ans4_nicotinic_2015

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ANS Nicotinic Receptors/Lisa Tee/ Curtin

Advanced Pharmacology for Pharmacists

Pharmacology for Pharmacists 1 ANS4

Nicotinic receptors: Autonomic ganglia

Neuromuscular junction

A/ Prof Lisa TeeSchool of Pharmacy



ANS Lectures

ANS 5SYMPATHETICAlpha & Beta

Receptor Agonists

ANS

Pharmacology

ANS 1 & 2PARASYMPATHETIC

Muscarinics &Antimuscarinics

ANS 3PARASYMPATHETICAnticholinesterase

ANS 4PARASYMPATHETIC

Drugs affectingAutonomic Ganglia &

Neuromuscular Junction

ANS 6SYMPATHETICAlpha & Beta

Receptor

Antagonists



ANS Nicotinic Receptors/Lisa Tee/Curtin

Lecture Outline

1. Nicotinic receptors

2. Pharmacological and adverse effects of

nicotine

3. Drugs acting in the neuro-muscular

junction

4. Neuromuscular blocking agents

-nondepolarising agents

-depolarising agents

5. Botulinum Toxin Type A Botox)




Classification of Receptors

Parasympathetic

MUSCARINIC RECEPTORS

M1 neuralM2 cardiac

M3 glandular

smooth muscleM4 CNS

M5 CNS

NICOTINIC RECEPTORS

NM skeletal muscle

NN autonomic ganglia




Classification of Receptors

“ Pharmacology for Nursing Care” Lehne, Saunders 5th Edition, fig13.6 pp 105

Parasympathetic

Nervous System

Sympathetic

Nervous System

Somatic Motor

System




Nicotinic Receptors

RECEPTOR LOCATION RESPONSES MECHANISM

Nicotinic NM

“muscular”

Skeletal muscle

Neuromuscular

end-plates (NMJ)

End-plate depolarisation, skeletal

muscle contraction

Excitatory

Opening of

Na+/K+

channelsCa2+

conductance

Nicotinic NN

“neural”

Autonomic ganglia

Adrenal medulla

CNS

Depolarisation and firing of post-

ganglionic neuron

Secretion of catecholamines

Complex; arousal, attention,

analgesia

Excitatory

Opening of

Na+/K+

channels

Ca2+

conductance

There are two broad classes of nicotinic receptors -

muscle-type (NM) and neuronal-type (NN)




Nicotine: Tolerance

Tolerance develops rapidly to these

effects

Tolerance, physical dependence andcompulsive use (psychological dependence)are all seen with nicotine use.

Nicotine is highly addictive.

Pharmacokinetics

Nicotine is metabolised, mainly in the liver,

within 1-2 hours. The inactive metabolite, cotinine, has a long

t1/2, and can be used in blood/urine tests tomonitor smoking habits.




Treatment of Nicotine Dependence

Varenicline:

Partial agonist acting on nicotinic receptors

Antagonist effect: blocks pleasurable effectsof smoking

Agonist effect: reduces withdrawal symptoms

Bupropion:

Mechanism of action poorly understood

May be due to inhibition of reuptake ofnoradrenaline and dopamine.

More in Pharmacy Primary Care…..



Nicotinic by A/ Prof Lisa Tee/ Curtin

Adverse effects of nicotine

Smoking reduces life expectancy

Ischaemic heart diseaseboth nicotine and CO may be responsible

Cancer

Lung, bladder and prostate cancerCarcinogenic tars are responsible

Smoking during pregnancy

Lowers birth weight

Retards childhood development

Increases abortion rate

Increased perinatal mortality




Nicotinic

N

Effects

“ Fundamentals of Pharmacology” (5th Edition, 2007) by Bul lock et al Fig 27.02 modification

