Benzodiazepines (Valium, Xanax, Klonopin, Ativan): Therapeutic Use, Side Effects

• Valium (Diazepam)
• Xanax(Alprazolam)
• Klonopin (Clonazepam)
• Ativan (Lorazepam)

• Invented by DR. Leo Sternbach for company La Roche, New Jercy, USA in 1963.
• Diazepam was the second benzodiazepine to be invented after chlordiazepoxide (Librium) in 1960 by DR. Leo Sternbach.
• It was the most popular medication prescribed by psychiatrist, anesthesiologist and family practitioner.

• Physical appearance – Solid white or yellow crystals.
• Melting point – of 131.5 to 134.5 degree C.
• Odor – odorless.
• Taste – slightly bitter taste.
• Solubility – 1 in 16 ethyl alcohol, 1 in 2 of chloroform, 1 in 39 ether, and practically insoluble in water.
• pH – of diazepam is neutral (pH = 7).
• Shelf life – five years for oral tablets and three years for IV/IM solutions.
• Storage – stored at room temperature (15–30^°C). The solution for parenteral injection should be protected from light and prevented from freezing. The oral forms should be stored in airtight containers and protected from light.

• Benzodiazepine binds to GABA-a receptor and amplifies the inhibitory effect of GABA. Coupling of GABA neurotransmitter with receptor opens up chloride channel, which inhibits forward progress of impulse. Inhibition of forward progress is magnified by benzodiazepines binding to GABA-a receptor.
• Diazepam has no effect on GABA levels and no effect on glutamate decarboxylase activity, but has a slight effect on gamma-aminobutyric acid transaminase activities.
• Anxiolytic effect of diazepam is a result of direct inhibitory action on areas of the limbic system, thalamus and hypothalamus. Anxiolytic effect is secondary to augmentation of GABA activities. Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.
• Diazepam inhibits acetylcholine release in mouse hippocampal synapsis. This may play a role in explaining diazepam’s anticonvulsant properties. Anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than binding GABA-a receptors. Benzodiazepines slows the recovery of sodium channels from inactivation, thus repetitive stimulation of cortex and sub cortical centers do not trigger epileptic activities.
• The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the ventral horn of spinal cord.

• Diazepam undergoes oxidative metabolism by demethylation, hydroxylation and glucoronidation in the liver by cytochrome P 450 enzyme system.
• Diazepam does not increase or decrease hepatic enzyme activities, and does not alter the metabolism of other compounds.
• Agents that have an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism.

• Benzodiazepine has several pharmacologically active metabolites. Active metabolites produce similar pharmacological effect as parent benzodiazepine.
• Most of the drug is metabolized to inactive or active metabolites and very little diazepam is excreted unchanged.
• Main active metabolite is desmethyldiazepam (also known as nordiazepam).
• Other active metabolites are temazepam and oxazepam.
• These metabolites are conjugated with glucoronide and are excreted primarily in the urine.
• Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug.
• Diazepam has a biphasic ½ life of about one to three days, and two to seven days for the active metabolite desmethyldiazepam.

Inhibition of cyclic 450 enzymes by following medications prolongs the metabolism of benzodiazepines.

• Cemetidine
• Omeprazole
• Ticlopidine
• Topiramine
• Ketoconzole
• Disulfiram
• Fluoxetine
• Valproic acid
• Oral contraceptive

Stimulation of liver enzyme by following medications leads to rapid metabolism of diazepam.Increase rate of metabolism causes decreases drug levels and therapeutic effects.

• Rifampin
• Phenytoin
• Carbamazepine
• Phenobarbital
• Dexamethasone

When administered orally, it is rapidly absorbed by intestinal mucosa and has a relatively fast onset of action.

• Absorption is further increased if patient is receiving Cisapride (propulsid) treatment. Cisapride causes increase absorption benzodiazepine by mucosal membrane. Blood level of benzodiazepine is rapidly increased to therapeutic level.
• Intramuscular injection of diazepam causes erratic or incomplete absorption of diazepam.

