treatment of moderate acne, premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and dysmenorrhea (painful menstruation). For use in menopausal hormone therapy, E2/DRSP is specifically approved to treat moderate to severe vasomotor symptoms (hot flashes), vaginal atrophy, and postmenopausal osteoporosis. The drospirenone component in this formulation is included specifically to prevent estrogen-induced endometrial hyperplasia. Drospirenone has also been used in combination with an estrogen as a component of hormone therapy for transgender women.Studies have found that EE/DRSP is superior to placebo in reducing premenstrual emotional and physical symptoms while also improving quality of life. E2/DRSP has been found to increase bone mineral density and to reduce the occurrence of bone fractures in postmenopausal women. In addition, E2/DRSP has a favorable influence on cholesterol and triglyceride levels and decreases blood pressure in women with high blood pressure. Due to its antimineralocorticoid activity, drospirenone opposes estrogen-induced salt and water retention and maintains or slightly reduces body weight.

Available forms
Drospirenone is available in the following formulations, brand names, and indications:
Drospirenone 4 mg (Slynd) – progestogen-only birth control pill
Drospirenone 3 mg and estetrol 14.2 mg (Nextstellis (US)) – combined birth control pill
Ethinylestradiol 30 μg and drospirenone 3 mg (Ocella, Syeda, Yasmin, Zarah, Zumandimine) – combined birth control pill
Ethinylestradiol 20 μg and drospirenone 3 mg (Gianvi,  Jasmiel, Loryna, Lo-Zumandimine, Nikki, Vestura, Yaz) – combined birth control pill, acne, PMS, PMDD, dysmenorrhea
Ethinylestradiol 30 μg, drospirenone 3 mg, and levomefolate calcium 0.451 mg (Beyaz, Tydemy) – combined birth control pill with vitamin B9 supplementation, acne, PMS
Estetrol 15 mg and drospirenone 3 mg (Nextstellis (CA)) – combined birth control pill
Estradiol 0.5 or 1 mg and drospirenone 0.25 or 0.5 mg (Angeliq) – menopausal hormone therapy (menopausal syndrome, postmenopausal osteoporosis)

Contraindications
Contraindications of drospirenone include renal impairment or chronic kidney disease, adrenal insufficiency, presence or history of cervical cancer or other progestogen-sensitive cancers, benign or malignant liver tumors or hepatic impairment, undiagnosed abnormal uterine bleeding, and hyperkalemia (high potassium levels). Renal impairment, hepatic impairment, and adrenal insufficiency are contraindicated because they increase exposure to drospirenone and/or increase the risk of hyperkalemia with drospirenone.

Side effects
Adverse effects of drospirenone alone occurring in more than 1% of women may include unscheduled menstrual bleeding (breakthrough or intracyclic) (40.3–64.4%), acne (3.8%), metrorrhagia (2.8%), headache (2.7%), breast pain (2.2%), weight gain (1.9%), dysmenorrhea (1.9%), nausea (1.8%), vaginal hemorrhage (1.7%), decreased libido (1.3%), breast tenderness (1.2%), and irregular menstruation (1.2%).

High potassium levels
Drospirenone is an antimineralocorticoid with potassium-sparing properties, though in most cases no increase of potassium levels is to be expected. In women with mild or moderate chronic kidney disease, or in combination with chronic daily use of other potassium-sparing medications (ACE inhibitors, angiotensin II receptor antagonists, potassium-sparing diuretics, heparin, antimineralocorticoids, or nonsteroidal anti-inflammatory drugs), a potassium level should be checked after two weeks of use to test for hyperkalemia. Persistent hyperkalemia that required discontinuation occurred in 2 out of around 1,000 women (0.2%) with 4 mg/day drospirenone alone in clinical trials.

Blood clots
Birth control pills containing ethinylestradiol and a progestin are associated with an increased risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). The incidence is about 4-fold higher on average than in women not taking a birth control pill. The absolute risk of VTE with ethinylestradiol-containing birth control pills is small, in the area of 3 to 10 out of 10,000 women per year, relative to 1 to 5 out of 10,000 women per year not taking a birth control pill. The risk of VTE during pregnancy is 5 to 20 in 10,000 women per year and during the postpartum period is 40 to 65 per 10,000 women per year. The higher risk of VTE with combined birth control pills is thought to be due to the ethinylestradiol component, as ethinylestradiol has estrogenic effects on liver synthesis of coagulation factors which result in a procoagulatory state. In contrast to ethinylestradiol-containing birth control pills, neither progestogen-only birth control nor the combination of transdermal estradiol and an oral progestin in menopausal hormone therapy is associated with an increased risk of VTE.Different progestins in ethinylestradiol-containing birth control pills have been associated with different risks of VTE. Birth control pills containing progestins such as desogestrel, gestodene, drospirenone, and cyproterone acetate have been found to have 2- to 3-fold the risk of VTE of birth control pills containing levonorgestrel in retrospective cohort and nested case–control observational studies. However, this area of research is controversial, and confounding factors may have been present in these studies. Other observational studies, specifically prospective cohort and case control studies, have found no differences in risk between different progestins, including between birth control pills containing drospirenone and birth control pills containing levonorgestrel. These kinds of observational studies have certain advantages over the aforementioned types of studies, like better ability to control for confounding factors. Systematic reviews and meta-analyses of all of the data in the mid-to-late 2010s found that birth control pills containing cyproterone acetate, desogestrel, drospirenone, or gestodene overall were associated with a risk of VTE of about 1.3- to 2.0-fold compared to that of levonorgestrel-containing birth control pills.Androgenic progestins have been found to antagonize to some degree the effects of ethinylestradiol on coagulation. As a result, more androgenic progestins, like levonorgestrel and norethisterone, may oppose the procoagulatory effects of ethinylestradiol and result in a lower increase in risk of VTE. Conversely, this would be the case less or not at all with progestins that are less androgenic, like desogestrel and gestodene, as well as with progestins that are antiandrogenic, like drospirenone and cyproterone acetate.In the early 2010s, the FDA updated the label for birth control pills containing drospirenone and other progestins to include warnings for stopping use prior to and after surgery, and to warn that such birth control pills may have a higher risk of blood clots.

