Benzodiazpines |

Benzodiazpines

Sat, 11/03/2007 - 11:18 — oxygen

Benzodiazepines Listen to Audio midazolam (versed) diazepam (valium) lorazapam (ativan) mechanism of action structure-activity relationships pharmacokinetics effects on organ systems drug interactions MECHANISM OF ACTION -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 PHARMACOKINETICS 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 PHARMACODYNAMICS 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 Drug Interactions: 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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