Alprazolam, sold under the brand name Xanax, among others, is a fast-acting, potent
tranquilizer
A tranquilizer is a drug that is designed for the treatment of anxiety, fear, tension, agitation, and disturbances of the mind, specifically to reduce states of anxiety and tension.
Etymology
Tranquilizer, as a term, was first used by F.F. Yonk ...
of medium duration in the
triazolobenzodiazepine upChemical structure of alprazolam, a common triazolobenzodiazepine
Triazolobenzodiazepines (TBZD) are a class of benzodiazepine (BZD) derivative pharmaceutical drugs. Chemically, they differ from other benzodiazepines by having an additional fu ...
(TBZD) class, which are
benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s (BZDs) fused with a
triazole
A triazole is a heterocyclic compound featuring a five-membered ring of two carbon atoms and three nitrogen atoms with molecular formula C2H3N3. Triazoles exhibit substantial isomerism, depending on the positioning of the nitrogen atoms within t ...
ring. It is most commonly used in management of
anxiety disorder
Anxiety disorders are a cluster of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal function are significantly impaired. Anxiety may cause physi ...
s, specifically
panic disorder
Panic disorder is a mental disorder, mental and Abnormal behavior, behavioral disease#Disorder, disorder, specifically an anxiety disorder characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear th ...
or
generalized anxiety disorder
Generalized anxiety disorder (GAD) is a mental and behavioral disorder, specifically an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily function ...
(GAD).
Other uses include the treatment of
chemotherapy-induced nausea, together with other treatments.
[ GAD improvement occurs generally within a week.] Alprazolam is generally taken by mouth
Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...
.
Common side effects include sleepiness, depression, headaches, feeling tired, dry mouth
Xerostomia, also known as dry mouth, is dryness in the mouth, which may be associated with a change in the composition of saliva, or reduced salivary flow, or have no identifiable cause.
This symptom is very common and is often seen as a side eff ...
, and memory problems.[ Some of the sedation and tiredness may improve within a few days.] Withdrawal
Withdrawal means "an act of taking out" and may refer to:
* Anchoresis (withdrawal from the world for religious or ethical reasons)
* ''Coitus interruptus'' (the withdrawal method)
* Drug withdrawal
* Social withdrawal
* Taking of money from a ban ...
or rebound symptoms may occur if use is suddenly decreased;[ gradually decreasing the dose over weeks or months may be required.] Alprazolam increases all-cause mortality. Alprazolam, like other benzodiazepines, acts through the GABAA receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
.[
Alprazolam was invented by Dr. Jackson Hester at the Upjohn Company
][Ainsworth, Susan J.]
"Hester Dies At 80 : Upjohn medicinal chemist designed major drugs"
American Chemical Society, December 9, 2013. A version of this story appeared in Volume 91, Issue 49 and patented in 1971 and approved for medical use in the United States in 1981. Alprazolam is a Schedule IV controlled substance and is a common drug of abuse. It is available as a generic medication
A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
. In 2020, it was the 37th most-commonly-prescribed medication in the United States, with more than 16million prescriptions.
Medical uses
Alprazolam is mostly used in management of anxiety disorder
Anxiety disorders are a cluster of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal function are significantly impaired. Anxiety may cause physi ...
s, panic disorder
Panic disorder is a mental disorder, mental and Abnormal behavior, behavioral disease#Disorder, disorder, specifically an anxiety disorder characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear th ...
s, and nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
due to chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
.[ Alprazolam is ]indicated
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...
for the treatment of generalized anxiety disorder
Generalized anxiety disorder (GAD) is a mental and behavioral disorder, specifically an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily function ...
and panic disorder
Panic disorder is a mental disorder, mental and Abnormal behavior, behavioral disease#Disorder, disorder, specifically an anxiety disorder characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear th ...
with or without agoraphobia
Agoraphobia is a mental and behavioral disorder, specifically an anxiety disorder characterized by symptoms of anxiety in situations where the person perceives their environment to be unsafe with no easy way to escape. These situations can in ...
in adults. The FDA label advises that the physician should periodically reassess the usefulness of the drug.
Panic disorder
Alprazolam is effective in the relief of moderate to severe anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
and panic attack
Panic attacks are sudden periods of intense fear and discomfort that may include palpitations, sweating, chest pain or chest discomfort, shortness of breath, trembling, dizziness, numbness, confusion, or a feeling of impending doom or of losing ...
s. Alprazolam is not recommended in Australia for the treatment of panic disorder because of concerns regarding tolerance, dependence, and abuse. Most evidence shows that the benefits of alprazolam in treating panic disorder last only four to ten weeks. However, people with panic disorder have been treated on an open basis for up to eight months without apparent loss of benefit.
Alprazolam is recommended by the World Federation of Societies of Biological Psychiatry (WFSBP) for treatment-resistant cases of panic disorder where there is no history of tolerance or dependence.