Breast cancer
Drospirenone has been found to stimulate the proliferation and migration of breast cancer cells in preclinical research, similarly to certain other progestins. However, some evidence suggests that drospirenone may do this more weakly than certain other progestins, like medroxyprogesterone acetate. The combination of estradiol and drospirenone has been found to increase breast density, an established risk factor for breast cancer, in postmenopausal women.Data on risk of breast cancer in women with newer progestins like drospirenone are lacking at present. Progestogen-only birth control is not generally associated with a higher risk of breast cancer. Conversely, combined birth control and menopausal hormone therapy with an estrogen and a progestogen are associated with higher risks of breast cancer.

Overdose
These have been no reports of serious adverse effects with overdose of drospirenone. Symptoms that may occur in the event of an overdose may include nausea, vomiting, and vaginal bleeding. There is no antidote for overdose of drospirenone and treatment of overdose should be based on symptoms. Since drospirenone has antimineralocorticoid activity, levels of potassium and sodium should be measured and signs of metabolic acidosis should be monitored.

Interactions
Inhibitors and inducers of the cytochrome P450 enzyme CYP3A4 may influence the levels and efficacy of drospirenone. Treatment for 10 days with 200 mg twice daily ketoconazole, a strong CYP3A4 inhibitor among other actions, has been found to result in a moderate 2.0- to 2.7-fold increase in exposure to drospirenone. Drospirenone does not appear to influence the metabolism of omeprazole (metabolized via CYP2C19), simvastatin (metabolized via CYP3A4), or midazolam (metabolized via CYP3A4), and likely does not influence the metabolism of other medications that are metabolized via these pathways. Drospirenone may interact with potassium-sparing medications such as ACE inhibitors, angiotensin II receptor antagonists, potassium-sparing diuretics, potassium supplements, heparin, antimineralocorticoids, and nonsteroidal anti-inflammatory drugs to further increase potassium levels. This may increase the risk of hyperkalemia (high potassium levels).

Pharmacology
Pharmacodynamics
Drospirenone binds with high affinity to the progesterone receptor (PR) and mineralocorticoid receptor (MR), with lower affinity to the androgen receptor (AR), and with very low affinity to the glucocorticoid receptor (GR). It is an agonist of the PR and an antagonist of the MR and AR, and hence is a progestogen, antimineralocorticoid, and antiandrogen. Drospirenone has no estrogenic activity and no appreciable glucocorticoid or antiglucocorticoid activity.

Progestogenic activity
Drospirenone is an agonist of the PR, the biological target of progestogens like progesterone. It has about 35% of the affinity of promegestone for the PR and about 19 to 70% of the affinity of progesterone for the PR. Drospirenone has antigonadotropic and functional antiestrogenic effects as a result of PR activation. The ovulation-inhibiting dosage of drospirenone is 2 to 3 mg/day. Inhibition of ovulation occurred in about 90% of women at a dose of 0.5 to 2 mg/day and in 100% of women at a dose of 3 mg/day. The total endometrial transformation dose of drospirenone is about 50 mg per cycle, whereas its daily dose is 2 mg for partial transformation and 4 to 6 mg for full transformation. The medication acts as a contraceptive by activating the PR, which suppresses the secretion of luteinizing hormone, inhibits ovulation, and alters the cervical membrane and endometrium.Due to its antigonadotropic effects, drospirenone inhibits the secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and suppresses gonadal sex hormone production, including of estradiol, progesterone, and testosterone. Drospirenone alone at 4 mg/day has been found to suppress estradiol levels in premenopausal women to about 40 to 80 pg/mL depending on the time of the cycle. No studies of the antigonadotropic effects of drospirenone or its influence on hormone levels appear to have been conducted in men. In male cynomolgus monkeys however, 4 mg/kg/day oral drospirenone strongly suppressed testosterone levels.

