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96 Cards in this Set
- Front
- Back
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What was the first barbituric acid with hypnotic activity? What was it's onset and duration?
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Diethylbarbituric acid
Slow onset, long duration |
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What barbiturate has rapid onset, short duration, and profound excitatory side effects?
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Hexobarbital
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What barbiturate was a new era in anesthesia?
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Sodium thiopental
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What is the onset, duration, and side effects of sodium thiopental?
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Rapid onset
Short duration Without excitatory side effects |
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What was one downfall of sodium thiopental?
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Poor understanding of pharmacokinetics: use as an infusion resulting in hypotension and prolonged sleeping times
"Ideal method of euthanasia" Used presently for lethal injection |
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What are all barbiturates derived from?
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Barbituric acid
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What is barbituric acid comprised of?
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A combination of urea and malonic acid
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What is barbituric acid's affect on CNS activity?
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Lacks CNS activity
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What does modifying the structure of barbituric acid do?
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Converts it to a hypnotic barbiturate
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How is hypnotic activity added to barbituric acid?
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Adding side chains at carbon-5
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What determines the potency and duration of action of barbituric acid?
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The length of the side chains
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What determines the class of barbiturate?
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Carbon-2
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What is thiobarbiturate?
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Sulfur atom at carbon-2
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What is oxybarbiturate?
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Oxygen atom at carbon-2
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Which has a faster onset and shorter duration of action? thiobarbiturates or oxybarbiturates?
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Thiobarbiturates
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What does methylation at the 1-nitrogen produce?
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Rapid onset
Short duration of action Increased incidence of excitatory side effects |
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What does a phenyl group at carbon-5 cause?
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Increased anticonvulsant activity
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What is the site of barbiturate action?
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Gamma-aminobutyric acid (GABA) receptor
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What does activation of the GABA receptor cause?
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Increased transmembrane chloride conductance
Hyperpolarization of the cell Functional inhibition of the postsynaptic neuron |
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Barbiturates both ___ and ___ GABA
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Enhance, mimic
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What is the 2-fold mechanism of barbiturates?
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1. Barbiturates decrease the rate of dissociation of GABA from the receptor
2. Barbiturates can directly activate the GABA receptor |
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What is the dose of sodium thiopental for GA?
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3-5 mg/kg
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What is the onset of sodium thiopental?
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10-20 seconds
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When is the peak effect of sodium thiopental?
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30-40 seconds
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What is the duration of sodium thiopental?
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5-15 minutes after single bolus
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What is the dose of methohexital?
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1-2 mg/kg
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What is the onset of methohexital?
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20-40 seconds
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When is the peak effect of methohexital?
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45 seconds
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What is the duration of methohexital?
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5-10 minutes
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What occurs to barbiturates following IV administration?
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The drug mixes rapidly within the central blood pool and is distributed throughout the body tissues
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What is distribution of barbiturates in the body tissues based upon?
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Lipid solubility
Protein binding Degree of ionization Tissue blood flow |
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How long does it take for barbiturates to undergo maximal uptake in the vessel-rich group (i.e. brain)?
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30 seconds: this correlates with induction of anesthesia and unconsciousness
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What does the initial high uptake of drug into the vessel-rich group do to plasma concentration?
What does this cause? |
Uptake into brain and highly perfused tissues causes the plasma concentration to decrease
Results in a reversal of the concentration gradient and for movement of drug between blood and tissue |
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What does the reversal of the concentration gradient cause?
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Redistribution of drug away from the brain to less perfused tissues: leads to recovery of anesthesia
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Where is the initial site of redistribution from the vessel-rich group?
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Muscle group
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How long does it take for skeletal muscle to equilibrate?
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15-20 minutes after injection
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What is the fat:blood partition coefficient for sodium thiopental?
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11:1
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What does the fat:blood partition coefficient of sodium thiopental entail?
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Drug will move from blood to fat as long as the concentration in fat is less than 11x that in blood
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What is a large reservoir for sodium thiopental?
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Fat
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Elimination half-time correlates ____ with the volume of distribution
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Directly
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Elimination half-time correlates ___ with clearance
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Inversely
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What is volume of distribution (Vd)?
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Apparent volume in the body into which a drug dissolves
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What is clearance (Cl)?
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Measure of the ability of the body to eliminate drug
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Are sodium thiopental and methohexital lipid or water soluble?
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Very lipid soluble
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Do sodium thiopental and methohexital have large or small Vd?
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Large Vd: corresponds to lipid solubility
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Which drug has a higher rate of clearance? Sodium thiopental or methohexital?
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Clearance of methohexital is 3x that of sodium thiopental
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What is the elimination half-time of sodium thiopental?
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Sodium thiopental: 12 hours
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What is the elimination half-time of methohexital?
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Methohexital: 4 hours
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Are barbiturates protein-bound?
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Protein binding parallels lipid solubility:
-Highly lipid soluble -Avidly protein bound |
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What part of drug is available to exert an effect?
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The unbound fraction of drug
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What effect does cirrhosis or uremia have on barbiturate action?
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An increased sensitivity to barbiturates
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What drug is most avidly bound?
At what percent? |
Sodium thiopental
80% |
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What plays an important role in the distribution of drug from blood to tissue?
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Ionization
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How does drug exist in the plasma?
