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Benzodiazepines sometimes called “benzos“, are a class of psychoactive drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. The benzodiazepines are a large class of medications that have multiple clinical uses including therapy of anxiety, insomnia, muscle spasm, alcohol withdrawal, and seizures. As a class, the benzodiazepines do not cause significant serum enzyme elevations and have been linked to only very rare instances of acute, symptomatic liver disease. The pharmacological effects of the benzodiazepines are a result of their interaction with the central nervous system, their effects being sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia, and anticonvulsant activity. At high doses, when given intravenously, the benzodiazepines may also cause coronary vasodilation and neuromuscular blockade. The CNS effects of benzodiazepines are believed to be mediated by activation of GABA A receptors and modulation of their inhibition of neurotransmission.
Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties. High doses of many shorter-acting benzodiazepines may also cause anterograde amnesia and dissociation.
Common Types of Benzodiazepines
- 2-keto compounds
- clorazepate, diazepam, flurazepam, halazepam, prazepam, and others.
- 3-hydroxy compounds:
- lorazepam, lormetazepam, oxazepam, temazepam
- 7-nitro compounds:
- clonazepam, flunitrazepam, nimetazepam, nitrazepam
- Triazolo compounds:
- adinazolam, alprazolam, estazolam, triazolam
- Imidazo compounds
- climazolam, loprazolam, midazolam
Overall classification of Benzodiazepines
Mechanism of action of Benzodiazepines
Benzodiazepines bind nonspecifically to benzodiazepine receptors which mediate sleep, affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell. Benzodiazepine generates the same active metabolite as chlordiazepoxide and clorazepate. In animals, diazepam appears to act on parts of the limbic system, the thalamus, and hypothalamus and induces calming effects. Diazepam, unlike chlorpromazine and reserpine, has no demonstrable peripheral autonomic blocking action, nor does it produce extrapyramidal side effects; however, animals treated with diazepam do have a transient ataxia at higher doses. Diazepam was found to have transient cardiovascular depressor effects in dogs. Long-term experiments in rats revealed no disturbances of endocrine function. Injections into animals have produced localized irritation of tissue surrounding injection sites and some thickening of veins after intravenous use.
Indications of Benzodiazepines
Benzodiazepines are often prescribed for a wide range of conditions:
- These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures
- They can be very useful in intensive care to sedate patients receiving mechanical ventilation or those in extreme distress. Caution is exercised in this situation due to the occasional occurrence of respiratory depression, and it is recommended that benzodiazepine overdose treatment facilities should be available.
- Benzodiazepines are effective as medication given a couple of hours before surgery to relieve anxiety. They also produce amnesia, which can be useful, as patients may not remember unpleasantness from the procedure. They are also used in patients with dental phobia as well as some ophthalmic procedures like refractive surgery; although such use is controversial and only recommended for those who are very anxious.
- Midazolam is the most commonly prescribed for this use because of its strong sedative actions and fast recovery time, as well as its water solubility, which reduces pain upon injection.
- Diazepam and lorazepam are sometimes used. Lorazepam has particularly marked amnesic properties that may make it more effective when amnesia is the desired effect.
- Benzodiazepines are well known for their strong muscle-relaxing properties and can be useful in the treatment of muscle spasms, although tolerance often develops to their muscle relaxant effects. Baclofen or tizanidine are sometimes used as an alternative to benzodiazepines. Tizanidine has been found to have superior tolerability compared to diazepam and baclofen.
- Benzodiazepines are also used to treat the acute panic caused by hallucinogen intoxication.
- Benzodiazepines are also used to calm the acutely agitated individual and can, if required, be given via an intramuscular injection. They can sometimes be effective in the short-term treatment of psychiatric emergencies such as acute psychosis as in schizophrenia or mania, bringing about rapid tranquillization and sedation until the effects of lithium or neuroleptics (antipsychotics) take effect.
- Lorazepam is most commonly used but clonazepam is sometimes prescribed for acute psychosis or mania; their long-term use is not recommended due to risks of dependence. Further research investigating the use of benzodiazepines alone and in combination with antipsychotic medications for treating acute psychosis is warranted.
- Clonazepam, a benzodiazepine is used to treat many forms of parasomnia. Rapid eye movement behavior disorder responds well to low doses of clonazepam. Restless legs syndrome can be treated using clonazepam as a third line treatment option as the use of clonazepam is still investigational.
