1. increase the inhibitory effects of GABA

2. Binds to specific site (b/w alpha and gamma) on the GABAÁ R

3. Binding of GABA to GABA R opens the Cl- channel leading to hyperpolarization

4. Binding of BZD to GABA R enhances binding of GABA to GABA R.

5. Barbiturates and ethanol can also bind the GABA R and cause Cl- influx.

1. low doses relieve anxiety

2. Sedation & hypnosis - sleep:

-decrease latency of onset

-increase duration of NREM

-Tolerance develops w/ continued use

3. REM rebound: insomnia & withdrawal

1. Situational anxiety

2. Generalized anxiety disorder

3. Panic disorders (high potency BZD)

- Alprazolam

-Clonazepam

4. Phobias - OCD

5. DOC: Long acting is more reliable in relief of anxiety (diazepam)

6. lorazepam & oxazepam prefered for elderly

1. triazolam (short)

2. temazepam (intermediate)

3. flurazepnam (long)

4. long term use is irrational and dangerous -- tolerance increases & rebound insomnia

1. preanesthetic -- increase sedation & amnesia

2. IV anesthesia -- endoscopy, colonoscopy, cardioversion (diazepam, midazolam)

3. anticonvulsant

- acute, status epilepticus (diazepam, lorazepam)

-chronic (diazepam, clonazepam)

4. Alcohol withdrawal (chlordiazepoxide, diazepam)

5. skeletal muscle spasm and spasticity due to ms or cerebral palsy (diazepam)

1. drowsiness, sedation

- start w/ lower dose and gradually increase dose. tolerance will occur

2. elderly patients are more susceptible:

- confusion

- increased falls & hip fractures

- caution cumulative effects

More SE of BZD

1. Paradoxical Psychological SE

2. Allergic rxns

3. Teratogenic

1. excitement, anxiety, euphoria (disinhibitory effect

2. rash, rare anaphylaxis

3. diazepam has caused cleft lip and palate

overdose toxicity of BZD

1. rarely life threatening alone

2. in combo w/ alcohol, barbiturates, etc. SERIOUS CNS depression & death can occur

1. Flumazenil (competitive BZD receptor AGONIST)

- reverse sedation w/ IV injection

- can cause confusion, agitation, anxiety, and convulsions in pts that are physically dependent on BZD

2. B-carboline derivatives act as inverse agonists & allosteric modulators of GABA-R function

- bind to BZD sites & decrease Cl- conductance

- anxiety & seizures

1. psychological dependence

2. physical dependence -- withdrawal symptoms

3. Abuse potential - controlled substance (schedule IV)

- rapid onset (diazepam) have higher abuse potential

- dependence is frequent in individuals w/ alcohol or drug abuse

1. selective BZD R agonist

2. structurally unrelated to BZD

3. selectively bind to BZD sites on GABA A R

- increases GABA mediated neuronal inhibition

4. minimal anticonvulsant

5. used as hypnotic for insomnia (schedule IV)

6. alpha1 - sedation, amnesia

7. alpha2 & 3 - anxiolytic, muscle relaxant

Zolpidem, Zaleplon, Eszopiclone  

(pharmacokinetics)

All used for insomnia (Catch your Zzz's)

1. rapid onset (30mins)

- half life is 2.5hr, 1hr, 6hr

2. hepatic oxidation

- eszopiclone -- CYP3A4

3. Esz increases sleep time

1. Z & Z -- decrease sleep latency, no withdrawal symptoms, no tolerance

2. E -- decrease sleep latency & night time awakenings. increase total sleep time

-rebound insomnia can occur

-no tolerance, dependence, or abuse

1. well absorbed orally and distributed widely throughout the body

2. Redistribute from brain to splanchnic areas, skeletal muscle, and finally adipose tissue. Redistribution is important for short duration of action of thiopental and other short acting drugs

3. cross placenta

4. all except Phenobarbital are metabolized in liver

1. bind to allosteric site on GABA A R.

