Benzodiazepines and GAs

Question 1

Major Drugs Used in Anesthesia

Answer 1

• Anesthetics (general, local)
• Sedatives
• Neuromuscular Relaxants
• Cholingerics (anticholinesterase agents)
• Analgesics

Question 2

Benzodiazepines

Answer 2

Technically, name refers only to A and B fused ring system. General usage commonly means the tricyclic structure, as all agonists include C ring.

Question 3

Diazepam

Answer 3

• Synthesized 1961 by Sternbach (Hoffmann-La Roche)
• Mw 284.7;
• Slight water solubility; highly lipid soluble.
• Each mL contains 5 mg diazepam compounded with 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate and benzoic acid as buffers, and 1.5% benzyl alcohol as preservative.

Question 4

Lorazepam

Answer 4

• Ativan. Mw 321.2;
• Sol. In H2O 0.08 mg/ml; less lipophilic than diazepam.
• Lorazepam is a nearly white powder almost insoluble in water.
• Each mL of sterile injection contains either 2.0 or 4.0 mg of lorazepam, 0.18 mL polyethylene glycol 400 in propylene glycol with 2.0% benzyl alcohol as preservative

Question 5

Midazolam

Answer 5

• Mw 325.8; Insoluble in H2O (pH > 4) Hydrochloride (Versed).
• Product label: Midazolam hydrochloride is a water-soluble benzodiazepine available as a sterile, parenteral dosage form for intravenous or intramuscular injection use only.
• Each mL contains midazolam hydrochloride equivalent to 1 mg midazolam compounded with 0.8% sodium chloride and 0.01% edetate disodium, and sodium hydroxide and/or hydrochloric acid for pH adjustment (pH 2.9 to 3.5).

Question 6

Flumazenil

Answer 6

• A benzodiazepine antagonist; Mw 303.3.
• It is insoluble in water, but slightly soluble in acidic aqueous solutions.
• Flumazenil injection is available as a sterile parenteral dosage form for intravenous administration. Each mL contains flumazenil 0.1 mg. In addition, the following inactive ingredients are included: methylparaben 1.8 mg, propylparaben 0.2 mg, sodium chloride 0.9 %, edetate disodium 0.01%, acetic acid 0.01%, hydrochloric acid and/or sodium hydroxide to adjust pH to 3.5 to 4.5, and water for injection.

Question 7

Barbiturates - Pentobarbital Sodium

Answer 7

• Nembutal; Mw248.26; pKa 8.0.
• Freely sol in H2O (conjugate acid insoluble in H2O). pH of soln for injection 9- 10.5.
• Aqueous solutions of pentobarbital sodium are unstable.
• Drug supplied for injection in alcohol 10% and propylene glycol 20-40%.

Question 8

Barbiturate Synthesis

Answer 8

Question 9

Tautomeric forms of barbituric acid

Answer 9

tautomeric forms involve simple bond rearrangements.

Question 10

Methohexital Sodium

Answer 10

• Brevital; Mw 284.3; pKa 8.3. pH of 1% soln in sterile H2O 10-11.
• Ultrashort- acting barbiturate anesthetic.
• Methohexital powder should be stored at room temperatures < 25° C. Solutions in sterile H2O are stable at least 6 weeks. Solutions in 5% dextrose or 0.9% NaCl stable ≤ 24 hours.
• Incompatible with acidic solutions (e.g. atropine sulfate, metocurine iodide, succinylcholine chloride) or those containing phenol as a preservative. Incompatible with silicone.

Question 11

Thiopental

Answer 11

• Pentothal; Mw 264.33; pKa 7.4. Sol in H2O (conjugate acid insoluble in H2O)
• Sterile thiopental sodium is a mixture of sterilized thiopental sodium (91.7%) with anhydr sodium carbonate as buffer. A 2.5% (w/v) aq soln is strongly alkaline, with pH about 10.5.

Question 12

Redistribution of thiopental after intravenous bolus injection

Answer 12

Question 13

Propofol

Answer 13

• Formulated as an emulsion (Diprivan) containing: soybean oil, glycerol, and egg lecithin
• adjusted to pH 7-8.5
• Generic formulations are now available that contain sulfite or benzyl alcohol.

Question 14

Why must emulsions be basic?

Answer 14

If acidic the emulsion will start “cracking” where the little droplets form to combine larger droplets and you can create an oil later on the top

Question 15

Eccipient

Answer 15

Eccipient- microbes loves fats and phospholipids so single use vials are the only used now so an EDTA (ethylene acid) was added that scavengers trace mets in the emulsions, trace mets are what microbes need to live.

Question 16

Ketamine

Answer 16

• Ketamine hydrochloride is a nonbarbiturate anesthetic.
• formulated as a slightly acidic (pH 3.5-5.5) sterile solution for IV/IM injection in concentrations containing the equivalent of either 10, 50 or 100 mg ketamine base per milliliter. The 10 mg/mL solution has been made isotonic with sodium chloride
• Note the structural similiarities between ketamine and phencyclidine

Question 17

Etomidate

Answer 17

• A short-acting anesthetic-hypnotic agent, undergoes hydrolysis pKa – 4.2
• Package insert: Etomidate Injection, USP is a sterile, nonpyrogenic solution. Each milliliter contains etomidate USP, 2 mg, propylene glycol 35% v/v.
• pH is 6.0 (4.0 to 7.0).
• intended for the induction of general anesthesia by intravenous injection.