Term
| What is the mechanism of action of barbiturates? |
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Definition
They enhance the inhibitory effects of the pentameric neurotransmitter, GABA. When GABA receptors are activated, chloride conductance increases resulting in hyperpolarization of post-synaptic cell membranes.
They also decrease the dissociation rate of GABA from its binding site, thus increasing the duration of action of GABA at the receptor
They also depress the reticular activating system (RAS) which is responsible for maintenance of wakefulness.
They also inhibit excitatory glutamate AMPA receptors |
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Term
| T/F. Barbiturates enhance the PRE and POST-synaptic effects of GABA. |
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Definition
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Term
What subunits does the GABA receptor consist of?
Where does GABA bind?
Where do benzodiazepines bind? |
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Definition
Two Beta-1, two alpha-1, and one gamma-2
GABA binds at the two Beta subunits
Benzos bind at the one Gamma-2 subunit |
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Term
| What is the onset and duration of action of barbiturates largely based on? |
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Definition
| Lipid solubility (partition coefficient). The more lipid soluble the more rapid the onset and the shorter the duration (highly redistributes) |
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Term
| What is the parent compound for barbiturates? |
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Definition
| Barbituric acid, which has no sedative properties |
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Term
A) Why do thiobarbiturates have such a high liid solubulity?
B) What does addition of a phenyl group at C-5 do to the structure of barbiturates?
C) What does addition of a methyl group at the ring N atom do? |
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Definition
A) D/T replacement of C-2 oxygen with sulfur
B) enhances anticonvulsant activity (phenobarbital)
C) shortens duration of action (methohexital) |
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Term
| Explain barbiturate metabolism |
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Definition
>Largely metabolized
>primary metabolic pathway is hydroxylation to inactive metabolites
> N-glucosylation also occurs (more evident in oriental populations)
> Barbs are potent inducers of the hepatic microsomal enzyme system (P450), which results in an increased metabolic rate of barbs as well as other drugs normally metabolized by this system. |
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Term
T/F. Barbs will (increase/decrease) the metabolic rate of drugs that are metabolized by hepatic microsomal enzyme system.
What are some examples of these drugs? |
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Definition
Increase;
oral anticoags, phenytoin, TCAs |
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Term
| What does hydroxylation do? |
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Definition
| Adds a hydroxyl group (-OH) which makes the compound more water soluble and ready for excretion |
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Term
| What are the clinical uses for barbiturates? |
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Definition
| Induction of anesthesia, anticonvulsants, neuropsychiatric exams (Wada speech test) prior to neurosurgery, cerebral edema and brain protection |
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Term
| Is the therapeutic window with barbs wide or narrow? |
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Definition
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Term
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Definition
> Onset 10-15 seconds
> Very lipid soluble
> Distributes into brain well and then rapidly redistributes into fatty tissues
> metabolized by P450 system
> half life: 6 hours
> half life of effect: few minutes
> repeated administration will fill storage sites (fats) and can lead to long DOA
> Lowers pain threshold- increases sensitivity to pain
> potent resp. depressant (often apnea during induction)
> myocardial depressant and vasodilatory effects lower BP |
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Term
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Definition
> similar to thiopental, but 3X potency
> metabolized by P450, but faster than thiopental (d/t less lipid solubility)
> Loss of effect still mainly d/t redistribution
> recovery faster than TPL with multiple doses |
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