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Alprazolam

Clinical data
Routes of administration	Oral
ATC code	N05BA12 (WHO)
Legal status
Legal status	US: WARNINGSchedule IV
Pharmacokinetic data
Bioavailability	80-90%
Metabolism	Hepatic, via Cytochrome P450 3A4
Elimination half-life	Immediate release: 11.2 hours; Extended release: 10.7-15.8 hours
Excretion	Renal
Identifiers
IUPAC name 8-chloro-1-methyl-6-phenyl-4H- triazolobenzodiazepine
CAS Number	28981-97-7
PubChem CID	2118
DrugBank	APRD00280
ChemSpider	2034
CompTox Dashboard (EPA)	DTXSID4022577
ECHA InfoCard	100.044.849
Chemical and physical data
Formula	C17H13ClN4
Molar mass	308.765 g·mol

Alprazolam, also known under the trade names Xanax, Reclam, Xanor and Niravam, is a short-acting drug of the benzodiazepine class used to treat moderate to severe anxiety disorders, panic attacks, and as an adjunctive treatment for anxiety associated with major depression. It is also available in an extended release form, Xanax XR. Both forms are now available generically. Long term use of alprazolam is potentially an addictive drug and may cause a physical dependence and benzodiazepine withdrawal syndrome. In the USA alprazolam is the most commonly misused benzodiazepines and is a schedule IV controlled drug.

History

Alprazolam was first synthesized by Upjohn (now a part of Pfizer). Its patent (#3,987,052) was filed on October 29, 1969, granted on October 19, 1976 and expired in September 1993. It was released in 1981. The first indication for which alprazolam was approved was panic disorder. Upjohn took this direction at the behest of a young psychiatrist David Sheehan. Sheehan's suggestion was to use the confusion DSM-III created in the classification of anxiety disorders (a distinction had just been made in DSM-III between generalized anxiety disorder (GAD) and panic disorder). Panic disorder was, at that point, perceived to be rare and treatable only with tricyclic antidepressants; benzodiazepines were thought to be ineffective. However, from his clinical experience, Sheehan knew panic disorder to be both widespread among the populace and well responding to benzodiazepines. He suggested to Upjohn that marketing alprazolam for panic disorder will both cover new diagnostic territory and stress the unique potency of this drug. Sheehan describes that the first group of patients treated by alprazolam was so impressed by its action that they knew outright—this drug was going to be a hit. A few of those patients actually pooled their money and purchased stock in Upjohn. Several months later, when alprazolam was approved by the FDA, they sold out and made a profit.

Pharmacology

Alprazolam is a triazolobenzodiazepine, that is, a benzodiazepine with a triazolo-ring attached to its structure. Benzodiazepines produce a variety of therapeutic and adverse effects by binding to the benzodiazepine site on the GABA_A and modulating the function of the GABA receptor, the most prolific inhibitory receptor within the brain. The GABA_A receptor is made up from 5 subunits out of a possible 19, and GABA_A receptors made up of different combinations of subunits have different properties, different locations within the brain and importantly, different activities in regards to benzodiazepines.

Pharmacokinetics

Alprazolam is readily absorbed from the gastrointestinal tract. The peak plasma concentration is achieved in 1-2 hours. Most of the drug is bound to plasma protein, mainly serum albumin. Alprazolam is hydroxylated in the liver to α-hydroxyalprazolam, which is also pharmacologically active. This and other metabolites are later excreted in urine as glucuronides. Some of the drug is also excreted in unchanged form.

Indications

The main medical uses for alprazolam include:

• Alprazolam is FDA-approved for the short term treatment (up to 8 weeks) of panic disorder, with or without agoraphobia. Alprazolam is very effective in preventing moderate to severe anxiety, essential tremor, panic attacks and other types of convulsive behaviors. Physicians who elect to prescribe alprazolam for longer than 8 weeks should be aware that continued efficacy has not been systematically demonstrated beyond 8 weeks use as tolerance to alprazolam's effects may occur after 8 weeks and necessitate discontinuation or physician-directed dose escalation. However, long-term maintenance therapy on alprazolam is not unheard-of in the medical community, and, if a genuine therapeutic need exists, benefits must be weighed against risks.