• After oral administration bioavailability is 100%.
• Rectal administration brings bioavailability to 90%.

Plasma protein binding rate is very high for benzodiazepine. 96 to 99% of the absorbed benzodiazepine binds to plasma protein. Thus only 1 to 4% of the absorbed diazepam in the blood is available for therapeutic (medicinal) effects.

Peak plasma level determines how soon a medication will cause desired therapeutic effects. Peak plasma level following administration through different route is as follows-

• Between 30 and 90 minutes after oral administration.
• Between 20 and 60 minutes after intramuscular administration.
• Between 10 to 45 minutes after rectal administration.

• The distribution half-life of diazepam is between 2 to 13 minutes.
• Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration.
• After absorption, diazepam is redistributed into muscle and adipose tissue.
• Continuous daily therapeutic dosage of diazepam will quickly build up to a high concentration in the body. Total accumulated benzodiazepine in body tissue is far in excess of the actual dose for any given day.

It easily crosses both the blood brain barrier and placenta. Blood brain barrier control the flow of diazepam to brain and spinal cord.

• Benzodiazepine elimination is faster in acidic urine. Urine pH becomes acidic because of excretion of some nutrition, metabolites and medications.
• Food that alkalinize the urine can lead to slower absorption and elimination of diazepam, thus increases benzodiazepine plasma levels and activities.
• In elderly rate of excretion is decreased. The elimination half-life of diazepam and also the active metabolite desmethyl-diazepam increases significantly in the elderly, which may result in prolonged action, as well as accumulation of the drug during repeated administration.

• Tablets – 5 mg and 10 mg
• IV and IM – 1 mg, 2 mg, 5 mg

• Oral – 15 to 30 minutes.
• Intravenous – 2 to 3 minutes.
• Intramuscular – 15–30 minutes.
• Rectal – 10 to 25 minutes.
• Inhalation – 5 to 10 minutes.

Benzodiazepine should be prescribed with care in following age group:

• Elderly
• Pregnancy
• Breast feeding

• Hypoventilation
• Respiratory disorder
• Ataxia
• Glaucoma
• Liver failure – hepatitis, cirrhosis
• Renal deficiencies – dialysis
• Sleep apnea
• Depression
• Psychosis
• Coma
• Myasthenia gravis
• Hypotension

• Sedatives
• Antihistaminic
• Opioids
• Alcohol
• Street drugs
• Muscle relaxants
• Anti depressants
• Anticonvulsants
• Antipsychotics

• Theophylline- inhibit action of diazepam.
• Levodopa- benzodiazepine antagonizes action effects of levodopa on dopamine receptors (antagonist).
• Digoxin- concentration is changed because of protein binding effect of benzodiazepine.
• Drug interaction- MAO inhibitor and ranitidine
• Caffeine- antagonizes effect of diazepam
• Smoking (tobacco)- enhances excretion and dose dependent action is decrease

• Anxiolytic- prescribed for anxiety, panic attack, agitation.
• Hypnotic- prescribed for insomnia.
• Muscle Relaxant – prescribed for muscle spasm.
• Spastic muscular paresis – prescribed for following musculo-skeletal diseases-
  1. Paraplegia
  2. Quadriplegia
  3. Stroke
  4. Multiple Sclerosis
  5. Spinal cord injury
• Antiepileptic- prescribed for seizure disorder
• Prescribed for following diseases-
  1. Restless legs syndrome
  2. Alcohol withdrawal
  3. Meniere’s disease
  4. Wclampsia with seizure
  5. Vertigo
• Sedation- Prescribed by anesthesiologist for sedation during surgery also described as MAC (Monitored Anesthesia Care)

• Anterograde (extended forward) amnesia (loss of memory)- patient may not remember events or experiences during the brief period following taking medication.
• Sedations- Benzodiazepine causes sedation and sleepiness.
• Paradoxical effects- Benzodiazepine when prescribed for seizure disorder causes excitement, rage an worsening of seizures
• Depression- prolonged treatment with Benzodiazepine induces depression.
• Tolerance and dependence- Frequent and prolonged treatment of Benzodiazepine results in increase tolerance and dependence to Benzodiazepine.
• Withdrawal- Abrupt (sudden) withdrawl of Benzodiazepine causes severe withdrawl symptoms, which could be life threatening.