Anxiety disorders
Anxiety associated with depression is responsive to alprazolam. Clinical studies have shown that the effectiveness is limited to 4 months for anxiety disorders. However, the research into antidepressant properties of alprazolam is poor and has only assessed its short-term effects against depression. In one study, some long term, high-dosage users of alprazolam developed reversible depression. In the US, alprazolam is FDA-approved for the management of anxiety disorders (a condition corresponding most closely to the APA ''Diagnostic and Statistical Manual'' DSM-IV-TR
The ''Diagnostic and Statistical Manual of Mental Disorders'' (DSM; latest edition: DSM-5-TR, published in March 2022) is a publication by the American Psychiatric Association (APA) for the classification of mental disorders using a common langua ...
diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. In the UK, alprazolam is recommended for the short-term treatment (2–4 weeks) of severe acute anxiety.[
]
Nausea due to chemotherapy
Alprazolam may be used in combination with other medications for chemotherapy-induced nausea and vomiting
Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of many cancer treatments. Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. In 1983, Coates et al. f ...
.[
]
Contraindications
Benzodiazepines require special precaution if used in children and in alcohol- or drug-dependent individuals. Particular care should be taken in pregnant or elderly people, people with substance use disorder
Substance use disorder (SUD) is the persistent use of drugs (including alcohol) despite substantial harm and adverse consequences as a result of their use. Substance use disorders are characterized by an array of mental/emotional, physical, and ...
history (particularly alcohol dependence
Alcohol dependence is a previous (DSM-IV and ICD-10) psychiatric diagnosis in which an individual is physically or psychologically dependent upon alcohol (also chemically known as ethanol).
In 2013, it was reclassified as alcohol use disorde ...
), and people with comorbid
In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary ...
psychiatric disorders
A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitti ...
. The use of alprazolam should be avoided or carefully monitored by medical professionals in individuals with: myasthenia gravis
Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, dro ...
, acute narrow-angle glaucoma
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...
, severe liver deficiencies (e.g., cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
), severe sleep apnea
Sleep apnea, also spelled sleep apnoea, is a sleep disorder in which pauses in breathing or periods of shallow breathing during sleep occur more often than normal. Each pause can last for a few seconds to a few minutes and they happen many times ...
, pre-existing respiratory depression, marked neuromuscular
A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber.
It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction.
Muscles require innervation t ...
respiratory
The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies grea ...
, acute pulmonary insufficiency
Pulmonary (or pulmonic) insufficiency (or incompetence, or regurgitation) is a condition in which the pulmonary valve is incompetent and allows backflow from the pulmonary artery to the right ventricle of the heart during diastole. While a small ...
, chronic psychosis
Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...
, hypersensitivity
Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune s ...
or allergy
Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...
to alprazolam or other benzodiazepines, and borderline personality disorder
Borderline personality disorder (BPD), also known as emotionally unstable personality disorder (EUPD), is a personality disorder characterized by a long-term pattern of unstable interpersonal relationships, distorted sense of self, and strong ...
(where it may induce suicidality
Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and subs ...
and dyscontrol).
Like all central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
depressant
A depressant, or central depressant, is a drug that lowers neurotransmission levels, which is to depress or reduce arousal or stimulation, in various areas of the brain. Depressants are also colloquially referred to as downers as they lower the ...
s, alprazolam in larger-than-normal doses can cause significant deterioration in alertness
Alertness is the state of active attention by high sensory awareness such as being watchful and prompt to meet danger or emergency, or being quick to perceive and act. It is related for psychology . A lack of alertness is a symptom of a ...
and increase drowsiness, especially in those unaccustomed to the drug's effects.
Elderly individuals should be cautious in the use of alprazolam due to the possibility of increased susceptibility to side-effects, especially loss of coordination
Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
and drowsiness.[
]
Side effects
Sedative drugs, including alprazolam, have been associated with an increased risk of death.
Possible side effects
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
include:
* Anterograde amnesia
In neurology, anterograde amnesia is the inability to create new memories after the event that caused amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. T ...
[ and ]concentration
In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', ''molar concentration'', ''number concentration'', an ...
problems
* Ataxia
Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
, slurred speech
Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. In other words, it is a condition in which problems effective ...
* Disinhibition
In psychology, disinhibition is a lack of restraint manifested in disregard of social conventions, impulsivity, and poor risk assessment. Disinhibition affects motor, instinctual, emotional, cognitive, and perceptual aspects with signs and sympto ...
* Drowsiness
Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
, dizziness
Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness.
Dizziness is a common medical c ...
, lightheadedness
Lightheadedness is a common and typically unpleasant sensation of dizziness or a feeling that one may faint. The sensation of lightheadedness can be short-lived, prolonged, or, rarely, recurring. In addition to dizziness, the individual may feel ...
, fatigue
Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
, unsteadiness, and impaired coordination, vertigo
Vertigo is a condition where a person has the sensation of movement or of surrounding objects moving when they are not. Often it feels like a spinning or swaying movement. This may be associated with nausea, vomiting, sweating, or difficulties w ...
* Dry mouth
Xerostomia, also known as dry mouth, is dryness in the mouth, which may be associated with a change in the composition of saliva, or reduced salivary flow, or have no identifiable cause.
This symptom is very common and is often seen as a side eff ...
(infrequent)
* Hallucination
A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinatio ...
s (rare)[
* ]Jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...
(very rare)
* Seizures
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or neural oscillation, synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much o ...
(less common)
* Skin rash
A rash is a change of the human skin which affects its color, appearance, or texture.
A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cr ...
, respiratory depression
Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapnia ...
, constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...
[
* ]Suicidal ideation
Suicidal ideation, or suicidal thoughts, means having thoughts, ideas, or ruminations about the possibility of ending one's own life.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal ideatio ...
or suicide
Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and s ...
* Urinary retention
Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include loss of bladd ...
