Pharmacology of Benzodiazepines and SSRIs

Benzodiazepines

• Classified by half-life:
  • Short half-life (less than 6 hours): Midazolam, Triazolam
  • Intermediate half-life (6-24 hours): Alprazolam, Lorazepam, Oxazepam, Temazepam
  • Long half-life (more than 24 hours): Diazepam, Clonazepam, Flurazepam, Nitrazepam

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Antidepressants effective for anxiety.
• Medium to long-term efficacy (3-4 weeks)
• Lack addictive potential
• Generally do not cause sedation.
• Examples: Fluoxetine, Paroxetine, Citalopram, Sertraline

Insomnia

• Characterized by:
  • Prolonged latency to onset (difficulty falling asleep)
  • Decreased sleep duration
  • Numerous nocturnal awakenings
  • Early morning awakening with difficulty falling back asleep

Hypnotic Drugs - Treatment of Insomnia

• Benzodiazepine hypnotics:
  • Lorazepam, Lormetazepam
  • Short action (10-20 hours), quickly removed from the body.
  • Decrease sleep onset latency, reduce nighttime awakenings, and increase total sleep time.
  • Adverse Drug Reactions (ADRs): daytime sleepiness, dizziness, headache, motor and cognitive impairment, memory loss, tolerance, dependence.
• Non-benzodiazepine hypnotics:
  • Zolpidem, Zopiclone
  • Structurally unrelated to benzodiazepines.
  • Agonists of the GABA-A receptor.
• Other hypnotics:
  • Melatonin

Anxiety

• Common disorder linked to work and social environment
• Normal feeling in certain situations, becomes pathological when adaptive capacity is exceeded.
• Symptoms:
  • Cognitive: fear, irritability, overwhelm, insomnia
  • Motor: tremor, muscle tension
  • Vegetative: palpitations, sweating, nausea, dry mouth
  • Behavioral: avoidance or flight from certain situations.
• Caused by excessive CNS activation:
  • Alteration in adrenergic and serotonergic systems
  • Attenuation of the GABAergic neurotransmitter system

GABAergic System

• GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the brain.
• Acts as a natural "calmer".

Serotonergic System

• Serotonin contributes to well-being and happiness.

Adrenergic System

• Noradrenaline regulates mood, attention, and vigilance.
• Hyperactivity in this system is linked to anxiety.

Glutamatergic System

• Glutamate is the main excitatory neurotransmitter in the brain.
• Imbalance in glutamatergic activity is linked to anxiety.

Anxiolytic Drugs

• Psychotropic drugs that relieve or suppress anxiety symptoms without causing sleepiness or sedation.
• Benzodiazepines: Also anticonvulsants, muscle relaxants, and sleep inducers.
• Serotonin Reuptake Inhibitors (SSRIs):

Benzodiazepines - Mechanism of Action

• GABA is the main inhibitory neurotransmitter in the CNS.
• GABA-A receptor is the most abundant inhibitory receptor in the CNS, coupled to a selective ion channel for chloride ions.
• Benzodiazepines potentiate the effect of GABA on its receptors, allowing greater chloride influx into neurons.
• This hyperpolarizes the neuron (makes it less excitable) and produces a state of neuronal inhibition.

Benzodiazepines - Pharmacokinetics

• Very liposoluble:
  • Good oral bioavailability (C max after approximately 1 hour).
  • High plasma protein binding.
  • Good tissue distribution (including adipose tissue).
  • Crosses the blood-brain barrier and placenta.
  • Administered orally, intravenously.
  • Children: Rectally and intravenously for febrile convulsions.
• Hepatic metabolism: Some give rise to active metabolites (e.g., diazepam) leading to a long half-life (t1/2 = 60 hours).
• Enterohepatic circulation (e.g., diazepam).
• Easily metabolized in patients with hepatic alterations or the elderly, resulting in an intermediate half-life (e.g., lorazepam).
• Excretion in urine as glucuronides.

Benzodiazepines - ADRs

• Wide therapeutic margin, generally safe and well-tolerated.
• At high doses: drowsiness, confusion, amnesia, incoordination, impaired ability to drive, dependence, and tolerance (treatments exceeding 6 months).

Benzodiazepines- Drug Interactions

• Increased effects when combined with:
  • Other CNS depressants
  • Alcohol
  • Antihistamines (affecting metabolism/elimination)
  • Hormonal contraceptives (affecting elimination)
  • Omeprazole (affecting metabolism).

Benzodiazepine - Pharmacological Effects

• Anxiolytic: Reduces anxiety and aggressiveness.
• Hypnosedative: Induces sleep and sedation.
• Myorelaxant: Reduces muscle tone.
• Anticonvulsant.

Benzodiazepine - Treatment Considerations

• Use the lowest effective dose.
• Never stop treatment abruptly; gradually reduce dosage over several weeks.
• Treatment duration should be as short as possible, not exceeding 8-12 weeks (including the phase-out phase).