Smoking Interactions

Smoking while using estrogen-containing oral contraceptives synergistically increases the risk of serious cardiovascular events including myocardial infarction, stroke, and venous thromboembolism. The risk is especially pronounced in women over 35 and increases with the number of cigarettes smoked.

Polycyclic aromatic hydrocarbons in tobacco smoke (not nicotine) potently induce CYP1A2, the enzyme responsible for roughly 70% of clozapine metabolism, lowering clozapine plasma levels by up to 50% in smokers. Sudden smoking cessation can cause clozapine levels to rise 50-72% within 3-5 days, risking sedation, seizures, and toxicity.

Polycyclic aromatic hydrocarbons in cigarette smoke induce CYP1A2, the primary enzyme that metabolizes olanzapine, increasing olanzapine clearance by roughly 37-48% in smokers. Meta-analysis data suggest olanzapine doses should be 30% lower in non-smokers than in smokers to reach the same plasma levels.

Polycyclic aromatic hydrocarbons in tobacco smoke induce CYP1A2, increasing theophylline clearance by 58-100% and shortening its half-life by roughly 63%. Smokers often need 1.5-2 times the usual theophylline dose, and abrupt cessation can rapidly produce toxic levels.

Smoking reduces subcutaneous insulin absorption through vasoconstriction and worsens insulin resistance through nicotine-driven catecholamine release, oxidative stress, and inflammation, with HbA1c rising progressively with cigarettes per day. Diabetic smokers typically need 15-30% more insulin than non-smokers to achieve the same glycemic control.

Smoking accelerates hepatic CYP-mediated metabolism of estradiol, lowering circulating estrogen levels and reducing the efficacy of oral hormone replacement therapy for menopausal symptoms and bone protection. It also compounds the venous thromboembolism risk of oral HRT.

Polycyclic aromatic hydrocarbons in tobacco smoke induce CYP1A2, the enzyme that performs about 95% of caffeine demethylation, raising caffeine clearance by 40-65% and shortening its half-life from roughly 6 hours to 3.5 hours in smokers. Quitting smoking can cause caffeine levels to rise sharply, contributing to jitters, anxiety, palpitations, and insomnia.

Cigarette smoking induces hepatic metabolism of propranolol via CYP1A2 and accelerated glucuronidation, increasing apparent oral clearance and reducing propranolol plasma concentrations in smokers compared with non-smokers. Nicotine also independently raises heart rate, blood pressure, and circulating catecholamines, partially counteracting propranolol's beta-blocking effect.

Cyanide in cigarette smoke binds to active forms of vitamin B12 (methylcobalamin and hydroxocobalamin), converting them to the inactive cyanocobalamin form which is excreted, and chronic smoking damages the gastric mucosa, reducing intrinsic factor production and B12 absorption.

Smoking increases oxidative stress and accelerates the metabolic turnover of vitamin C, lowering plasma and leukocyte ascorbic acid levels. The NIH Food and Nutrition Board officially recommends that smokers consume an additional 35 mg of vitamin C daily above the standard RDA.

Varenicline (Chantix) is a partial agonist at the alpha4-beta2 nicotinic acetylcholine receptor; continued smoking or concurrent nicotine replacement therapy can increase side effects such as nausea, headache, vomiting, dizziness, and fatigue. Varenicline blocks much of nicotine's rewarding effect.