Thursday Mar 1

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Thursday Mar 1 Exam I is Tuesday, Mar
6 Benzodiazepines and Other Medications for
Anxiety
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• Benzodiazepines (BZD)
• defined by the presence of a benzene ring fused
  with a 7 membered diazepine ring
• 1st one introduced in 1960 Librium
  (chlordiazepoxide)
• 1963 Valium (diazepam) 3-10 times more
  potent than Librium
• now gt 40 on market
• Xanax (Alprazolam) and Ativan (lorazepam) most
  used among newer ones
• BZDs vary structurally by attachments on
  diazepine ring effects binding affinity and
  amount needed effects half-life, time to work,
  and specific sites of action (dosing frequency
  and indication)
• used as antianxiety meds, anticonvulsants
  muscle relaxants sleep aids sedatives

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Importance of half-life to choice of use A
particular BZD is chosen for one condition vs
another mostly based on half-life and rapidity of
effect. - short half life quick onset of
action anticonvulsant muscle relaxant sleep
aid panic disorder - long half life days
to work (blood protein binding) chronic
treatments for anxiety seizure disorders some
muscular disorders
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• Necessary GABAA binding sites for specific
  indications
• Muscle relaxation spinal level receptors
• Sleep reticular activating system
• Sedation/Anesthesia multiple areas
• Anticonvulsant brainstem and cortex
• Antianxiety cortex and limbic system
• Therapy for alcohol withdrawal
• All current BZDs are non-selective, but still may
  have different ratio of effect in one area vs
  another.
• Selection depends on acute vs chronic treatment
  need (half life issues time to peak issues
  rapidity of onset of action)

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• Pharmacokinetics and Distribution
• well-absorbed from oral route (peak within 30
  min for some 6-8 hours for others)
• can be given IM or IV
• onset of action 30 minutes to 7 days
• highly lipid soluble (half-life increases in
  overweight fat depot)
• some bind highly to blood proteins (albumin)
  must saturate via high administered dose or
  saturation through repeated dosing). Diazepam
  shows 99 binding.

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• Pharmacokinetics and Distribution
• some bind highly to blood proteins (albumin)
  must saturate via high administered dose or
  saturation through repeated dosing). Diazepam
  shows 99 binding.
• metabolized primarily in the liver
• certain BZDs have active metabolites that
  prolong action
• (Diazepam half-life is 20 hours desmethyl
  diazepam also 20 hours)
• cannot use if liver disease or impaired
  functioning is present builds up causing too
  much sedation
• Safety across BZDs, TI gt 20. In overdose,
  respiratory depression not a serious problem,
  unless a drug combo with alcohol, etc)

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• Pharmacodynamics
• act on one subunit of the multiunit GABAA
  receptor
• in presence of GABA, BZDs cause increased rate
  of opening of Cl- channels so GABA binding causes
  more inhibition
• 500 different variations of the BZD subunit
  binding site
• 2 major families of BZD subtypes
• Type I high in cerebellum and cortex low in
  hippocampus
• Type II high in hippocampus, spinal cord, basal
  ganglia
• Binding affinities of drugs at these subtypes
  causes variation in response.
• Prescription Drugs not yet available that are
  selective for specific sites (test agents have
  been identified that discriminate the 500
  variations)

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• Pharmacodynamics
• no apparent effects on the GABAB receptor family
• Cellular Tolerance
• limited for anxiety or muscular indications in
  context of oral use
• establishment depends on dose and length of use
• for the most-used BZDs, withdrawal mild if used
  as indicated and for less than 8 months rebound
  anxiety/anxiety
• no drug craving during pure BZD withdrawal
• nevertheless, tapering of dose is routinely done
  if drug is to be discontinued

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Main side effects Sedation and interference with
new memory formation (anterograde
amnesia) Tolerance for these effects within a few
days for oral dosing regimens. BZDs used as
sleeping pills are usually indicated for short
term use no more than 1-2 months. The
particular BZDs show less tolerance. Dalmane
(flurazepam) common sleep aid Ambien not a
BZD Zolpidem tartrate does enhance GABA action
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• Main side effects
• Sedation and interference with new memory
  formation (anterograde amnesia)
• Drug Interactions
• Alcohol receptor level additive effects and
  increased alcohol effects as respiratory
  depressant
• Fluoxetine (Prozac) and Xanax metabolic enzyme
  competition enhanced sedation
• Erythromycin enzyme competition enhanced
  sedation
• Cimetidine (Tagamet) a stomach acid reducer
  enzyme competition causes enhanced sedation from
  BZDs

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• History of Attention to Addiction
• 1963 Valium entered US market
• by late 1970s, 15-20 of population had
  prescription
• epidemic use/abuse (housewives, retirees,
  unemployed women gt men) multiple deaths
• 1979 Edward Kennedy called Congressional
  hearings to investigate
• Result 1)biggest problems found due to drug
  interactions, esp. alcohol
• 2) Changes in prescriptions
• Sleeping pills 2 mo
• Antianxiety 4 mo
• No longer strictly adhered to.
• 3) public and medical perception of dangers of
  overdose and addiction

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• BZD Withdrawal
• treatment for lt 6 months, low dependence
  potential
• gt 8 months, greater potential for withdrawal
  symptoms
• mild symptoms resembling anxiety and agitation
• effects are the same after differing lengths of
  treatment, but seen in higher of people
  following longer treatment
• difficult to distinguish from rebound anxiety
  studied more easily when BZDs used for other
  indications
• handled on outpatient basis or avoided through
  drug tapering

