Module 3.1.1 (Treatment of Nicotine Abuse)

Question 1

How long does CNS effects take when nicotine is absorbed pulmonary? Where does nictonine act?

Answer 1

Occur in as little as 7 seconds with pulmonary absorption

> At neuronal level nicotine acts on nAChRs

> Chronic nicotine administration –> increase in the number of nAChRs –> an adaptive response to prolonged receptor desensitisation

Question 2

What are the two broad classes of nicotoinic receptors?

> Made up of five subunits that traverse the membrane surrounding a central pore

> Two Alpha, one Beta, one Gamma and one Delta

Answer 2

muscle-type (N_M) and neuronal-type (N_N)

• both result in excitatory opening of Na+/K+ channels –> increased Ca2+ conductance

Question 3

What type of channels are nicotinic receptors? What does activation by ACh cause?

Answer 3

Nicotinic receptors (nAChRs) are ligand-gated ion channels

• Activation by ACh causes rapid (millisecond) increase in permeability to Na+ and Ca2+ , depolarisation and excitation
• ACh must bind to both the a-subunits –> open channel

Question 4

Where is the Nicotinic_N receptor found? What effects does it have in the CNS when activated (e.g. by smoking)?

Answer 4

• Autonomic ganglia
• Adrenal medulla
• Sensory nerve terminals
• Many regions of the central nervous system (CNS)

In CNS

• pre-synaptic and post-synaptic locations
• presynaptic nerve terminals of neurones which secrete dopamine, ACh, and glutamate.
• Activation of such receptors by nicotine facilitate the release of these transmitters, and thus increase their actions in the brain.
• At spinal level –> inhibits spinal reflexes –> skeletal muscle relaxation

Question 5

What are the pharmacological actions of nicotine? What does it act on and what does it release

Answer 5

Stimulant and depressant actions

• Increased alertness
• Muscle relaxation

> Acts on nicotinic acetylcholine receptors in CNS and adrenal glands releasing adrenaline and noradrenaline

Also release many neurotransmitters in CNS:

> acetlycholine enhances memory and concentration

> endorphins decreasing pain and anxiety

> dopamine trigges brain’s reward circuits

Question 6

What are the cellular effects and behavioural effects of nicotine?

Answer 6

Behavioural effects

• Rewarding, pleasurable properties associated with increased activity of the mesolimbic dopaminergic pathway
• Increases alertness
• Decreases anxiety and tension
• Facilitates learning

Cellular effect

• Acts on nicotinic receptors –> neuronal excitation

Question 7

Peripheral effects of nicotine are due mainly to ganglionic stimulation, what are these effects?

Answer 7

• Nausea & vomiting
• Tachycardia, increased cardiac output
• Increased blood pressure
• Increased gut motility
• Sweating

Question 8

For nictoine

A) What are other acute effects (clue, surge of catecholamines …)

B) short half life and intense effects causes..

C) withdrawal effects

Answer 8

A)

• Surge of catecholamines causes sudden increase in glucose, BP, respiration and heart rate. Also suppresses insulin output from pancreas leading to elevated BSL

B)

• Causes nicotine to be highly re‐inforcing

C)

• Irritability, anxiety, dysphoria, restlessness, decreased heart rate, increased appetite, reduced concentration

Question 9

How is nicotine metabolised? How about the active metabolite cotinine?

Answer 9

Nicotine is metabolised, mainly in the liver, within 1-2 hours.

• The active metabolite, cotinine, has a long t1/2, and can be used in blood/urine tests to monitor smoking habits.

nicotine half life = 30 minutes

Question 10

What are some adverse effects of nicotine?

Answer 10

• Smoking reduces life expectancy
• Ischaemic heart disease

> both nicotine and CO may be responsible

• Cancer

> Lung, bladder and prostate cancer

> Carcinogenic tars are responsible

• Smoking during pregnancy

> Lowers birth weight

> Retards childhood development

> Increases abortion rate

> Increased perinatal mortality

stimulates both Nicotinic_N and Nicotinic_M receptors (see image for more)

Question 11

Tolerance, physical dependence and compulsive use (psychological dependence) are all seen with nicotine use. Explain why

Answer 11

Nicotine is highly addictive –> excitation of mesolimbic pathway = increased dopamine release

• Rapid tolerance –> The effects of nicotine associated with peripheral ganglionic –> desensitisation of nAChR
• Tolerance to the central effects of nicotine (arousal) is much less than in the periphery

Question 12

What are the some symptomns of physical withdrawal syndrome of nicotine? How long does it last?

Answer 12

increased irritability

impaired performance of psychomotor tasks, aggressiveness

sleep disturbance

> Less severe than opioids

> Can be alleviated by nicotine or amphetamine

> Last for 2-3 weeks

> Craving may last for longer –> risk of relapse

Question 13

What is used to alleviate nicotine withdrawal syndrome?

Answer 13

• Nicotine Replacement Therapy (NRT)
• Varenciline
• Bupropion

Question 14

What is nicotine replacement therapy used for? What forms does it come in?

Answer 14

Reduces the severity of tobacco withdrawal and improves the chances of quitting

• Nicotine replacement therapy is available in the form of nicotine gum, inhalers, lozenges, patches or sublingual tablets

Question 15

What is the MOA of varenicline?

Answer 15

• Partial agonist acting on α4β2 nicotinic receptor subtype
• Antagonist effect: blocks pleasurable effects of smoking
• Agonist effect: reduces withdrawal symptoms

Question 16

What is the MOA of bupropion?

Answer 16

• Mechanism of action poorly understood
• Increasing DA activity in nucleus accumbens
• Weak inhibition of reuptake of noradrenaline and dopamine.