(infrequent)
*Muscle weakness
Muscle weakness is a lack of muscle strength. Its causes are many and can be divided into conditions that have either true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, includi ...
In September 2020, the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) required the boxed warning
In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because
the U.S. Food and Drug Administration specifies that it ...
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.
Paradoxical reactions
Although unusual, the following paradoxical reaction A paradoxical reaction (or paradoxical effect) is an effect of a chemical substance, such as a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication.
Parad ...
s have been shown to occur:
* Aggression
Aggression is overt or covert, often harmful, social interaction with the intention of inflicting damage or other harm upon another individual; although it can be channeled into creative and practical outlets for some. It may occur either reacti ...
* Mania
Mania, also known as manic syndrome, is a mental and behavioral disorder defined as a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together wit ...
, agitation, hyperactivity
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...
, and restlessness
* Rage, hostility
* Twitches and tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...
Food and drug interactions
Alprazolam is primarily metabolized
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
via CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
. Combining CYP3A4 inhibitors such as cimetidine
Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers.
The development of longer-acting H2 rec ...
, erythromycin
Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used duri ...
, norfluoxetine, fluvoxamine
Fluvoxamine, sold under the brand name Luvox and Faverin among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and obsessive–compulsive disorder ...
, itraconazole
Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mouth ...
, ketoconazole, nefazodone
Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued. BMS withdrew it from ...
, propoxyphene
Dextropropoxyphene is an analgesic in the opioid category, patented in 1955 and manufactured by Eli Lilly and Company. It is an optical isomer of levopropoxyphene. It is intended to treat mild pain and also has antitussive (cough suppressant) a ...
, and ritonavir
Ritonavir, sold under the brand name Norvir, is an antiretroviral drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor a ...
delay the hepatic
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
clearance of alprazolam, which may result in its accumulation and increased severity of its side effects.
Imipramine
Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. The drug is also used to treat bedwetting. ...
and desipramine
Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activiti ...
have been reported to increase an average of 31% and 20% respectively by the concomitant
Concomitance is the condition of accompanying or coexisting. A concomitant is something that accompanies something else.
Concomitant or concomitance may refer to:
* Concomitance (doctrine), a Christian doctrine
* Concomitant (classical algebraic ...
administration of alprazolam tablets. Combined oral contraceptive pill
The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be taken orally by women. The pill contains two important hormones: progest ...
s reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.
Alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
is one of the most common interactions; alcohol and alprazolam taken in combination have a synergistic effect on one another, which can cause severe sedation, behavioral changes, and intoxication. The more alcohol and alprazolam taken, the worse the interaction. Combination of alprazolam with the herb kava
Kava or kava kava (''Piper methysticum'': Latin 'pepper' and Latinized Greek 'intoxicating') is a crop of the Pacific Islands. The name ''kava'' is from Tongan and Marquesan, meaning 'bitter'; other names for kava include ''ʻawa'' (Hawaiʻi), ...
can result in the development of a semi-coma
A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...
tose state. Plants in the genus ''Hypericum
''Hypericum'' is a genus of flowering plants in the family Hypericaceae (formerly considered a subfamily of Clusiaceae). The genus has a nearly worldwide distribution, missing only from tropical lowlands, deserts and polar regions. Many ''Hype ...
'' (including St. John's wort
''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus ''Hypericum''.
Possibly a hybrid between ''Hypericum maculatum, H. maculatum'' and ''Hypericum attenuatum, H. ...
) conversely can lower the plasma levels of alprazolam and reduce its therapeutic effect.
Pregnancy and breastfeeding
Benzodiazepines cross the placenta
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...
, enter the fetus
A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal deve ...
, and are also excreted in breast milk
Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by mammary glands located in the breast of a human female. Breast milk is the primary source of nutrition for newborns, containing fat, protein, carbohydrates ( lacto ...
. Chronic administration of diazepam
Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, a ...
, another benzodiazepine, to nursing mothers has been reported to cause their infants to become lethargic and to lose weight.
The use of alprazolam during pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ca ...
is associated with congenital abnormalities
A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can r ...
, and use in the last trimester may cause fetal drug dependence and withdrawal symptoms
Drug withdrawal, drug withdrawal syndrome, or substance withdrawal syndrome, is the group of symptoms that occur upon the abrupt discontinuation or decrease in the intake of pharmaceutical or recreational drugs.
In order for the symptoms of wit ...
in the post-natal period as well as neonatal flaccidity and respiratory problems. However, in long-term users of benzodiazepines, abrupt discontinuation due to concerns of teratogenesis
Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related ...
has a high risk of causing extreme withdrawal symptoms and a severe rebound effect
The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re ...
of the underlying mental health disorder
A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitti ...
. Spontaneous abortions
Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the death of an embryo or fetus before it is fetal viability, able to survive independently. Miscarriage before 6 weeks of gestation is defined by ESHRE a ...
may also result from abrupt withdrawal of psychotropic medications, including benzodiazepines.
Overdose
The maximum recommended daily dose is 10 milligrams per day.
Overdoses of alprazolam can be mild to severe depending on the quantity ingested and if other drugs are taken in combination.
Alprazolam overdoses cause excess central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
(CNS) depression and may include one or more of the following symptoms:[
* Coma and death if alprazolam is combined with other substances.