- increase duration of Cl- channel opening

2. directly increase Cl- influx in the absence of GABA

3. no ceiling effect

Sedative Hypnotic & Antianxiety Drugs

1. Sedative

2. Hypnotic

3. Antianxiety

1. decrease excitement, relief of anxiety

2. induces sleep

3. anxiolytic. relief of anxiety

1. w/ increasing dose, all sedative hypnotics can produce:

- relief of anxiety

- sedation

- hypnosis

2. potential for dependence and abuse

3. Ceiliing effect (unlike barbiturates) thus preventing Severe CNS depression

1. oral - lipophilic, thus rapidly absorbed and distributed

2. IM - lorazepam & midazolam are well absorbed

3. IV - Diazepam & Lorazepam for status epilepticus

All undergo hepatic metabolism

1. many are oxidized to active compounds w/ longer half lives than parent compound

2. some are oxidized to short acting or inactive

3. oxazepam, lorazepam, temazepam are glucuronized to inactive compounds - may be safer for elderly

1. Chlordiazepoxide - alcohol withdrawal

2. Diazepam - anxiety

3. Flurazepam - insomnia

1. Alprazolam - panic disorder

2. Lorazepam - acute status epilepticus

3. Temazepam - insomnia

4. Clonazepam - anti convulsant, chronic seizures

1. Triazolam - insomnia

2. Midazolam - anesthesia like stage

1. Anesthesia with IV:

- Midazolam

- Lorazepam

- Diazepam (good anterograde amnesia)

2. Anticonvulsant - decrease seizure

- Clonazepam (very selective)

- Diazepam, Lorazepam (Tolerance increases)

3. Muscle relaxant:

- Diazepam (decreases transmission an NMJ)

1. occur after abrupt discontinuation of BZD

2. Confusion, anxiety (life threatening)

3. more intense w/ short & intermediate acting

4. Do not abruptly discontinue

5. Treat withdrawal with diazepam or chlordiazepoxide

1 & 2. Contraindications and Cautions

Drug Interactions

1. History of Alcoholism and Drug abuse

2. Elderly: lower the dose

3. alcohol and other CNS depressents increase CNS depressant effects

4. Cimetidine decreases metabolism

Zolpidem, Zaleplon, Eszopiclone

1. Adverse Effects

2 & 3. Drug Interaction

1. Somnolence, Dizziness

2. CYP3A4 inhibitors (Intraconazole, Clarithromycin, Ritonavir) increases concentration of the BZD R agonists

3. Rifampin decreases concentration

1. Melatonin (MT1 & MT2) R agonist

2. approved for sleep onset insomnia, Jet Lag

3. First pass metabolism in liver by CYP1A2

4. Plasma half life is 1 - 3 hrs

5. decrease latency to sleep by 8 - 15 mins

6. Increase total sleep time by 12 - 19 mins

1. Somnolence, dizziness

2. increased serum prolactin can result in infertility & decreased libido

3. Anaphylaxis

4.No abuse potential and no rebound insomnia

5. Dx interactions:

- CYP1A2 inhibitors (cipro) increase level

- Rifampin decreases level

Barbiturates

1. Long Acting

2. Short to Intermediate

3. Ultrashort

All metabolized in liver except Phenobarbital

1. Phenobarbital - anticonvulsant

2. Pentobarbital

3. Thiopental - anesthesia, IV

1. CNS depressant

2. Small TI

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Barbiturates 

1. Uses

2. Adverse Rxns

3. Drug Interaction

1. Anticonvulsant (Phenobarbital)

Anesthesia (IV Thiopental) - most potential for dependence or abuse b/c it's ultra short acting

2. 

A) acute:

- drowsiness

-overdose toxicity -- barbiturate poisoning

B) Chronic:

-dependence & abuse (esp short acting)

-physical dependence (withdrawal) -- rebound hyperexciteability of CNS can cause convulsions, CV collapse, and death

-treatment -- reintroduce a sedative hypnotic (long acting)

3. Enzyme induction: ↑ metabolism

- oral contraceptives

- oral anticoagulants

1 Chloral hydrate

2. Meprobamate

3. Antihistamine

1.  short acting hypnotic

2.  similar to intermediate acting barbiturates

3. Antihistamines

1. Nonsedating anxiolytic drug

2. partial agonist at 5HT 1A Receptor (hyperpolarization)

3. lacks hypnotic effects, does not potentiate depressant effects, no abuse potential, no rebound anxiety or withdrawal

1. Delayed onset: 7-10 days for anxiolytic effects and 3-4 weeks for optimal effects

2. DOC in chronic anxiety esp in elderly or those w/ history of substance abuse

3. Less sedating - minial cognitive & psychomotor impairment

4. dizziness, nausea, headache, and nervousness