Alprazolam
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Alprazolam
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| Systematic (IUPAC) name | |
| 8-chloro-1-methyl-6-phenyl-4H- [1,2,4]triazolo[4,3-a][1,4]benzodiazepine |
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| Identifiers | |
| CAS number | |
| ATC code | N05 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C17H13ClN4 |
| Mol. mass | 308.765 |
| Pharmacokinetic data | |
| Bioavailability | 80-90% |
| Metabolism | Hepatic |
| Half life | 6-12 hours |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. |
D(US) |
| Legal status | |
| Routes | Oral |
Alprazolam is a short-acting drug in the benzodiazepine class used to treat anxiety disorders and as an adjunctive treatment for depression. It is also used as a medication to aid the beginning of treatment with SSRI type drugs, since these can cause anxiety in the initial stages of use.
Alprazolam was first synthesized by Upjohn (now a part of Pfizer) and is marketed under various trade names. Its patent (#3,987,052 [1]) was filed on October 29, 1969, granted on October 19, 1976 and expired in September 1993.
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[edit] Pharmacology
Alprazolam is a triazolobenzodiazepine, 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 major depression in out patient settings, evidence for inpatients is lacking [2]; 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:
- Treatment 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. However, despite its efficacy, many psychiatrists are reluctant to use alprazolam for this condition because of the possibility of dependence and interdose ("breakthrough") anxiety due to its short-acting nature.
- Treatment of panic attacks. Alprazolam is taken as needed (PRN); 4 to 6 doses per day are the acceptable limit. If dependence seems to develop and/or the limit is exceeded, therapy may be reconsidered and/or discontinued.
- Long-term treatment of severe anxiety disorders. Alprazolam may be used for long-term treatment of anxiety if other therapies either do not work or are contraindicated. Duration of therapy in this case is often four months or longer. The decision to use alprazolam for this purpose must be carefully made by a specialized psychiatrist, taking into account the individual's suffering, quality of life, loss of social performance and risk of dependence.
- Adjunctive treatment of depression. SSRIs (e.g. sertraline or fluoxetine) are often co-administered with alprazolam at the outset of long-term SSRI anxiety treatment in order to counteract the initial anxiogenic (anxiety-producing) effects of SSRI treatment. Tricyclic antidepressants and buspirone are also used with alprazolam in refractory (resistant) cases of generalized anxiety disorder.
- Other uses. Alprazolam has been used by specialists to treat severe cases of Borderline Personality Disorder. Some studies have shown positive results.[citation needed] Alprazolam may be used off-label to treat insomnia.
[edit] Availability
Alprazolam is generally sold in generic form in Italy and the United States. It is also sold under many other brand names, depending on the country:
- Aceprax® - Uruguay
- Afobam® - Poland
- Alplax® - Argentina
- Alpralid® - Israel
- Alpravecs® - Italy
- Alprax® - India
- Alprazig® - Italy
- Alprox® - Finland
- Altrox® - Philippines
- Alviz® - Indonesia
