Nicotine binds selectively to acetylcholine receptors at the autonomic ganglia, in the adrenal medulla, at neuromuscular junctions, and in the brain. Two types of central nervous system (CNS) effects are believed to be the basis of nicotine’s positively reinforcing properties. A stimulating effect, exerted mainly in the cortex via the locus ceruleus, produces increased alertness and cognitive performance. A ‘reward’ effect via the ‘pleasure system’ in the brain is exerted in the limbic system. At low doses the stimulant effects predominate, while at high doses the reward effects predominate. Intermittent intravenous administration of nicotine activates neurohormonal pathways, releasing acetylcholine, noradrenaline, dopamine, serotonin, vasopressin, beta-endorphin, growth hormone and ACTH. The action is very complex and depends on many variables including, dose, rate, presence of other stimulants, individual variations and tolerance.

Nicotine also effects the heart, causing it to go faster (tachycardia). It also affects blood vessals in the body, causing them to constrict (peripheral vasoconstriction) resulting in higher blood pressure (hypertension).

Acute and chronic tolerance to nicotine develops from smoking tobacco or ingesting nicotine preparations. Acute tolerance (a reduction in response for a given dose) develops rapidly (less than one hour), but at distinct rates for different physiological effects (skin temperature, heart rate, subjective effects). Withdrawal symptoms, such as cigarette craving, can be reduced in some individuals by plasma nicotine levels lower than those for smoking. Withdrawal from nicotine in addicted individuals is characterised by craving, nervousness, restlessness, irritability, mood lability, anxiety, drowsiness, sleep disturbances, impaired concentration, increased appetite, minor somatic complaints (headache, myalgia, constipation, fatigue) and weight gain. Nicotine toxicity is characterised by nausea, abdominal pain, vomiting, diarrhoea, diaphoresis, flushing, dizziness, disturbed hearing and vision, confusion, weakness, palpitations, altered respiration and hypotension.

Progressive severity of renal impairment is associated with decreased total clearance of nicotine. The pharmacokinetics of nicotine are unaffected in cirrhotic patients with mild liver impairment (Child score 5) and decreased in cirrhotic patients with moderate liver impairment (Child score 7). Raised nicotine levels have been seen in smoking patients undergoing haemodialysis.

The volume of distribution following intravenvous administration of nicotine is approximately 2 to 3 L/kg and the half-life ranges from two to three hours. The major eliminating organ is the liver, and the average plasma clearance is about 1.2 L/minute; the kidney and lung also metabolise nicotine. More than 20 metabolites of nicotine have been identified, all of which are believed to be less active than nicotine. The primary metabolite of nicotine in plasma is cotinine, which has a half-life of 15 to 20 hours and which reaches concentrations that exceed nicotine by tenfold.

Nicotine itself does not appear to be a carcinogen in laboratory animals. However, nicotine and its metabolites increased the incidence of tumours in the cheek pouches of hamsters and forestomach of F344 rats, respectively, when given in combination with tumour initiators. One study, which could not be replicated, suggested that cotinine, the primary metabolite of nicotine, may cause lymphoreticular sarcoma in the large intestine in rats.