* ]Fainting
Syncope, commonly known as fainting, or passing out, is a loss of consciousness and muscle strength characterized by a fast onset, short duration, and spontaneous recovery. It is caused by a decrease in blood flow to the brain, typically from ...
* Hypotension
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...
(low blood pressure)
* Hypoventilation
Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapnia ...
(shallow breathing)
* Impaired motor functions
Motor control is the regulation of movement in organisms that possess a nervous system. Motor control includes reflexes as well as directed movement.
To control movement, the nervous system must integrate multimodal sensory information (both f ...
** Dizziness
Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness.
Dizziness is a common medical c ...
** Impaired balance
** Impaired or absent reflexes
In biology, a reflex, or reflex action, is an involuntary, unplanned sequence or action and nearly instantaneous response to a Stimulus (physiology), stimulus.
Reflexes are found with varying levels of complexity in organisms with a nervous s ...
** Muscle weakness
Muscle weakness is a lack of muscle strength. Its causes are many and can be divided into conditions that have either true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, includi ...
* Orthostatic hypotension
Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when standing up or sitting down. Primary orthostatic hypertension is also often referred to as neurogenic orthostatic hyp ...
(fainting while standing up too quickly)
* Somnolence
Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
(drowsiness)
Dependence and withdrawal
The potential for misuse among those taking it for medical reasons is controversial, with some expert reviews stating that the risk is low and similar to that of other benzodiazepine drugs. Others state that there is a substantial risk of misuse and dependence in both patients and non-medical users and that the short half-life and rapid onset of action may increase the risk of misuse.[ Compared to the large number of prescriptions, relatively few individuals increase their dose on their own initiative or engage in ]drug-seeking behavior
Substance dependence, also known as drug dependence, is a biopsychological situation whereby an individual's functionality is dependent on the necessitated re-consumption of a psychoactive substance because of an adaptive state that has develope ...
.
Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA ( gamma-aminobutyric acid) receptor. When bound to these sites, which are referred to as benzodiazepine receptors, it modulates the effect of GABAA receptors and, thus, of GABAergic neurons. Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and thus making the drugs less potent.
Withdrawal
Withdrawal means "an act of taking out" and may refer to:
* Anchoresis (withdrawal from the world for religious or ethical reasons)
* ''Coitus interruptus'' (the withdrawal method)
* Drug withdrawal
* Social withdrawal
* Taking of money from a ban ...
and rebound symptoms commonly occur and necessitate a gradual reduction in dosage to minimize withdrawal effects when discontinuing.[
Not all withdrawal effects are evidence of true dependence or withdrawal. Recurrence of symptoms such as anxiety may simply indicate that the drug was having its expected anti-anxiety effect and that, in the absence of the drug, the symptom has returned to pretreatment levels. If the symptoms are more severe or frequent, the person may be experiencing a ]rebound effect
The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re ...
due to the removal of the drug. Either of these can occur without the person actually being drug dependent.
Alprazolam and other benzodiazepines may also cause the development of physical dependence
Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certai ...
, tolerance, and benzodiazepine withdrawal symptoms
Benzodiazepine withdrawal syndrome often abbreviated to benzo withdrawal or BZD withdrawal is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines, either medically or recreationally develops a p ...
during rapid dose reduction or cessation of therapy after long-term treatment. There is a higher chance of withdrawal reactions if the drug is administered in a higher dosage than recommended, or if a person stops taking the medication altogether without slowly allowing the body to adjust to a lower-dosage regimen.
In 1992, Romach and colleagues reported that dose escalation is not a characteristic of long-term alprazolam users and that the majority of long-term alprazolam users change their initial pattern of regular use to one of symptom control only when required.
Some common symptoms of alprazolam discontinuation include malaise
As a medical term, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. The word has existed in French since at least the 12th century.
The term is often used ...
, weakness, insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
, tachycardia
Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...
, lightheadedness, and dizziness.
Those taking more than 4 mg per day have an increased potential for dependence. This medication may cause withdrawal symptoms upon abrupt withdrawal or rapid tapering, which in some cases have been known to cause seizures, as well as marked delirium
Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances in ...
similar to that produced by the anticholinergic
Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system.
These agents inhibit the parasympathetic nervous system ...
tropane alkaloids of Datura ( scopolamine and atropine
Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically given i ...
). The discontinuation of this medication may also cause a reaction called ''rebound anxiety''.
In a 1983 study, only 5% of patients who had abruptly stopped taking long-acting benzodiazepines after less than 8 months demonstrated withdrawal symptoms, but 43% of those who had been taking them for more than 8 months did. With alprazolam – a short-acting benzodiazepine – taken for 8 weeks, 65% of patients experienced significant rebound anxiety. To some degree, these older benzodiazepines are self-tapering.
The benzodiazepines diazepam
Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, a ...
and oxazepam
Oxazepam is a short-to-intermediate-acting benzodiazepine. Oxazepam is used for the treatment of anxiety and insomnia and in the control of symptoms of alcohol withdrawal syndrome.
It is a metabolite of diazepam, prazepam, and temazepam, and ha ...
have been found to produce fewer withdrawal reactions than alprazolam, temazepam
Temazepam (sold under the brand names Restoril among others) is a medication of the benzodiazepine class which is generally used to treat severe or debilitating insomnia. It is taken by mouth. Temazepam is rapidly absorbed, and significant hypno ...
, or lorazepam
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 c ...