Antimineralocorticoid activity
Drospirenone is an antagonist of the MR, the biological target of mineralocorticoids like aldosterone, and hence is an antimineralocorticoid. It has about 100 to 500% of the affinity of aldosterone for the MR and about 50 to 230% of the affinity of progesterone for the MR. Drospirenone is about 5.5 to 11 times more potent as an antimineralocorticoid than spironolactone in animals. Accordingly, 3 to 4 mg drospirenone is said to be equivalent to about 20 to 25 mg spironolactone in terms of antimineralocorticoid activity. It has been said that the pharmacological profile of drospirenone more closely resembles that of progesterone than other progestins due to its antimineralocorticoid activity. Drospirenone is the only clinically used progestogen with prominent antimineralocorticoid activity besides progesterone. For comparison to progesterone, a 200 mg dose of oral progesterone is considered to be approximately equivalent in antimineralocorticoid effect to a 25 to 50 mg dose of spironolactone. Both drospirenone and progesterone are actually weak partial agonists of the MR in the absence of mineralocorticoids.Due to its antimineralocorticoid activity, drospirenone increases natriuresis, decreases water retention and blood pressure, and produces compensatory increases in plasma renin activity as well as circulating levels and urinary excretion of aldosterone. This has been shown to occur at doses of 2 to 4 mg/day. Similar effects occur during the luteal phase of the menstrual cycle due to increased progesterone levels and the resulting antagonism of the MR. Estrogens, particularly ethinylestradiol, activate liver production of angiotensinogen and increase levels of angiotensinogen and angiotensin II, thereby activating the renin–angiotensin–aldosterone system. As a result, they can produce undesirable side effects including increased sodium excretion, water retention, weight gain, and increased blood pressure. Progesterone and drospirenone counteract these undesirable effects via their antimineralocorticoid activity. Accumulating research indicates that antimineralocorticoids like drospirenone and spironolactone may also have positive effects on adipose tissue and metabolic health.

Antiandrogenic activity
Drospirenone is an antagonist of the AR, the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has about 1 to 65% of the affinity of the synthetic anabolic steroid metribolone for the AR. The medication is more potent as an antiandrogen than spironolactone, but is less potent than cyproterone acetate, with about 30% of its antiandrogenic activity in animals. Progesterone displays antiandrogenic activity in some assays similarly to drospirenone, although this issue is controversial and many researchers regard progesterone as having no significant antiandrogenic activity.Drospirenone shows antiandrogenic effects on the serum lipid profile, including higher HDL cholesterol and triglyceride levels and lower LDL cholesterol levels, at a dose of 3 mg/day in women. The medication does not inhibit the effects of ethinylestradiol on sex hormone-binding globulin (SHBG) and serum lipids, in contrast to androgenic progestins like levonorgestrel but similarly to other antiandrogenic progestins like cyproterone acetate. SHBG levels are significantly higher with ethinylestradiol and cyproterone acetate than with ethinylestradiol and drospirenone, owing to the more potent antiandrogenic activity of cyproterone acetate relative to drospirenone. Androgenic progestins like levonorgestrel have been found to inhibit the procoagulatory effects of estrogens like ethinylestradiol on hepatic synthesis of coagulation factors, whereas this may occur less or not at all with weakly androgenic progestins like desogestrel and antiandrogenic progestins like drospirenone.

Other activity
Drospirenone stimulates the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1). Certain other progestins act similarly in this assay, whereas progesterone acts neutrally. It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies.

Pharmacokinetics
Absorption
The oral bioavailability of drospirenone is between 66 and 85%. Peak levels occur 1 to 6 hours after an oral dose. Levels are about 27 ng/mL after a single 4 mg dose. There is 1.5- to 2-fold accumulation in drospirenone levels with continuous administration, with steady-state levels of drospirenone achieved after 7 to 10 days of administration. Peak levels of drospirenone at steady state with 4 mg/day drospirenone are about 41 ng/mL. With the combination of 30 μg/day ethinylestradiol and 3 mg/day drospirenone, peak levels of drospirenone after a single dose are 35 ng/mL, and levels at steady state are 60 to 87 ng/mL at peak and 20 to 25 ng/mL at trough. The pharmacokinetics of oral drospirenone are linear with a single dose across a dose range of 1 to 10 mg. Intake of drospirenone with food does not influence the absorption of drospirenone.

Distribution
The distribution half-life of drospirenone is about 1.6 to 2 hours. The apparent volume of distribution of drospirenone is approximately 4 L/kg. The plasma protein binding of drospirenone is 95 to 97%. It is bound to albumin and 3 to 5% circulates freely or unbound. Drospirenone has no affinity for sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG), and hence is not bound by these plasma proteins in the circulation.

Metabolism
The metabolism of drospirenone is extensive. It is metabolized into the acid form of drospirenone by opening of its lactone ring. The medication is also metabolized by reduction of its double bond between the C4 and C5 positions and subsequent sulfation. The two major metabolites of drospirenone are drospirenone acid and 4,5-dihydrodrospirenone 3-sulfate, and are both formed independently of the cytochrome P450 system. Neither of these metabolites are known to be pharmacologically active. Drospirenone also undergoes oxidative metabolism by CYP3A4.

