Understanding Anxiety Disorders and Treatments

• Anxiety is a common mental disorder characterized by tension, apprehension, or uneasiness.
• Severe anxiety's physical symptoms are similar to fear and involve sympathetic activation like tachycardia, sweating, trembling, and palpitations.
• Mild anxiety episodes are common and usually do not require treatment.
• Severe, chronic anxiety is treatable with anti-anxiety drugs or anxiolytics.

Anxiety Classification (Primary)

• Generalized Anxiety Disorder (GAD): Apprehension and tension for no particular reason.
• Panic Disorder: Unexpected anxiety attacks.
• Phobic Disorders: Fears related to specific situations like agoraphobia.
• Obsessive-Compulsive Disorder: Repetitive, anxiety-driven behavior or obsessive thoughts and doubts.
• Post-Traumatic Stress Disorder: May result from rape or warfare.
• Anxiety can be secondary to medical causes or substance use.
• A sedative reduces excitement and calms the person.
• A hypnotic produces sleep resembling normal sleep.
• Sedative-hypnotic drugs are sedatives at low doses and hypnotics at high doses.
• Both sedation and hypnosis are different levels of CNS depression.

Classification of Sedatives and Hypnotics

• Benzodiazepines (BZDs): Divided into short-action (trizolam), intermediate-action (alprazolam), and long-action (flurazepam).
• Barbiturates: Divided into ultra-short action (thiopental), short action (secobarbital), and long action (phenobarbital).
• Nonbenzodiazepine hypnotics: Include zolpidem, zopiclone, zaleplon, and eszopiclone.
• Others: Melatonin, ramelteon, and suvorexant.
• Benzodiazepines (BDZs) include alprazolam, clonazepam, chlordiazepoxide, diazepam, lorazepam, triazolam, flurazepam, and Estazolam.
• Benzodiazepines are widely used as anxiolytics, and replaced barbiturates due to increased safety.
• Antidepressants with anxiolytic action (SSRIs) may be preferred in some cases like non-benzodiazepine hypnotics and antihistamines for insomnia.
• GABA is the primary inhibitory neurotransmitter in the CNS.
• GABA acts via GABA A and GABA B receptors.
• BZDs bind to GABA A receptors at a different site than GABA.
• BZDs increase the affinity of GABA for its receptors.
• GABA increases chloride ion conduction through its receptor which is enhanced by BZDs.
• BZDs enhance the frequency of chloride channel openings in response to GABA, leading to hyperpolarization and CNS inhibition.

Pharmacological Actions

• Reduction of anxiety: Low doses of benzodiazepines are anxiolytic by selectively enhancing GABAergic transmission in the limbic system.
• BZDs have sedative and calming properties and produce hypnosis at higher doses.
• Anterograde amnesia: Temporary memory impairment with benzodiazepines is mediated by α1-GABAA receptors, impairing the ability to learn and form new memories.
• Anticonvulsant effect: mediated by α1-GABAA receptors.
• Muscle relaxant: At high doses, BZDs relax skeletal muscle spasticity.

Uses of BZDs

• Insomnia: BZDs decrease the time to fall asleep and reduce night awakenings, total sleep time increases, and produce refreshing sleep.
  • Short-acting triazolam helps with falling asleep.
  • Intermediate-acting temazepam is useful for frequent awakenings and difficulty staying asleep.
  • Long-acting flurazepam is seldomly used due to extended half-life, resulting in excessive daytime sedation and accumulation, especially if old.
• Diazepam treats skeletal muscle spasms and spasticity from degenerative disorders, for example, multiple sclerosis and cerebral palsy.
• BZDs treat anxiety disorders and anxiety related to depression and schizophrenia; anxiety may require prolonged treatment through the use of long-acting agents like clonazepam, lorazepam, and diazepam.
• Antiprazolam is effective for short and long-term treatment of panic disorders.
• Diazepam, lorazepam, clonazepam, and clobazam have anticonvulsant effects.
• IV diazepam/lorazepam manages life-threatening seizures in status epilepticus, tetanus, drug-induced convulsions, and febrile convulsions.
• Clonazepam treats absence seizures.
• IV BZDs are used for diagnostic procedures (endoscopies) and minor operative procedures (dental) for their sedative-amnesic-analgesic and muscle relaxant properties.
• BZDs are used as pre-anesthetic medication for their sedative-amnesic and anxiolytic effects in preanesthetic medication and general anesthesia (GA).
• Long-acting BZDs such as chlordiazepoxide and diazepam manage alcohol-withdrawal symptoms.