. Factors that determine the risk of psychological dependence
Psychological dependence is a cognitive disorder that involves emotional–motivational withdrawal symptoms—e.g. anxiety and anhedonia—upon cessation of prolonged drug abuse or certain repetitive behaviors. It develops through frequent exp ...
or physical dependence
Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certai ...
and the severity of the benzodiazepine withdrawal symptoms
Benzodiazepine withdrawal syndrome often abbreviated to benzo withdrawal or BZD withdrawal is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines, either medically or recreationally develops a p ...
during dose reduction of alprazolam include: dosage used, length of use, frequency of dosing, personality characteristics of the individual, previous use of cross-dependent/cross-tolerant drugs (alcohol or other sedative-hypnotic drugs), current use of cross-dependent/-tolerant drugs, use of other short-acting, high-potency benzodiazepines, and method of discontinuation.
Pharmacology
Alprazolam is a positive allosteric modulator of the gamma-aminobutyric acid (GABA) type A receptor. When it binds to the receptor, effects of GABA are enhanced leading to inhibition of neurons in the brain. This results in effects including reduced anxiety, muscle relaxant, antidepressant and anticonvulsant activity. The activity of alprazolam in the central nervous system is dose dependent.
Mechanism of action
Alprazolam is classed as a high-potency triazolobenzodiazepine upChemical structure of alprazolam, a common triazolobenzodiazepine
Triazolobenzodiazepines (TBZD) are a class of benzodiazepine (BZD) derivative pharmaceutical drugs. Chemically, they differ from other benzodiazepines by having an additional fu ...
: a benzodiazepine with a triazole ring attached to its structure. As a benzodiazepine, alprazolam produces a variety of therapeutic and adverse effects by binding to the GABAA benzodiazepine receptor site and modulating its function; GABA receptor
The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and ...
s are the most prolific inhibitory receptor within the brain. The GABA chemical and receptor system mediates inhibitory or calming effects of alprazolam on the nervous system. Binding of alprazolam to the GABAA receptor, a chloride ion channel, enhances the effects of GABA, a neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
. When GABA binds the GABAA receptor the channel opens and chloride enters the cell which makes it more resistant to depolarisation. Therefore, alprazolam has a depressant effect on synaptic transmission to reduce anxiety.
The GABAA receptor is made up of 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 with regard to benzodiazepines. Alprazolam and other triazolobenzodiazepines such as triazolam
Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives. It possesses pharmacological properties ...
that have a triazole ring fused to their diazepine ring appear to have antidepressant
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
properties. This is perhaps due to the similarities shared with tricyclic antidepressant
Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...
s, as they have two benzene rings fused to a diazepine ring. Alprazolam causes a marked suppression of the hypothalamic–pituitary–adrenal axis
The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus (a part of the brain located below the thalamus), the pituitary gland (a ...
. The therapeutic properties of alprazolam are similar to other benzodiazepines and include anxiolytic
An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxi ...
, anticonvulsant
Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...
, muscle relaxant
A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...
, hypnotic
Hypnotic (from Greek ''Hypnos'', sleep), or soporific drugs, commonly known as sleeping pills, are a class of (and umbrella term for) psychoactive drugs whose primary function is to induce sleep (or surgical anesthesiaWhen used in anesthesia ...
and amnesic
Amnesia is a deficit in memory caused by brain damage or disease,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be caused temporarily by the use ...
; however, it is used mainly as an anxiolytic.
Giving alprazolam, as compared to lorazepam
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 c ...
, has been demonstrated to elicit a statistically significant increase in extracellular dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
D1 and D2 concentrations in the striatum
The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...
.
Pharmacokinetics
Alprazolam is taken orally, and is absorbed well – 80% of alprazolam binds to proteins in the serum (the majority binding to albumin
Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
). The concentration of alprazolam peaks after one to two hours.
Alprazolam is metabolized in the liver, mostly by the enzyme cytochrome P450 3A4 (CYP3A4). Two major metabolites are produced: 4-hydroxyalprazolam and α-hydroxyalprazolam, as well as an inactive benzophenone
Benzophenone is the organic compound with the formula (C6H5)2CO, generally abbreviated Ph2CO. It is a white solid that is soluble in organic solvents. Benzophenone is a widely used building block in organic chemistry, being the parent diarylket ...
. The low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they have little to no contribution to the effects of alprazolam.
The metabolites, as well as some unmetabolized alprazolam, are filtered out by the kidneys and are excreted in the urine.
Chemistry
Physical properties
Alprazolam is a triazole
A triazole is a heterocyclic compound featuring a five-membered ring of two carbon atoms and three nitrogen atoms with molecular formula C2H3N3. Triazoles exhibit substantial isomerism, depending on the positioning of the nitrogen atoms within t ...
and benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
derivative substituted with a phenyl
In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...
group at position 6, with a chlorine
Chlorine is a chemical element with the Symbol (chemistry), symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate betwee ...
atom at position 8 and with a methyl
In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
group at position 1. It is an analogue of triazolam
Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives. It possesses pharmacological properties ...
, the difference between them being the absence of a chlorine atom in the ortho position of the phenyl ring. It is slightly soluble in chloroform
Chloroform, or trichloromethane, is an organic compound with chemical formula, formula Carbon, CHydrogen, HChlorine, Cl3 and a common organic solvent. It is a colorless, strong-smelling, dense liquid produced on a large scale as a precursor to ...