NicotinicN

receptor agonists

Stimulate Nicot inicN receptors

Adrenaline &

Noradrenaline

release

Stimulates

Adrenal

medulla

Sympatheticstimulation

Increased

Heart rate

Sense ofwell-being

Induces

behavioural

changes

Bodyrelaxation

Increases in

Gastrointestinal

motility

Increases

Autonomic nervous

System tone

Increases

in blood

pressure

Hypertension Diarrhoea

CNS




Nicotinic

M

Effects

“ Fundamentals of Pharmacology” (5th Edition, 2007) by Bullock et al Fig 27.02

NicotinicM

receptor agonists

Stimulate NicotinicM receptors

Muscle spasm Rigidity

Increased

Muscle

tension

Increasesskeletal

muscle tone

Tremor

The main locations of

the muscle-type are at

the skeletal neuro-

muscular junction NMJ)




Nicotine Replacement Therapy

• 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:

• Nicorette® Classic, Mint, Citrus Gum 2mg, 4mg

• Nicorette CQ7®, CQ Clear® Patch 7, 14, or 21mg/24 hours.

• Nicorette® Inhaler 10mg

• Nicorette® Microtab 2mg

• Nicotinell® Mint, Fruit Gum 2mg, 4 mg

• Nicabate CQ® Transdermal Patch 7, 14 and 21mg/24 hours

• Nicabate CQ® Lozenge 2mg, 4mg• Nicotinell® Patch 7, 14, or 21mg/24 hours

• QuitXl® Classic, Mint Gum 2mg, 4 mg.

• QuitX Patches 7, 14 and 21mg/24 hours.

See AMH section 18.7: Drugs for nicotine dependence




Drugs acting in theneuromuscular junction




AChE

Nerve Terminal

ACh

ACh

Choline

Acetate

Choline

ACh AcCoA

CoA

ACh+

ACh

RESPONSE

ACh

Nondepolarising

& Depolarising

blockers

Botulinum toxin

inhibits

ACh release

Drugs acting on NMJ: Sites of action

Cholinesterase

inhibitors inhibit

destruction of ACh





• Skeletal (voluntary) muscle is innervated by motor

neurons.

• Axons are able to propagate action potential at highvelocities.

• The muscle which l ies below the axon terminal is

called motor end-plate.• The chemical synapse between the neurons and motor

end-plate is called the neuromuscular junction (NMJ).

• The main locations of the

muscle-type are at the skeletal NMJ.





1. When two molecules of ACh bind to the two alpha units (one each)

2. Channel opens immediately, causing influx of Na+

3. Resul ts in depolar isat ion of motor end-plate

4. Depolarisation triggers the muscle action potential leading to muscle contraction.

“ Pharmacology for Health Professionals” Bryant B, Knights KM, Salerno E. , Fig 13.2 pp203




Neuromuscular Blocking Agents:

Drugs used to paralyse skeletal muscles duringanaesthesia and surgery

Image of surgery from

http://www.musictherapyworld.de/modules/mmmagazine/issues/20051117100407/20051117101003/Fig1.jpg




Neuromuscular Blocking Agents

Non-depolarising Blockers

• Atracurium

• Cisatracurium• Mivacurium

• Pancuronium

• Rocuronium• Vecuronium

Depolarising Blockers• Suxamethonium

http://www.unholylegacy.woerlee.org/images/anesthesia%20old.jpg




Non-depolarising Neuromuscular Blockers

Atracurium, Cisatracurium, Mivacurium,Pancuronium, Rocuronium, Vecuronium

Clinical UsesUse to paralyse skeletal muscles duringanaesthesia and surgery

Mechanism of Action• Competit ive antagonists - nicotinic ACh receptor

• Causes non-depolarisation of motor end-plate

• Complete paralysis without fasciculation• Action reversible by increasing Ach levels withanticholinesterase

• Main difference between these drugs is their duration

of action




Non-depolarising Neuromuscular Blockers:

Mechanism and site of action

“ Pharmacology for Health Professionals” Bryant B, Knights KM, Salerno E. , Fig 13.4, pp 208

Antidote for

Non-depolarsing

Blockade:

Anticholinesterase

Sugammadex




Non-depolarising Neuromuscular Blockers

Drug Speed of

onset

(min)

Duration of

action

(min)

Main side effects Notes

Pancuronium Intermediate

1.5-2.5

Long

ID 60-120MD 25-60

Slight tachycardia

No hypotension

The first steroid-based compound

Better side effect profile thantubocurarine. Widely used.

