Altering ethanol pharmacokinetics to treat alcohol use disorder: Can you teach an old dog new tricks?

Abstract

Disulfiram was the first pharmacotherapy approved to treat alcohol use disorder (AUD) in the 1950s. Disulfiram alters ethanol pharmacokinetics (PK) and causes uncomfortable reactions (e.g.: headache, tachycardia, nausea, flushing and hypotension) when alcohol is consumed. Subsequently, a better understanding of the neurobiological pathways involved in AUD led to the development of other medications (e.g.: naltrexone and acamprosate) to treat AUD. These neurobiological-based medications act on AUD-related phenotypes including craving, stress, and/or withdrawal. The original approach to treat AUD, by altering ethanol PK has been much less investigated. Recent research on ethanol PK has shed light on the mechanisms of action underlying AUD and how some medications that alter ethanol PK may be helpful in treating AUD. This review summarizes and discusses the complex PK of ethanol, and proposes that altering ethanol PK via novel pharmacological approaches may be a viable approach to treat AUD.

The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study

“…We found that PF-5190457 has an acceptable concentration-time profile for daily oral dosing and is safe when given with alcohol. This information is critical from a medication development perspective 32 . Therefore PF-5190457 represents a promising compound to investigate GHS-R1a inverse agonism as a novel pharmacotherapy for patients with AUD 5 .…”

“…PF-5190457 may increase sedation/sleepiness and heart rate and lower blood glucose concentrations 31 . These are side-effects that may be exacerbated by alcohol co-administration in addition to other potentially serious consequences of drug-alcohol interactions 32 .…”

Noradrenergic targets for the treatment of alcohol use disorder

“…These results in non-alcohol-dependent rodents are in line with a human laboratory study in non-dependent social drinkers, which indicated that idazoxan altered subjective effects of alcohol intoxication and hemodynamic parameters possibly by affecting the biphasic effects of alcohol (Haass-Koffler et al, 2015). A pharmacokinetics/pharmacodynamics model that linked alcohol concentration and alcohol effects (Wright et al, 2011), adopted in this study, showed that idazoxan was able to affect the biphasic effects of alcohol by altering alcohol pharmacokinetic parameters, such as reduce maximus concentration ( C max ) and delay of time of maximum concentration ( t max ) (Haass-Koffler et al, 2015, Haass-Koffler et al, 2017a).…”

“…Furthermore, there is a considerable scientific literature that supports the role of alcohol in the dysregulation of the stress system, generally resulting in enhanced stress responses (Kreek and Koob, 1998, Koob and Le Moal, 1997). There is evidence that stress can affect the rewarding effect of alcohol which, in turn, can detrimentally affect drinking behaviors (Haass-Koffler et al, 2017b). Finally, stress does not halt when individuals stop drinking.…”

Bruk av medikamenter for alkoholbrukslidelser i Norge 2004–16

“…Legemidlene finnes kun i tablettform. Disulfiram blokkerer enzymet aldehyddehydrogenase (12). Om man drikker mens man bruker medikamentet, får man en opphopning av acetaldehyd som kan gi symptomer og ubehag som hjertebank, rødming, hodepine og hjerterytmeforstyrrelse.…”