, soluble in alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
, slightly soluble in acetone
Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour.
Acetone is miscib ...
and insoluble in water. It has a melting point
The melting point (or, rarely, liquefaction point) of a substance is the temperature at which it changes state from solid to liquid. At the melting point the solid and liquid phase exist in equilibrium. The melting point of a substance depends ...
of .[ ]
Synthesis
For the synthesis of alprazolam the same method can be used as for triazolam
Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives. It possesses pharmacological properties ...
, excepting that it starts from 2-amino-5-chlorobenzophenone.[ ][ ] However, an alternative easier synthesis starting with 2,6-dichloro-4-phenylquinoline has been suggested, in which it reacts with hydrazine
Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly toxic unless handled in solution as, for example, hydrazine ...
giving 6-chloro-2-hydrazino-4-phenylquinoline. Boiling the mixture with triethyl orthoacetate
Triethyl orthoacetate is the organic compound with the formula CH3C(OC2H5)3. It is the ethyl orthoester of acetic acid. It is a colorless oily liquid.
Triethyl orthoacetate is used in organic synthesis for acetylation.
It is also used in the ...
results in cyclization with the formation of the triazole
A triazole is a heterocyclic compound featuring a five-membered ring of two carbon atoms and three nitrogen atoms with molecular formula C2H3N3. Triazoles exhibit substantial isomerism, depending on the positioning of the nitrogen atoms within t ...
ring. The product undergoes oxidative degradation in the presence of periodate
Periodate is an anion composed of iodine and oxygen. It is one of a number of oxyanions of iodine and is the highest in the series, with iodine existing in oxidation state +7. Unlike other perhalogenates, such as perchlorate, it can exist in two ...
and ruthenium dioxide in acetone
Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour.
Acetone is miscib ...
solution, giving 2- -(3'-methyl-1,2,4-triazolo)5-chlorobenzophenone. Oxy-methylation with formaldehyde
Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...
results in a product that is treated with phosphorus tribromide, when 2- -(3'-methyl-5'-bromomethyl-1,2,4-triazolo)5-chlorobenzophenone is obtained. By substituting the bromine
Bromine is a chemical element with the symbol Br and atomic number 35. It is the third-lightest element in group 17 of the periodic table (halogens) and is a volatile red-brown liquid at room temperature that evaporates readily to form a simila ...
atom with an amino group conferred by ammonia, it forms alprazolam triazolobenzophenone, following which an intermolecular heterocyclization takes place to obtain alprazolam.
Detection
Quantification of alprazolam in blood and plasma samples may be necessary to confirm a diagnosis of intoxication in hospitalized patients, or to provide evidence in the case of crimes e.g., impaired driving arrest, or to assist in a thorough forensic investigation, e.g., in a medicolegal death investigation. Blood or plasma alprazolam concentrations are usually in a range of 10–100 μg/L in persons receiving the drug therapeutically, 100–300 μg/L in those arrested for impaired driving, and 300–2,000 μg/L in victims of acute overdosage. Most of the commercial immunoassays
An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoass ...
used for the benzodiazepine class of drugs cross-react with alprazolam, but confirmation and quantitative determination are usually done by chromatographic
In chemical analysis, chromatography is a laboratory technique for the separation of a mixture into its components. The mixture is dissolved in a fluid solvent (gas or liquid) called the ''mobile phase'', which carries it through a system (a ...
techniques.
Forms of alprazolam
Alprazolam regular release and orally disintegrating tablets are available as 0.25 mg, 0.5 mg, 1 mg, and 2 mg tablets, while extended release tablets are available as 0.5 mg, 1 mg, 2 mg, and 3 mg. Liquid alprazolam is available in a 1 mg/mL oral concentrate. Inactive ingredients in alprazolam tablets and solutions include microcrystalline cellulose Microcrystalline cellulose (MCC) is a term for refined wood pulp and is used as a texturizer, an anti-caking agent, a fat substitute, an emulsifier, an extender, and a bulking agent in food production. The most common form is used in vitamin sup ...
, corn starch
Corn starch, maize starch, or cornflour (British English) is the starch derived from corn (maize) grain. The starch is obtained from the endosperm of the kernel. Corn starch is a common food ingredient, often used to thicken sauces or sou ...
, docusate sodium
Docusate is the common chemical and pharmaceutical name of the anion bis(2-ethylhexyl) sulfosuccinate, also commonly called dioctyl sulfosuccinate (DOSS).
It is on the World Health Organization's List of Essential Medicines.
Salts of this anion ...
, povidone, sodium starch glycolate, lactose monohydrate, magnesium stearate
Magnesium stearate is the chemical compound with the formula . It is a soap, consisting of salt containing two equivalents of stearate (the anion of stearic acid) and one magnesium cation (Mg2+). Magnesium stearate is a white, water-insoluble pow ...
, colloidal silicon dioxide
Silicon dioxide, also known as silica, is an oxide of silicon with the chemical formula , most commonly found in nature as quartz and in various living organisms. In many parts of the world, silica is the major constituent of sand. Silica is one ...
, and sodium benzoate
Sodium benzoate is the sodium salt of benzoic acid, widely used as a food preservative (with an E number of E211) and a pickling agent. It appears as a white crystalline chemical with the formula C6H5COONa.
Production
Sodium benzoate is commo ...