- Alzolam® - India, Malaysia
- Apo-Alpraz® - Canada (also made by other companies under different names)
- Apraz® - Brazil
- Azor® - South Africa
- Calmax® - Ireland
- Constan® - Japan
- Dormonoct® - Portugal
- Farmapram® - Mexico
- Frontal® - Brazil, Italy
- Frontal XR® - (an extended release formulation) Brazil
- Frontin® - Hungary, Slovak Republic, Czech Republic
- Helex® - Croatia, Slovenia
- Jialeding® (佳乐定）- China
- Kalma® - Australia
- Kinax® (景安寧) - Taiwan
- Ksalol® - Serbia
- Manorest® - Sri Lanka
- Mialin® - Italy
- Misar® - Croatia
- Neurol® - Czech Republic, Slovak Republic
- Niravam® - (formulation that dissolves on the tongue) United States
- Paxal® - Iceland
- Ralozam® - Australia
- Restyl® - Bahrain, Cyprus, Egypt, India, Iran, Iraq, Jordan, Kuwait, Lebanon, Libya, Oman, Qatar, Republic of Yemen, Saudi Arabia, Syria, United Arab Emirates
- Sedipral® - Paraguay
- Solanax® - Japan
- Tafil® - Austria, Costa Rica, Germany, Mexico, Portugal, Switzerland, Venezuela
- Trankimazin® - Spain
- Xanax XR® - (an extended release formulation) Israel [3], United States, Portugal
- Xanax® - Australia, Belgium, Bulgaria, Croatia, France, Germany, Greece, Hungary, Ireland, Italy, Netherlands, New Zealand, Pakistan, Poland, Portugal, Romania, Serbia, Singapore, Slovak Republic, Switzerland, Turkey, United Kingdom, United States
- Xanor® - Austria, Finland, Norway, Philippines, South Africa, Sweden
- Xanor SR® - (slow release) South Africa
- Zamhexal® - Australia
- Zolarem® - Bahrain, Benin, Burkina-Faso, Cyprus, Egypt, Ethiopia, Gambia, Ghana, Guinea, Iran, Iraq, Israel, Ivory Coast, Jordan, Kenya, Kuwait, Lebanon, Liberia, Libya, Malawi, Mali, Mauritania, Mauritius, Morocco, Niger, Nigeria, Oman, Qatar, Republic of Yemen, Saudi Arabia, Senegal, Seychelles, Sierra-Leone, South Africa, Sudan, Syria, Tanzania, Tunisia, Uganda, United Arab Emirates, Zambia, Zimbabwe
- Zoldac® - Benin, Burkina-Faso, Ethiopia, Gambia, Ghana, Guinea, India, Ivory Coast, Kenya, Liberia, Malawi, Mali, Mauritania, Mauritius, Morocco, Niger, Nigeria, Senegal, Seychelles, Sierra-Leone, South Africa, Sudan, Tanzania, Tunia, Uganda, Zambia, Zimbabwe
- Zomiren® - Poland
[edit] Packaging
The inscriptions on tablets vary depending on manufacturer and on the country where it is marketed. Appearance is generally as follows in the United States [4].
Usually, Xanax® comes in the following dosages:
- 0.25 mg white oval or round tablet, scored.
- 0.5 mg peach oval or round tablet scored (0.5 mg Alprazolam may also be found in white round tablet scored)(Equivalent to 5 mg Diazepam and 0.5 mg Clonazepam)
- 1 mg blue oval or round scored tablet. May also be called a football, most commonly a "blue football".
- 2 mg white rectangle multi-scored tablet. May also be called a bar or stick, or a "monkey bar" or "dog bone". Recreational users may also call this a "totem pole."
The Xanax XR® formulation is usually marketed as:
- 2 mg blue round tablet Imprinted "X / 2" (Equivalent to 10 mg Diazepam and 1 mg Clonazepam)
- 3 mg green triangular tablet Imprinted "X / 3"
[edit] Side effects
Common side effects of alprazolam can include:
- Somnolence (drowsiness)
- Amnesia (minor memory impairment)
- Euphoria (Note: The official Pfizer drug information does not list euphoria as a side effect,[5] nor does RxList,[6] although there are subjective reports that it does in fact cause euphoria.)
