Lorazepam(Ativan)

CHEM 270Case Study #2

Jessica Morgan and Valerie Chen

Key Points

1. Benzodiazepines such as lorazepam are positive allosteric modulators of the GABAA receptor and increase the receptor’s apparent affinity for GABA leading to a depressant effect in the CNS

2. 3’-hydroxy benzodiazepines (lorazepam) are intermediate-duration drugs due to their rapid elimination through glucuronidation.

3. Lorazepam is a safe, useful drug that aids in easing anxiety for intermediate periods of time, with minimal side effects

4. Addiction to the drug is the ‘worst’ side effect, and therefore long term usage of the drug is discouraged

5. Unlawful possession of the drug could cost thousands, and lead to jail time

GABAA Receptor

γ-Aminobutyric acid

• Major inhibitory neurotransmitter receptor

• Regulates neuronal excitability

• Rapid mood change and stress response• Sedation, amnesia,

muscle-relaxationNayeem et al. 1994

Nutt DJ et al. 2001

Lorazepam (1977)

Benzodiazepine core chemical structure

R2

R1

R4

R3

Diazepam, ValiumHoffman La-Roche (1963)

Serum half life: 20-80 hrsSerum half life: 10-20 hrs

Pharmacokinetics

• oral administration: mean peak plasma concentrations of free lorazepam at 2 hours

• Conjugated to a glucuronide (inactive metabolite)

• 88% is excreted in the urine, with 75% excreted as the glucuronide

• 85% of lorazepam is bound to plasma proteins

Benzodiazepine Site

Richter et al. 2006

Lorazepam Mechanism of Action

Lorazepam

benzodiazepine

benzodiazepine

Reduction in excitability of neurons

Sigel E et al. 2012

Double-blind study with 8 healthy volunteers

Patent information

• 1977 double blind study

• 129 patients, broad range of disorders

How are patients scored?

Treatment of alcohol withdrawal

• Lorazepam is a great method oftreatment in the short term

• Not ideal for long term alcohol withdrawal

Adverse side effects

• In a sample of about 3500 patients treated for anxiety, the most frequent adverse reaction to Lorazepam was:• sedation (15.9%)

• dizziness (6.9%),

• weakness (4.2%)

• unsteadiness (3.4%)

• Additional common side effects include fatigue, drowsiness and confusion.

Continued…

• This benzodiazepine has also been reported to elicit paradoxical reactions:• anxiety, hostility, rage and hallucinations

• This drug is only recommended for short-term use, and is not recommended for long-term anxiety treatment, for this reason a majority of these side effects are short lived and the patient can terminate usage of the drug to alleviate adverse effects.

Post market surveillance

• 3rd prescribed anti-anxiety medication

• Very widely used for general anxiety, and treatment of phobias

It’s a schedule VI narcotic, penalty group III

• Possession of Penalty Group III (PG-3) substances are punishable as follows:

• Class A misdemeanor if the amount of the substance is less than 28 grams. A conviction for this offense can result in a jail sentence of up to one year and/or a fine up to $4,000

• Felony of the third degree if the amount of the substance is more than 28 grams but less than 200 grams. A conviction for this offense can result in a sentence of two to ten years in prison and/or a fine up to $10,000.

• Felony of the second degree if the amount of the substance is 200 grams or more but less than 400 grams. A conviction for this offense can result in a prison sentence of two to 20 years and/or a fine up to $10,000.

• An amount of 400 grams or more is punishable by life in prison or a term of five to 99 years and/or a fine up to $50,000.