Intensive Course in Controlled Substance Management

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Intensive Course in Controlled Substance
Management

• Benzodiazepine Pharmacology

Ted Parran MD, FACP Associate Clinical Professor
of Medicine CWRU School of Medicine
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Overview of Benzodiazepine Pharmacology

• Mechanism of action
• Receptor activity
• Pharmacokinetics
• Adverse effects
• Drug interactions
• Use in clinical practice

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Receptors

• GABA-A GABA-B
• BZ receptors on GABA-A
• ?1-GABA-A sedative and amnestic effects most
  abundant
• ?2-GABA-A Anxiolytic effects
• ?3-GABA-A noradrenergic, seratonergic and
  cholinergic neurons
• Currently available BZ have no specificity for BZ
  receptor subtypes

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More on Receptors

• ETOH dependence
• BZ receptors reduced by 30 in the hippocampus
  and by 25 in the frontal cortex
• ? worsening of ETOH withdrawal symptoms over time
  

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Flumazenil (Romazicon)

• GABA-A receptor antagonist
• Competitively occupies the receptor and
  blocks/reverses binding of other ligands without
  affecting GABA mediated chloride conduction
• Not effective against barbiturates alcohol or
  tricyclic antidepressants

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Pharmacokinetics Absorption

• Readily absorbed following oral administration
• Diazepam is the most rapidly absorbed
  orally
• Temazepam is slowly absorbed
• Chlordiazepoxide and Diazepam are poorly
  and erratically absorbed after IM
  administration NO IMs
• Lorazepam and Midazolam are rapidly and
  completely absorbed after IM administration

IM (intramuscular)
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Pharmacokinetics Distribution

• BZ are all relatively lipophilic
• Lipophilicity is important in determining
  the duration of clinical effect after single
  dose administration
• Diazepam and clorazepate have the highest lipid
  solubility ? quickest onsets of action
• CNS is the central compartment of BZ distribution
  
• After a single dose, BZ will redistribute rapidly
  out of the CNS to other lipophilic tissues

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Pharmacokinetics Distribution

• BZ with a longer half-life but a higher
  lipophilicity (Diazepam) can have a shorter
  duration of action after a single dose than a
  drug with a shorter half-life but lower
  lipophilicity (Lorazepam)
• BZ are widely distributed into body tissues,
  cross the blood-brain-barrier, and highly bound
  to plasma proteins (70-99)

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Pharmacokinetics Elimination

• All BZ are hepatically metabolized and renally
  excreted
• Oxidation (P450 3A4)
• Glucuronide conjugation
• Lorazepam, Oxazepam, Temazepam are
  conjugated only
• Clonazepam undergoes nitroreduction

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Adverse Effects-CNS

• Sedation
• Drowsiness
• Psychomotor impairment
• Ataxia
• Disorientation
• Depression/confusion
• Aggression, irritability and excitement
• Cognitive impairment (memory)
• Paradoxical disinhibition (initial)

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Adverse Effects

• Cardiovascular
• Hypotension and bradycardia with rapid IV
  injection of Diazepam
• Respiratory depression
• Clinically relevant in patients with respiratory
  disease, in overdose situations, when combined
  with alcohol and when given rapid IV injection

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Drug-drug interactions

• Pharmacodynamic
• Other CNS depressants (EtOH, barbiturates,
  opioids)
• Pharmacokinetic
• CYP P 450 3A4 metabolism

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Tolerance

• Usually develops to the disinhibition, sedation,
  euphoria and drowsiness seen initially with BZ
• Problematic when used for insomnia
• Tolerance to the anxiolytic effect is rare

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Physical Dependence

• Becomes apparent when withdrawal occurs upon
  discontinuation of the drug
• Can occur after continued use over 2 to 4 months
• Reported in 50 of patients on treatment for gt
  4-6 months

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Benzodiazepine Abuse

• Recreational use with amphetamines, cocaine or
  heroin to reverse, reduce withdrawal effects
• To augment euphoria in narcotic and methadone
  users
• Short acting (lorazepam, alprazolam) and quick
  onset (diazepam) BZ are preferred
• Oxazepam, clorazepate and chlordiazepoxide appear
  to have lower reinforcing effects

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References

• Brunton L, Lazo J, Parker K. Goodman and Gilmans
  The pharmacological basis of therapeutics. 11th
  edition. McGraw-Hill Company 2006.
• DiPiro JT, Talbert LT et al. Pharmacotherapy a
  pathophysiologic approach.6th edition.
  McGraw-Hill Medical 2005.
• Koda Kimble MA, Young LY, Dradian W et al.
  Applied Therapeutics The Clinical Use of
  Drugs.8th edition. Lippincott Williams Wilkins
  2004.
• Duthie Practice of Geriatrics, 3rd ed. W.B.
  Saunders Company 1998.314
• Jacobson Psychiatric Secrets, 2nd ed. Hanley and
  Belfus 2001. 268-271
• Longo LP, Johnson B. Addiction Part I
  Benzodiazepines side effects, abuse risk and
  alternatives. Am Fam Physician 2000612121-8.

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Management ofBenzodiazepine and Sedative
Hypnotic Withdrawal

• Theodore V. Parran, M.D.
• Associate Clinical Professor of Medicine
• Case Western Reserve UniversitySchool of Medicine

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Assessing Withdrawal Liability

• Can you stop using?
• When did you last stop?
• Did you get sick?
• Do you use eye-openers (or compulsively use the
  benzodiazepines even on days when you did not
  intend to do so)?

