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Questions and Answers
What is the primary factor determining the duration of action for drugs with high lipophilicity?
Which of the following statements regarding 1,4-benzodiazepine-4-oxides is true?
For the benzodiazepine derivatives, which structural modification is necessary to increase binding activity at the receptor?
What is the main advantage of drugs having a high protein binding characteristic?
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Which of the following benzodiazepines structures was first marketed for clinical use?
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What is the effect of substituting the 6th, 8th, or 9th positions on benzodiazepine derivatives?
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Which modification at the 7th position (R1) of benzodiazepine derivatives markedly increases activity?
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How does the clearance of many drugs relate to their metabolism?
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Which benzodiazepine was the first member introduced in the benzodiazepine-2-one group?
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What is a key characteristic of L.O.T. drugs in relation to their metabolism?
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Which benzodiazepine undergoes rapid decarboxylation in the stomach to an active compound?
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What is the half-life of diazepam?
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Which of the following benzodiazepines is characterized as an ultra-short-acting hypnotic?
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What factor contributes to the rapid absorption of diazepam?
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What is the main reason clinicians favor L.O.T. drugs for the elderly?
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Which benzodiazepine is commonly used as a short-acting sedative-hypnotic for induction anesthesia?
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Which class of drugs includes benzodiazepines and is known for its role as GABAA receptor modulators?
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What is the main desired effect of hypnotics in comparison to sedatives?
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Which of the following factors significantly impacts the pharmacokinetic profile of sedative-hypnotics?
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How does lipophilicity affect the pharmacokinetics of sedative-hypnotic agents?
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Which of the following is NOT typically classified as a sedative-hypnotic agent?
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Which sedative-hypnotic agent was the first to be introduced specifically as a sedative in 1857?
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What effect do most sedative-hypnotics have during pregnancy?
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Which class of sedative-hypnotic agents is defined as producing mild depression and calming of anxiety without inducing sleep?
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Study Notes
Benzodiazepines
- Benzodiazepine refers to a structure composed of a benzene ring fused to a seven-membered diazepine ring.
- The currently used benzodiazepine drugs are related to 5-aryl-3H-1,4-benzodiazepine structure.
Classification of Benzodiazepines
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1, 4-Benzodiazepine-4-oxides
- First marketed for clinical use.
- Long acting due to long half-life of parent drug and active metabolites.
- Example: Chlordiazepoxide (Librium) (1960)
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SAR (Structure-Activity Relationship)*
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Ring A
- Aromatic or heteroaromatic ring is a requirement for 5-phenyl-1,4-benzodiaipin-2-one derivatives.
- Electronegative group (halo or nitro) at position R1 (7 position) increases activity and binding affinity.
- Substitution on 6, 8, and 9 positions decreases activity.
- Heterocyclic ring replacement of Ring A has weak activity and affinity compared to phenyl derivatives.
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Ring B
- Alkyl substitution at position R2 increases activity.
- A proton accepting group C=O (carbonyl oxygen) at the 2nd position of ring B is necessary for receptor binding.
- Hydroxy substitution at the 3rd position has comparable potency to CH analogue but is excreted faster.
- Phenyl substitution at the 5th position increases activity.
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Ring C
- Replacing Ring C with an aromatic heterocyclic ring increases anxiolytic activity.
- Halogen substitution at R3 (2’ position) increases activity.
- Substitution at 4’ position is unfavorable for activity.
1,4-Benzodiazepine-2-ones
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Diazepam (Valium)
- First member of the benzodiazepine-2-one group to be introduced.
- Very lipophilic, rapidly and completely absorbed after oral administration.
- Half-life of approximately 46 hours.
- Repeated administration leads to accumulation of active nordazepam.
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Clorazepate Dipotassium
- Considered a prodrug.
- Inactive, but undergoes rapid decarboxylation in the stomach to nordazepam.
- Nordazepam has a long half-life and undergoes hepatic conversion to oxazepam.
- Despite being polar, its rapid conversion in the GI tract to an active nonpolar compound results in a quick onset and long half-life.
L.O.T. Drugs
- Lorazepam, Oxazepam, and Temazepam.
- Do not require oxidative metabolism in the liver.
- No active metabolites.
- Favorable for use in the elderly.
1,2-Annealated 1,4-Benzodiazepines (Triazolobenzodiazepines)
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Alprazolam (Xanax)
- Rapidly absorbed from the GI tract.
- Protein binding is lower (~70%) than most benzodiazepines due to lower lipophilicity.
- Rapid α-hydroxylation of the methyl group to methyl alcohol followed by conjugation results in a short duration of action.
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Triazolam (Halcion)
- Ultra-short-acting hypnotic because it is rapidly α-hydroxylated to 1-methyl alcohol followed by conjugation and excretion.
- Popular for sleep induction, especially in elderly patients, due to less daytime sedation.
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Midazolam
- Short-acting sedative-hypnotic and an induction anesthetic.
- Short half-life (~2 hours).
- Used intravenously.
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Description
This quiz explores the classification and structure of benzodiazepines, focusing on their chemical composition and pharmacological properties. Learn about the significance of the different rings and substitutions that influence their activity and affinity. Brush up your knowledge on the structure-activity relationship of these important drugs.
