Benzodiazpines
Benzodiazepines
midazolam (versed)
diazepam (valium)
lorazapam (ativan)
mechanism of action
structure-activity relationships
pharmacokinetics
effects on organ systems
drug interactions
-interact with receptors in the CNS (mainly the cerebral cortex) which facillitate GABA conductance of chloride ions intracellular
-affects the membrane polarization which inhibits normal neuronal function hence generally causes sedative effects
STRUCTURE-ACTIVITY RELATIONSHIPS
-benzene ring + seven membered diazepine ring
-potency and biotransformation affected by varying positions of substitutions on the ring structures
ex.midazolam exist as a imidazole ring at a physiologic pH which allows for IV injection for less painful than other benzodiazepines
midazolam exist as a open water soluable molecule at a more acidic environment
short-acting potent benzodiazepine which is very lipid soluable with rapid redistribution
Absorption:
-commonly administered: orally, IM, and IV
-orally: diazepam and lorazepam well absorbed by the GI tract: peak levels 1 hour, and 2 hours, respectively
midazolam not approved by USDA although more commonly used for oral premedication of pediatric patients
-intramuscular: diazepam is painful and unpredictable when given IM
IM midazolam and lorazepam well absorbed with peak levels in 30 and 90 minutes, respectively
intravenous: midazolam exist as imidazole ring at physiologic pH which is very lipid soluable with rapid onset
Distribution
-diazepam is lipid soluable therefore rapidly penetrates the BBB
-midazolam is initially water soluable at low pH but then closes at physiologic pH and becomes highly lipid soluable
-lorazepam is moderately lipid soluable therefore has a slower onset of action associated with a slower uptake from the brain
redistribution for benzodiazepines is rapid and is responsible for awakening of the patient from sedation
initial distribution half life is 3-10 minutes
Biotransformation
-benzodiazepines are metabolized by the liver to form water soluable glucuronide end products
-phase I metabolites of diazepam are active therefore may have prolonged effects
elimination half life of diazepam: 30 hours
elimination half life of lorazepam 15 hours
elimination half life of midazolam 2 hours
elimination half life and Vd account for the differing times
ex. midazolam has a very high hepatic extraction ratio
Excretion
-metabolites mainly excreted in the urine
-renal failure pts may have prolonged sedative effects after recieving midazolam due to the accumulation of a conjugated metabolite
-conjugated metabolite: alpha-hydroxymidazolam
Effects on Organ Systems
Central nervous system
-reduce CMR02
-reduce CBF
-reduce ICP (less reductions than from barbituates)
-effective in preventing and controlling grand mal seizures
-antegrade amnesia
Cardiovascular system
-at inductions doses: minimal cardiodepressant effects
-slight decline in blood pressure, cardiac output, and peripheral vascular resistance
-heart rate may increase perhaps from drug induced vagolysis
-midazolam may reduce blood pressure more than diazepam
Respiratory system
-blunted reponse to increasing PaCO2
-ventilatory depressant effects
-careful titration especially with midazolam
Diazepam: cimetidine reduces metabolism due to inhibition of cytochrome p450
heparin increases the free drug concentration by displacing diazepam from binding proteins
Midazolam: erythromycin decreases metabolism therefore an increases of 2-3 times the prolongation
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