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• BZD Withdrawal
• abrupt discontinuation of short acting BZDs
  (Xanax Ativan) withdrawal within 6-12 hours
  peak at 2-4 days, subsides after 1-3 weeks
• abrupt discontinuation of long acting (Valium
  Tranxene Klonopin) withdrawal in 24-36 hours
  peaks at 4-7 days subsides within 2-4 weeks
• drug craving not associated (no major reward
  center effects)

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• Anxiety Disorders (DSM-IV)
• All share the experience of a diffuse emotional
  state resembling fear or apprehension of a vague
  future threat.
• Collectively effect 15 of adults.
• Panic Disorder sudden attacks of anxiety that
  trigger a strong physical reaction without
  apparent cause.
• 1-2 of general population 50 also have
  agoraphobia.
• Sympathetic stimulation increased heart rate,
  shortness of breath intense and provokes
  emergency room visits
• Also dizziness, nausea, sweating, chest pain,
  choking sensations.
• Most attacks are unexpected and may last seconds
  or hours.
• Most research has been on Panic Disorder because
  of agreement on characteristics and ease of
  measuring symptoms.

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• Biological Characteristics of Individuals with
  Panic Disorder
• Heritability higher concordance for monozygotic
  than dizygotic twins. No specific genes known.
• Lactate Response
• Decreased exercise tolerance perhaps related to
  abnormal lactate regulation/response.
• Sodium lactate potent respiratory stimulant
  (hyperventilation) and panic inducer.
• At an IV dose that produces panic in lt10 of
  healthy normal subjects, 50-70 of panic disorder
  sufferers have a panic attack

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• Biological Characteristics of Individuals with
  Panic Disorder
• Heritability higher concordance for monozygotic
  than dizygotic twins. No specific genes known.
• Lactate Response
• CO2 response
• Elevated carbon dioxide levels in air (7.5)
  trigger anxiety in some normals within 2-20
  minutes. In people with Panic Disorder, 50-80
  response shown at 5 CO2 level.
• Inferred increased sensitivity of neurons that
  serve as sensors located in medulla and monitor
  CO2 levels.

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4. Serotonergic response mCPP is a serotonergic
receptor agonist that has the ability to induce
anxiety and panic in some normal individuals.
Among panic disordered, reaction occurs at a
lower threshold and among high percentage of
people. Similar for fenfluramine, a drug that
causes release of serotonin lower threshold for
induction of panic in panic-disordered than
normals.
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5. Caffeine (acts at adenosine receptor inhibits
it) Too much makes anyone anxious panic at
lower threshold in panic-disordered. Caffeine
also enhances taste sensitivity occurs at lower
dose in panic disordered than normals. So not
just an anxiety category effect ------------------
--------------------------------------------------
- In anxious strains of rats decreased number
of GABAA BZD receptors Preliminary human
evidence for less GABA activity in humans with
anxiety disorders.
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Treatments for Panic Disorder 1. fast-acting,
short half-life BZDS Alprazolam (Xanax) Lorazepam
(Ativan) 2. Some antidepressants older
tricyclics 3. newer serotonin agonist, BuSpar
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2. Phobic Disorder Phobia extreme fear of a
specific stimulus or situation without rational
basis Agoraphobia fear of being alone in a
public place or somewhere where help may not be
available. Sufferers recognize that degree of
fear is unwarranted but cannot control it. Many
people with Panic Disorder have agoraphobia as
well. Treatments Paxil (an SSRI) beta-blockers
(propanolol Inderal) suppresses sympathetic
reaction during fear
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3. Obsessive-Compulsive Disorder Obsessions
intrusive, persistent ideas or worries (Did I
lock the door? Am I clean? Will I get
hurt?) Compulsions repetitive behaviors
performed in a stereotyped manner according to
rigid rules. Lock checking hand washing
cleaning specific route that must be taken to
avoid danger (step only on certain blocks in
sidewalk) Jack Nicholson in As Good As It Gets
Mr. Monk Treatments selective serotonin
reuptake inhibitors
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• 4. Post-Traumatic Stress Disorder
• anxiety or panic attacks following a traumatic
  event also intrusive memories that reexpereince
  the traumatic event
• Treatments as for panic mostly BZDs and SSRIs
• 5. Generalized Anxiety Disorder diffuse state
  of anxiety that is present more than absent
  during a 6 month period and has no apparent cause
• High comorbidity with depression.
• Treatments longer acting BZDs (Valium,
  Librium) SSRIs older antidepressants

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• Serotonergic Drugs Used to Treat Anxiety
  Disorders
• Anxiety disorders may result in part from
  disorders in the GABA or Serotonin systems both
  present in neural control centers within the
  limbic system
• In limbic system, serotonin (5HT) receptors are
  5HT1A type when bound, inhibition results.
• Knockout mice without these receptors are fearful
  and anxious.
• Buspirone (BuSpar) 5HT1A agonist gradual
  onset of action
• Relieves anxiety without sedation or amnesia or
  motor impairment little potential for
  dependence does not potentiate alcohol also has
  antidepressant properties
• SSRIs reuptake inhibitors Paxil Prozac,
  Zoloft, etc