CNS 32-67

Definition of anxiety

Unpleasant feeling of tension/fear with symptoms like tachycardia, tremors, sweating

When to treat anxiety

When it affects longevity

Benzodiazepines mechanism

Act on GABA-A receptors, increase Cl⁻ channel opening frequency → hyperpolarization

Safety profile of benzodiazepines

Lethal dose >1000x therapeutic dose, safer than barbiturates

Low-dose benzodiazepine effect

Anxiolytic via limbic system inhibition (α2 subunit)

Hypnotic effect of benzodiazepines

Sedation to sleep induction (α1 subunit)

Anterograde amnesia cause

BZ impair learning/memory formation (α1 subunit)

Anticonvulsant effect of benzodiazepines

Inhibit excessive excitation during seizures (α1 subunit)

Muscle relaxation by benzodiazepines

High doses inhibit motor system in spinal cord

Common anxiety disorders treated with BZ

Panic disorder, GAD, social anxiety, OCD, phobias

BZ choice for anxiety

Long half-life preferred (less withdrawal risk)

BZ choice for panic disorder

Short half-life preferred

Cross-reactivity of benzodiazepines

Alcohol → additive CNS depression and addiction risk

Long-acting benzodiazepines examples

Clorazepate, Chlordiazepoxide, Diazepam, Flurazepam, Quazepam

Intermediate-acting benzodiazepines examples

Alprazolam, Estazolam, Lorazepam, Temazepam

Short-acting benzodiazepines examples

Oxazepam, Triazolam, Midazolam

BZ use in sleep disorders

Reduce sleep latency, extend stage II, decrease REM

Temazepam use

Medium half-life, for frequent awakenings, taken 1–2h before bed

Triazolam use

Short half-life, helps sleep onset, risk of dependence/rebound insomnia

Midazolam use

Short half-life, used for procedural sedation (endoscopy, dental, angio)

BZ use in seizures

Clonazepam for acute seizures; Diazepam/Lorazepam for status epilepticus

BZ use in alcohol withdrawal

Long-acting BZ prevent withdrawal signs

Diazepam use in muscle stiffness

For neurodegenerative disease, cerebral palsy, MS

BZ pharmacokinetics

Highly lipophilic, good PO absorption, CNS penetration, variable half-life

BZ elimination

Excreted in urine

BZ safety in pregnancy

Contraindicated (cross placenta, passes in milk)

BZ dependence

High doses/long use → withdrawal syndrome (confusion, anxiety, seizures)

Withdrawal more common in

Short-acting benzodiazepines

BZ common side effects

Drowsiness, confusion

BZ less common side effects

Ataxia, impaired fine motor skills, learning deficits

BZ contraindication

Acute glaucoma (anticholinergic effect)

BZ antidote

Flumazenil (GABA antagonist), IV, short half-life, risk of withdrawal seizures

Other anxiolytics first-line

SSRIs/SNRIs (Escitalopram, Paroxetine, Venlafaxine, Duloxetine)

Buspirone mechanism

Acts on serotonin/dopamine receptors, less sedative, low dependence risk

Buspirone use

Chronic GAD treatment, not for acute anxiety

Buspirone advantage

Less motor impairment, safer in elderly

Barbiturates mechanism

Act on GABA receptors, prolong Cl⁻ channel opening time

Phenobarbital use

Anticonvulsant, anesthesia (Na⁺ channel block)

Thiopental use

Ultra-short acting, anesthesia for short procedures

Barbiturates pharmacokinetics

Good PO absorption, rapid CNS→muscle/fat distribution, liver metabolism (P450 induction), urine excretion

Barbiturates side effects

Drowsiness, vertigo, tremors, nausea, enzyme induction

Barbiturates withdrawal

Severe: tremors, anxiety, delirium, cardiac arrest

Barbiturates poisoning

Respiratory/cardiovascular suppression, supportive treatment only

Zolpidem mechanism

Binds BZ site, hypnotic only, minimal sleep cycle changes

Zolpidem use

Short-term insomnia, PO absorption, 2–3h duration

Zolpidem side effects

Nightmares, agitation, amnesia, headaches, GI upset, daytime fatigue

Zaleplon use

Shorter duration (~1h), fewer psychomotor/cognitive side effects

Eszopiclone use

Longer treatment of insomnia, t½ ~6h, side effects: anxiety, dry mouth, headaches, sleepwalking

Ramelteon mechanism

Melatonin receptor agonist, minimal abuse potential, safe for long-term use

Antihistamines for sleep

Diphenhydramine, Hydroxyzine, Doxylamine; anticholinergic side effects

Antidepressants with hypnotic activity

Doxepin, Mirtazapine, Trazodone (due to antihistamine effect)

BZ disadvantages

Potential dependence, cognitive/motor impairment, rebound insomnia, withdrawal seizures

BZ advantages

Effective for anxiety, seizures, muscle relaxation, safer in hepatic impairment (Lorazepam, Temazepam)

Non-BZ advantages

Buspirone, Z-drugs, Ramelteon → low dependence, minimal withdrawal, safe long-term

Barbiturates summary

Induce tolerance, enzyme induction, dependence, severe withdrawal, rapid onset (Pentobarbital, Secobarbital, Amobarbital, Thiopental)