Pharmacology of Benzodiazepines

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Pharmacology of Benzodiazepines

• A Project CREATE Module

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Benzodiazepines Outline

• Three sections in this presentation
• Pharmacology of benzodiazepines
• Principles of safe prescribing
• Benzodiazepine dependence

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Section IPharmacology of Benzodiazepines

• Epidemiology
• Site of action
• Classification
• Metabolism elimination
• Pharmacokinetics

• Therapeutic uses
• Intoxication and overdose
• Tolerance, abuse liability
• Adverse effects

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Epidemiology

• 5-Aryl-14-benzodiazepine (Benzene 5-Aryl
  substituted ring)
• One of the most commonly prescribed drugs
• Most patients only short-term use
• Shift towards short-acting benzos
• Disproportionate number of prescriptions written
  for the elderly, women

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Site of Action

• Receptors mainly in cerebral cortex
• Benzodiazepine receptor linked to GABA receptor
• Benzodiazepines open chloride channel,
  potentiating GABA effects
• GABA decreases neuronal excitation

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Agonists, Antagonists

• Agonist
• Diazepam, chlordiazepoxide, lorazepam
• Antagonist (blocks benzodazepine action)
• Flumazenil
• Inverse agonist (opposite effect - increased
  neuronal excitation)
• Beta-carbolines

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Classification by Elimination Half-Life

• Long-acting (gt 24 hours)
• diazepam, chlordiazepoxide, clorazepate,
  flurazepam
• Intermediate-acting (6-24 hours)
• oxazepam, loraxepam, ntrazepam, temazepam,
  alprazolam
• Short-acting (lt 6 hours)
• triazolam, midazolam

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Metabolism and Elimination

• Hepatic metabolism
• des-methylation or oxidation (cytochrome P450)
• glucuronic conjugation (oxazepam lorazepam)
• Many have active metabolites
• Biotransformation affected by liver disease, age,
  individual variation

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Pharmacokinetics

• Oral route peak plasma concentration 1-3 hours
• Extensive protein binding
• Lipophilic, readily cross blood-brain barrier
• Distributed widely thoughout body

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Therapeutic Uses

• Anticonvulsant
• Muscle relaxant
• cerebral palsy, dystonia
• Amnesia with sedation
• peri-operative or medical procedures

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Therapeutic Uses

• Severe acute anxiety
• Severe generalized anxiety disorder, unresponsive
  to other treatments
• Panic disorder
• Adjunctive treatment of depression, bipolar
  affective disorder and schizophrenia

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Therapeutic UsesAlcohol Withdrawal

• Alcohol use causes compensatory increase in
  glutamate receptors
• Enhanced activity of glutamate when alcohol
  abruptly stopped
• Glutamate causes neuroexcitation, leading to
  withdrawal syndrome
• Benzodiazepines cause neuroinhibition

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Therapeutic Uses Alcohol Withdrawal

• Diazepam 20 mg PO every 1-2 hours until symptoms
  abate
• Long half-life covers duration of withdrawal - no
  need for take-home doses
• If history of withdrawal seizures 20 mg PO q1-2
  H for at least three doses
• If elderly, severe liver disease use lorazepam
  1-2 mg SL q2-4 H

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Intoxication

• Resembles alcohol intoxication
• Sedation, slurred speech, drowsiness, agitation
• Disinhibition and rage

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Overdose

• Sedation
• Respiratory depression if alcohol or other CNS
  depressants
• Can be fatal if given IV
• Treat with Flumazenil (but causes seizures)

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Tolerance

• Sedative and sleep-inducing effects diminish
  after several weeks
• Anxiolytic effects persist over time
• Alcohol and other sedatives cause cross-tolerance

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Abuse Liability

• Potency as reinforcer
• Rapid entry into the brain
• rapid GI absorption
• lipophilic
• High intrinsic pharmacological activity

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Adverse Effects

• Depression
• Falls (including hip fractures), confusion in
  elderly
• Motor vehicle accidents especially early in
  therapy

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Adverse Effects

• Decreased respiratory drive
• Floppy baby syndrome
• Disinhibition
• Rebound insomnia
• occurs after 3 weeks of continuous therapy
• vivid dreams, fitful sleep

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Section IIBenzodiazepines - Principles of Safe
Prescribing

• Assessment and management of anxiety
• Assessment and management of insomnia
• Alternatives to benzodiazepines
• Prescribing precautions

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Assessment of Anxiety

• Psychiatric causes
• panic disoder, obsessive-compulsive disorder,
  mixed depression/anxiety
• Organic causes
• dementia, cardiorespiratory, hyperthyroidism
• Psychosocial causes
• work and family difficulties, abuse

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Management of AnxietyNon-pharmacologic
Approaches

• Cognitive/behavioural therapies
• Progressive muscle relaxation,deep breathing
• Counselling for psychosocial issues
• Lifestyle changes
• exercise
• adequate sleep
• avoid excess coffee and alcohol
• modify work and other responsibilities
• spend more time with family and friends

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Assessment of Insomnia

• Sleep history
• sleep pattern, timining of difficulty, bedtime
  activities
• Physical causes
• medications, cardiorespiratory conditions, sleep
  apnea, restless legs syndrome, prostatism,
  chronic pain
• Mood disorders
• Alcohol and drug use

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Management of InsomniaSleep Hygiene

