Pharmacological approach to smoking cessation

Question 1

Noradrenaline and dopamine reuptake inhibitors (NDRI) prototype

Answer 1

Buproprion
twice daily
target quit date - 2nd week

Question 2

NDRI MOA

Answer 2

Inhibits pre-synaptic reuptake of DA and NE
DA believed to be key NT in reward pathway
Increased level of DA in synapse help to mimic reward associated with smoking
Attenuate withdrawal symptoms

Some evidence as nicotinic receptor antagonist

Question 3

Indications of Buproprion

Answer 3

depression

smoking cessation

Question 4

Contraindications of buproprion

Answer 4

seizures (lower seizuer threshold)

MAO inhibitors - inhibit the breakdown of NTs, can lead to complications

Question 5

SEs of buproprion

Answer 5

dry mouth
nausea
insomnia
rare: seizures

Question 6

Nicotinic agonist prototypes

Answer 6

full: nicotine
partial: varenicline (target 1 week)
- varenicline better than buproprion

Question 7

SEs of varenicline

Answer 7

nausea

psychiatric adverse effects

Question 8

MOAs of nicotinic agonists

Answer 8

alpha and beta nicotinic receptors
alpha4beta2 one most common in the brain - most responsible for nicotinic addiction
nicotine binds to receptor, release DA as well as ACh, serotonin, NE, GABA, endorphins, glutamate
associated with mood/calming effect
chronic smoking also reduces breakdown enzymes

chronic smoking –> upregulation of alpha4beta2 due to desensitization
a3b4: CV effects - v/c, increase contractility/HR, damage endothelium

Partial agonist - low level release of nicotine when not smoking
decreases nicotine binding to nicotinic receptor, decrease reward for smoking

Question 9

PKs of nicotinics

Answer 9

Rapidly absorbed/onset of action when inhaled, short elimination
Oral absorption poor / gastric irritant

Other forms all bypass the gut (irritant)
gum/lozenges - chewed briefly, then placed in cheek
patch
inhaler - absorption occurs in the oral cavity, not lungs
nasal spray - faster absorption

Varenicline relies on renal filtration

Question 10

SEs of full nicotinic agonists

Answer 10

Local irritation
Systemic:
- difficult to separate from effects of nicotine withdrawal
- insomnia, vivid dreams (DA release)

Question 11

SEs of partial nicotinic agonists

Answer 11

Nausea (may be due to DA release)

Neuropsychiatric

Question 12

CV effects of nicotine

Answer 12

Nicotine alone - not well-studied

Question 13

Pharmacogenetics of nicotine

Answer 13

Rate of nicotine metabolism determined by polymorphism of CYP2A6 as well as UDP-gluronosyl transferases (UGT), secondary pathway of elimination
women metabolizes more rapidly
Caucasians and hispanics metabolize more rapidly

Question 14

Nortryptiline

Answer 14

inhibits reuptake of serotonin + NE
minimal effects on DA reuptake

anticholinergic SE