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Ionized and nonionized forms
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What form of the drug is lipid soluble and what does this mean?
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Nonionized: drug has access to tissues
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What is pKa?
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The pH value at which 50% of drug exists in ionized form and 50% exists in nonionized form
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What 3 things determines how a drug dissociates?
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1. pKa
2. Drug is a base or acid 3. Environment (pH) |
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"Like drug into like environment"
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More nonionized
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"Like drug into unlike environment"
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More ionized
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Drugs beginning with an electrolyte: acid or base?
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Weak acid
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Drugs ending in "-ide" or "-ate": acid or base?
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Weak base
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Local anesthetics: acid or base?
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Base
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Barbiturates: acid or base?
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Acid
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Morphine: acid or base?
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Base
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Lidocaine:
pKa = 8.1 weak base What happens when injected into patient (pH 7.4)? |
More in the ionized form
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Sodium thiopental:
Weak acid What happens when injected into pH 7.15? |
More in nonionized form
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How is sodium thiopental metabolized?
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Primarily in the liver with a small amount of metabolism in extra-hepatic sites
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Sodium thiopental metabolism:
Where does oxidation occur? Where does desulfuration occur? |
Oxidation of side chain on carbon-5
Desulfuration on carbon-2 |
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What kind of end products does barbiturate metabolism result in and how are these excreted?
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Water soluble end products
Excreted by the kidneys |
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How is methohexital metabolized?
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Exclusively in the hepatocytes
Side chain oxidation to water soluble metabolites |
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Does cirrhosis alter the metabolism of sodium thiopental or methohexital?
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No
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How are barbiturates filtered in the kidney?
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Freely filtered by the glomeruli
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How are barbiturates excreted in the urine?
Why? |
Less than 1% excreted unchanged in urine
High protein binding High lipid solubility (favors reabsorption in tubules) |
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What do barbiturates do to the CNS?
What do they treat? |
Cerebral protection
Treatment of increased intracranial pressure (ICP): administered to decrease ICP that remains elevated despite hyperventilation of the lungs and drug-induced diuresis |
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Barbiturates are potent vaso___.
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Vasoconstrictors
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What is the affect of barbiturates on CBF, cerebral blood volume, and ICP?
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Decreased CBF
Decreased cerebral blood volume Decreased ICP |
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What is the affect of barbiturates on CMRO2? Compared to CBF?
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Reduction in CMRO2: greater than reduction of CBF
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What is the affect of barbiturates on EEG activity?
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Induced electrical silents-- isoelectric EEG
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What is the relationship between maximum suppression of EEG and reduction in CMRO2?
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Maximum suppression of EEG = 55% reduction in CMRO2
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What does of sodium thiopental is required for induced electrical silence?
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40 mg/kg
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What is the relationship between barbiturates and hemodynamics?
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Potential for hemodynamic compromise with high-dose barbiturates
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What can high-dose barbiturates jeopardize?
What treatment would this require? |
May jeopardize cerebral perfusion pressure
Be prepared with inotropes and vasopressors |
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When do barbiturates provide cerebral protection?
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During focal ischemic events (embolic phenomena, focal hemorrhagic events/CVA)
No protection provided during global ischemia |
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Do barbiturates have anticonvulsant activity?
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Sodium thiopental: potent anticonvulsant
Methohexital: seizure activity on EEG seen after administration (methyl = excitatory) |
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Barbiturates affect on blood pressure and 3 reasons why:
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Mild and transient decrease in systemic blood pressure:
1. Depression of medullary vasomotor centers 2. Decreased SNS outflow 3. Peripheral vasodilation |
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What compensates for barbiturates' affect on cardiovascular/hemodynamics?
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Baroreceptor reflex response
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What is the affect of barbiturates on respiration? 2 results?
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Dose-dependent depression of medullary and pontine ventilatory centers:
1. Decreased response to hypercarbia and hypoxia 2. Apnea likely after induction dose |
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Are laryngeal reflexes depressed with barbiturate administration?
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No, unless large doses given
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What occurs after 2-7 days of sustained barbiturate administration?
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Enzyme induction:
-Stimulate 20-40% increase in hepatic microsomal enzyme activity -Accelerate metabolism of drugs |
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What enzyme activity do barbiturates stimulate?
What does this result in? |
Stimulate activity of the enzyme D-aminolevulinic acid synthetaste
Production of heme is accelerated: precipitate/exacerbate acute intermittent porphyria |
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Do barbiturates have an effect on uterine tone?
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No
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Do barbiturates cross the placenta?
What is the affect on the fetal circulation? |
Readily crosses placental barrier
Fetal plasma concentrations less than maternal: -Fetal liver clearance -Dilution by fetal blood |
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What is a major potential complication of barbiturate administration?
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Intraarterial injection
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What does intraarterial injection result in?
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Immediate vasoconstriction and intense pain
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What are possible sequelae from intraarterial injection?
How does this occur? |
Gangrene and nerve damage
From precipitation of thiopental crystals in the artery leading to occlusion of distal circulation |
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What are 4 treatments for intraarterial injection of barbiturates?
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1. Saline injection to dilute the drug
2. Lidocaine, papaverine, phenoxybenzamine, phentolamine-- vasodialton 3. Heparin 4. Stellate ganlion or brachial plexus block-- block sympathetic tone, dilate |