Elimination
Drospirenone is excreted in urine and feces, with slightly more excreted in feces than in urine. Only trace amounts of unchanged drospirenone can be found in urine and feces. At least 20 different metabolites can be identified in urine and feces. Drospirenone and its metabolites are excreted in urine about 38% as glucuronide conjugates, 47% as sulfate conjugates, and less than 10% in unconjugated form. In feces, excretion is about 17% glucuronide conjugates, 20% sulfate conjugates, and 33% unconjugated.The elimination half-life of drospirenone is between 25 and 33 hours. The half-life of drospirenone is unchanged with repeated administration. Elimination of drospirenone is virtually complete 10 days after the last dose.

Chemistry
Drospirenone, also known as 1,2-dihydrospirorenone or as 17β-hydroxy-6β,7β:15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone, is a synthetic steroidal 17α-spirolactone, or more simply a spirolactone. It is an analogue of other spirolactones like spironolactone, canrenone, and spirorenone. Drospirenone differs structurally from spironolactone only in that the C7α acetylthio substitution of spironolactone has been removed and two methylene groups have been substituted in at the C6β–7β and C15β–16β positions.Spirolactones like drospirenone and spironolactone are derivatives of progesterone, which likewise has progestogenic and antimineralocorticoid activity. The loss of the C7α acetylthio group of spironolactone, a compound with negligible progestogenic activity, appears to be involved in the restoration of progestogenic activity in drospirenone, as SC-5233, the analogue of spironolactone without a C7α substitution, has potent progestogenic activity similarly to drospirenone.

History
Drospirenone was patented in 1976 and introduced for medical use in 2000. Schering AG of Germany has been granted several patents on the production of drospirenone, including WIPO and US patents, granted in 1998 and 2000, respectively. It was introduced for medical use in combination with ethinylestradiol as a combined birth control pill in 2000. Drospirenone is sometimes described as a "fourth-generation" progestin based on its time of introduction. The medication was approved for use in menopausal hormone therapy in combination with estradiol in 2005. Drospirenone was introduced for use as a progestogen-only birth control pill in 2019. A combined birth control pill containing estetrol and drospirenone was approved in 2021.

Society and culture
Generic names
Drospirenone is the generic name of the drug and its INN, USAN, BAN, and JAN, while drospirénone is its DCF. Its name is a shortened form of the name 1,2-dihydrospirorenone or dihydrospirenone. Drospirenone is also known by its developmental code names SH-470 and ZK-30595 (alone), BAY 86-5300, BAY 98-7071, and SH-T-00186D (in combination with ethinylestradiol), BAY 86-4891 (in combination with estradiol), and FSN-013 (in combination with estetrol).

Brand names
Drospirenone is marketed in combination with an estrogen under a variety of brand names throughout the world. Among others, it is marketed in combination with ethinylestradiol under the brand names Yasmin and Yaz, in combination with estetrol under the brand name Nextstellis, and in combination with estradiol under the brand name Angeliq.

Availability
Drospirenone is marketed widely throughout the world.

Generation
Drospirenone has been categorized as a "fourth-generation" progestin.

Litigation
Many lawsuits have been filed against Bayer, the manufacturer of drospirenone, due to the higher risk of venous thromboembolism (VTE) that has been observed with combined birth control pills containing drospirenone and certain other progestins relative to the risk with levonorgestrel-containing combined birth control pills.In July 2012, Bayer notified its stockholders that there were more than 12,000 such lawsuits against the company involving Yaz, Yasmin, and other birth control pills with drospirenone. They also noted that the company by then had settled 1,977 cases for US$402.6 million, for an average of US$212,000 per case, while setting aside US$610.5 million to settle the others.As of July 17, 2015, there have been at least 4,000 lawsuits and claims still pending regarding VTE related to drospirenone. This is in addition to around 10,000 claims that Bayer has already settled without admitting liability. These claims of VTE have amounted to US$1.97 billion. Bayer also reached a settlement for arterial thromboembolic events, including stroke and heart attacks, for US$56.9 million.

Research
A combination of ethinylestradiol, drospirenone, and prasterone is under development by Pantarhei Bioscience as a combined birth control pill for prevention of pregnancy in women. It includes prasterone (dehydroepiandrosterone; DHEA), an oral androgen prohormone, to replace testosterone and avoid testosterone deficiency caused by suppression of testosterone by ethinylestradiol and drospirenone. As of August 2018, the formulation is in phase II/III clinical trials.Drospirenone has been suggested for potential use as a progestin in male hormonal contraception.Drospirenone has been studied in forms for parenteral administration.

