CABREXXA 0,5

Indications

• Smoking cessation
• Nicotine dependence

Dosage

Adults: Initially, 500 micrograms once daily for 3 days, increased to 500 micrograms twice daily for 4 days, then 1 mg twice daily for 11 weeks. Dosage may be reduced if not tolerated.

Mechanism of action

Varenicline selectively binds to alpha-4 beta-2 nicotinic acetylcholine receptors in the brain. It acts as a partial agonist, stimulating these receptors to a lesser extent than nicotine, which helps alleviate withdrawal symptoms. Additionally, it competitively inhibits nicotine from binding to these receptors, reducing the rewarding effects of smoking and consequently aiding in smoking cessation.

Pharmacodynamics

As a partial agonist of the nicotinic acetylcholine receptor, varenicline activates the receptor to a modest degree, leading to a moderate release of dopamine associated with pleasure and reward, which is crucial for addiction treatment. This mechanism helps to reduce cravings and withdrawal symptoms by providing a dopamine release that is less intense than that associated with nicotine itself.

Pharmacokinetics

Varenicline is rapidly absorbed after oral administration, with peak plasma concentrations typically reached within 3 to 4 hours. The drug is primarily eliminated through the kidneys, with a half-life of approximately 24 hours. It does not undergo significant metabolism in the liver, making it less susceptible to drug-drug interactions. The pharmacokinetics can be influenced by renal function; thus, dose adjustments may be needed in patients with impaired renal function.

Adverse effects

• Irritability
• Depression
• Insomnia
• Nausea
• Vomiting
• Constipation
• Gas
• Dry mouth
• Abnormal dreams
• Headache
• Dizziness
• Fatigue
• Increased appetite

Interactions

• May interact with other medications affecting the central nervous system
• Caution advised with concurrent use of antidepressants or other psychotropic medications

Precautions

• Caution in patients with a history of psychiatric disorders
• Monitor for changes in mood or behavior
• Consider dose adjustment in renal impairment

Pregnancy

Avoid-toxicity in animal studies.

Breast-feeding

Avoid-present in milk in animal studies.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets, 0.5 mg
• Tablets, 1 mg
• Lozenges, sugar-free, 1 mg
• Lozenges, sugar-free, 4 mg

Mechanism of action

Varenicline is an alpha-4 beta-2 neuronal nicotinic acetylcholine receptor partial agonist. The drug shows high selectivity for this receptor subclass, relative to other nicotinic receptors (>500-fold alpha-3 beta-4, >3500-fold alpha-7, >20,000-fold alpha-1 beta gamma delta) or non-nicotinic receptors and transporters (>2000-fold). The drug competitively inhibits the ability of nicotine to bind to and activate the alpha-4 beta-2 receptor. The drug exerts mild agonistic activity at this site, though at a level much lower than nicotine; it is presumed that this activation eases withdrawal symptoms. Varenicline is a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist. The drug binds with high affinity and selectivity to alpha4beta2 nicotinic acetylcholine receptors located in the brain and stimulates receptor-mediated activity, but at a substantially lower level than nicotine;1 6 this low-level receptor stimulation and subsequent moderate, sustained release of mesolimbic dopamine are thought to reduce craving and withdrawal symptoms associated with smoking cessation. Varenicline also blocks the ability of nicotine to activate alpha4beta2 receptors, preventing nicotine-induced stimulation of the mesolimbic dopaminergic system and thereby reducing the reinforcement and reward effects of cigarette smoking. ... The rationale for and the design of alpha(4)beta(2) neuronal nicotinic acetylcholine receptor (nAChR) partial agonists as novel treatments for tobacco addiction. Such agents are expected to exhibit a dual action by sufficiently stimulating alpha(4)beta(2)-nAChR-mediated dopamine release to reduce craving when quitting and by inhibiting nicotine reinforcement when smoking. Potent and selective alpha(4)beta(2) nAChR partial agonists that exhibit dual agonist and antagonist activity in preclinical models can be identified. The validity of this approach is demonstrated by the clinical efficacy of the alpha(4)beta(2) nAChR partial agonist varenicline, which has significantly better quit rates than do other treatments and offers a new option for smoking cessation pharmacotherapy. ... Varenicline has been shown to be a partial agonist of alpha4beta2 receptors, and in equilibrium binding assays, it is highly selective for the alpha4beta2 receptor. ... The functional activity of varenicline at a variety of rat neuronal nicotinic receptors expressed in Xenopus laevis oocytes and assayed under two-electrode voltage clamp /was examined/ . Varenicline is a potent, partial agonist at alpha4beta2 receptors, with an EC50 of 2.3 +/- 0.3 microM and an efficacy (relative to acetylcholine) of 13.4 +/- 0.4%. Varenicline has lower potency and higher efficacy at alpha3beta4 receptors, with an EC50 of 55 +/- 8 microM and an efficacy of 75 +/- 6%. Varenicline also seems to be a weak partial agonist at alpha3beta2 and alpha6-containing receptors, with an efficacy <10%. It is remarkable that varenicline is a potent, full agonist at alpha7 receptors with an EC50 of 18 +/- 6 microM and an efficacy of 93 +/- 7% (relative to acetylcholine). Thus, whereas varenicline is a partial agonist at some heteromeric neuronal nicotinic receptors, it is a full agonist at the homomeric alpha7 receptor. Some combination of these actions may be involved in the mechanism of varenicline as a smoking cessation aid.

Pharmacodynamics

Varenicline is a partial nicotinic acetylcholine receptor agonist, designed to partially activate this system while displacing nicotine at its sites of action in the brain.