Module 3.1.1 (Treatment of Nicotine Abuse) Flashcards
How long does CNS effects take when nicotine is absorbed pulmonary? Where does nictonine act?
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
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
muscle-type (NM) and neuronal-type (NN)
- both result in excitatory opening of Na+/K+ channels –> increased Ca2+ conductance
What type of channels are nicotinic receptors? What does activation by ACh cause?
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
Where is the NicotinicN receptor found? What effects does it have in the CNS when activated (e.g. by smoking)?
- 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
What are the pharmacological actions of nicotine? What does it act on and what does it release
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
What are the cellular effects and behavioural effects of nicotine?
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
Peripheral effects of nicotine are due mainly to ganglionic stimulation, what are these effects?
- Nausea & vomiting
- Tachycardia, increased cardiac output
- Increased blood pressure
- Increased gut motility
- Sweating
For nictoine
A) What are other acute effects (clue, surge of catecholamines …)
B) short half life and intense effects causes..
C) withdrawal effects
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
How is nicotine metabolised? How about the active metabolite cotinine?
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
What are some adverse effects of nicotine?
- 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 NicotinicN and NicotinicM receptors (see image for more)
Tolerance, physical dependence and compulsive use (psychological dependence) are all seen with nicotine use. Explain why
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
What are the some symptomns of physical withdrawal syndrome of nicotine? How long does it last?
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
What is used to alleviate nicotine withdrawal syndrome?
- Nicotine Replacement Therapy (NRT)
- Varenciline
- Bupropion
What is nicotine replacement therapy used for? What forms does it come in?
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
What is the MOA of varenicline?
- Partial agonist acting on α4β2 nicotinic receptor subtype
- Antagonist effect: blocks pleasurable effects of smoking
- Agonist effect: reduces withdrawal symptoms