. In addition, the 0.25 mg tablet contains D&C Yellow No. 10 and the 0.5 mg tablet contains FD&C Yellow No. 6 and D&C Yellow No. 10.
Society and culture
Patent
Alprazolam is covered under , which was filed on 29 October 1969, granted on 19 October 1976, and expired in September 1993.
Recreational use
There is a risk of misuse and dependence in both patients and non-medical users of alprazolam; alprazolam's high affinity binding, high potency, and rapid onset increase its abuse potential. The physical dependence and withdrawal syndrome of alprazolam also add to its addictive nature. In the small subgroup of individuals who escalate their doses there is usually a history of alcohol or other substance use disorders.[ Despite this, most prescribed alprazolam users do not use their medication recreationally, and the long-term use of benzodiazepines does not generally correlate with the need for dose escalation. However, based on US findings from the Treatment Episode Data Set (TEDS), an annual compilation of patient characteristics in substance abuse treatment facilities in the United States, admissions due to "primary tranquilizer" (including, but not limited to, benzodiazepine-type) drug use increased 79% from 1992 to 2002, suggesting that misuse of benzodiazepines may be on the rise. In 2011, '']The New York Times
''The New York Times'' (''the Times'', ''NYT'', or the Gray Lady) is a daily newspaper based in New York City with a worldwide readership reported in 2020 to comprise a declining 840,000 paid print subscribers, and a growing 6 million paid ...
'' reported, "The Centers for Disease Control and Prevention last year reported an 89 percent increase in emergency room visits nationwide related to nonmedical benzodiazepine use between 2004 and 2008."
Alprazolam is one of the most commonly prescribed and misused benzodiazepines in the United States. A large-scale nationwide U.S. government study conducted by SAMHSA
The Substance Abuse and Mental Health Services Administration (SAMHSA; pronounced ) is a branch of the U.S. Department of Health and Human Services. It is charged with improving the quality and availability of treatment and rehabilitative services ...
found that, in the U.S., benzodiazepines are recreationally the most frequently used pharmaceuticals due to their widespread availability, accounting for 35% of all drug-related visits to hospital emergency
An emergency is an urgent, unexpected, and usually dangerous situation that poses an immediate risk to health, life, property, or environment and requires immediate action. Most emergencies require urgent intervention to prevent a worsening ...
and urgent care facilities. Men and women are equally likely to use benzodiazepines recreationally. The report found that alprazolam is the most common benzodiazepine for recreational use, followed by clonazepam
Clonazepam, sold under the brand names Klonopin and Rivotril, is a medication used to prevent and treat seizures, panic disorder, anxiety disorders, and the movement disorder known as akathisia. It is a tranquilizer of the benzodiazepine class ...
, lorazepam
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 c ...
, and diazepam
Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, a ...
. The number of emergency department visits due to benzodiazepines increased by 36% between 2004 and 2006.
Those at a particularly high risk for misuse and dependence are people with a history of alcoholism or drug abuse and/or dependence and people with borderline personality disorder
Borderline personality disorder (BPD), also known as emotionally unstable personality disorder (EUPD), is a personality disorder characterized by a long-term pattern of unstable interpersonal relationships, distorted sense of self, and strong ...
.
Alprazolam, along with other benzodiazepines, is often used with other recreational drugs. These uses include aids to relieve the panic or distress of dysphoric
Dysphoria (; ) is a profound state of unease or dissatisfaction. It is the semantic opposite of euphoria. In a psychiatric context, dysphoria may accompany depression, anxiety, or agitation.
In psychiatry
Intense states of distress and unea ...
("bad trip
A bad trip (also known as challenging experiences, acute intoxication from hallucinogens, psychedelic crisis, or emergence phenomenon) is an acute adverse psychological reaction to classic hallucinogens. With proper screening, preparation, and su ...
") reactions to psychedelic drugs
Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness (known as psychedelic experiences or "trips").Pollan, Michael (2018). ''How to Change Your Mind: What the New Science of ...
, such as LSD
Lysergic acid diethylamide (LSD), also known colloquially as acid, is a potent psychedelic drug. Effects typically include intensified thoughts, emotions, and sensory perception. At sufficiently high dosages LSD manifests primarily mental, vi ...
, and the drug-induced agitation and insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
in the " comedown" stages of stimulant
Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
use, such as amphetamine
Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
, cocaine
Cocaine (from , from , ultimately from Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...
, and MDMA
3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in Tablet (pharmacy), tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for Recreational dru ...
allowing sleep. Alprazolam may also be used with other depressant drugs, such as ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...
, heroin
Heroin, also known as diacetylmorphine and diamorphine among other names, is a potent opioid mainly used as a recreational drug for its euphoric effects. Medical grade diamorphine is used as a pure hydrochloride salt. Various white and brow ...
, and other opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...
s, in an attempt to enhance their psychological effects. Alprazolam may be used in conjunction with cannabis
''Cannabis'' () is a genus of flowering plants in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized: ''Cannabis sativa'', '' C. indica'', and '' C. ruderalis''. Alternatively ...
, with users citing a synergistic effect achieved after consuming the combination.
The poly-drug use
Polysubstance use or poly drug use or refers to the use of combined psychoactive substances. Polysubstance use may be used for entheogenic, Recreational drug use, recreational, or Indication_(medicine)#Label_indications_vs._off-label_indicat ...
of powerful depressant drugs poses the highest level of health concerns due to a significant increase in the likelihood of experiencing an overdose
A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. , which may cause fatal respiratory depression
Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapnia ...