Vecuronium Intermediate

2-3

Intermediate

ID 20-40

MD 20-40

Few side effects Widely used Occasionally causes

prolonged paralysis

Atracurium Intermediate

1.5

Intermediate

ID 30-40

MD 15-25

Transient

hypotension

(histamine release)

Unusual mechanism of elimination

(spontaneous non-enzymic chemical

degradation in plasma); degradation

slowed by acidosis. Widely used

Mivacurium Fast

2-2.5

Short

ID 15-30

MD 15

Transient

hypotension

(histamine release)

New drug, chemically similar to

atracurium but rapidly inactivated by

plasma cholinesterase (thereforelonger acting in patients with liver

disease or with genetic

cholinesterase deficiency)

“ Pharmacology” (6th Edit ion, 2007) by Rang et al, modi fication of Table 10.7 pp158, modification; 7th

edition 2011, Table 13.6

AMH 2014, Modif ication of Table 2.2 pp 22

ID = Initial Dose; MD = Maintenance Dose




Depolarising Neuromuscular Blockers

Suxamethonium (only one available)Mechanism of Action

• Agonist - nicotinic receptors like Ach

• Maintains a state of depolarisation of endplate;prevents transmission of another action potential

• Depolarising block produces initial muscle

fasciculations (twitches) and often post-operativemuscle pain.

Short duration of action (approx 10 mins)

• Rapidly hydrolysed by plasma cholinesterase

• Very short acting

• Long-lasting paralysis in a small group of people whoare congenitally cholinesterase-deficient.




Depolarising Neuromuscular Blockers:

Mechanisms and sites of action

“ Pharmacology for Health Professionals” Bryant B, Knights KM, Salerno E. , Fig 13.4, pp 208




Depolarising Neuromuscular Blockers

CLINICAL USES:

• Tracheal intubation

• Electroconvulsive shock therapy

ADVERSE EFFECTS of Suxamethonium

• Bradycardia, cardiac arrhythmias due to K+

release, especially in burns or trauma

patients.

• Increased intra-ocular pressure and (rarely)

hyperthermia.

• Contraindicated in open-angle glaucoma.




Neuromuscular Blockers: Products

Products available in Australia:

• Atracurium Besylate Injection (Tracrium®):

• Cisatracurium Besylate Injection (Nimbex®)

• Mivacurium Chloride Injection (Mivacron®)

• Pancuronium Bromide Injection (Pavulon®)

• Rocuronium Bromide (Esmeron®)

• Vecuronium Bromide (Norcuron®).See AMH Section 2.3.1: Non-depolarisingNeuromuscular Blockers

• Suxamethonium Chloride.See AMH Section 2.3.2: Depolarising

Neuromuscular Blockers




Pharmacological Targets in NMJ

There are three major targets within the NMJ for clinically

useful drugs

1. The nicotinic acetylcholine receptor - blockade

Depolarising and non-depolarising blockers

2. The presynaptic release - inhibition.

Aminoglycoside antibiotics,

Botulinum Toxin Type A Purif ied Neurotoxin Complex.

