Smoking Cessation

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for smoking cessation is the data available most trusted based on the clinical trial base.

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PARTIAL NICOTINIC ACETYLCHOLINE (œ4ß2) AGONISTS AS PROMISING NEW MEDICATIONS FOR SMOKING CESSATION:

PARTIAL NICOTINIC ACETYLCHOLINE ( œ 4 ß 2 ) AGONISTS AS PROMISING NEW MEDICATIONS FOR SMOKING CESSATION Presented By: RAJDIP L VAISHNAV, M.PHARM 1 ST YEAR, DEPT. OF PHARMACOLOGY, SRINIVAS COLLEGE OF PHARMACY .

INTRODUCTION:

INTRODUCTION Smoking is widely recognized as a serious health problem. According to current estimates, there are 1.1 billion smokers worldwide. Recent study shows about 5 million premature deaths in the world due to smoking. More ever, smoking is a high risk factor for coronary heart disease, cancer, chronic obstructive pulmonary disease and other health related problem

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Nicotine is the main active substance of tobacco products responsible for positive reinforcement in humans. According to US public health services guidelines, patients attempting to quit smoking should be encouraged to use pharmacotherapeutic agents. Nicotine therapies are used as substitution for tobacco smoking.

Slide 4:

Nicotine can replace by patch, gum, lozenge, inhaler, nasal spray or bupropion, clonidine are believed that after long term use, it will reduce cigarette consumption. Bupropion - dopamine and N.E. reuptake inhibitors. Clonidine reduces withdrawal effect

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Antidiuretic effect Respiratory rate Ephedrine release Sympathetic activity Release of vasopressin Partial depolarization in carotid body & other ganglia Nicotine Blood pressure Partial depolarization of baroreceptor Partial depolarization of autonomic ganglia Parasympathetic activity Vasoconstriction Vasoconstriction Defecation, diarrhea Glycogenolysis , lipolysis Blood glucose & free fatty acid Bowel motility

Nicotine Dependence:

Nicotine Dependence Numerous neural pathways and neurotransmitter including GABA, serotonin, nor adrenaline have shown imp. role in nicotinic dependence. Nicotine induce central pharmacological effects by acting on nAChR. nAChR are ligand gated ion channels consist five subunits. An adult skeletal muscle has the composition ( α 1)2 β 1 γ ε , in case of neuronal nAChR α 4 β 2, α 3 β 4, α 7 predominates.

Slide 7:

nAChR - Ligand gated ion channel

Nicotine Dependence:

Nicotine Dependence Neuronal nAChR belongs 2 categories : one which agonist bind with low affinity e.g. α 7 receptor. Another in which agonist bind with high affinity- α 4 β 2 nAChR(>90%). In CNS neuronal localization of nAChR α 4 β 2 playing a major role in reinforcing effects of nicotine. Smoking activates cortex and thalamus and increase dopamine concentration in nucleus accumbens.

How nicotine acts at CNS level::

How nicotine acts at CNS level:

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Effect of nicotine on dopaminergic function could be mediated by the α 4 β 2 nAChR located on neurons in the nucleus accumbens. The important role of β 2 subunit of α 4 β 2 nAChR for firing of the dopaminergic neurons and release of dopamine from these neuron. Activation of β 2-nAChR switch/sense from resting to an excited states, further tuned by other subunit dopamine release. Ultimately β 2 subunit reinforcing the nicotine dependence.

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By looking to a compulsive habitual may leads to long term potentiating or synaptic plasticity of neurons in their respective location. Neuronal pathway other than dopamine like glutamate , GABA , endogenous opioids and endocannabinoid are still needs to be explored to understand the nicotinic/tobacco dependence.

Role of partial agonist α4β2 nAChR on nicotine addiction :

Role of partial agonist α 4 β 2 nAChR on nicotine addiction Smoking Smoking cessation ↑ dopamine release ↓ dopamine release Partial agonist α 4 β 2 nAChR Addiction Withdrawal symptoms -ve -ve

Role of partial agonist at nAChR α4β2 :

Role of partial agonist at nAChR α 4 β 2 Recently partial agonists of the α 4 β 2 nAChR studied for Alzheimer, dementia and attention deficit or hyper activity in adults. Nicotine abstinence is associated with low levels of dopamine in the particular area of brain. It also associated with withdrawal symptoms and craving for nicotine. Partial agonist through intrinsic activation, produce a moderate and sustained increase in dopamine levels.

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Partial agonist counteract low levels of dopamine in the reward pathway. nAChR agonist binds to α 4 β 2 nAChR will prevent binding of nicotine. Protect smokers from reward effect produced by dopaminergic activation while smoking.

Preclinical trials:

Preclinical trials In neurochemical model varenicline has less efficacy in stimulating dopamine release from rat brain slices in vitro. (nicotine stimulates more) Sprague Dawley rats were selected for effects of partial agonist, varenicline and cystine on mesolimbic dopamine recover. Vernicline was more potent for blocking the central effects of nicotine.

Preclinical trials:

Preclinical trials Conclusion : In Vitro and in vivo studies suggest that partial agonist of α 4 β 2 nAChR moderately increase the dopamine level. Minimize the addictive effects of nicotine by decreasing the dopamine level.

Clinical trials:

Clinical trials Smoking cessation was demonstrated in seven clinical study. 3 comparative trials with bupropion. Systematically analyzed the effectiveness of different therapies for smoking cessation. On evaluation 4 studies proves vernicline superiors to nicotine replacement therapy

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In 2 multicenter , randomized ,placebo controlled trials : >2500 smokers treated with placebo or vernicline – 0.5-1mg.o.d./b.d. for 12 weeks and follow up was done up to 1 year. These trials shows that varenicline is efficacious for smoking cessation. In 2 randomized , double blind , multicenter trials >2000 smokers treated with varenicline, bupropion sustained release and placebo were given for 12 weeks and then followed up to 52 weeks.

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Varenicline treated group shows more effectively (44%) in case of quit smoking than the other group. CO confirms the quit rate and is followed during 9-12 weeks of treatment. Conclusion : The reports of clinical studies suggest that partial agonist of α 4 β 2 nAChR represent promising alternative to the agent currently used for the therapy of smoking cessation.

Pharmacokinetic parameters::

Pharmacokinetic parameters: C max after 1mg oral dose of varenicline is 3.2-4.7ng/ml and achieved within 2-7 hrs. Metabolism : Undergoes minimal metabolism metabolites occurs via N-carbonyl glucuronidation and oxidation. Elimination : 17 hrs. 92% excreted in unchanged in urine. Renal elimination primarily through G.F. with active tubular secretion.

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Adverse effects : Sleep disturbance , vomiting , depressed mood, changes in behavior. Indication : smoking cessation treatment Contraindication : hypersensitivity noted in the treatment of varenicline Drug interaction : no drug-drug interaction have been identified.

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The treatment currently available is unsatisfactory . The relapse rate is very high. Most of the patients relapse even after the best type of treatment. US FDA approved varenicline as a partial agonist of the α 4 β 2 nAChR by 11 may 2006 for smoking cessation.

Data source:

Data source Indian journal of pharmacology –vol.42 Color atlas of pharmacology 2 nd edition www.pubmed.org