ETOH abuse and MAC

heartICU · Jan 29, 2005

Would someone mind explaining why chronic ETOH abuse increases MAC? I'm thinking it has something to do with down-reglation of GABA receptors but can't convine myself of it ... am I way off base? Thanks in advance!
- Kat

I'm just guessing here (only finished my first semester) but I would imagine it has something to do with cytochrome P450 system....with chronic ETOH abuse, the P450s are constantly "on guard" ready to metabolize whatever comes along. Since many of the drugs we use are metabolized by P450, the fact that they are ready to go at a moment's notice may explain why these patients need more. It would make sense that someone who is acutely intoxicated (not a chronic ETOH-er) will require less anesthetic....their liver enzymes are not used to the constant influx of alcohol, and therefore are all busy metabolizing the ETOH that is already in the system, and do not have the capacity to metabolize anything else until the alcohol is done. This is a very rudimentary way of explaining it....hopefully that made sense...

BigDave · Jan 29, 2005

I think it is a little bit of both answers, GABAa down regulation and P450 interaction. Actually chronic ETOH use is an inducer of the 2E1 substrate. This would tend to require an increase in MAC for halo/iso/sevo/enflurane (cause quicker metabolism). I can assume that there are an increased number of the 2E1 enzymes thanks to tipping the bottle.

Here is a great chart of the P-450 drug interactions:

http://medicine.iupui.edu/flockhart/table.htm

TraumaNurse · Jan 29, 2005

HeartICU is correct. In chronic ETOH abuse (as well as other drugs such as barbs, benzos and ketamine), there is an increase in the synthesis of cytochrome P-450. This increases the amount of hepatic microsomal enzyme activity and therefore more rapid metabolism of certain drugs that also use the P450 pathway. This increases patient tolerance levels.

Acute intoxication will decrease MAC because of the CNS depression of the ETOH that already exists.

The opposite occurs with drugs such as cimetidine which can prolong the effects of many drugs because the hepatic enzymes are inhibited.

I find this whole thing amazing to witness. I had to give a slight female about 700mg of Propofol, plus versed and fentanyl for a relatively short MAC case yesterday. She was a heavy smoker and drinker (and probably other stuff too) and therefore VERY enzyme induced! The flip side is the non-enzyme induced healthy person who is completely snowed and apneic with 0.5 mg of versed and 40mg of propofol.

Okay, back to studying now.

jewelcutt · Jan 29, 2005

I'm just vaguely trying to pull it from my head but I think it has to do with an up regulation and drug metabolizing enzymes

deepz · Jan 29, 2005

......I had to give a slight female about 700mg of Propofol, plus versed and fentanyl for a relatively short MAC case ....

One hard-partying patient I had for a 4-quad bleph MAC sedation required a total of 2600 mg propofol (yes, 13 vials) plus a total of 20 mg Versed to keep her on the table, and some ketamine and fentanyl also. The Bard InfusOR pump at the end was turned up to the max pump rate and *still* she required boluses on top of that. Amazing what people do to themselves.

deepz

mwbeah · Jan 29, 2005

the induction of the enzyme system is one component and here is an explanation of the gaba component.

use-dependent regulation of gabaa receptors.

barnes em jr.

department of biochemistry, baylor college of medicine, houston, texas 77030, usa.

prolonged occupancy of gabaa receptors by ligands, including gaba and benzodiazepine agonists, sets in motion a series of mechanisms that can be termed use-dependent regulation. these mechanisms can be subdivided into two distinct pathways, one for gabaa receptor downregulation and another for upregulation. treatment of cortical neurons with gaba or benzodiazepines in cultures opens the pathway for gabaa receptor downregulation, which includes (in putative temporal order): (1) desensitization (tachyphylaxis), (2) sequestration (endocytosis) of subunit polypeptides and uncoupling of allosteric interactions between gaba and benzodiazepine binding sites, (3) subunit polypeptide degradation, and (4) repression of subunit gene expression. the end-point of gabaa receptor downregulation, a reduction in receptor number, is postulated to be established initially by degradation of the receptor protein and then maintained by a diminished level of de novo synthesis. benzodiazepine treatment of many preparations, including cells expressing recombinant gabaa receptors, may elicit only desensitization, sequestration, or uncoupling, without a decline in receptor number. components of the gabaa receptor downregulation pathway are also evoked by chronic administration of gabamimetics, benzodiazepines, barbiturates, and neurosteroids in animals. this downregulation correlates with the establishment of tolerance to and physical dependence on the pharmacological effects of these drugs, suggesting a cellular model for this behavior. the upregulation of gabaa receptors is observed as one of the neurotrophic actions of gaba, primarily in cultured cerebellar granule cells. upregulation in culture is caused by enhanced expression of genes for gabaa receptor subunits and correlates with the establishment of gabaergic circuitry in the developing cerebellum. thus, both the upregulation and downregulation of gabaa receptors appear to represent use-dependent pathways for guiding synaptic plasticity in the vertebrate central nervous system.

