Benzodiazepines

Benzodiazepines (BZD) are a group of drugs whose core chemical structure is a fusion of a benzene ring and a diazepine ring.  They were discovered by Dr. Leo Sternbach who was researching GABAA receptor binding agents. He created the first benzodiazepine, chlordiazepoxide in 1956. It was later marketed under the name Librium and approved for use in 1960. Since then more than 1000 benzodiazepines have been synthesized and about 30 have been introduced for clinical use.  BZDs enhance the effect of the inhibitory neurotransmitter GABA and are used in the treatment of anxiety, insomnia and agitation.

In this document we will focus on four particular BZDs: Alprazolam (Xanax), Diazapam (Valium), Clonazepam (Klonopin) and Lorazepam (Ativan). These are listed among the 200 most commonly prescribed drugs in the US. Benzodiazepines are typically administered orally.

Alprazolam (trade name Xanax)

Alprazolam is commonly used in the treatment of panic disorder and anxiety disorders.

Chemical Structure: C17H13ClN4

Molecular Weight: 308.77 (Reference 8)

Dosage:  Each alprazolam tablet, (for oral administration), contains 0.25, 05, 1 or 2 mg. Tablets are available as immediate release tablets, orally disintegrating tablets and extended release tablets. The dosage depends on the condition to be treated.

For anxiety, the initial dose 0.25 – 0.5 mg orally 3 times per day. This dose may be increased every 3-4 days if needed and tolerated. Maintenance Dose: may increase up to a maximum daily dose of 4mg in divided doses.

For panic disorder, initial dose 0.5 – 1.0 mg once daily. Maintenance dose: 1 - 10mg per day in divided doses.

For depression, initial dose 0.5 mg orally 3 times per day with an average effective dose of 3mg orally daily in divided doses.

The risk of dependence may increase with dose and duration of treatment.

 

Half –life: 7.31 – 17.18 hours (single value 11.01).  (Ref 4)

Alprazolam is metabolized primarily by hepatic microsomal oxidation, yielding alpha-hydroxy- and 4-hydroxy-alprazolam as the principal initial metabolites.

After a single 1mg oral dose, peak plasma concentration of 12 -22ug/L at 0.7 – 1.8 hours post dose, a volume of distribution of 0.8- 1.3 L/kg, elimination half-life of 9 to 16 hours and clearance of 0.7 – 1.5 ml/kg/min. (Ref 1)

 

Clonazepam (trade name Klonopin)

Clonazepam has more anticonvulsant properties than most of the other BZDs. It is used to treat epilepsy, panic disorders and mania.

Chemical structure: C15H10ClN3O3

Molecular weight: 315.72   (Reference 8)

Half – life: 21.40 – 49.40 hours (single value 32.37) (Ref 1)

 

 

Diazepam (trade name Valium)

Diazepam is used to treat anxiety.

Chemical Structure: C16H13ClN2O

Molecular weight: 284.74 (Reference 8)

Half-life: Range 24.73 - 65.30 hours (Single value 54.0) – Reference 1

Half-life: 44.5 +/- 16.5 hours (n = 7; 20 – 30 years of age (mean age 25.3 +/-3.9 years); weight range 57.6 – 90.0 Kg) – Reference 5

Half Life: 71.5+/-27.6 hours (n = 6; 60 – 75 years of age (mean = 68.3 +/- 5.3 years); weight range 69.2 – 98.4 kg. There is an age related decrease in the rate of elimination which appears to be due to an increase in the volume of distribution (steady state) in elderly patients.  There is no difference in the initial volume of distribution of the drug. However there is a difference in the steady state volume of distribution. Changes in the relative proportions of adipose and lean tissues with aging may be responsible. ) – Reference 5.

 

Half Life: 40.4 hours (range 31.5 – 51.8); n = 12; 20-29 years of age; body weight: 50 – 78KG – Reference 6.

 

Volume of distribution (steady state) (: 1.22L/Kg (range 0.83 – 1.78) – Reference 6.

 

Clearance rate: 0.29 +/- 0.09 ml/kg/min (n = 7, Young subjects); 0.26+/- 0.09 ml/kg/min (n = 6; elderly subjects). Reference 5.

 

Lorazepam (trade name Ativan)

Lorazepam is used as a sedative, anxiolytic and anticonvulsant.

Chemical Structure: C23H21ClN6O3

Molecular weight: 464.91 (Reference 8)

 

Half life: 10.13 – 23.30 hours (Single value 12.90) (Ref 1)

 

Elimination half life: 8 -25 hours (ref 7); 11.5+/- 2.0 hours (ref 9)

Volume of distribution: 1.0 -1.3 L/Kg (Reference 7); 1.89+/- 0.05 L/Kg (Reference 9)

Clearance: 0.7 – 1.2 ml/kg/min  (Reference 7); 2.08 +/- 0.22 ml/kg/min (Reference 9)

 

References

1.     PMID: 8513649. Greenblatt DJ, Wright CE. Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet 24: 453 – 471, 1993.

 

2.     PMID: 6133268. Alprazolam: pharmacokinetics, clinical efficacy, and mechanism of action. Pharmacotherapy 2: 243 – 254, 1982. 

 

3.     PMID: 21353710. Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci 34: 188 – 197, 2011.

 

4.     PMID: 1356276. Woods JH, Katz JL, Winger G. Benzodiazepines: use, abuse, and consequences. Pharmacological reviews 44: 151 – 347, 1992.

 

5.     PMID: 8864311. Herman RJ, Wilkinson GR. Disposition of diazepam in young and elderly     

subjects after acute and chronic dosing. Br J Clin Pharmacol 42: 147 – 155, 1996.

 

      6.   PMID: 8864328. Gugler R, Hartmann M, Rudi J, Brod I, Huber R, Steinijans VW, Bliesath H,              Wurst W, Klotz U. Lack of pharmacokinetic interaction of pantoprazole with diazepam in man.      Br. J Clin Pharmacol 42: 249 – 252, 1996.

 

      7.   PMID: 6111408. Greenblatt DJ. Clinical pharmacokinetics of oxazepam and lorazepam. Clin             Pharmacokinet. 6: 89 – 105, 1981.

 

      8.   The Merck Index. Twelfth edition 1996.

 

      9.   PMID: 2746493. Greenblatt DJ, Ehrenberg BL, Gunderman J, Scavone JM, Tai NT, Harmatz JS,        Shader RI. Kinetic and dynamic study of intravenous lorazepam: comparison with intravenous         diazepam. J Pharmacol Exp Ther 250: 134 – 140, 1989.

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