Alprazolam

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Alprazolam chemical structure
Alprazolam
Systematic (IUPAC) name
8-Chloro-1-methyl-6-phenyl-4H-
1,2,4-triazolo(4,3-a)(1,4)benzodiazepine
Identifiers
CAS number 28981-97-7
ATC code N05BA12
PubChem 2118
DrugBank APRD00280
Chemical data
Formula C17H13ClN4
Mol. weight 308.8
Pharmacokinetic data
Bioavailability 80-90%
Metabolism Hepatic
Half life 6-12 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat.

D (USA)
Legal status

Schedule IV(US)
Routes Oral

Alprazolam is a short-acting drug in the benzodiazepine class used to treat anxiety disorders and as an adjunctive treatment for depression.

Alprazolam was invented by Pfizer and is marketed under various trade names (see #Availability). Its patent (#3,987,052) was filed on October 29, 1969, granted on October 19, 1976 and expired in September 1993. [1]

Contents

[edit] History

Alprazolam was originally marketed as an atypical benzodiazepine, but only classified as anxiety neurosis. Researchers later speculated, however, that alprazolam could be studied for serotonergic effects. On October 20, 1976, Dr. Guy Chouinard was the first to conduct a clinical trial of alprazolam in panic disorder. Patients diagnosed with panic disorder were included among participants in the study. 50 patients were given either the alprazolam or a placebo during an 8-week double-blind controlled study. Results proved that both somatic and psychic anxiety was decreased significantly in those who took the alprazolam, compared to the placebo.

[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.

Clinical evidence of antidepressant activity is lacking, other benzodiazepines are not antidepressant.

[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 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

alprazolam 2mg tablet bottle
Enlarge
alprazolam 2mg tablet bottle

The main medical uses for alprazolam include:

  • Treatment of panic disorder, with or without agoraphobia.
    Alprazolam is very effective in preventing panic attacks. 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. An extended-release formulation of alprazolam known as Xanax XR® was introduced in 2001 and is often preferred.
  • 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.

[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
  • Alplax® - Argentina
  • Alpralid® - Israel
  • Alpravecs® - Italy
  • Alprax® - India
  • Alprazig® - Italy
  • Alviz® - Indonesia
  • Alzolam® - India, Malaysia
  • Apo-Alpraz® - Canada (also made by other companies under different names)
  • Apraz® - Brazil
  • Calmax® - Ireland
  • Constan® - Japan
  • Frontal XR® - (an extended release formulation) Brazil
  • Frontal® - Brazil, Italy
  • Frontin® - Hungary, Slovak Republic, Czech Republic
  • Helex® - Croatia, Slovenia
  • 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 AP® - (an extended release formulation) Mexico
  • Tafil® - Costa Rica, Denmark, El Salvador, Germany, Guatemala, Honduras, Mexico, Nicaragua, Panama, Venezuela
  • Trankimazin® - Spain
  • Tranquinal® - Ecuador, Peru
  • Valeans® - Italy
  • Xanax XR® - (an extended release formulation) Israel [1], United States, Portugal
  • Xanax® - Australia, Belgium, Croatia, Germany, Greece, Hungary, Ireland, Italy, Netherlands, New Zealand, Pakistan, Portugal, Slovak Republic, Switzerland, Turkey, United Kingdom, United States
  • Xanor® - Austria, Finland, Norway, Philippines, South Africa, Sweden
  • 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, Tunia, 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

[edit] Packaging

Appearance is generally as follows in the United States.

[edit] Alprazolam

Inscriptions on tablet vary depending on manufacturer.
.25 mg White oval tablet scored
.5 mg Peach oval or round tablet scored (.5 mg and .25 mg Alprazolam may also be found in White round tablet scored)
1 mg Blue oval or round scored tablet. May also be called a "football."
2 mg White rectangle multi-scored tablet. May also be called a "bar" or "stick."

[edit] Xanax XR®

1 mg Yellow square tablet Imprinted "X / 1"
2 mg Blue round tablet Imprinted "X / 2"
3 mg Green triangular tablet Imprinted "X / 3"

Source: [2]

[edit] Side effects

Common side effects of alprazolam can include:

Less common side effects can include:

  • Fatigue
  • Headache
 dizziness

Rare side effects can include:

Rare paradoxical side effects can include:

  • Nervousness
  • Anxiety
  • Agitation
  • Rage
  • Insomnia
  • Muscle spasms and rigidity

Paradoxical side effects are usually a result of too high a dose (sometimes deliberate) and/or combination with alcohol. Adjusting the dosage usually causes them to cease.

Concentrations of alprazolam in cigarette smokers may be reduced up to 50% when compared to non-smokers.[3].

Long-term treatment with alprazolam may lead to physical and/or psychological dependence. Users often develop a tolerance to the drug's sedative effects, though tolerance to its anxiolytic efficacy rarely develops when used at theraputic dosage levels.

There is now a general consensus among psychiatrists that alprazolam (a so-called 'high-potency' benzodiazepine) poses a particularly high risk for misuse, abuse and dependence. Withdrawal after long-term treatment 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 have a somewhat lower risk of dependency.

Patients taking a dosing regimen larger than 4mg per day have an increased potential for emotional and physical dependence.[citation needed] Patients who have this dependence may find it difficult to discontinue use and should seek a healthcare professional immediately so they may put you on a proper regimen to discontinue use. In addition to dependence, this medication may cause withdrawal symptoms, and in some cases has been known to cause seizures. The use 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, but this is usually short lived. Symptoms may also be accompanied 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.

[edit] Contraindications

Use of alprazolam should be avoided in individuals with the following conditions:

Women who are pregnant should avoid alprazolam. 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. [4] [5]

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. [6]

Eating grapefruits or drinking grapefruit juice should be avoided by those taking alprazolam.

[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 2mg tablets
Enlarge
alprazolam 2mg tablets

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 highly dangerous. When crushed in water, it will not dissolve, potentially causing severe damage to arteries. While it is somewhat soluble in alcohol, the combination of the two, particularly when injected, can easily cause a serious (and potentially fatal) overdose. Alprazolam may also be insufflated.

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). It is also often used in conjunction with marijuana or heroin to potentiate the relaxing effect. It is also sometimes used by heroin addicts to suppress withdrawal symptoms.

[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[7].

[edit] References

  1. ^ US Patent 3,987,052

[edit] External links


Benzodiazepines edit

Adinazolam, Alprazolam, Bentazepam, Bromazepam, Brotizolam, Camazepam, Chlordiazepoxide, Cinolazepam, Clobazam, Clonazepam, Clorazepate, Clotiazepam, Cloxazolam, Cyprazepam, Diazepam, Doxefazepam, Estazolam, Ethyl loflazepate, Etizolam, Fludiazepam, Flunitrazepam, Flurazepam, Flutazolam, Flutoprazepam, Gidazepam, Halazepam, Haloxazolam, Ketazolam, Loprazolam, Lorazepam, Lormetazepam, Medazepam, Mexazolam, Midazolam, Nimetazepam, Nitrazepam, Nordazepam, Oxazepam, Oxazolam, Phenazepam, Pinazepam, Prazepam, Quazepam, Temazepam, Tetrazepam, Tofisopam, Triazolam, Zolazepam
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