• Alprazolam is recommended for the short-term treatment (2-4 weeks) of severe acute anxiety. Alprazolam should only very rarely be used for longer periods of time -- the body becomes rapidly tolerant to the drug's effects, which may translate to decreased efficacy.

• Alprazolam is sometimes prescribed for anxiety with associated depression. There is some evidence for antidepressant treatment of clinical depression in outpatient settings, evidence for inpatients is lacking. The antidepressant effects of alprazolam may be due to its effects on beta-adrenergic receptors. Other benzodiazepines are not known to have antidepressant activity. Studies show that any antipressant action of alprazolam is questionable and generally weak in comparison to antidepressant medications. Conversely, whilst alprazolam in acute or short term treatment may have some antidepressant properties there is evidence that up to a third of long term users of alprazolam may develop depression.

Availability

Alprazolam is available in English-speaking countries under the following brand names: Alprax, Alprox, Alzam, Anxirid, Apo-Alpraz, Azor, Calmax, Gerax, Kalma, Niravam, Novo-Alprazol, Nu-Alpraz, Xanax, Xanor, Zopax.

Side effects

Side effects of alprazolam may occur in patients and are more likely the higher the dosage taken. If signs of an allergic reaction occur such as hives, difficulty breathing, swelling of face, lips, tongue or throat occur medical attention should be sought immediately. Medical attention should also be sought immediately if signs of jaundice appear such as yellowing of the skin or eyes. Other side effects which may occur are as follows:

• euphoria
• drowsiness
• decreased inhibitions, no fear of danger (increased risk taking behavior)
• depressed mood with thoughts of suicide or self harm or elevated mood and confidence
• hallucinations, agitation and hostility
• feeling dizziness, light headed or fainting
• urinating less than usual or not at all
• headache, fatigue, joint pain and unusual weakness (flu like symptoms)
• speech problems,
• Short term memory loss (anterograde amnesia) and concentration problems
• changes in appetite (including changes in weight)
• blurred vision, unsteadiness and clumsiness (impaired coordination and balance)
• constipation, diarrhea, nausea and vomiting
• decreased or increased sex drive
• dry mouth or, more likely, increased salivation
• sweating
• increase in appetite aka "the munchies"
• skin inflammation
• Aggression
• Mania

Paradoxical side effects

Paradoxical side effects occasionally occur. Severe paradoxical effects such as seizures only rarely occur.

• hyperactivity
• nervousness
• restlessness
• sleeplessness
• muscle twitching
• tremor
• seizure (convulsions)

Physical dependence and withdrawal

Alprazolam and other benzodiazepines cause the development of a physical dependence, tolerance and benzodiazepine withdrawal symptoms during dose reduction or cessation of therapy after long-term treatment. Discontinuation should be done gradually over a period of months (or even up to a year) to avoid serious withdrawal symptoms such as agitation, panic attacks, rebound anxiety, muscle cramps and seizures. Some patients on alprazolam (Xanax) may benefit from a substitution with a benzodiazepine equivalent dose of another benzodiazepine drug such as diazepam (Valium) or chlordiazepoxide (Librium) as these drugs remain in the bloodstream longer and therefore have less potential for abuse and dependence. There is a higher chance of withdrawal symptoms if the drug is administered in a higher dosage than recommended, or if a patient stops taking the medication altogether without slowly allowing the body to wean itself off the drug.

If a consumer of the drug feels the need to end treatment with alprazolam, they should consult their doctor/physician before discontinuing medication. Some immediate symptoms of alprazolam withdrawal include:

Common Withdrawal Symptoms

• A rapid heartbeat (Tachycardia)
• Depression
• Dry mouth/chapped lips
• Temporary inability to stop talking/moving
• Mental sensitivity
• Strong loss of appetite
• Extreme Insomnia
• Anxiety
• Dizziness
• Minor tremors

Possible/Less Common Withdrawal Symptoms

• Nausea, vomiting, or diarrhea
• Panic attacks
• Mood swings
• Heart palpitations
• Hallucinations
• Memory loss
• Seizures
• Fever

Patients treated with alprazolam or other benzodiazepines for generalized anxiety disorder were found (when abruptly discontinuing their medication) to experience withdrawal symptoms such as a worsening of anxiety, as well as the development of physical withdrawal symptoms.