References
Further reading
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Oelkers WH (October 2005). "Drospirenone in combination with estrogens: for contraception and hormone replacement therapy". Climacteric. 8 Suppl 3: 19–27. doi:10.1080/13697130500330341. PMID 16203652. S2CID 42837148.
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<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Atracurium besilate and explain in detail? [/INST] Atracurium besilate, also known as atracurium besylate, is a medication used in addition to other medications to provide skeletal muscle relaxation during surgery or mechanical ventilation. It can also be used to help with endotracheal intubation but suxamethonium (succinylcholine) is generally preferred if this needs to be done quickly. It is given by injection into a vein. Effects are greatest at about 4 minutes and last for up to an hour.Common side effects include flushing of the skin and low blood pressure. Serious side effects may include allergic reactions; however, it has not been associated with malignant hyperthermia. Prolonged paralysis may occur in people with conditions like myasthenia gravis. It is unclear if use in pregnancy is safe for the baby. Atracurium is in the neuromuscular-blocker family of medications and is of the non-depolarizing type. It works by blocking the action of acetylcholine on skeletal muscles.Atracurium was approved for medical use in the United States in 1983. It is on the World Health Organizations List of Essential Medicines. Atracurium is available as a generic medication.

Medical uses
Atracurium is a medication used in addition to other medications in to provide skeletal muscle relaxation during surgery or mechanical ventilation. It can be used to help with endotracheal intubation but takes up to 2.5 minutes to result in appropriate intubating conditions.

Duration of action
Neuromuscular-blocking agents can be classified in accordance to their duration of pharmacological action, defined as follows:

Side effects
Cardiovascular
The tetrahydroisoquinolinium class of neuromuscular blocking agents, in general, is associated with histamine release upon rapid administration of a bolus intravenous injection. There are some exceptions to this rule; e.g., cisatracurium (Nimbex) is one such agent that does not elicit histamine release even up to 5xED95 doses. The liberation of histamine is a dose-dependent phenomenon such that, with increasing doses administered at the same rate, there is a greater propensity for eliciting histamine release and its ensuing sequelae.  Most commonly, the histamine release following administration of these agents is associated with observable cutaneous flushing (facial face and arms, commonly), hypotension and a consequent reflex tachycardia. These sequelae are very transient effects: The total duration of the cardiovascular effects is no more than one to two minutes, while the facial flush may take around 3–4 minutes to dissipate.  Because these effects are so transient, there is no reason to administer adjunctive therapy to ameliorate either the cutaneous or the cardiovascular effects.

Bronchospasm
Bronchospasm has been reported on occasion with the use of atracurium. However, this particular undesirable effect does not appear to be observed nearly as often as that seen with rapacuronium, which led to the latters withdrawal of approval for clinical use worldwide.
The issue of bronchospasm acquired prominence in the neuromuscular-blocking agents arena after the withdrawal from clinical use of rapacuronium (Raplon - a steroidal neuromuscular-blocking agent marketed by Organon) in 2001 after several serious events of bronchospasm, including five unexplained fatalities, following its administration. Bronchospasm was not an unknown phenomenon prior to rapacuronium: occasional reports of bronchospasm have been noted also with the prototypical agents, tubocurarine and succinylcholine, as well as alcuronium, pancuronium, vecuronium, and gallamine.

Seizures
Seizures rarely occur.Because atracurium undergoes Hofmann elimination as a primary route of chemodegradation, one of the major metabolites from this process is laudanosine, a tertiary amino alkaloid reported to be a modest CNS stimulant with epileptogenic activity and cardiovascular effects such a hypotension and bradycardia.  As part of the then fierce marketing battle between the competing pharmaceutical companies (Burroughs Wellcome Co. and Organon, Inc.) with their respective products, erroneous information was quickly and subtly disseminated very shortly after the clinical introduction of atracurium that the clinical use of atracurium was likely to result in a terrible tragedy because of the significant clinical hazard by way of frank seizures induced by the laudanosine by-product - the posited hypothesis being that the laudanosine produced from the chemodegradation of parent atracurium would cross the blood–brain barrier in sufficiently high enough concentrations that lead to epileptogenic foci. Fortunately, both for the public and for atracurium, rapid initial investigations irrefutably failed to find any overt or EEG evidence for a connection between atracurium administration and epileptogenic activity. Indeed, because laudanosine is cleared primarily via renal excretion, a cat study modelling anephric patients went so far as to corroborate that EEG changes, when observed, were evident only at plasma concentrations 8 to 10 times greater than those observed in humans during infusions of atracurium. Thus, the cat study predicted that, following atracurium administration in an anephric patient, laudanosine accumulation and related CNS or cardiovascular toxicity were unlikely - a prediction that correlated very well with a study in patients with kidney failure and undergoing cadaveric renal transplantation. Furthermore, almost a decade later, work by Cardone et al.. confirmed that, in fact, it is the steroidal neuromuscular-blocking agents pancuronium and vecuronium that, when introduced directly into the CNS, were likely to cause acute excitement and seizures, owing to accumulation of cytosolic calcium caused by activation of acetylcholine receptor ion channels. Unlike the two steroidal agents, neither atracurium nor laudanosine caused such accumulation of intracellular calcium. Just over two decades later with availability of atracurium, there is little doubt that laudanosine accumulation and related toxicity will likely never be seen with the doses of atracurium that are generally used.Laudanosine is also a metabolite of cisatracurium that, because of its identical structure to atracurium, undergoes chemodegradation via Hofmann elimination in vivo. Plasma concentrations of laudanosine generated are lower when cisatracurium is used.

