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 fairlyrapid 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 minimalcardiovaskuler 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.