Ethanol pharmacodynamics

The pharmacodynamic effects of ethanol are complex, and any attempt to link its actions to specific neurotransmitters or isolated brain regions is simplistic. A complicated neural network involved in the actions of ethanol accounts for its reinforcing, intoxicating, and abstinence effects. At the present time, use of medications that target neurotransmitters and neuromodulators affected by ethanol represents a reasonable strategy for the development of pharmacotherapies that reduce the reinforcing effects of alcohol and the craving and withdrawal symptoms that commonly occur in the context of alcohol dependence. 

The effects of ethanol on bodily functions, e.g., those of the brain, heart, and liver, are dependent upon the systemic concentrations of ethanol over time. Therefore, the pharmacokinetics of ethanol play a pivotal role in the pharmacodynamic actions of ethanol and of its metabolic product acetaldehyde [6],... 

Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (see Chapter 23)—a feature of some clinical importance, as explained below. The mechanisms responsible for tolerance to sedative-hypnotics are not well understood. An increase in the rate of drug metabolism (metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates, but changes in responsiveness of the central nervous system (pharmacodynamic tolerance) are of greater importance for most sedative-hypnotics. In the case of benzodiazepines, the development of tolerance in animals has been associated with down-regulation of brain benzodiazepine receptors. Tolerance has been reported to occur with the extended use of zolpidem. Minimal tolerance was observed with the use of zaleplon over a 5-week period and eszopiclone over a 6-month period. 

Interactions between ethanol and other drugs can have important clinical effects resulting from alterations in the pharmacokinetics or pharmacodynamics of the second drug. 

A pharmacodynamic interaction involves either inhibition or enhancement of the clinical effects of the victim drug as a consequence of similar or identical end-organ actions. Examples are the increase or decrease of the sedative-hypnotic actions of benzodiazepine agonist drugs due to coadministration of ethanol or... 

Tuk B, van Gool T, Danhof M. 2002. Mechanism-based pharmacodynamic modeling of the interaction of midazolam, bretazenil, and zolpidem with ethanol. J Pharmacokinet Pharmacodyn 29 235-250. 

Pharmacokinetic and pharmacodynamic profiles of olanzapine have been extensively reviewed (266). Olanzapine does not inhibit CYP isozymes, and no clinically significant metabolic interactions were found of olanzapine with aminophylline, biperiden, diazepam, ethanol, fluoxetine, imipramine, lithium, or R/S-warfarin. 

Alcohols and aldehydes are metabolized by liver dehydrogenases that are nonmicrosomal and by nonspecific liver enzymes that are important in the catabolism of endogenous compounds. Ethanol is a special example of a compound whose metabolism is clinically relevant in that ethanol may interact with prescribed pharmaceuticals either metabol-ically or pharmacodynamically. Ethanol is metabolized first to acetaldehyde by alcohol dehydrogenase and then to acetic acid by aldehyde dehydrogenase, as shown in Scheme 11.29. These enzymes also play an important role in the metabolism of other... 

Except for additive effects with other sedative or hypnotic drugs, reports of clinically important pharmacodynamic interactions between benzodiazepines and other drugs have been infrequent. Ethanol increases both the rate of absorption of benzodiazepines and the associated CNS depression. Valproate and benzodiazepines in combination may cause psychotic episodes. 

Describe the pharmacodynamics and pharmacokinetics of acute ethanol ingestion. 

B. Toxicodynamics Toxicodynamics is a term used to denote the injurious effects of toxins, ie, their pharmacodynamics. A knowledge of toxicodynamics can be useful in the diagnosis and management of poisoning. For example, hypertension and tachycardia are typically seen in overdoses with amphetamines, cocaine, and antimuscarinic drugs. Hypotension with bradycardia occurs with overdoses of calcium channel blockers, beta-blockers, and sedative-hypnotics. Hypotension with tachycardia occurs with tricyclic antidepressants, phenothiazines, and theophylline. Hyperthermia is most frequently a result of overdose of drugs with antimuscarinic actions, the salicylates, or sympathomimetics. Hypothermia is more likely to occur with toxic doses of ethanol and other CNS depressants. Increased respiratory rate is often a feature of... 

Dorian P, Sellers EM, Reed KL, Warsh JJ, Hamilton C, Kaplan HL, Fan T. Amitriptyline and ethanol pharmacokinetic and pharmacodynamic interaction. EurJ Clin Pharmacol (1983)... 

Crean CS, Tompson DJ. The effects of ethanol on the pharmacokinetics, pharmacodynamics, safety, and tolerability of ezogabine (retigabine). Clin Ther January 2013 35(l) 87-93. 

Chen Y-C, Peng GS, Wang MF, Tsao TP, Yin SJ. Polymorphism of ethanol-metabohsm genes and alcoholism Correlation of allelic variations with the pharmacokinetic and pharmacodynamic consequences. Chem Biol Interact. 2009 178 2-7. 

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