Patients taking a dosing regimen larger than 4 mg per day have an increased potential for dependence. This medication may cause withdrawal symptoms, which in some cases have been known to cause seizures. The discontinuation of this medication may also cause a reaction called rebound anxiety. Other withdrawal effects reported from discontinuing alprazolam therapy include homicidal ideation, rage reactions, hyperalertness, increased nightmares, and intrusive thoughts.

After 8 - 9 weeks of alprazolam taken at a fixed prescribed dose, the following symptoms have been found to occur during abrupt discontinuation: dysphoric mood, fatigue, low energy, confusion, and elevated systolic blood pressure, severe anxiety.

When a patient discontinues use, they may experience the symptoms they had before taking medication. Symptoms may also be accompanied by other reactions including changes in mood, anxiety, or sleep. Rebound anxiety is usually a result of abrupt discontinuation of this medication; patients who taper off are less likely to experience these symptoms.

Physical dependence is the major limiting factor against long-term use of alprazolam and other benzodiazepines.

Factors which determine the severity of the benzodiazepine withdrawal syndrome experienced during dose reduction of alprazolam include:

• dosage
• length of use
• frequency of dosing
• method of withdrawal
• personality characteristics of the individual
• previous use of cross dependent/cross tolerant drugs (alcohol or other sedative hypnotic drugs)
• current use of cross dependent/cross tolerant drugs (alcohol or other sedative hypnotic drugs)
• Use of short-acting high potency benzodiazepines for example alprazolam or lorazepam

Alprazolam has an exceptional history insofar soon after its introduction a large number of case reports were published in the medical literature of severe withdrawal symptoms related case reports of withdrawal psychoses, seizures and intense rebound anxiety upon discontinuation of alprazolam. In the United States a survey of physicians showed that 84% of physicians reported alprazolam as being extremely problematic in terms of the severity and prolonged nature of the benzodiazepine withdrawal syndrome after discontinuation.

The benzodiazepines diazepam (Valium) and oxazepam (Seresta) were found to produce less severe withdrawal symptoms than alprazolam (Xanax) or lorazepam (Temesta/Ativan).

Alprazolam should never be abruptly discontinued if taken regularly for any length of time because severe withdrawal symptoms may occur. Severe psychosis and seizures have been reported in the medical literature from abrupt alprazolam withdrawal, and one death occurred from withdrawal-related seizures after gradual dose reduction.

Contraindications

Use of alprazolam should be avoided, or carefully monitored by medical professionals, in individuals with the following conditions:

• Myasthenia gravis
• Acute narrow-angle glaucoma
• Severe liver deficiencies (e.g., cirrhosis)
• Severe sleep apnea
• Pre-existing respiratory depression
• Marked neuromuscular respiratory weakness including unstable myasthenia gravis
• Acute pulmonary insufficiency
• Chronic psychosis
• Hypersensitivity or allergy to alprazolam or other drugs in the benzodiazepine class
• Borderline personality disorder (may induce suicidality and dyscontrol),

Overdose

Overdoses can be mild to severe depending on how much of the drug is taken and if any other depressants have been taken. Xanax overdose reflect the central nervous system depression of the brain and may include one or more of the following symptoms:

• Somnolence (difficulty staying awake)
• Mental confusion
• Hypotension
• Impaired motor functions
  • Impaired or absent reflexes
  • Impaired balance
  • Dizziness
• Hypoventilation (Respiratory Depression)
• Coma
• Death

About 50% of the cases of death involving alprazolam were attributed to combined drug toxicity of alprazolam and another drug, most often cocaine and methadone. Only 1% of such deaths was attributed to alprazolam alone.

Pregnancy

Women who are pregnant or are planning on becoming pregnant should avoid starting alprazolam. If one is currently planning to become pregnant, one should discuss this and all medicines with their obstetrician or other doctor.

Teratogenicity classification

Marked Pregnancy Category D by the U.S. FDA.

Effects on the fetus

It should be considered that the child born of a mother who is receiving benzodiazepines may be at risk of developing withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.

Labor and delivery

Alprazolam has no established use in labor or delivery.

Nursing mothers (neonates)

Benzodiazepines, including alprazolam are known to be excreted in human milk. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who use alprazolam.

Geriatric use

Elderly individuals should be cautious in the use of alprazolam due to the possibility of increased susceptibility to side effects, especially loss of coordination and drowsiness.