Benzodiazepine discontinuation after short-term use does not cause any side effects. But if Benzodiazepine is discontinued after long term use then side effects can be mild to severe in intensity. The reason for withdrawal symptoms is as follows-

• Prolonged ½ life- ½ life is 70 days, thus residual drug remains in the body for prolonged period.
• Recovery from withdrawal symptoms without any active treatment takes approximately 4 to 6 months.

Anaphylaxis (Hypersensitivity or Severe Generalized Allergic Reaction)- Anaphylaxis is rarely seen following Benzodiazepine treatment. Symptoms of anaphylaxis are as follows-

• Skin reactions – itching, flushed or pale skin.
• A feeling of warmth.
• Bronchospasm – wheezing and difficult breathing.
• Palpitation
• Rapid heart beats
• Severe hypotension
• Vomiting
• Dizziness and fainting.
• Angioedema

• Skin rash
• Hives (urticaria)
• Itching
• Fever
• Facial swelling
• Shortness of breath
• Pruritus
• Hives

• Anterograde amnesia
• Sedation
• Ataxia
• Cognitive deficit
• Hypotension
• Respiratory depression
• Dizziness
• Reflex tachycardia
• Seizure
• Agitation
• Suicidal tendency

• Benzodiazepines are potentially addicting medications.
• Psychological or physical dependence can develop within a few weeks or months of prescription.
• Psychological dependence is addiction and physical dependence is pseudo-addiction.
• Pseudoaddiction is developed when therapeutic dosage does not give same clinical benefit as before. Patient needs higher dosage and frequency to achieve same clinical effect. Patient is dependent on medication. Resistance or tolerance to medication will impose increased need of dosage and frequency. Patient will run short of medication, if treating physician does not give him adequate amount and dosage of benzodiazepine.
• Patient will be considered as drug addict since he is running short of medications frequently.

• Need more pills or higher strength of medication than previously prescribed dosage.
• Continue taking medication for disease, which is considered, cured or absent.
• Lowering dosage result in withdrawal symptoms and unable to discontinue.
• Craving for next dose.
• Frequent visit to doctor’s office.
• Often short of medication.
• Doctor shopping for prescription.
• Taking other sedatives or opioids to overcome withdrawal or benzodiazepine craving symptoms.
• Frequent visits to physician office claiming insomnia and anxiety are not responding in spite to higher dosage.

• Same dosage of benzodiazepine is not as effective as in the past.
• Need higher concentration and dosage to achieve same therapeutic effect.

• Uncoupling of receptor sites.
• Alterations in gene expression.
• Down-regulation of receptor sites.
• Desensitization of receptor sites to the effect of GABA.

Mild withdrawal symptoms after discontinuation of benzodiazepine is observed in few patients treated for short period. Severe withdrawal symptoms are observed in patients treated with benzodiazepine for prolonged period, if abruptly discontinued. Withdrawal syndrome may be short or prolonged as described below-

• Short period – 1 to 4 days. Symptoms are anxiety and insomnia.
• Intermediate period – last for 10 to 14 days.
• Prolonged period – may last up to 6 months.
• Predominant symptom is anxiety in all 3 durations of withdrawal.