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Assessing Prior Withdrawal Symptoms

• Category I Tachycardia, hypertension,
  hyperreflexia, tremors, diaphoresis, anxiety,
  insomnia, nausea
• Category II Benign hallucinosis (tactile or
  visual not auditory) with a clear sensorium
• Category III Withdrawal seizures (rumfits)
• Category IV Delirium tremens, hyperautonomic
  signs, global confusion, hallucinations

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Predicting Withdrawal Syndrome

• Onset
• Blood alcohol level and benzo / barbiturate
  toxicology results
• Intensity
• Prior withdrawal symptoms
• Characteristics
• Prior Category I, II, III, or IV
• Duration
• Prior Cat IV?

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Withdrawal Pharmacokinetics Short acting
benzodiazepines
IV
I II III
0
1
2
3
4
5
6
7
8
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Withdrawal Time Course long T1/2 benzo

• The onset and duration of withdrawal Sx depends
  on the half-life of the BZ used starting within
  24 hours and lasting 5-7 days with short
  half-lives, or within 5 days and lasting 10-14
  days with longer half-lives.

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Treating Benzodiazepine WithdrawalWithdrawal
Seizures

• Characteristics
• Generalized, tonic/clonic, brief, can be
  multiple, limited to the withdrawal phase.
• Status Eplipticus reported with barbiturate or
  aprazolam W/D
• Management
• Intensive PRN phenobarb regimen to keep CIWA lt 8
• OR loading dose of phenobarb 7-10 mg/kg in first
  24h.

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Benzo Withdrawal ManagementThe CIWA-B

• Score
• 07 no significant withdrawal
• 815 minimal withdrawal
• 1520 mild withdrawal
• 2025 moderate withdrawal
• 25 severe withdrawal

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Treating Sedative Hypnotic WithdrawalOther
Concerns alcohol related medical issues

• Hypokalemia
• Hypophosphatemia
• Hyponatremia
• Hypomagnesemia
• Hypoglycemia
• Thiamin and 0ther vitamin deficiencies
• MANAGEMENT OF UNDERLYING PSYCH SX!

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Sedatives-Hypnotics

• Withdrawal
• Considerable inter-patient variations
• Daily benzodiazepine use for 10 days or less can
  lead to transient insomnia upon discontinuation
• Mild withdrawal syndrome could follow the
  discontinuation of a short term (lt2-3 months) low
  dose therapeutic use.

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Sedatives-Hypnotics

• Withdrawal
• Moderate to severe withdrawal syndrome can follow
  the ABRUPT discontinuation of
• a long term (gt1 year) typical therapeutic dose
  use,
• a high dose (gt2 times the high end of the
  therapeutic range) even for a duration of 6-12
  weeks.

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Clinical Manifestations of Sedative-Hypnotic
Withdrawal

• Gastrointestinal
• Anorexia
• Diarrhea
• Nausea

• Vital Signs
• Tachycardia
• Hypertension
• Fever
• Ears
• Tinnitus

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Clinical Manifestations of Sedative-Hypnotic
Withdrawal
Central Nervous System

• Agitation
• Anxiety
• Delirium
• Hallucinations
• Insomnia

• Irritability
• Nightmares
• Sensory disturbances
• Tremors

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Clinical Manifestations of Sedative-Hypnotic
Withdrawal

• High-Dose (Severe) Withdrawal
• Seizures
• Delirium
• Death

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Management of Sedative-Hypnotic Withdrawal

• Taper off OR Acute detox
• Acute Detox SHORT T1/2 agents
• Utilize Detoxification protocols with either
  Phenobarbital, Carbamazepine, Valproic Acid,
  Gabepentin or Topirimate
• Start maintenance therapy with anti-seizure/mood
  stabilizer for 6 months.

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Treating Sedative Hypnotic WithdrawalSymptom
Triggered Phenobarbital Protocol

• Phenobarbital 3090 mg, PO or IM, q 14 h
  prn(CIWA-B gt7)

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Treating Benzodiazepine WithdrawalFIXED DOSE for
Short Acting Benzos

• ? Phenobarb 90-130 mg, PO or IM, q 2 h for 35
  doses
• ? Phenobarb 90 mg, PO, q 4 h for 24 doses
• ? Stat phenobarb serum level and repeat q.d.
• ? Rebolus phenobarb based upon level
• ? Phenobarb 180 mg, hs for 2 or 3 nights
• ? D/C phenobarbital

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Treating Benzodiazepine WithdrawalFIXED DOSE for
Long T1/2 agents

• ? Phenobarbital 60 mg, PO, tid,
• ? Then check a serum phenobarb level qod
• ? Rebolus if level is subtherapeutic on day 4
• ? D/C phenobarb after 1014 days

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TAPERING off of Sedative-Hypnotics

• To Taper Off the benzodiazepine
• Short switch to intermediate onset, long T1/2
  agent administered nightly and taper.
• Long switch to intermediate onset, nightly and
  taper.
• The Taper (Outpatient setting)
• 10 weekly reduction for the first 70 of the
  usual dose
• 5 weekly / biweekly reduction thereafter
• Avoid PRN benzos entirely!

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Benzodiazepine W/D Adjuncts (6-12 mos)

• Tegretal 200mg 400-600mg / day
• Valproic acid 250 1500 mg/day
• Gabepentin 300 1500 mg / day
• Topirimate 50-200 mg/d
• Give for 6-12 months
• Improves abstinence rates over time
• Also give SSRIs / SNRIs / high dose buspirone /
  prn hydroxyzine / etc for TX of underlying
  anxiety sx.