benzodiazepin

mechanism of action

benzodiazepin interact with specific receptors in the central nervous system, particularly in the cerebral cortex. BEnzodiazepin receptor binding enhances the inhibitor effects of various neurotransmitters. for example benzodiazepin receptor binding, which increases the membrane conductance of chloride ions. this causes a change in membrane polarization that inhibits normal neuronal function. flumazenil(an imidazobenzodiazepin) is as specific benzodizepin receptor antagonist that effectively reverses most of the central nervous system effect of benzodiazepines (see chapter 15).

structure activity relationship

the chemical structure of benzodizepines includes a benzene ring and a seven member dizepine ring (figure 8-5). subtitutions at various positions on these rings affect potency and biotransformation. the imidazole ring of midazolam contributes to its water solubility at low pH.The insolubility of diazepam and lorazepam in water requires parenteral preparations to contain propylene glycol, which has been associated with venous irritation.

pharmacokinetics

a. absorption : benzodiazepines are commonly administered orally, intramuscularly and intravenously to provide sedation or induction of general anesthesia (table 8-3). diazepam and lorazepam are well absorbed from the gastrointestinal tract, with peak plasma levels usually achieved in 1 and 2 hours,recpectively. although oral midazolam has not been approved by the U.S. Food and Drug Administration, this route of administration has been popular for pediatric premedication.

intramuscular injection of diazepam is painful and unreliable. in contrast, midazolam and lorazepam are well absorbed after intramuscular injection, with peak levels achieved in 30 and 90 minutes, respectively.

induction of general anesthesia relies upon intravenous administration.

b. distribution : diazepam is quite lipid soluble and rapidly penetrates the blood brain barrier. Although midazolam is water soluble at low pH, its imidazolam ring closesat physiologic pH, causing an increase in its lipid solubility (figure 8-5). the moderate lipid solubility of lorazepam accounts for its slower brain uptake and onset of action. redistribution is fairly rapid for the bonzodiazepines (initial distribution half- life is 3-10 minutes) and, like the barbiturates, is reponsible for awakening. although midazolam is frequently used as an induction agent, none of the benzodiazepines can match thiopental's rapid onset and short duration of action. all three benzodiazepines are highly protein-bound.

c. biotransformation

the benzodiazepin rely upon the liver for biotransformation into water soluble glucuronide and products. the phase I metabolites of diazepam are pharmacological active.

slow hepatic extraction and a large volume of distribution result in a long elimination half life for diazepam (30 hours). although lorazepam also has a low hepatic extraction ratio, its lower lipid solubility limits its volume of distribution, resulting in a shorter elimination half life (15 hours). nonetheless, the clinical duration of lorazepam is often quite prolonged owing to a very high receptor affinity. in contrast, midazolam shares diazepam's volume of distribution, but its elimination half- life (2 hours) is the shortest of the group because of its high hepatic extraction ratio.

d. excretion

the metabolites of benzodiazepin biotransformation are excreted chiefly in the urine. enterohepatic circulation produce a secondary peak in diazepam plasma concentration 6-12 hours following administration.

effects on organ system

a. cardiovaskuler : the benzodiazepin display minimal cardiovaskuler depressant effects even at induction doses. arterial blood pressure, cardiac out put, and peripheral vascular resistance usually decline slighly, while heart rate sometimes rises. Midazolam tends to reduce blood pressure and peripheral vascular resistance more than dose diazepam.

b.respiratory : benzodizepines depress the ventilatory response to CO2. this depressions is usually insignificant unless the drugs are administered intravenously or in association with other respiratory depressants. although apnea may be less common than following barbiturate induction, even small intravenous doses of diazepam and midazolam have resulted in respiratory arrest. the steep dose-response curve, slightly prolonged onset ( compared to thiopental or diazepam), and high potency of midazolam necessitate careful titration to avoid overdosage and apnea. ventilation must be monitored an all patients receiving intravenous benzodiazepines and resucitation equipment must be immediately available.

c. cerebral : benzodiazepines reduce cerebral oxygen consumption, cerebral blood flow, and intracranial pressure but not to the extent the barbiturates do. they are very effective in preventing and controling grand mal seizure. oral sedative doses often produce antegrade amnesia,useful premedication property . the mild muscle- relaxant properties of these drugs is mediated at the spinal cord level, not at the neuromuscular junction. the antianxiety, amnesic, and sedative effects seen at low doses progress to stupor and unconsciousness at induction doses.