- Benzodiazepines are sometimes used for obsessive-compulsive disorder (OCD), although they are generally believed ineffective for this indication. Effectiveness was, however, found in one small study.
- Benzodiazepines can be considered as a treatment option in treatment-resistant cases.
- Antipsychotics are generally the first-line treatment for delirium; however, when delirium is caused by alcohol or sedative-hypnotic withdrawal, benzodiazepines are the first-line treatment.
- There is some evidence that low doses of benzodiazepines reduce adverse effects of electroconvulsive therapy.
Contraindications of Benzodiazepines
- muscle relaxant action,
- benzodiazepines may cause respiratory depression
- myasthenia gravis,
- sleep apnea,
- personality disorders or
- intellectual disability
- paradoxical reactions
- major depression,
- suicidal tendencies and are sometimes used for suicidal overdoses.
- Individuals with a history of alcohol, opioid, and barbiturate abuse should avoid benzodiazepines, as there is a risk of life-threatening interactions with these drugs
Side Effects of Benzodiazepines
The most common
- Depression or even suicidal ideation, as well as nightmares
- Anxiety, especially of the social anxiety variant
- Xerostomia or dry mouth
- Gastrointestinal disturbances such as diarrhea or constipation
- A headache or a migraine
- Myalgia or muscle aches, arthralgia or joint pain, or paresthesia (“pins and needles”)
- Restless legs syndrome (RLS)
- Decreased alertness, awareness, and wakefulness
- Impaired attention,
- Decreased desire, and motivation
- Fatigue or lassitude
- Sedation or drowsiness or somnolence or sleepiness
- Agitation or restlessness
- Cognitive and memory impairment
- Abdominal or stomach pain, discomfort, or tenderness
- chills or fever
- difficulty with moving
- a headache, severe and throbbing
- joint or back pain
- muscle aching or cramping
- muscle pains or stiffness
- chest pressure or squeezing pain in the chest
- discomfort in arms, shoulders, neck or upper back
- excessive sweating
- feeling of heaviness, pain, warmth and/or swelling in a leg or in the pelvis
- sudden tingling or coldness in an arm or leg
- sudden slow or difficult speech
- sudden drowsiness or need to sleep
- fast breathing
- sharp pain when taking a deep breath
- fast or slow heartbeat
- coughing up blood
- rust colored urine
- decreased amount of urine
- change in vision
- chest pain or tightness
- arm, back, or jaw pain
- blurred vision
- chest pain or discomfort
- extra heartbeats
- mood or mental changes
- muscle pain or cramps
- muscle spasm or jerking of all extremities
Benzodiazepines may interact with following drugs, supplements & may change the efficacy of the drugs
- alpha blockers (e.g., alfuzosin, doxazosin, silodosin, tamsulosin)
- amphetamines (e.g., dextroamphetamine, lisdexamphetamine)
- anti-cancer medications (e.g., cabazitaxel, docetaxel; doxorubicin; etoposide, ifosfamide, irinotecan, vincristine)
- antihistamines (e.g., cetirizine, doxylamine, diphenhydramine, hydroxyzine, loratadine)
- antipsychotics (e.g., chlorpromazine, clozapine, haloperidol, olanzapine, quetiapine, risperidone)
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- benzodiazepines (e.g., chlordiazepoxide, clonazepam, diazepam, lorazepam)
- beta-adrenergic blockers (e.g., atenolol, propranolol, sotalol)
- calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
- oral corticosteroids (e.g., dexamethasone, hydrocortisone, prednisone)
- estrogens (e.g., conjugated estrogen, estradiol, ethinyl estradiol)
- folic acid
- “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
- macrolide antibiotics (e.g., clarithromycin, erythromycin)
- progestins (e.g., dienogest, levonorgestrel, medroxyprogesterone, norethindrone)
- proton pump inhibitors (e.g., lansoprazole, omeprazole)
- selective serotonin reuptake inhibitors (SSRIs;e.g., citalopram, duloxetine, fluoxetine,paroxetine, sertraline)
- “statin” anti-cholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
- theophyllines (e.g., aminophylline, oxtriphylline, theophylline)
- thiazide diuretics (e.g., chlorothiazide, hydrochlorothiazide)
- tricyclic antidepressants (e.g., amitriptyline, clomipramine, desipramine, trimipramine)
- valproic acid