hope this helps.

mike

An Yogi · Jan 29, 2005

I'm just guessing here (only finished my first semester) but I would imagine it has something to do with cytochrome P450 system....with chronic ETOH abuse, the P450s are constantly "on guard" ready to metabolize whatever comes along. Since many of the drugs we use are metabolized by P450, the fact that they are ready to go at a moment's notice may explain why these patients need more. It would make sense that someone who is acutely intoxicated (not a chronic ETOH-er) will require less anesthetic....their liver enzymes are not used to the constant influx of alcohol, and therefore are all busy metabolizing the ETOH that is already in the system, and do not have the capacity to metabolize anything else until the alcohol is done. This is a very rudimentary way of explaining it....hopefully that made sense...

The question referred to MAC...inhaled agents. Question for you (or other SRNAs)--How much are inhaled anesthetics metabolized (in particular, desflurane, isoflurane, and sevoflurane; halothane is an exception)? Do you think enzyme induction would be a factor?

Acute vs chronic intoxication: A chronic drinker can be acutely intoxicated. The immediate effect of alcohol on the CNS will enhance the sedative-hypnotics effects, i.e. need less to go to sleep. They're already started without you! However, with enzyme induction, many drugs will be metabolized more rapidly than in a nonalcoholic patient.

BigDave · Jan 29, 2005

They're already started without you! I like that....

versatile_kat · Jan 30, 2005

The question referred to MAC...inhaled agents. Question for you (or other SRNAs)--How much are inhaled anesthetics metabolized (in particular, desflurane, isoflurane, and sevoflurane; halothane is an exception)? Do you think enzyme induction would be a factor?
Acute vs chronic intoxication: A chronic drinker can be acutely intoxicated. The immediate effect of alcohol on the CNS will enhance the sedative-hypnotics effects, i.e. need less to go to sleep. They're already started without you! However, with enzyme induction, many drugs will be metabolized more rapidly than in a nonalcoholic patient.

This is the reason I didn't think P450 had THAT much to do with it ... Iso and Des are less than 1% metbolized, while Sevo and Enflurane are 2-3% and 2-5%, respectively. Which led me to believe that it dealt more with the GABA receptor. So is it more GABA effect than P450? Thanks for all the insight everyone.

jwk · Jan 30, 2005

One hard-partying patient I had for a 4-quad bleph MAC sedation required a total of 2600 mg propofol (yes, 13 vials) plus a total of 20 mg Versed to keep her on the table, and some ketamine and fentanyl also. The Bard InfusOR pump at the end was turned up to the max pump rate and *still* she required boluses on top of that. Amazing what people do to themselves.
deepz

I think her eyelids are the least of her problems :cheers: :rotfl:

An Yogi · Jan 30, 2005

This is the reason I didn't think P450 had THAT much to do with it ... Iso and Des are less than 1% metbolized, while Sevo and Enflurane are 2-3% and 2-5%, respectively. Which led me to believe that it dealt more with the GABA receptor. So is it more GABA effect than P450? Thanks for all the insight everyone.

That was exactly my point. The low lipid soluble inhaled anesthetics have a VERY LOW rate of metabolism. Even if enzyme induction lead to a doubling of metabolic rate, there would still be a minimal effect on MAC.

Ethanol has effects on many receptors including GABAa, serotonin (5HT3A, ion channel), NMDA, and neuronal nicotinic acetylcholine receptors. Inhaled anesthetics also work on these receptors. Chronic alcohol consumption leads to the development of tolerance, or a reduced behavioral or physiological response to the same dose. Cross-tolerance can develop, i.e. receptor changes due to chronic etoh consumption can reduce the receptor's response to other drugs, in this case, inhaled anesthetics.

(paraphrased from Goodman and Gilman).

An Yogi