• Insomnia – Sleep disturbance
• Irritability
• Anxiety and panic attacks
• Hand tremor
• Sweating
• Difficulty in concentration
• Dry retching
• Nausea, vomiting and abdominal pain
• Weight loss
• Palpitations
• Headache
• Muscular pain and stiffness

• Drowsiness and dizziness
• Mental confusion
• Low blood pressure
• Dizziness
• Absent reflexes
• Impaired balance
• Impaired coordination
• Coma

Overdose with alcohol, opiates and/or other depressants may be fatal.

• I.V. fluid and hydration
• Diuretics
• Symptomatic treatment
• Airway management
• Stabilized cardiovascular system
• Activated charcoal, stomach lavage,
• Emesis
• Dialysis

Patient continues with benzodiazepine during pregnancy because of dependence and necessity of continuation of treatment. Treatment of benzodiazepine is necessary in few patients with history of seizure disorder who are resistance to all other antiepileptic medications. Following complication may occur with infants if medication is continued during third trimester.

Floppy Infant Syndrome– Persists for several hours after birth.

• Decrease muscle tone – hypotonia.
• Decrease muscle power – unable to lift head and weak cry.
• Decrease reflex- tired suckling.
• Muscle exhaustion – lethargy.

• Apneic spell
• Cyanosis
• Impaired metabolic response
• Cold baby

• Benzodiazepine is excreted into breast milk.
• Consult neonatologist if mother is taking Benzodiazepine while nursing baby.

• Immunoassay test is a screening test to detect benzodiazepine in urine and blood. Immunoassay is followed by a confirmatory chromatography studies if results are suggesting possible addiction or illegal behavior.
• Blood examination and urine drug test is mandatory and necessary to monitor patient’s prescription behavior to deter abuse and sharing medications with family members and colleagues.
• Benzodiazepines like opioids are frequently abused or sold for profit. Immunoassay of urine with dipstick study is rapid and not always reliable screening investigation. Urine screening test will indicate if benzodiazepine is present or absent in urine sample. Positive or presence of benzodiazepine suggest patient is taking prescribed medications and negative or absence of benzodiazepine in urine indicate patient may not be taking medication as prescribed. Absence of urine benzodiazepine indicates need for chromatographic urine examination of left over sample to confirm the dipstick result.
• In ER or hospital similar studies are performed to find out medico legalcause of death in case patient is receiving benzodiazepines medications.
• Blood or plasma benzodiazepine concentrations are usually in a range of 0.1-1.0 mg/L in persons receiving the drug therapeutically, 1–5 mg/L in those arrested for impaired driving and 2–20 mg/L in victims of acute over dosage.
• Benzodiazepine class of drugs will cross-react with diazepam. In most of the cases immunoassay is usually followed by chromatographic study to conform the values.

• Insomnia is a psychiatric illness seen in-patientsecondary to chronic tobacco smoking, excessive caffeine consumption and taking recreational stimulants. Insomnia patients are treated by psychiatrist and given prescription of one of the benzodiazepine. Few patients may not get prescription from physician and instead prefer to purchase from other sources. Favorable effect of diazepam eventually leads to potential abuse and can cause serious side effects.
• Diazepam leads to addiction in most of the patients after continuous use for prolonged period as therapeutic medications.
• Benzodiazepinesare found to be most frequently abused medication in USA. 35% of drug-related visits to the emergency department involve benzodiazepine. They are more commonly abused than opiate pharmaceutical, which accounted for 32% of visits to the emergency department.
• Males abuse benzodiazepines as commonly as females.
• Benzodiazepine is the number one drug use in attempted suicide. 26% of attempted suicides involve benzodiazepine.
• Most abuse benzodiazepine in order of highest to lowest are Alprazolam (Xanax), Clonazepam (Klonopin), Lorazepam (Ativan) and Diazepam (Valium).

• In USA physician prescribes diazepam only.
• Not available on shelf in any pharmacy.
• Diazepam is classified as schedule 4-control substance and has low potential for abuse relative to the drugs or other substances in schedule III.