Alprazolam
From Wikipedia, the free encyclopedia
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| Alprazolam | |
| Systematic (IUPAC) name | |
| 8-chloro-1-methyl-6-phenyl-4H- [1,2,4]triazolo[4,3-a][1,4]benzodiazepine | |
| Identifiers | |
| CAS number | |
| ATC code | N05 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C17H13ClN4 |
| Mol. mass | 308.765 |
| Pharmacokinetic data | |
| Bioavailability | 80-90% |
| Metabolism | Hepatic, via Cytochrome P450 3A4 |
| Half life | Immediate release: 11.2 hours;[1] Extended release: 10.7-15.8 hours[2] |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. | D(US) |
| Legal status | |
| Routes | Oral |
Alprazolam, also known under the trade names Xanax 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.
Contents[hide] |
[edit] History
"[The public often] underestimate the extent to which certain disorders affect the general populace. When you treat them, it can make a tremendous amount of difference in their lives." (David Sheehan, first discovered alprazolam's efficacy in treating panic disorder.[3])
Alprazolam was first synthesized by Upjohn (now a part of Pfizer). Its patent (#3,987,052)[4] was filed on October 29, 1969, granted on October 19, 1976 and expired in September 1993. It was released in 1981.[5][6] 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.[7]
[edit] Pharmacology
Alprazolam is a triazolobenzodiazepine,[8] that is, a benzodiazepine with a triazolo-ring attached to its structure. Benzodiazepines produce a variety of effects by modulating the GABAA subtype of the GABA receptor, the most prolific inhibitory receptor within the brain. The GABAA receptor is made up from 5 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain and importantly, different activities in regards to benzodiazepines.
In order for GABAA receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, where the benzodiazepine binds. Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated Chloride ion channel and hyperpolarising the membrane. This potentiates the inhibitory effect of the available GABA leading to sedatory and anxiolytic effects. As mentioned, different benzodiazepines can have different affinities for GABAA receptors made up of different collection of subunits. For instance, benzodiazepines with high activity at the α1 are associated with sedation whereas those with higher affinity for GABAA receptors containing α2 and/or α3 subunits have greater anxiolytic activity. The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABA receptor.
There is some evidence for antidepressant treatment of clinical depression in outpatient settings, evidence for inpatients is lacking;[9] other benzodiazepines are not known to have antidepressant activity.
[edit] 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.
[edit] 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.[10] 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.[11][12] Decreased efficacy can lead to dose escalation, and the use of high doses puts the patient at higher risk for withdrawal if the drug is discontinued suddenly.
- However, in 1992 Romach and colleagues reported that dose escalation was not a characteristic of long-term alprazolam users, and the majority of patients indicated that alprazolam continued to be effective.[13] A 2003 study did not support the hypothesis that long-term use of benzodiazepines frequently results in notable dose escalation.[14]In a 1-year follow-up study of patients with panic disorder continuing treatment with clonazepam, 90% maintained a positive response without developing significant tolerance. In a 2.5-year follow-up study of alprazolam therapy, little evidence of tolerance emerged.[15]
[edit] Availability
 | This section does not cite any references or sources. Please help improve this section by adding citations to reliable sources. Unverifiable material may be challenged and removed. (May 2008) |
Xanax is the main and most commonly known brand name for Alprazolam. There is a large variety of generic brand names for Alprazolam in use throughout the world. In English-speaking countries, Alprazolam is sold under the following brand names: Aloram, Alprax, Alprox, Alzam, Anxirid, Apo-Alpraz, Azor, Calmax, Frontal, Frontin, Gerax, Helex, Kalma, Kinax, Neurol, Novo-Alprazol, Nu-Alpraz, Restyl, Trankimazin, Xanax, Xanor, Zopax, Trika. It is also commonly known as "Handles", "T-Bars", "White Tees", "Xanies (Pronounced ZAN-eez)", "Sticks", "Totem Poles", "Ladders", "Bars", "Yellow Buses", "French Fries", "Footballs" and "Paint Thinner" when laced, when sold or used illicitly.
[edit] Packaging
Imprints vary depending on drug manufacturer. The imprints above refer to the name-brand design in the United States and other first world countries,[16] however, every variety of alprazolam is generically available and thus individual pill design is left up to the manufacturer.