Less common side effects can include:
- Fatigue
- Headache
- Dizziness
Rare side effects can include:
- Sleep apnea
- Hypoventilation (Respiratory depression)
- Blurred vision
- Difficulty in depth perception
- Slurred speech or dysarthria
- Changes in personality
- Disorientation
- Vivid dreams and/or nightmares
- Jaundice
- Tachycardia
- Bradycardia
- Changes in plasma cortisol and ACTH levels
- Blood dyscrasias
- Decreased salivation
- Increased salivation
- Diarrhea
- Constipation
- Nausea
- Elevated hepatic (liver) enzymes
- Incontinence
There is now a general consensus among psychiatrists that alprazolam and other benzodiazepines can cause withdrawal symptoms after long-term treatment and should be done slowly over a period of weeks (or even months) to avoid serious withdrawal symptoms such as agitation, panic attacks, rebound anxiety, muscle cramps and seizures. Some patients may benefit from a substitution with diazepam or clonazepam as these drugs remain in the bloodstream longer and therfore have less potential for abuse and dependence. 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. 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. Most patients do not experience negative side effects to stop taking alprazolam. Consult your doctor for more information on how benzodiazepines can successfully treat anxiety disorders.
[edit] Contraindications
Use of alprazolam should be avoided in individuals with the following conditions:
- Myasthenia gravis
- Acute intoxication with alcohol, narcotics, or other psychoactive substances
- Ataxia
- Severe hypoventilation
- Acute narrow-angle glaucoma
- Severe liver deficiencies (e.g. hepatitis and cirrhosis)
- Severe sleep apnea
- Hypersensitivity or allergy to any drug in the benzodiazepine class
- Borderline Personality Disorder (may induce an episode)
[edit] Pregnancy
Women who are pregnant or are planning on becoming pregnant should avoid alprazolam [7].
[edit] Teratogenicity
Teratogenic effects: Pregnancy Category D.
[edit] Nonteratogenic Effects
Nonteratogenic Effects: It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for 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.
[edit] Labor and Delivery
Alprazolam has no established use in labor or delivery.
[edit] Nursing Mothers/Neonatal
Benzodiazepines are known to be excreted in human milk. It should be assumed that alprazolam is as well. 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 must use XANAX.
Children of mothers who are taking alprazolam are considered at risk for withdrawal symptoms during the postnatal period. Some children born under these conditions have been reported to have neonatal flaccidity and respiratory problems. Likewise, nursing mothers should avoid alprazolam due to the fact that benzodiazepines are known to be passed into breast milk. This can cause infants to become lethargic and lose weight. [8] [9]
[edit] Geriatric use
Elderly individuals should be cautious in the use of alprazolam due to the possibility of increased sensitivity to side effects, especially loss of coordination and drowsiness. [10]
[edit] Food and drug interactions
Eating grapefruits or drinking grapefruit juice while using alprazolam increases blood concentrations by inhibiting the intestinal metabolism.[1]
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.
[edit] Patients at a High Risk for Abuse and Dependence
At a particularly high risk for misuse, abuse, and dependence are:
- Patients with a history of alcohol or drug abuse and/or dependence
- Emotionally unstable patients
- Patients with severe personality disorders
- Patients with chronic pain or other physical disorders
Patients from the aforementioned group should be monitored very closely during therapy for signs of abuse and development of dependence. Discontinue therapy if any of these signs are noted. Long-term therapy in these patients is not recommended.
[edit] Recreational use
Alprazolam, like all benzodiazepines, has the potential for abuse. Although it is not manufactured illegally, it is often diverted to the black market. The state of relaxation, anxiolysis, disinhibition and euphoria induced by benzodiazepines is the main reason for their illicit use.
Injecting alprazolam is considered especially dangerous by medical professionals due to the fact that, 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[11]), 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, have the potential to cause a serious, and potentially fatal overdose. Alprazolam may also be insufflated; clinical testing dispels the rumor about less activity via insufflation.[2]
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. It is also often used by heroin addicts to suppress withdrawal symptoms, as its effects in conjunction with methadone produce a high which closely resembles that of heroin.
[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. Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances.[3]
[edit] References
[edit] External links
- Inchem.org - Alprazolam
- Medline Plus - Alprazolam
- Erowid.org - Alprazolam
- Rxlist.com - Alprazolam
- Article on Xanax Addiction
- Teratogenicity and non-teratogenic effects; pregnancy.
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