Metabolic rate, nicotine effects

Repeated exposure, as occurs in habitual smokers, leads to an increased rate of metabolism of nicotine and decreased sensitivity of the receptors to the nicotine. More nicotine is therefore required to satisfy the needed stimulation, and tolerance develops. This is a separate effect from addiction which seems to be due to increased levels of a substance called dopamine in the brain. This is due to the nicotine activating nerve cells which results in increased release of dopamine and causes a reduction in the amount of an enzyme that destroys dopamine. It seems that other addictive drugs may also work by increasing dopamine levels. 

Table III. Effect of a Meal and/or Nicotine on Metabolic Rate In Rats ...

Altschtjl, R., and A. Hoffer Effect of nicotinic acid upon serum cholesterol and upon basal metabolic rate of young normal adults. Arch. Biochem. 73, 420 (1958). 

Toluene, volatile nitrites, and anesthetics, like other substances of abuse such as cocaine, nicotine, and heroin, are characterized by rapid absorption, rapid entry into the brain, high bioavailability, a short half-life, and a rapid rate of metabolism and clearance (Gerasimov et al. 2002 Pontieri et al. 1996, 1998). Because these pharmacokinetic parameters are associated with the ability of addictive substances to induce positive reinforcing effects, it appears that the pharmacokinetic features of inhalants contribute to their high abuse liability among susceptible individuals. 

Accurate prediction of the rate of nicotine metabolism based on CYP2A6/D6 genotype could make adjusting the dose of nicotine replacement to avoid side effects and ensure effectiveness much simpler. It may be that information technology could help in making decisions about the choice [63] and dose [64] of drug based on genetic data. 

An implication of the high degree of hepatic extraction is that clearance of nicotine should be dependent on liver blood flow. Thus, physiological events, such as meals, posture, exercise, or drugs perturbing hepatic blood flow, are predicted to affect the rate of nicotine metabolism. Meals consumed during a steady state infusion of nicotine result in a consistent decline in nicotine concentrations, the maximal effect seen 30-60 min after the end of a meal (Gries et al. 1996 Lee et al. 1989). Hepatic blood flow increases about 30% and nicotine clearance increases about 40% after a meal. 

Johansson CJ, Olsson P, Bende M, Carlsson T, Gunnarsson PO (1991) Absolute bioavailabUity of nicotine applied to different nasal regions, Eur J Clin Pharmacol 41(6) 585-588 Johnstone E, Benowitz N, Cargill A, Jacob R, Hinks L, Day 1, Murphy M, Walton R (2006) Determinants of the rate of nicotine metabolism and effects on smoking behavior, Chn Pharmacol Ther 80(4) 319-330... 

Adverse effects The CNS effects of nicotine include irritability and tremors. Nicotine may also cause intestinal cramps, diarrhea, and increased heart rate and blood pressure. In addition, cigarette smoking increases the rate of metabolism of a number of drugs. [Note It is not known which of the over 3,000 components of cigarette smoke are responsible for this phenomenon, although the benzopyrenes have been implicated.]... 

A recent study has employed deuterium labeling to show that the mechanism for the oxidative N-demethylation of nicotine may involve two modes of breakdown for a proposed carbinolamine intermediate, dealkylation with formaldehyde formation and dehydration to an iminium ion.72 The formation of such an sp2-hybrid intermediate may help to explain why both a primary and substantial / -secondary deuterium isotope effect were observed for the N-deethylation of the antiarrhythmic agent, lidocaine.73 In contrast, only a primary isotope effect was observed on the rate of oxidative O-deethylation of deuterated analogs of the analgesic, phenacetin. 77 These results indicate differences in the mechanism of oxidative 0- and N-dealkylation. A final example of the use of secondary deuterium isotope effects in studying enzymes involved in drug metabolism revealed an SN-2-like transition state for the transfer of a methyl group catalyzed by catechol-O-methyl transferase.73... 

Smoking tobaeco increases heart rate, blood pressure and the severity of myocardial ischaemia, probably as a direct effect of the nicotine and due to the reduced oxygen-carrying capacity of the blood. - These actions oppose and may even totally abolish the beneficial actions of the beta blockers. In addition, smoking stimulates the liver enzymes concerned with the metabolism of some beta blockers (e.g. propranolol) so that their serum levels are reduced. 

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