Food and drug interactions

The effect of drinking grapefruit juice or consuming grapefruit while using alprazolam is not certain. Some web sites suggest that it increases blood concentrations by inhibiting the intestinal metabolism. However, there is a published paper , which suggests that the effect are in fact negligible because the effect on the inhibition of the CYP3A4 enzyme did not correlate, in a statistically significant manner, to the increase of blood plasma concentrations of alprazolam due to alprazolam's high bioavailability.

Alprazolam, like all benzodiazepines can have a fatal drug interaction with Buprenorphine (Reckitt Benckiser trade names suboxone, subutex)

Tagamet (cimetidine) is a widely used H2 blocker antacid that inhibits numerous cytochrome P450 enzymes.

Oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.

Special precautions

Like all central nervous system depressants, including alcohol, alprazolam in doses of 0.5 mg and above can cause significant deterioration in alertness, combined with increased feelings of sleepiness. People driving or conducting activities which require vigilance should exercise caution in using alprazolam or any other depressant.

Recreational misuse

Alprazolam, like all benzodiazepines, has the potential for abuse. Although its abuse is considerably less than other benzodiazepines like flunitrazepam, nimetazepam, and temazepam, it is still often diverted to the black market, particularly in the United States, where alprazolam is the most widely prescribed benzodiazepine. The state of relaxation, anxiolysis, and disinhibition induced by benzodiazepines is the main reason for their illicit use.

Most alprazolam abusers "are generally but not entirely limited to patients involved in a polydrug use pattern" Dose escalation is not typically a characteristic of long-term prescribed alprazolam users. In fact, according to an April 2004 report by the U.S. SAMHSA, "over three-quarters (78%) of benzodiazepine-related (emergency room) visits involved 2 or more drugs.".

Injection of alprazolam is considered especially dangerous by medical professionals because, when crushed in water it will not fully dissolve (40µg/ml of H₂O at pH 7, and 12 mg/mL at pH 1.2 per 1mg of alprazolam), potentially causing severe damage to arteries if not filtered properly. While it is somewhat soluble in alcohol, the combination of the two, particularly when injected, has the potential to cause a serious, and potentially fatal overdose. Alprazolam may also be insufflated; clinical testing indicates potent activity through insufflation yet some sources indicate sublingual activity is greater.

Alprazolam is sometimes used with other recreational drugs to relieve the panic or distress of dysphoric reactions to psychedelics such as LSD and also to promote sleep in the "come-down" period following use of recreational drugs with stimulant or insomniac properties (such as LSD, cocaine, amphetamines, DXM, and MDMA along with the related amphetamines). It is also often used in conjunction with marijuana or heroin to potentiate the relaxing effect. Long term daily use of high or even low doses may totally eliminate the euphoric properties of the drug due to drug tolerance, leaving the user the desire to take it to only delay withdrawal symptoms or because of a "placebo" euphoric effect that is actually not due to the drug itself but due to psychological conditioning.

Patients at a high risk for abuse and dependence

At a particularly high risk for misuse, abuse, and dependence are polydrug abusers (someone who already uses at least one substance in a recreational context). However, the following can also indicate potential problems in the future:

• Patients with a history of alcohol or drug abuse and/or dependence
• Patients with severe personality disorders or emotional instability
• Patients with chronic pain or other physical disorders

Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence because it may cause addiction. Discontinue therapy if any of these signs are noted. Long-term therapy in these patients is not recommended, unless the net benefit to the patient outweighs the net risk.

A large scale nation wide USA government study conducted by SAMHSA found that benzodiazepines in the USA are the most frequently abused pharmaceutical with 35% of drug related visits to the Emergency Department involved benzodiazepines. Benzodiazepines are more commonly abused than opiate pharmaceuticals which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly abused than benzodiazepines. Males abuse benzodiazepines as commonly as women. Of drugs used in attempted suicide benzodiazepines are the most commonly used pharmaceutical drug with 26% of attempted suicides involving benzodiazepines.

Legal status

In the United States, alprazolam is a prescription drug and is assigned to Schedule IV of the Controlled Substances Act by the Drug Enforcement Administration. Under the UK drug misuse classification system benzodiazepines are class C drugs. Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.

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