Pharmacokinetics
Atracurium is susceptible to degradation by Hofmann elimination and ester hydrolysis as components of the in vivo metabolic processes. The initial in vitro studies appeared to indicate a major role for ester hydrolysis but, with accumulation of clinical data over time, the preponderance of evidence indicated that Hofmann elimination at physiological pH is the major degradation pathway vindicating the premise for the design of atracurium to undergo an organ-independent metabolism.Hofmann elimination is a temperature- and pH-dependent process, and therefore atracuriums rate of degradation in vivo is highly influenced by body pH and temperature: An increase in body pH favors the elimination process, whereas a decrease in temperature slows down the process. Otherwise, the breakdown process is unaffected by the level of plasma esterase activity, obesity, age, or by the status of renal or hepatic function.  On the other hand, excretion of the metabolite, laudanosine, and, to a small extent, atracurium itself is dependent on hepatic and renal functions that tend to be less efficient in the elderly population.
The pharmaceutical presentation is a mixture of all ten possible stereoisomers. Although there are four stereocentres, which could give 16 structures, there is a plane of symmetry running through the centre of the diester bridge, and so 6 meso structures (structures that can be superimposed by having the opposite configuration then 180° rotation) are formed. This reduces the number from sixteen to ten. There are three cis-cis isomers (an enantiomeric pair and a meso structure), four cis-trans isomers (two enantiomeric pairs), and three trans-trans isomers (an enantiomeric pair and a meso structure). The proportions of cis−cis, cis−trans, and trans−trans isomers are in the ratio of 10.5 :6.2 :1. [cis-cis isomers ≈ 58% cis-trans isomers ≈ 36% trans-trans isomers ≈ 6%]. One of the three cis-cis structures is marketed as a single-isomer preparation, cisatracurium (trade name Nimbex); it has the configuration 1R, 2R, 1′R, 2′R at the four stereocentres. The beta-blocking drug Nebivolol has ten similar structures with 4 stereocentres and a plane of symmetry, but only two are presented in the pharmaceutical preparation.

Intramuscular function parameters
ED95: the dose of any given intramuscular-blocking agent required to produce 95% suppression of muscle twitch (e.g., the abductor pollicis) response with balanced anesthesia
Clinical duration: difference in time between time of injection and time to 25% recovery from neuromuscular block
Train-of-Four (TOF) response: stimulated muscle twitch response in trains of four when stimuli are applied in a burst of four as opposed to a single stimulus, equal depression in depolarizing and fading response with non-depolarizing blocker.
25%-75% recovery index: an indicator of the rate of skeletal muscle recovery - essentially, the difference in time between the time to recovery to 25% and time to recovery to 75% of baseline value
T4:T1 ≥ 0.7: a 70% ratio of the fourth twitch to the first twitch in a TOF - provides a measure of the recovery of neuromuscular function
T4:T1 ≥ 0.9: a 90% ratio of the fourth twitch to the first twitch in a TOF - provides a measure of the full recovery of neuromuscular function

History
Atracurium besilate was first made in 1974 by George H. Dewar, a pharmacist and a medicinal chemistry doctoral candidate in John B. Stenlakes medicinal chemistry research group in the Department of Pharmacy at Strathclyde University, Scotland. Dewar first named this compound "33A74" before its eventual emergence in the clinic as atracurium. Atracurium was the culmination of a rational approach to drug design to produce the first non-depolarizing non-steroidal skeletal muscle relaxant that undergoes chemodegradation in vivo. The term chemodegradation was coined by Roger D </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Tretinoin and explain in detail? [/INST] Tretinoin, also known as all-trans retinoic acid (ATRA), is a medication used for the treatment of acne and acute promyelocytic leukemia. For acne, it is applied to the skin as a cream, gel or ointment. For leukemia, it is taken by mouth for up to three months. Topical tretinoin is also the most extensively investigated retinoid therapy for photoaging.Common side effects when used as a cream are limited to the skin and include skin redness, peeling, and sun sensitivity. When used by mouth, side effects include shortness of breath, headache, numbness, depression, skin dryness, itchiness, hair loss, vomiting, muscle pains, and vision changes. Other severe side effects include high white blood cell counts and blood clots. Use during pregnancy is contraindicated due to the risk of birth defects. It is in the retinoid family of medications.Tretinoin was patented in 1957, and approved for medical use in 1962. It is on the World Health Organizations List of Essential Medicines. Tretinoin is available as a generic medication. In 2019, it was the 244th most commonly prescribed medication in the United States, with more than 1 million prescriptions.