Pharmacokinetics

• BZDs are usually administered orally or IV, and occasionally rectally (diazepam for children).
• Rate of absorption varies with oral administration, erratic with i.m. route, and has a large distribution volume.
• Rapid redistribution causes short duration of action with occasional use.
• BZDs are metabolized in the liver, may undergo enterohepatic recycling, and some produce active metabolites with long half-lives, leading to cumulative effects.
• Oxazepam is not significantly metabolized in the liver.
• Metabolites are excreted in urine.
• BZDs cross the placental barrier and are not recommended for use during pregnancy.

Adverse Effects

• BZDs have a wide safety margin and are generally well-tolerated.
• Common side effects: drowsiness, confusion, amnesia, lethargy, weakness, blurred vision, ataxia, daytime sedation, and impaired motor coordination which requires avoiding driving.
• Tolerance and dependence less potential compared to barbiturates.
• Withdrawal symptoms: Mild and slow in onset for long-acting BZDs, more intensive and abrupt for short-acting BZDs.
• Neonates may develop hypotonia and respiratory depression if administered to pregnant women during labor.
• Flumazenil antagonizes BZDs and reverses the effects of both BZD agonists (CNS depression) and BZD inverse agonists (β-Carboline).
• Administered via I.V. route because it has a high first-pass metabolism.
• Treats BZD overdose and reverses the sedative effects of BZDs, zolpidem, zaleplon, and eszopiclone.
• The barbiturates replaced by BZDs because barbiturates induce tolerance and dependence.

Barbiturate Classification

• Ultra-short-acting: Thiopentone
• Short-acting: Pentobarbitone
• Long-acting: Phenobarbitone

Mechanism of Action

• Sedative-hypnotic action of barbiturates results from interaction with GABA A receptors, which enhances GABAergic transmission.
• The barbiturate binding site on the GAB A receptor is distinct from the BZD binding site.
• Barbiturates potentiate GABA action on chloride entry into the neuron by prolonging the duration of chloride channel openings.
• In addition, they block excitatory glutamate receptors which results in decreased neuronal activity.
• High concentrations of barbiturates have a GABA-mimetic effect, directly increasing Cl conductance into the neuron.

Pharmacological Action

• Depresses all excitable tissues, except the liver that is most sensitive to CNS.
• Sedation and hypnosis, induces sleep, prolongs sleep duration, alters NREM-REM sleep cycle, and causes residual sedation and hangover upon awakening.
• Reduces anxiety, impairs short-term memory and judgment.
• Causes euphoria and has addiction potential.
• Causes paradoxical dysphoria and hyperalgesia in some patients.
• Anesthesia: is caused at high doses with ultra-short-acting barbiturates (IV thiopentone).
• Anticonvulsant: All barbiturates are anticonvulsants in conventional doses.
• This effect is seen with sub-hypnotic doses of phenobarbitone.
• Respiratory system: They leads to significant respiratory depression, additional paralysis of medullary center, suppresses the hypoxic and chemoreceptor response to CO2, and overdose because of respiratory depression and death.
• CVS: Hypnotic doses slightly decrease BP and HR, toxic doses significantly decreases BP because of direct depression of myocardium and vasomotor center.
• Skeletal muscles: Decreased excitability.
• Liver: induction of liver enzyme.

Therapeutic Uses

• Not preferred currently because of respiratory depression and abuse potential.
• Sedation and hypnosis: BZDs preferred.
• Anesthesia: Ultra-short-acting barbiturates were historically used intravenously to induce anesthesia but have been replaced by other agents.
• Anticonvulsant: Phenobarbitone has anticonvulsant effects and is used to treat status epilepticus and generalized tonic-clonic seizures.
• Phenobarbital can depress cognitive development in children and decrease cognitive performance in adults, only treat seizures if other therapies have failed.
• Neonatal jaundice: Phenobarbitone is a microsomal enzyme inducer.
• It increases production of glucoronyl transferase which metabolizes and excretes bilirubin, reducing jaundice.

Adverse Effects

• Impaired judgment and fine motor skills.
• Excitement and irritability in children.
• Respiratory depression, severe in patients with respiratory disorders.
• Tolerance on prolonged use.
• Physical and psychological dependence with high abuse potential.
• Withdrawal symptoms: Anxiety, restlessness, hallucinations, delirium, and convulsions.