Local Anesthetic failure in the above scenario, when hepatic parameters are normal/near-normal, is explained based on the factors leading to decreased bioavailability of the drug in the target area.

        For local Anesthetic failure, since the drug is made available directly at the site where the action is necessary (local drug delivery), any factor however remote the origin, should be capable of acting at the site of drug delivery (in this case, the site of local anesthetic injection).

For any drug to fail in its action, the reason can be either

1. the decreased bioavailability of the drug, in other words the decreased active form of the drug at the site of action (and/or)

2. the lack of the receptor site for binding of the drug.

        Any of the above conditions is the primary cause of the drug failure and can be caused by numerous ways, some dependent and some independent of one another. It is various factors that decide the final outcome.

In our case of a neo-alcoholic (to mean a new alcoholic) or a party drinker (occasional alcoholic) both of whom have a greater chance of having a healthy and properly functioning liver and have taken a slightly excess alcohol in the night and "hangs over" (comes over) to the dental clinic for a procedure necessiting local anesthetic use. The local anesthetic fails.

Before we go to this particular scenario, let us analyse a few causes of local anesthetic failure...

1. Wrong technique

2. Inadequate dose

3. Lipid solubility-->related to efficacy or success!

4. Local environment-->relates to efficacy or success!

5. Protein Binding-->relates to potency or duration!

        The first two are clinician controlled and let us assume the clinician to have used the perfect technique and appropriate dose and hence assumed to be without any bearing on the outcome in our case!
 

        The last three factors each can play a variable role in the outcome.

Lipid solubility:

        The alcohol, metabolises to acetaldehyde, acetic acid and later finally to carbon di oxide and water. The details of the reaction pathways are beyond the scope of this discussion and the readers are referred to any standard biochemistry and/or pharmacology texts.

        Alcohol metabolism takes place at constant rate irrespective of the amount consumed based on the enzyme action of alcohol dehydrogenase of liver, which in turn is dependent on the liver function ( in our case, we have a patient with normal healthy liver!)
 

        The alcohol enters circulation and begins to distribute in its native form in the tissues in proportion to the alcohol consumed! The metabolites, acetaldehyde (toxic), acetic acid (non toxic) and the final products, carbon di oxide and water too circulate and distribute with time gradually getting eliminated by the various excretory routes.

        Now, when the patient presents to the clinic, variable amount of metabolism might have occured and variable amounts of alcohol and its metabolites will be circulating in the blood and concentrated in the tissues. (depending on the time elapsed since and the amount of alcohol consumed the previous day/night!)

        Alcohol-->acetaldehyde--->acetic acid...themselves being lipid solvents and local anesthetics being lipid soluble the alcohol and its metabolites may directly inactivate the local anesthetic or in other wards dissolve the local anesthetic and consequently interfere with their availability and action(??)**

Local environment:

        Acidemia can cause local anesthetic failure due to consequent acidic enviroment in the tissue or the target site.The
action being because of the high fraction of ionised form of drug which cannot cross the lipid nerve membrane and hence the inability to reach the receptors in the internal nerve membrane.
 

Alcohol consumption in large quantities can result in acidosis in many mechanisms:

1. Due to increased glycolysis resulting in increased lactate-->lactic acidosis.

2. alcohol is a central respiratory depressant--> causing respiratory acidosis secondary to hypoventilation.

3. Carbon di oxide is also a metabolic end product of alcohol metabolism and can accumulate in blood causing acidemia!

4. Tissue hypoperfusion resulting in inefficient buffering action leading to acidic environment

5. Ketoacidosis especially in the case of binge drinking without calorie intake (though more common in chronic abusers..so let us consider this as the last possibility in our case!)

        The efficacy of the local anesthetic is related to its lipid solubility and its availability at the receptor site after it crossed the nerve membrane which in turn is mainly dependent on the local pH (among various other factors!).
 

        But it must be mentioned that if an acute alcoholic binge induces extensive vomiting, potentially severe alkalosis may result from losses of fluid, salt, and stomach acid.

The potency or duration of action:

        This is related to its protein binding and its metabolism as also its affinity to the receptor site or release from the receptor site:The serum protein levels are not changed much with a single dose of alcohol since albumin has a long half life of around 10.5 days and hence decreased protein levels and consequent increased free plasma level of LA, secondary to single alcohol binge is NOT possible.

        But, the serum protein binding is impaired in the case of acidemia and hypercarbia. This infact, can result in toxicity though the effects might not be manifested until the blood chemistry returns to normal when there can be sudden increase in free plasma concentration of the local anesthetic which might be disproportionate with the rate of protein binding.(??) But again the drug if metabolised and cleared rapidly might not produce toxicity!

        Another risk is that due to the decreased clinical efficacy observed on local anesthetic administration in this patient, there is a chance for excess dose administration to the patient (for the sake of anesthesia which is still not achieved!), which will NOT produce clinical toxicity at once due to its ionised state (due to acidemia), but when blood chemistry reverts to normal later, the local anesthetic might easily overwhelm the serum proteins available for binding the local anesthetic and consequent local anesthetic toxicity!(??) Again the toxic effect of course may not occur since the local anesthetic might as well be metabolised by liver and excreted before attaining toxic levels!
 

Conclusion

        The clinically common local anesthetic failure observed in a person with normal hepatic parameters ter an acute alcohol consumption appears to be related to the tissue chemistry which in turn is related to the blood chemistry. The acidemia, secondary to alcohol consumption which in turn results in local acidic environment can be the cause of decreased non-ionised form of the drug available for transfer across the nerve membrane to reach the receptor site in the internal nerve cell membrane!
 

        Explanations related to decreased metabolism due to impaired hepatic clearance or decreased serum proteins available for binding secondary to liver disease can only explain the potential risk of toxiciy and cannot explain the local anesthetic failure in the tissues since, the drug first reaches the site of action (nerve) before entering the circulation before entering the metabolic pathway. A "neo-alcoholic" or a really "controlled occasional party drinker" has very less chance of having alcoholic hepathopathy and hence the above toxicity consideration does not apply to our scenario too.

        All the above discussion has almost exclusively amide local anesthetics in consideration since they are the most commonly used local anesthetics! The esters however, can begin to be metabolised at the site itself where it will be hydrolysed by the enzymes in plasma itself as soon as it is exposed to the tissue fluids and blood and have not been considered in this scenario though many of the considerations do apply to them also!
 

        The explanation was arrived at by inference from the various pharmacokinetic and pharmacodynamic factors of local anesthetic and metabolic pathways of alcohol and not from any single reference which is largely missing in literatures in this particular context of acute alcohol consumption.