Medical uses
Skin use
Tretinoin is most commonly used to treat acne, both inflammatory and noninflammatory. Multiple studies support the efficacy of topical retinoids in the treatment of acne vulgaris. It is sometimes used in conjunction with other topical acne medications to enhance their penetration. In addition to treating active acne, retinoids accelerate the resolution of acne-induced postinflammatory hyperpigmentation. It is also useful as maintenance therapy for people who have responded to their initial treatment, reducing the prolonged use of antibiotics for acne.

Leukemia
Tretinoin is used to induce remission in people with acute promyelocytic leukemia who have a mutation (the t(15;17) translocation 160 and/or the presence of the PML/RARα gene) and who do not respond to anthracyclines or cannot take that class of drug.  It is not used for maintenance therapy.The evidence is very uncertain about the effect of tretinoin in addition to chemotherapy for patients with an acute myeloid leukemia on diarrhoea, nausea/vomiting and heart-related toxicity grades III/IV. Furthermore, tretinoin in addition to chemotherapy probably results in little to no difference in the mortality, relapse, progress, mortality during the trial and infections grade III/IV.

Photoaging
Photoaging is premature skin aging resulting from prolonged and repeated exposure to solar radiation.  Features of photoaging include fine and coarse wrinkles, change in skin pigmentation, and loss of elasticity.  In human skin, topical retinoids increase collagen production, induce epidermal hyperplasia, and decrease keratinocyte and melanocyte atypia.  Topical tretinoin is the most extensively investigated retinoid therapy for photoaging. Topical tretinoin can be used for mild to severe photoaging in people of all skin types. Several weeks or months of use are typically required before improvement is appreciated.  The benefits of topical tretinoin are lost upon discontinuation. Although it has only been studied for a duration of two years, it may be continued indefinitely. A long-term maintenance regimen with a lower concentration or less frequent application may be an alternative to continued use.

Side effects
Skin use
Topical tretinoin is only for use on the skin and should not be applied to eyes or mucosal tissues.  Common side effects include skin irritation, redness, swelling, and blistering. If irritation is a problem, a decrease in the frequency of application to every other or every third night can be considered, and the frequency of application can be increased as tolerance improves. The fine skin flaking that is often seen can be gently exfoliated with a washcloth. A non-comedogenic facial moisturizer can also be applied if needed.  Delaying application of the retinoid for at least 20 minutes after washing and drying the face may also be helpful.  Topical retinoids are not true photosensitizing drugs, but people using topical retinoids have described symptoms of increased sun sensitivity. This is thought to be due to thinning of the stratum corneum leading to a decreased barrier against ultraviolet light exposure, as well as an enhanced sensitivity due to the presence of cutaneous irritation.

Leukemia use
The oral form of the drug has boxed warnings concerning the risks of retinoic acid syndrome and leukocytosis.Other significant side effects include a risk of thrombosis, benign intracranial hypertension in children, high lipids (hypercholesterolemia and/or hypertriglyceridemia), and liver damage.There are many significant side effects from this drug that include malaise (66%), shivering (63%), hemorrhage (60%), infections (58%), peripheral edema (52%), pain (37%), chest discomfort (32%), edema (29%), disseminated intravascular coagulation (26%), weight increase (23%), injection site reactions (17%), anorexia (17%), weight decrease (17%), and myalgia (14%).Respiratory side effects usually signify retinoic acid syndrome, and include upper respiratory tract disorders (63%), dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), pneumonia (14%), rales (14%), and expiratory wheezing (14%), and many others at less than 10%.Around 23% of people taking the drug have reported earache or a feeling of fullness in their ears.Gastrointestinal disorders include bleeding (34%), abdominal pain (31%), diarrhea (23%), constipation (17%), dyspepsia (14%), and swollen belly (11%) and many others at less than 10%.In the cardiovascular system, side effects include arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%), phlebitis (11%), and cardiac failure (6%) and for 3% of patients: cardiac arrest, myocardial infarction, enlarged heart, heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary hypertension, secondary cardiomyopathy.In the nervous system, side effects include dizziness (20%), paresthesias (17%), anxiety (17%), insomnia (14%), depression (14%), confusion (11%), and many others at less than 10% frequency.In the urinary system, side effects include chronic kidney disease (11%) and several others at less than 10% frequency.

Mechanism of action
For its use in cancer, its mechanism of action is unknown, but on a cellular level, laboratory tests show that tretinoin forces APL cells to differentiate and stops them from proliferating; in people there is evidence that it forces the primary cancerous promyelocytes to differentiate into their final form, allowing normal cells to take over the bone marrow. Recent study shows that ATRA inhibits and degrades active PIN1.For its use in acne, tretinoin (along with other retinoids) are vitamin A derivatives that act by binding to two nuclear receptor families within keratinocytes: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). These events contribute to the normalization of follicular keratinization and decreased cohesiveness of keratinocytes, resulting in reduced follicular occlusion and microcomedone formation. The retinoid-receptor complex competes for coactivator proteins of AP-1, a key transcription factor involved in inflammation. Retinoids also down-regulate expression of toll-like receptor (TLR)-2, which has been implicated in the inflammatory response in acne. Moreover, tretinoin and retinoids may enhance the penetration of other topical acne medications.The combination of the 10% benzoyl peroxide and light results in more than 50% degradation of tretinoin in about 2 hours and 95% in 24 hours. This lack of stability in the presence of light and oxidizing agents has led to the development of novel formulations of the drug.  When microencapsulated tretinoin is exposed to benzoyl peroxide and light only 1% degradation takes place in about 4 hours and only 13% after 24 hours.

