During chronic caffeine use, caffeine-induced dopamine release within the nucleus accumbens core is markedly reduced due to drug tolerance. Enzyme targets
Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor. As a competitive nonselective phosphodiesterase inhibitor, caffeine raises intracellular cyclic AMP, activates protein kinase A, inhibits TNF-alpha and leukotriene synthesis, and reduces inflammation and innate immunity. Caffeine also affects the cholinergic system where it is a moderate inhibitor of the enzyme acetylcholinesterase. Pharmacokinetics
Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and distributed throughout all bodily tissues. Peak blood concentration is reached within 1–2 hours. It is eliminated by first-order kinetics. Caffeine can also be absorbed rectally, evidenced by suppositories of ergotamine tartrate and caffeine (for the relief of migraine) and of chlorobutanol and caffeine (for the treatment of hyperemesis). However, rectal absorption is less efficient than oral:  the maximum concentration (Cmax) and total amount absorbed (AUC) are both about 30% (i.e., 1/3.5) of the oral amounts.Caffeines biological half-life – the time required for the body to eliminate one-half of a dose – varies widely among individuals according to factors such as pregnancy, other drugs, liver enzyme function level (needed for caffeine metabolism) and age. In healthy adults, caffeines half-life is between 3 and 7 hours. The half-life is decreased by 30-50% in adult male smokers, approximately doubled in women taking oral contraceptives, and prolonged in the last trimester of pregnancy.
Parasitic infections
In the body, disulfiram is rapidly metabolized to diethyldithiocarbamate (ditiocarb), which binds to metal ions such as zinc or copper to form zinc or copper diethyldithiocarbamate (zinc or copper ditiocarb). The zinc diethyldithiocarbamate (zinc-ditiocarb) metabolite of disulfiram is extremely potent against the diarrhea and liver abscess-causing parasite Entamoeba histolytica and might be active against other deadly parasites. HIV
Disulfiram has also been identified by systematic high-throughput screening as a potential HIV latency reversing agent (LRA). Reactivation of latent HIV infection in patients is part of an investigational strategy known as "shock and kill" which may be able to reduce or eliminate the HIV reservoir. Recent phase II dose-escalation studies in patients with HIV who are controlled on antiretroviral therapy have observed an increase in cell-associated unspliced HIV RNA with increasing exposure to disulfiram and its metabolites. Disulfiram is also being investigated in combination with vorinostat, another investigational latency reversing agent, to treat HIV. COVID-19
Disulfiram has been shown to inhibit the papain-like proteases of MERS-CoV and SARS-CoV. It has been examined in a small inconclusive retrospective observational study for its effects on COVID-19 symptoms and is currently in Phase 2 clinical trials. References
External links
"Disulfiram". Drug Information Portal. U.S. National Library of Medicine. Toxicity, Mushroom - Disulfiramlike Toxins at eMedicine
CDC - NIOSH Pocket Guide to Chemical Hazards