Barbiturates
BARBITUATES
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
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
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
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