BARBITURATES Listen to Audio Thiopental Pentobarbital Phenobarbital Methohexital Secobarbital Thiamylal mechanism of action structure-activity relationships pharmacokinetics effects on organ system drug interactions MECHANISM OF ACTION -depress the reticular activating system (RAS) within the brainstem -preferentially affect the function of nerve synapses rather than axons at clinical concentrations -supress transmission of excitatory neurotransmitters (ex. Acetylcholine) -enhance transmission of inhibitory neurotransmitters (ex. GABA) STRUCTURE-ACTIVITY RELATIONSHIPS derivatives of barbituric acid -hypnotic potency from C5 substitution -anticonvulsant activity from C5 substitution ex. adding a phenyl group instead of C5 -lipid solubility increased from C2 substitution ex. adding a sulfer group instead of C2 -shorter duration of action from methyl substitution at the N1 position PHARMACOKINETICS Absorption -most frequently administered intravenously for induction of general anesthesia in both pediatric and adult patients Distribution -duration of action generally determined by redistribution of the highly soluable barbiturates (ex. thiopental, thiamylal, methohexital) -rapid brain uptake of thiopental due to high lipid solubility and high nonionized fraction despite high protein binding -maximal brain uptake of thiopental within 30 seconds -loss of consciousness generally within 30 seconds -awakening generally within 20 minutes -elimination half life of thiopental approximately 3-12 hours Higher brain and heart concentrations for a given dose in the following conditions: -hypovolemic shock: central compartment volume contraction -severe liver disease: low serum albumin -acidosis: decreased nonionized fractions Biotransformation -primarily involves hepatic oxidation to create inactive water soluable metabolites of barbiturates -methohexital is cleared from the liver 3-4 x's more rapidly than thiopental due to methohexitals high hepatic extraction Excretion -renal excretion is limited to water soluable end products of hepatic biotransformation -high protein binding decreases the glomerular filtration of barbiturates -high lipid solubility increases the renal tubular reabsorption of barbiturates -methohexital is exreted via feces PHARMACODYNAMICS Effects on the Organ Systems Central nervous system -decreased CBF and ICP via cerebral vascular constriction -possible increased cerebral perfusion pressure due a greater decrease in ICP compared to the decrease in MAP -decreased CBF avoids a cerebral injury due to a corresponding decrease in CMR02 -may provide cerebral protection from transient focal episodes of cerebral ischemia (ex.cerebral embolus) -does not protect the brain during global complete cerebral ischemia -may occasionaly have an antianalgesic effect, lowering the threshold to pain stimuli -grand mall seizures are generally rapidly controlled with small doses of thiopental Cardiovascular system -decrease in blood pressure with induction doses due to increased venous capacitance via vasodilation -vasodilation occurs do to depression of the medullary vasomotor center therefore decreases preload to the right atrium -decreased blood pressure stimulates an intact baroreceptor which results in tachycardia -cardiac output generally is maintained with the compensatory increase in heart rate secondary to the decreased blood pressure -cardiac output can dramatically decrease in which the baroreceptors and no longer intact or diminished generally cardiac output changes with administration of thiopental are reflective of: -volume status -basline autonomic tone -pre-existing cardiovascular disease Conditions in which cardiac output may decrease dramatically with the administration of thiopental: -hypovolemia -heart failure CHF -beta blockade Respiratory system -decreases and blunts the medullary ventillatory center response to hypercarbia and hypoxia -possible upper airway obstruction with sedation -apnea generally follows induction doses -decreased tidal volume and respiratory rates associated with emergence and awakening of barbiturates possible bronchospasm during induction using thiopental may be from: -excessive cholinergic nerve stimulation -histamine release -direct bronchial smooth muscle stimulation Hepatic system -decreased hepatic blood flow -stimulating hepatic enzymes increases rate of metabolism of some drugs (ex. digitoxin) -inhibition of cyto p450 slows the rate of metabolism of some drugs (ex. TCA) -may stimulate the enzyme aminolevulinic acid synthase which forms porphyrins which may precipitate acue intermittent porphria Renal system -decreases renal blood flow and GFR proportionally to the decrease in mean arterial pressure Drug Interactions -contrast media -sulfonamides -drugs which compete for the same binding sites of protein binding molecules may increase the free fraction of barbiturates Potentiate the sedative effects of barbiturates: -ethanol -antihistamines -cns depressant medications