Benzodiazepines (Long Acting)

1. Preferred in Generalized Anxiety Disorder
2. Clonazepam (Klonopin)

Benzodiazepines (Short-acting)

1. Indicated in the elderly or with decreased clearance
2. Alprazolam (Xanax)
3. Lorazepam (Ativan)
4. Oxazepam (Serax)

• Is effective in the treatment of generalized anxiety disorders but not panic disorders.
• Buspirone is used as an adjunct in the treatment of OCD, depression and social phobia
• Busipirone attain maximal efficacy at 4-6 week

Zolpidem and Zaleplon:

1. Are hypnotics
2. Act at the Omega-1 receptors of GABAa complex
3. Unlike benzodiazepines these two medications have no anxiolytic effect, muscle relaxants, or anticonvulsant properties
4. Maximum adult daily dose for Zolpidem is: 10 mg/night
5. Maximum adult daily dose for Zaleplom is: 20 mg/night

SSRI:

1. Indicated for concurrent depression
2. SSRI attain maximal efficacy at 4-6 weeks
3. Paroxetine (Paxil); (first line FDA approved option)
4. Venlafaxine (Effexor); (first line FDA approved option)
5. Nefazodone (Serzone)

TCAs:

1. Imipramine (Tofranil)
2. Desipramine (Norpramin)

MAOi:

1. Indicated for concurrent phobia
2. Phenelzine (Nardil)
3. Tranylcypromine (Parnate)

Benzodiazepines

• Block Gaba-receptors, subtype-A in the brain
• They are anxiolytics, sedatives, muscle relaxant, anticonvulsant and hypnotics (in hospital setting)
• Benzodiazepines are also used to treat akathisia and catatonia
• As adjunct treatment of acute mania
• Used for alcohol and barbiturate withdrawal and detoxification
• Alcohol and barbiturates act directly at chloride ion channel at high doses whereas benzodiazepines have no direct effect on those channels and their effect is limited by the amount of endogenous GABA
• Are good choice for acute generalized anxiety disorders and panic disorders

Selection of Benzodiazepines

• The choice of benzodiazepines is based on half-life, rapidity of onset, metabolism, and potency
• Benzodiazepines are metabolized in liver
• It may be safe to avoid benzodiazepines in patients with moderate to severe hepatic dysfunction to prevent increased risk of sedation and confusion.
• Lorazepam and oxazepam are better choice in patients with liver failure because they are predominantly eliminated by kidneys

Buspirone:

• Is partial serotonin A agonist and unlike benzodiazepines, alcohol and barbiturate it does not interact with the GABA receptors. Because of such mechanism of action, it does not cause sedation, does not impair motor performance, and does not pose risk of abuse. For the same reasons, it is not a treatment option for alcohol or barbiturate dependence

Zolpidem and Zaleplon:

• Are short acting hypnotics
• Because of short half-life they can be administered in the middle of the night
• There is minimal daytime sedation

Beta Blockers

1. Indicated for excessive autonomic symptoms
2. Propranolol (Inderal)

Generalized Anxiety Disorder

• Paroxetine
  • Maximum 20-60 mg daily
  • first line FDA approved
• Venlafaxine XR
  • Maximum 75 to 225 mg daily
  • first line FDA approved
• Buspirone
  • start at 5 mg BID
  • maximum 30 mg BID
  • Patients previously exposed to benzodiazepines may respond less favorably to busipirone
• Benzodiazepines
• SSRIs

Obsessive-Compulsive Disorders

• SSRIs
• Clomipramine

Panic Disorders

• SSRIs: are the first line because of no risk of dependence and abuse
• TCAs: are second line treatment
• MAOIs: are third line treatment only for those who cannot tolerate SSRIs or whose symptoms have not responded to SSRIs or TCAs
• Benzodiazepines
  • High potency BNZDs such as clonazepam and alprazolam are preferred because they are well tolerated at the higher doses that often needed to control panic attacks
  • Clonazepam has longer half-life which results in more stable serum levels and alows for a BID dosing.
  • Alprazolam which has a very short half-life is a better choice for acute titration

Performance anxiety

• B-Blockers: are the best choice with the least side effects
• Benzodiazepines: only for severe cases that does not respond to B-Blockers

Social Phobia

• SSRIs
• MAOIs
• Benzodiazepines
• Buspirone
• Venlafaxine
• TCAs: although highly effective in the treatment of panic disorders they are the least effective for panic disorders
• B-Blockers: has been found to ineffective for the treatment of social phobia

Insomnia:

• Zolpidem
• Zaleplon
• Benzodiazepines

Benzodiazepine side effects

• Impairment of performance
• Dependence
• Withdrawal:
  • Withdrawal from benzodiazepines with shorter half-life peak more rapidly and more intensely
  • Signs: Tachycardia, hypertension, muscle cramps, anxiety, insomnia, panic attacks, poor memory, perceptual disturbances, hallucination, delirium, seizure, psychosis, hyperpyrexia, death
  • To avoid withdrawal symptoms benzodiazepines should be discontinued gradually. Usually, a dose reduction of 10% per week is recommended
• Memory impairment is anterograde and is highly linked to intravenous use
• Rebound effects
• Disinhibition: benzodiazepines should be used with cautious in patients with impulse control and aggression
• Overdose:
  • Benzodiazepines are highly safe in overdose when used alone. Dangerous effects occur when patients use multiple sedatives with benzodiazepines
  • Antidote: Flumazenil
• Drug interaction:
  • Sedatives, narcotics, alcohol
  • Medications that inhibit cytochrome P450 3A3/4 may increase the serum level of benzodiazepines (except lorazepam and oxazepam and temazepam that are cleared from kidney)

Buspirone side effects:

• Signs and symptoms: Headache, Nausea, Nervousness, Insomnia, Dizziness, Lightheadedness, Restlessness
• Overdose: no fatal overdose have been reported
• Drug interactions:
  • is metabolized by CYP3A3/4
  • Should not be administered with MAOIs

Zolpidem and Zaleplon side effects:

• SImilar to short-acting benzodiazepines
• Potential for abuse has been reported
• Overdose: although they appear to be nonfatal in overdose however when used in combination with other CNS depressants pose a greater risk
•  Drug interactions:
  • Zolpidem and Zaleplon are metabolized by hepatic enzymes CYP3A3/4. Inhibitors of these enzymes may increase blood levels and result in toxicity
  • Should not be administered with MAOIs