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Thursday – Mar 1 Exam I is Tuesday, Mar 6 Benzodiazepines and Other Medications for Anxiety. Benzodiazepines (BZD) defined by the presence of a benzene ring fused with a 7 membered diazepine ring 1 st one introduced in 1960 – Librium (chlordiazepoxide)

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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 > 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 > 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 > 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 < 6 months, low dependence potential

  • > 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 <10% 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 Disorder

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) Disorder

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

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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 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 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 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 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 Disorder

  • 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