.
A 1990 study found that diazepam has a higher misuse potential relative to many other benzodiazepines and that some data suggest that alprazolam and lorazepam resemble diazepam in this respect.
Anecdotally, injection of alprazolam has been reported, causing dangerous damage to blood vessels, closure of blood vessels (embolization) and decay of muscle tissue (rhabdomyolysis
Rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of th ...
). Alprazolam is not very soluble in water—when crushed in water it does not fully dissolve (40 µg/ml of H2O at pH 7). There are also reports of alprazolam being snorted. Due to the low weight of a dose, alprazolam, in one case, was distributed on blotter paper
Blotting paper, called bibulous paper, is a highly absorbent type of paper or other material. It is used to absorb an excess of liquid substances (such as ink or oil) from the surface of writing paper or objects. Blotting paper referred to as b ...
in a manner similar to LSD.
Popular culture
Slang terms for alprazolam vary from place to place. Some of the more common terms are modified versions of the trade name "Xanax", such as Xannies (or Xanies) and the phonetic equivalent of Zannies; references to their drug classes, such as benzos or downers; or remark upon their shape or color (most commonly a straight, perforated tablet or an oval-shaped pill): bars, ladders, Xanbars, Xans, Z-bars, handle bars, beans, footballs, planks, poles, sticks, blues, or blue footballs.
The film "Take Your Pills: Xanax" (2022) gives the drug's history and usage.
Availability
Alprazolam is available in English-speaking countries under the following brand names:
* Alprax, Alprocontin, Alzam, Alzolam, Anzilum, Apo-Alpraz, Helex, Kalma, Mylan-Alprazolam, Niravam, Novo-Alprazol, Nu-Alpraz, Pacyl, Restyl, Tranax, Trika, Xycalm, Xanax, Xanor, Zolam, Zopax.
In December 2013, in anticipation of the rescheduling of alprazolam to Schedule 8 in Australia, Pfizer Australia announced they would be discontinuing the Xanax brand in Australia as it was no longer commercially viable.
Legal status
Alprazolam has varied legal status depending on jurisdiction:
* In the United States, alprazolam is a prescription drug and is assigned to Schedule IV of the Controlled Substances Act
The Controlled Substances Act (CSA) is the statute establishing federal government of the United States, federal drug policy of the United States, U.S. drug policy under which the manufacture, importation, possession, use, and distribution of ...
by the Drug Enforcement Administration
The Drug Enforcement Administration (DEA; ) is a Federal law enforcement in the United States, United States federal law enforcement agency under the U.S. Department of Justice tasked with combating drug trafficking and distribution within th ...
.
* Under the UK drug misuse classification system, benzodiazepines are Class C drugs (Schedule 4). In the UK, alprazolam is not available on the NHS
The National Health Service (NHS) is the umbrella term for the publicly funded healthcare systems of the United Kingdom (UK). Since 1948, they have been funded out of general taxation. There are three systems which are referred to using the " ...
and can only be obtained on a private prescription.
* In Ireland, alprazolam is a Schedule 4 medicine.
* In Sweden, alprazolam is a prescription drug in List IV (Schedule 4) under the Narcotics Drugs Act (1968).
* In the Netherlands, alprazolam is a List 2 substance of the Opium Law
The Opium Law (or ''Opiumwet'' in Dutch) is the section of the Dutch law which covers nearly all psychotropic drugs.
Origin and history
In 1912, the First International Opium Conference took place in The Hague, where agreements were made abou ...
and is available for prescription.
* In Germany, alprazolam can be prescribed normally in doses up to 1 mg. Higher doses are scheduled as Anlage III
Anlage may refer to:
* Allele, a specific version of a gene, as used by Gregor Mendel
* Anlage Süd, a headquarters facility of the German Third Reich in Strzyżów, Poland
* Primordium, the initial clustering of embryonic cells from which a body ...
drugs and require a special prescription form
Special prescription forms, sometimes called narcotic prescription forms, controlled prescription forms, psychotropic prescription forms or triplicate prescription forms (because they often have to be signed in triplicate) are forms required in so ...
.
* In Australia, alprazolam was originally a Schedule 4 (Prescription Only) medication; however, as of February 2014, it has become a Schedule 8 medication, subjecting it to more rigorous prescribing requirements.
* In the Philippines, alprazolam is legally classified as a "dangerous drug" under the Comprehensive Dangerous Drugs Act of 2002
Comprehensive may refer to:
*Comprehensive layout, the page layout of a proposed design as initially presented by the designer to a client.
*Comprehensive school, a state school that does not select its intake on the basis of academic achievement o ...
, along with other schedule drugs listed in the 1971 Convention on Psychotropic Substances. The importation of dangerous drugs including alprazolam, requires authorization from the Philippine Drug Enforcement Agency
The Philippine Drug Enforcement Agency (PDEA, , ; Filipino: ''Ahensiya ng Pilipinas sa Pagpapatupad ng Batas Laban sa Bawal na Gamot'') is the lead anti-drug law enforcement agency, responsible for preventing, investigating and combating any ...
.
Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances
The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as #Amphetamine-type stimulants, amphetamine-type stimulants, barbiturates, benzodiazepines, and Psychedelic drug, psychede ...
as Schedule IV.
References
External links
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