[edit] 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:[17][18][19][20]
- drowsiness
- decreased inhibitions, no fear of danger (increased risk taking behavior)
- depressed mood with thoughts of suicide or self harm
- hallucinations, agitation and hostility
- hyperactivity
- 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,
- complete memory loss, (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 sex drive
- dry mouth or increased salivation
- nervousness, restlessness, sleeplessness (insomnia) and sweating
- pounding in the chest or rapid heartbeat
- skin inflammation
- muscle twitching, tremor and seizure (convulsions)
[edit] Physical dependence and withdrawal
- See also: Benzodiazepine withdrawal syndrome
There is a consensus among psychiatrists today that alprazolam and other benzodiazepines cause withdrawal symptoms after long-term treatment and 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.[citation needed] Some patients on alprazolam (Xanax) may benefit from a substitution with 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 helping your body wean itself off the drug. If you feel the need to end treatment with alprazolam, consult your doctor/physician before discontinuing medication. Some immediate symptoms of alprazolam withdrawal include:
Common Withdrawal Symptoms
- A rapid/random heartbeat (Tachycardia)
- Depression
- Dry mouth/chapped lips
- Temporary inability to stop talking/moving (OCD)
- 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.[21]
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.[22]
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.[23]
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:[24]
- dosage
- length of use
- frequency of dosing
- method of withdrawal[25]
- 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.
However, in 1993 the New England Journal of Medicine reported there is no reliable evidence to support the existence of a persistent benzodiazepine withdrawal syndrome, and this syndrome has been described only in anecdotal reports, with patients typically reporting "withdrawal" symptoms not present during or before benzodiazepine treatment that persist for many months or years after treatment is stopped. Experimental neuropharmacologic studies document that all the side effects of benzodiazepines, whether behavioral or neurochemical, disappear within several days or weeks after the drug is eliminated. The weight of evidence indicates that any new symptoms that persist for more than two months after the last dose of a benzodiazepine either are part of the premorbid condition or have appeared by coincidence or as a consequence of the natural history of the underlying illness.[26]
The benzodiazepines diazepam(Valium) and oxazepam(Seresta) were found to produce less severe withdrawal symptoms than alprazolam(Xanax) or lorazepam(Temesta/Ativan).[24]
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,[27][28] and one death occurred from withdrawal-related seizures after gradual dose reduction.[28]
[edit] Contraindications
Use of alprazolam should be avoided, or carefully monitored by medical professionals, in individuals with the following conditions:[29][30]
- 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),[31] however correlation does not imply causation, as these behaviors are seen in unmedicated BPD patients.
[edit] 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.[32]
[edit] Pregnancy
Women who are pregnant or are planning on becoming pregnant should avoid starting alprazolam.[33] If one is currently planning to become pregnant, one should discuss this and all medicines with their obstetrician or other doctor.
[edit] Teratogenicity classification
Marked Pregnancy Category D by the U.S. FDA.
[edit] 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.[34]
[edit] Labor and delivery
Alprazolam has no established use in labor or delivery.
[edit] Nursing mothers (neonates)
Benzodiazepines, including alprazolam are known to be excreted in human milk.[35] Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight.[36] As a general rule, nursing should not be undertaken by mothers who use alprazolam.
[edit] 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.[37]
[edit] Food and drug interactions
Eating grapefruits or drinking grapefruit juice while using alprazolam increases blood concentrations by inhibiting the intestinal metabolism.[38]
In fact, any drug that inhibits CYP3A4, for which alprazolam is a substrate, will increase serum concentrations of alprazolam significantly if administered prior or concurrently. 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.[39]
[edit] 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.[40] People driving or conducting activities which require vigilance should exercise caution in using alprazolam or any other depressant.
[edit] Recreational use
Alprazolam, like all benzodiazepines, has the potential for abuse. Although it is not manufactured illegally[citation needed], and its misuse and 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"[41] 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."[42].
Injection of alprazolam is considered especially dangerous by medical professionals[43] 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[44]), 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.[45]
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.
[edit] 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. The most commonly abused benzodiazepine is however, alprazolam. Clonazepam is the 2nd most abused benzodiazepine. Lorazepam is the third most commonly abused benzodiazepine and diazepam the 4th most commonly abused benzodiazepine in the USA. Alprazolam is also commonly abused in combination with alcohol.[46]
[edit] 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.[47] Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.[48]
[edit] References
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[edit] External links
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