3. Acetylcholinesterase – inhibition

Reversible and irreversible inhibitors




AChE

Nerve Terminal

ACh

ACh

Choline

Acetate

Choline

ACh AcCoA

CoA

ACh

+

ACh

RESPONSE

ACh

Nondepolarising

& Depolarising

blockers

Botulinum toxin

inhibits

ACh release

Cholinergic: Sites of drug action

Cholinesterase

inhibitors inhibit

destruction of ACh




Botulinum Toxin Type A (Botox®)

Botulinum Toxin Type A Purified Neurotoxin

Complex

• Derived from Clostridium botulinum• Blocks neuromuscular conduction

• Irreversibly inhibiting the release of Ach at the

neuromuscular junction.Botox Powder for Injection (100U)®

• IM at therapeutic doses produce localised

chemical denervation muscle paralysis• Produces flaccid paralysis for about 2-3 months

until new motor endplates form.




Botox® is used for….

Focal spasticity

Cervical dystonia spasmodic torticollis)

Blepharospasm

Hemifacial spasm

Glabellar and other upper facial lines

Severe primary hyperhidrosis of axillae

Strabismus

Laryngeal dystonia spasmodic dysphonia)

Oromandibular dystonia




Botox® is used for….

http://www.botoxcosmetic.com/how_botox_works/before_after.aspx




http://www.youtube.com/watch?v=OII3pGyw4Mk




Adverse effects of Botox®

Common adverse effects of Botox® include:

• Weakness of muscle groups adjacent to the site ofinjection,

• Ptosis (droopy eyelids), eye irritation• Increased lacrimation (tear formation)

• Dysphagia (difficulty swallowing)

Infrequent adverse effects include:• Paralysis of distant muscles (due to misplaced injections

or excessive doses)

• Keratitis (inflammation of the cornea)

• Diplopia (double vision)

• Entropion (infolding of the margin of an eyelid)

• Ectropion (rolling out of the margin of an eyelid)




Summary Notes: Nicotinic Receptor Antagonists

• The nicotinic receptor antagonists include ganglionicblocking agents (e.g., trimethaphan) and neuromuscularblocking agents (e.g., the curariform drugs, which are

nondepolarising, and succinylcholine, which isdepolarizing).

• Trimethaphan is used to produce controlled hypotensionduring surgery and to treat hypertensive emergencies.

• Neuromuscular blockers are used primarily to producemuscle relaxation during surgery.

• Curariform drugs competitively block nicotinic receptors inskeletal muscle. They do not cause muscle fasciculations,and their effects can be reversed by cholinesteraseinhibitors.

• Suxamethonium produces muscle fasciculations that arefollowed by muscle paralysis. The effects cannot bereversed by cholinesterase inhibitors.

“ Pharmacology” (2nd Edition, 2006) by Brenner & Stevens with modif ication pp69-70




Learning Outcomes

On completing this lecture, you will be

able to:

1. Describe the nicotinic receptors and thepharmacological effects of nicotine.

2. Compare and contrast the mechanismsof action and pharmacological effects of

non-depolarising and depolarising

neuromuscular blockers.3. Name some therapeutic and adverse

effects of these agents.




References1. Pharmacology. Rang HP, Dale MM, Ritter JM, Moore PK.

Churchill Livingstone, Edinburgh 6th edit ion 2007, Chapter 10,pp 144-167; 7th Edit ion 2012, Chapter 13 pp 151-173.

2. Goodman &Gilman 11th edn. 2007: Chapter 9, pp 217-236; 12th

edition 2011, Chapter 11 pp 255-275.

3. Pharmacology for Health Professionals. Bryant B, KnightsKM, Salerno E. Mosby, St Louis, 2nd edn. 2006, Chapter 11 pp177-184; Chapter 13, pp 201-211.

4. Principles of Pharmacology. Golan DE et al., LippincottWilliams & Wilkins, 2005, Chapter 7, pp 89-106.

5. Fundamentals of Pharmacology. Bullock S, Manias E,Galbraith A, Pearson publication, 5th Edition, 2007, Chapter

28 pp283-308; 6th Edition Bullock S, Manias E, 2011, Chapter28, pp292-307.

6. Pharmacology. Brenner GM, Stevens CW. Saunders Elsevier,2nd edition 2006, Chapter 7, pp 64-70; 3rd Edition, 2010,Chapter 7, pp 71-74

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