Diazepam

Mechanism

Chemical and Commercial Profile

Common trade names: Valium, Ansium, Gobanal.
Group: Anxiolytic, anticonvulsant and muscle relaxant benzodiazepine with long half-life.

Mechanism of Action

Diazepam acts by facilitating and enhancing the inhibitory synaptic transmission of the GABA_A receptor. It does not act as a direct agonist of the receptor, but as a positive allosteric modulator:

Allosteric Dynamics of the GABA_A Receptor \text{Diazepam binding} \longrightarrow \text{Increase in the opening frequency of the Chlorine channel } (\text{Cl}^-) \longrightarrow \text{Membrane hyperpolarization}

By binding to the specific α-γ interphase subunit (BZD1 and BZD2 type receptors), it increases the affinity of the presynaptic membrane for the endogenous neurotransmitter GABA, resulting in immediate effects:

• Anxiolytic and sedative: By modulation in the amygdala and hippocampus.
• Anticonvulsant: By suppression of cortical epileptogenic foci.
• Myorelaxant: By facilitating presynaptic inhibition in the spinal cord.

Pharmacokinetics

Pharmacokinetics

• Absorption: Rapid and complete orally; 99% bioavailability. C_max at 30-90 minutes. Highly lipid soluble, it crosses the BBB extremely quickly.
• Metabolism: Hepatic oxidative pathway via CYP2C19 and CYP3A4, generating multiple active metabolites with long half-life: nordiazepam (demoxepam), temazepam and oxazepam.
• Excretion: Renal (70%) in the form of inactive conjugated glucuronides.
• Half-life (t_1/2): Diazepam parent: 20 to 50 hours. Active metabolite Nordiazepam: 50 to 100 hours. It explains the prolonged cumulative effect and the low rate of acute inter-dose withdrawal symptoms.

Indicators and dose

Indications

• Symptomatic relief of severe anxiety, panic attacks and psychomotor agitation.
• Reflex muscle spasms of central and peripheral origin (tetanus, cerebral palsy, severe paravertebral contracture).
• First-line treatment in acute repetitive epileptic seizures and Status Epilepticus (rectally in pediatrics or intravenously in emergencies).
• Prevention and treatment of acute alcohol withdrawal syndrome (Delirium Tremens).

Dosage and Settings

• Anxiolytic: 2 mg to 10 mg divided into two or three daily doses; preferably prescribe the highest dose before going to bed.
• Status Epilepticus (Emergency): 10 mg to 20 mg slowly intravenously (maximum rate of 5 mg/min to avoid acute apnea due to solvents in the vial); repeat if necessary after 10-15 minutes.
• Geriatric Population: Limit doses to 50% of the standard and prescribe formulations without prolonged active metabolites (such as lorazepam or oxazepam) to avoid systemic accumulation phenomena.
• Kidney Failure:
  • Cl_Cr < 15 ml/min: Reduce the dose by at least 50% due to greater central sensitivity of the receptor in uremia.
• Liver Failure: Moderate to severe: Reduce dose by 50-75% and closely monitor consciousness levels.

Security

Contraindications

• Myasthenia Gravis: The intrinsic muscle-relaxing effect can precipitate lethal respiratory crises.
• Decompensated chronic respiratory failure or severe obstructive sleep apnea (OSA).
• Uncontrolled acute narrow-angle glaucoma.
• Severe decompensated liver failure due to risk of portosystemic encephalopathy.

Adverse Effects (ADR)

Phenomenon of Tolerance, Dependence and Abuse

Continuous use of diazepam for a period greater than 4-12 weeks induces a downregulation of GABAergic receptors and an alteration of synaptic plasticity, resulting in progressive pharmacological tolerance and severe physical dependence. Abrupt withdrawal of stable therapeutic doses after months of use can precipitate an acute withdrawal syndrome characterized by rebound insomnia, tremor, sensory hallucinations, delirium, and life-threatening withdrawal seizures.

• CNS: Refractory daytime sedation, somnolence, motor ataxia with gait instability, fine psychomotor disturbance, transient anterograde amnesia (inability to consolidate new memories after taking the drug).
• Geriatric Population: Multiplies by 3 the risk of accidental falls and hip fractures due to the abolition of postural reflexes, and is also frequently confused with pseudodementia or nocturnal delirium.
• Paradoxical reactions: Aggression, motor disinhibition and excitement (especially in children and the elderly with previous brain damage).

Clinical Interactions

• CNS Depressants and Opiates (Critical Interaction): Extreme pharmacodynamic synergy that strongly depresses the bulbar respiratory center. Concomitant co-prescription with opioid analgesics or alcohol is not recommended due to the risk of fatal cardiorespiratory arrest.
• CYP3A4 and CYP2C19 inhibitors: Ketoconazole, fluoxetine, cimetidine or omeprazole substantially prolong the elimination half-life of diazepam.

Pregnancy and Breastfeeding

FDA Category: D. Chronic use during the first trimester is associated with the risk of mild orofacial clefts. Its use at the end of the third trimester precipitates "Floppy Infant Syndrome", characterized by systemic hypotonia, hypothermia, profound drowsiness and severe neonatal respiratory distress. Breastfeeding: Avoid. It is excreted in milk in high concentrations and its very slow clearance induces accumulation in the infant.