Biosynthesis
Tretinoin is synthesized from beta-carotene. The beta-carotene is firstly cleaved into beta-carotene 15-15-monooxygenase through site 1 double bond oxidized to epoxide. The epoxide is attacked by water to form diol in site 1. NADH, as a reduction agent, reduce the alcohol group to aldehydes.

History
Tretinoin was co-developed for its use in acne by James Fulton and Albert Kligman when they were at University of Pennsylvania in the 1960s. Phase I trials, the first conducted on human subjects, were performed on inmates at Holmesburg Prison during a long-running regime of non-therapeutic and unethical testing on prison inmates at Holmesburg </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Valaciclovir and explain in detail? [/INST] Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster (shingles). It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases. It is taken by mouth.Common side effects include headache and vomiting. Severe side effects may include kidney problems. Use in pregnancy appears to be safe. It is a prodrug, which works after being converted to aciclovir in a persons body.Valaciclovir was patented in 1987 and came into medical use in 1995. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 110th most commonly prescribed medication in the United States, with more than 5 million prescriptions.

Medical uses
Valaciclovir is used for the treatment of HSV and VZV infections, including:
Oral and genital herpes simplex (treatment and prevention)
Reduction of HSV transmission from people with recurrent infection to uninfected individuals
Herpes zoster (shingles): the typical dosage for treatment of herpes is 1,000 mg orally three times a day for seven consecutive days.
Prevention of cytomegalovirus following organ transplantation
Prevention of herpesviruses in immunocompromised people (such as those undergoing cancer chemotherapy)
Chickenpox in children (ages 2–18)It has shown promise as a treatment for infectious mononucleosis and is preventively administered in suspected cases of herpes B virus exposure.Bells palsy does not seem to benefit from using valaciclovir as its only treatment.

Adverse effects
Common adverse drug reactions (≥1% of people) associated with valaciclovir are the same as for aciclovir, its active metabolite. They include: nausea, vomiting, diarrhea and headache. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo, confusion, dizziness, edema, arthralgia, sore throat, constipation, abdominal pain, rash, weakness and/or renal impairment. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia, leukopenia, tremor, ataxia, encephalopathy, psychotic symptoms, crystalluria, anorexia, fatigue, hepatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis and/or anaphylaxis.

Pharmacology
Valaciclovir is a prodrug, an esterified version of aciclovir that has greater oral bioavailability (about 55%) than aciclovir. It is converted by esterases to the active drug, aciclovir, and the amino acid valine via hepatic first-pass metabolism. Aciclovir is selectively converted into a monophosphate form by viral thymidine kinase, which is more effective (3000 times) in phosphorylation of aciclovir than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into a disphosphate by cellular guanylate kinase and then into the active triphosphate form, aciclo-GTP, by cellular kinases.

Mechanism of action
Aciclo-GTP, the active triphosphate metabolite of aciclovir, is a very potent inhibitor of viral DNA replication. Aciclo-GTP competitively inhibits and inactivates the viral DNA polymerase. Its monophosphate form also incorporates into the viral DNA, resulting in chain termination. It has also been shown that the viral enzymes cannot remove aciclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolized within the cell, possibly by cellular phosphatases.Aciclovir is active against most species in the herpesvirus family. In descending order of activity:
Herpes simplex virus type I (HSV-1)
Herpes simplex virus type II (HSV-2)
Varicella zoster virus (VZV)
Epstein–Barr virus (EBV)
Cytomegalovirus (CMV)The drug is predominantly active against HSV and, to a lesser extent, VZV. It is only of limited efficacy against EBV and CMV. However, valaciclovir has been shown to lower or eliminate the presence of the Epstein–Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms. Valaciclovir and acyclovir act by inhibiting viral DNA replication, but as of 2016 there was little evidence that they are effective against Epstein–Barr virus, they are expensive, they risk causing resistance to antiviral agents, and (in 1% to 10% of cases) can cause unpleasant side effects. Acyclovir therapy does prevent viral latency, but has not proven effective at eradicating latent viruses in nerve ganglia.As of 2005, resistance to valaciclovir has not been significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase and mutations to viral thymidine kinase and/or DNA polymerase that alter substrate sensitivity.It also is used for herpes B virus postexposure prophylaxis.

Chemistry
Details of the synthesis of valaciclovir were first published by scientists from the Wellcome Foundation.

Aciclovir was esterified with a carboxybenzyl protected valine, using dicyclohexylcarbodiimide as the dehydrating agent. In the final step, the protecting group was removed by hydrogenation using a palladium on alumina catalyst.

History
Valaciclovir was patented in 1987 and came into medical use in 1995 </s>