Pharmacological approaches to smoking cessation Flashcards
1. Describe the pharmacology of nicotine 2. Describe the various forms of nicotine replacement therapies 3. Describe the mechanisms of action of drugs used as smoking cessation therapies as well as their side effects and any safety issues associated with their use 4. Compare the efficacy and tolerability of all agents used in smoking cessation.
Route of entry of nicotine
-inhaled and absorbed from alveoli
-also absorbed from skin and mucous membranes
(is very lipophilic so is readily absorbed)
How quickly does nicotine get to the brain
When inhaling it, get to the brain in about 10 seconds
*important for immediate reward
Half life of nicotine
1-2 hours
*why people can’t just smoke 1 cigarette a day
Metabolism of nicotine
CYP2A6
*may explain why some people can smoke more infrequently than those who are rapid metabolizers (chain smokers)
Major metabolite of nicotine + purpose
cotinine (is inactive)
- can use as marker for nicotine use because it has a longer half life (15 hours)
- can’t rely on smoker word to say that they quit - a good trial back up with samples from patient - evidence that they are smoking
Plasma continine levels required for addiction
50-70nm/mL (approx 5 cigarettes/day)
MOA nicotine
- is a Nicotinic receptor agonist
- increases dopamine release
- dopamine stimulates reward pathways in the brain
- can also cause release of acetylcholine, norepinephrine, serotonin, beta-endorphin, GABA
Net effect of nicotine (low dose, high dose)
Low doses: stimulant predominates
Higher doses: reward predominates
Effect chronic exposure of nicotine
Chronic exposure to nicotine leads to nicotinic receptor upregulation
-may be due to receptor desensitization
Withdrawal from Nicotine (symptoms and duration)
1) Lightheadedness < 2 week
5) Irritability or aggressiveness < 4 weeks
7) Restlessness < 10 weeks
Interventions for smoking cessation
1) Non-pharmacological
- cognitive behavioral therapy (CBT)
- acupuncture
- hypnosis
2) Phamacological
- nicotine replacement
- other drugs
Modalities of nicotine replacement
1) Gum
2) Patch
3) Inhaler
4) Spray
What do all replacement forms of nicotine have in common + why (2)
- they all bypass the gut
- don’t want to swallow nicotine because:
1) Low oral bioavailability
2) In higher doses, nicotine is a gastric irritant
Nicotine replacement gum available doses
-2mg or 4 mg of nicotine (cigarette is 1-3 mg)
How to use nicotine gum
1) Chewed briefly, the placed in cheek (buccal absorption)
Side effects of nicotine gum
- local irritation
- gastrointestinal upset
Nicotine replacement lozenges - use
Very similar to gum (similar use and pharmacokinetics)
-the more you suck on it and swallow it the more your stomach will be upset
Nicotine replacement patch
Transdermal delivery
Provides continuous 24 hours release of nicotine
- was easy to invent because nicotine is so lipophilic -just have membrane against the skin allowing nicotine to percolate through the skin (skin determines rate of deliver of the drug)the
Negative of patch
- will irritate the skin
- can’t be titrated acutely - people often associate activities with smoking -cant put on a patch prior to these activities to receive enough nicotine to not crave smoking - is very gradual onset whereas the lozenge and gum are more rapidly acting
Combination of nicotine replacement therapies
Can safely combine two nicotine replacement therapies (i.e. patch + gum/lozenge)
Nicotine replacement inhalers -purpose
-look like cigarettes so replicate the behaviour of smoking
Nicotine replacement inhalers - absorption
- absorption occurs in oral cavity not in the lungs
- because is a water vapor can’t travel as far as the lungs (and cannot absorb as rapidly into the bloodstream as smoke can)
Side effects of nicotine replacement inhalers
- cough
- local irritation (throat/mouth)
Nicotine replacement-nasal spray advantages
-must faster absorption
Side effects of nasal spray
- local irritation (nose/throat)
- fastest absorption -might get people addicted to the nasal spray
Nicotine replacement -sublingual spray
Spray under tongue
Pretty good absorption
Still causes irritation
Varenicline (Champix) - MOA
- is a partial agonist at nicotine receptors (alpha4beta2)
- therefore will stimulate receptor but produces less than a full response (less release of dopamine - mimics rewarding feeling from smoking)
- if taking Varenicline and relapse (start smoking) a lot receptors occupied by partial agonist so will not get as big of a high from smoking
treatment duration Varenicline
- twice daily x 12 weeks
- target quit date should be at least 1 week after starting Varenicline (because need to get to steady state and deal with main side effect = nausea)
Issue with Varenicline
Psychiatric adverse effects -depression -agitation -hostility -behavioral changes -suicidality * only thing that sets this list apart from nicotine withdrawal BUT conflicting evidence -problem with assessing psychiatric effects is that they are difficult to separate from effects of nicotine withdrawal
Patients with cardiovascular disease and champix
- was effective
- but small increase in risk of cardiovascular event
Bupropion (Zyban) - MOA
- developed as an antidepressant and still used for this
- reuptake inhibitor - block reuptake pumps that remove NT from synapse
- get more NT in synapse
- more binding to receptors
- greater activity of the neurotransmitter
- inhibits reuptake of dopamine and noradrenaline in brain (helps to feel better during withdrawal) and may also act as nicotinic receptor antagonist (if relapse and go to smoke won’t get as much as a reward from smoking
Buproprion treatment regimen
- don’t quit until started buproprion and comfortable on it -target to quit usually 2nd week
- twice daily x7-12 weeks
Side effects of buproprion
- insomnia
- dry mouth
- nausea
Safety issues of bupropion
-all antidepressants may stimulate impulsive (suicidal) behaviour in youth
Nortriptyline - MOA
- inhibits reuptake of serotonin and noradrenaline
- minimal effects on dopamine reuptake
Disadvantage of nortriptyline
-antichonlinergic side effects
Evidence for use of nicotinic replacement therapies
- comparing efficacy of various nicotine replacement therapies (NRT)
- all NRT were statistically better than control (placebo)
- no clear advantage of one NRT over another
- cochrane review
NRT versus other drugs -evidence
- few trials directly compare NRT versus buproprion or varenicline
- results suggest that bupropion may have similar efficacy to NRT
Buproprion vs. varenicline
-more varenicline subjects were abstinents at 12 months vs. BUP
(not by very much though)
-but nauses might occur more frequently with varenicline versus bupropion
Future direction of smoking cessation
Nicotine vaccines
- formation of antibodies to nicotine
- antibody-nicotine complex unable to cross the blood-brain barrier
- in phase 3 not doing so well in animal studies
Electronic cigarettes
- deliver nicotine (and other substances) in vapour form
- intended to more closely resemble an actual cigarette