• Avoid excess alcohol, coffee, cola
• Exercise regularly
• Dont overeat before bed
• Use bedroom for sleep sex only
• If trouble sleeping, get up, do something else
  for 15-20 minutes
• Dont take daytime naps or go to sleep before
  9-10 pm

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Alternatives to Benzodiazepines

• Buspirone
• non-addicting
• as effective as diazepam
• takes several weeks to work
• will not help benzodiazepine withdrawal

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Alternatives to Benzodiazepines

• Selective serotonin reuptake inhibitors
• panic disorder
• mixed anxiety/depression
• obsessive compulsive disorder
• Other sedatives (chloral hydrate, tricyclic
  antidepressants, Zopiclone)

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Prescribing Precautions

• Alcohol and drug use
• COPD, sleep apnea
• Psychiatric disorders
• depression
• personality disorders
• schizophrenia

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Prescribing Precautions

• Use caution in prescribing with other
  psychoactive drugs
• two benzodiazepines together
• benzodiazepine plus barbiturates, opioids,
  antidepressants
• Warn patient about
• combining with alcohol and other drugs
• driving (until tolerant to sedative effects)

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Prescribing Precautions

• Use caution with benzodiazepines that have a high
  dependence liability
• diazepam, lorazepam, alprazolam, triazolam
• Avoid long-acting benzodiazepines in the elderly
• diazepam, chlordiazepoxide, flurazepam
• Prescribe for no more than three weeks
• Give periodic drug holidays

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Section IIIBenzodiazepine Dependence

• Prevalence
• Diagnostic criteria
• General management
• Withdrawal
• Benzodiazepine tapering

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Benzodiazepine Dependence

• Not common
• Greater risk in patients dependent on other drugs
• Physical dependence does not necessarily mean
  psychological dependence

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Benzodiazepine Dependence DSM-IV Criteria

• Three or more of the following in a 12 month
  period
• frequently take larger dose than intended
• withdrawal with cessation of the drug
• great deal of time spent using and acquiring the
  drug
• neglect of major activities because of drug use
• continued use despite knowledge of physical or
  social harm

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Management ofBenzodiazepine Dependence

• Benzodiazepine tapering
• Alcohol and drug treatment program
• Mutual aid groups
• Alternate strategies for managing anxiety
• buspirone, SSRIs
• psychotherapy, cognitive therapy

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Benzodiazepine Withdrawal

• Chronic use leads to down-regulation of GABA
• Neuronal hyperexcitability if BZD abruptly
  stopped
• Severity of withdrawal related to
• dose, duration, high intrinsic activity
• short half-life, rapid exit from brain

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Benzodiazepine Withdrawal

• Can occur even with therapeutic doses when given
  for two months or more
• Onset 1-2 days (short-acting), 2-4 days
  (long-acting)
• Peak at 5-7 days
• May last several weeks
• May be subacute, prolonged withdrawal

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Benzodiazepine Withdrawal

• Two groups of symptoms
• anxiety-related symptoms (irritability, insomnia,
  panic attacks, poor concentration)
• neurologic (tinnitus, blurry vision,
  dysperceptions, depersonalization)
• Note Suicidal ideation can occur in patients
  with mixed anxiety and depression

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Benzodiazepine Withdrawal

• Withdrawal should be distinguished from
• rebound anxiety (temporary intensification of
  anxiety after abrupt cessation)
• symptom recurrence

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Benzodiazepine Withdrawal

• Abrupt cessation of doses above 50 mg
  diazepam/day or the equivalent can result in
  seizures, psychosis or delirium

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Benzodiazepine Tapering

• Try slowly tapering patients on long-term
  benzodiazepines, even if they are not dependent.
  Possible benefits
• more alert, energetic better able to make
  positive life changes not need drug anymore
  avoid future adverse effects
• Wait until a treatment plan is in place
• Provide regular support
• Stop or reverse taper if patient becomes worse

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Benzodiazepines Outpatient Tapering

• Convert to equivalent dose of diazepam (except in
  elderly, liver disease)
• Taper over 6-12 weeks (2-5 mg /wk)
• May need to slow taper at doses lt 20 mg
• Be cautious about equivalent doses
• Use scheduled rather than PRN doses
• Alprazolam, triazolam taper with these agents

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Benzodiazepine Equivalence to5 mg Diazepam

• Bromazepam (Lectopam) 3
• Chlordiazepoxide (Librium) 10-25
• Clonazepam (Rivotril) 0.5
• Clorazepate (Tranxene) 7.5
• Flurazepam (Dalmane) 15
• Lorazepam (Ativan) 0.5 - 1
• Nitrazepam (Mogadon) 5-10
• Oxazepam (Serax) 15
• Temazepam (Restoril) 10-15
• Alprazolam 0.5
• Triazolam 0.25

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Inpatient Diazepam Tapering

• Typical daily use over past 2 months is
  equivalent to diazepam 80-100 mg or more
• Heavy use of barbiturates, alcohol, other drugs
• Elderly patients
• Patients with illnesses that may make tapering
  more dangerous, e.g., serious heart disease

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High Dose Benzodiazepine Withdrawal Above 80-100
mg Diazepam/Day

• Hospitalization, addiction consult
• Start at 1/2 - 2/3 the equivalent diazepam dose
  (except alprazolam, triazolam)
• Taper by 5-15 mg per day (no more than 10 of
  daily dose)
• May switch to outpatient protocol at doses less
  than 80 mg