Pharmacology of Barbiturates

Actions of Barbiturates on the CNS

• Sedative action that leads to drowsiness
• Hypnotic action that causes abnormal sleep, leading to hang-over and rebound paradoxical sleep after tolerance or stopping the drug
• Cause amnesia
• Can induce general anesthesia, especially with ultra-short acting barbiturates
• Act as anti-convulsants, treating all types of convulsions (all barbiturates), while phenobarbital specifically treats Grand Mal epilepsy but worsens Petit mal epilepsy

Effects on Vital Centers

• Large doses can suppress respiratory centers, leading to hypoventilation and hypoxia
• Can suppress vasomotor centers, leading to hypotension
• Affect heat regulating centers, causing hypothermia

Other Effects of Barbiturates

Cardiovascular System

• Therapeutic doses have minimal effects
• Large doses cause hypotension due to suppression of vasomotor centers, heart, and vasodilation

Respiratory System

• Large doses cause hypoventilation and hypoxia

Gastrointestinal Tract

• Cause hypomotility and hyposecretion

Kidneys

• Cause oliguria due to suppression of blood pressure and antidiuretic hormone

Hormonal Effects

• Suppress antidiuretic hormone and adrenocorticotropic hormone

Uterus

• Suppress uterine contractility, leading to post-partum hemorrhage, and can pass the placental barrier, causing neonatal asphyxia

Skeletal Muscle

• Large doses cause mild relaxation

Liver

• Barbiturates induce hepatic microsomal enzymes, leading to increased metabolism of the drug itself, resulting in tolerance and cross-tolerance
• Affect the metabolism of other drugs, leading to drug interactions

CNS Depressants

• CNS Depressants: sedatives and hypnotics
• Sedatives: calm behavior, produce drowsiness
• Hypnotics: induce or maintain a state like sleep
• Small dose: sedation, large dose: hypnosis
• Reticular Activating System (RAS): responsible for alertness and wakefulness
• Barbiturates: non-selective CNS depressants, interact with GABA-A receptors, leading to hyperpolarization and post-synaptic inhibition

Barbiturates

• Classification:
  • Long-acting (e.g. phenobarbital)
  • Intermediate-acting (e.g. amobarbital)
  • Short-acting (e.g. pentobarbital)
  • Ultra-short acting (e.g. thiopentone)
• Mechanism of Action:
  • Stimulate specific barbiturate receptors
  • Facilitate GABA-A transmission
  • Increase Cl- influx, leading to hyperpolarization and post-synaptic inhibition
• Actions:
  • Sedative and hypnotic effects
  • Anticonvulsant and anti-epileptic effects (phenobarbital)
  • Anesthetic effects (ultra-short acting barbiturates)
• Adverse Effects:
  • Idiosyncrasy (acute porphyria)
  • Induction of hepatic microsomal enzymes, leading to tolerance and drug interactions
  • Dependence and addiction
  • Respiratory depression and hypoventilation

Benzodiazepines (Bz)

• Pharmacokinetics:
  • Well absorbed orally
  • Highly bound to plasma proteins
  • Metabolized by hepatic microsomal enzymes
  • Excreted renally
• Mechanism of Action:
  • Bind to specific Bz receptors (Bz1 and Bz2)
  • Activate GABA-A transmission
  • Increase Cl- influx, leading to hyperpolarization and post-synaptic inhibition
• Actions:
  • Anxiolytic (anti-anxiety) effects
  • Sedative and hypnotic effects
  • Muscle relaxant effects
  • Anticonvulsant effects
• Adverse Effects:
  • Dependence and addiction
  • Withdrawal symptoms
  • Interactions with other drugs
  • Respiratory depression and hypoventilation

Anxiety and Anxiety Disorders

• Anxiety: a normal response to stressful or fearful situations

• Anxiety Disorders:

  • Generalized Anxiety Disorder (GAD)
  • Panic Disorder (PD)
  • Social Anxiety Disorder (SAD)
  • Post-Traumatic Stress Disorder (PTSD)

• Treatment:

  • Benzodiazepines (short-term management of acute anxiety symptoms)
  • Antidepressants (long-term management of anxiety disorders)
  • Buspirone (non-benzodiazepine anxiolytic)
  • Hydroxyzine (5-HT2A receptor antagonist)
  • Psychotherapy (cognitive-behavioral therapy)### Panic Disorder (PD)

• A panic attack typically lasts 20-30 minutes, with peak intensity within the first 10 minutes.

• Common symptoms include anxiety about being in places or situations where escape might be difficult or help might not be available.

• Agoraphobia often develops secondary to panic attacks, where patients avoid specific situations due to fear of a panic attack.

Treatment of PD

• Pharmacological therapy: Antidepressants (TCAs, SSRIs, SNRIs, MAOIs), Benzodiazepines
• Non-pharmacological therapy: Psychoeducation, Cognitive-behavioral therapy (CBT), Avoid stimulants
• Patients with PD experience greater rebound anxiety and relapse when discontinuing benzodiazepines than GAD patients.

Social Anxiety Disorder (SAD)

• Fear of social or performance situations in which the person is exposed to possible scrutiny by others.
• Physical symptoms include blushing, diarrhea, sweating, tachycardia, and trembling.

Treatment of SAD

• Pharmacological therapy: Antidepressants, Benzodiazepines (Clonazepam)
• Non-pharmacological therapy: Cognitive-behavioral therapy (CBT), Psychotherapy
• Patients with SAD generally respond slowly to treatment, and many will not achieve a full response.

Benzodiazepines (Bz)

• Classification: Hypnotic, Anxiolytic, Anticonvulsant, Skeletal muscle relaxant, Antidepressant
• Mechanism of action: Enhance GABA transmission, bind to GABA receptors
• Pharmacological actions: Anxiolytic, Sedative-hypnotic, Anticonvulsant, Skeletal muscle relaxant, Antidepressant

Adverse Effects of Bz

• Dependence and addiction
• Daytime sedation, anxiety, and rebound anxiety
• Affect mental, psycho-motor, and sexual functions
• Anterograde amnesia, especially with Triazolam
• Aged patients: mental confusion, hypotension
• Additive effects with alcohol, ataxia, and teratogenic effects

Barbiturates vs. Benzodiazepines

• Barbiturates: Marked suppression of REM sleep, tolerance, and dependence, low therapeutic index
• Benzodiazepines: Less suppression of REM sleep, less tolerance and dependence, high therapeutic index

Non-Benzodiazepines (Z-Drugs)

• Zolpidem and Zopiclone: GABA-A receptor agonists, hypnotics with minimal REM suppression, minimal muscle relaxation or anticonvulsant effect
• Minimal tolerance and dependence, short-acting

Flumazenil (Anexate)

• Selective and competitive block of Bz-receptors, antagonizes ALL actions of Bz
• Used to treat benzodiazepine overdose, extensive hepatic first-pass metabolism, short half-life