Muscarinic & Nicotinic drugs

Question 1

What are Muscarinic receptors and what are the 2 types?

Answer 1

G-protein coupled receptors

Excitatory - M1, M3, M5

Inhibitory = M2, M4

Question 2

What happens at the excitatory Muscarinic receptors?

Answer 2

ACh binds to the orthosteric site - triggers second messengers

Second messengers:

• Phospholipase C (PLC)
• Inositol triphosphate (IP3)
• Diacylglycerol (DAG)

Causes an increase in:

• Ca2+
• MAP kinase
• Phospholipase C-β

Question 3

What happens at the inhibitory Muscarinic receptors?

Answer 3

ACh binds to either orthosteric or allosteric binding site

Regulates the Gi/o protein coupled receptor - reduces the conc of cAMP

Causes increases of:

• Adenylyl cyclase
• MAP kinase
• G protein coupled inwardly-rectifying potassium channel (GIRK)

Question 4

What are Nicotinic Receptors?

Answer 4

Ligand gated Ion channels

Made up of 5 subunits - (α, β, γ, δ, ε)

Subunit combination - determines ligand binding properties

Question 5

What are the clinical targets for Nicotinic drugs?

Answer 5

• Cognitive performance
• Neurodegenerative disease
• Schizophrenia
• Anxiety & Depression
• Tourette’s Syndrome
• Epilepsy
• Pain
• Smoking Cessation
• Ulcerative Colitis

Question 6

What drugs are used clinically as Nicotinic agonists?

Answer 6

Nicotine

• Full agonist of nicotinic receptors
• Smoking cessation aid

Varenicline

• Partial agonist of nicotinic receptors
• Smoking cessation aid

Suxamethonium

• Neuromuscular blocking agent
• Muscle relaxant

Galantamine

• Allosteric nicotinic receptor agonist
• Used for Alzheimer’s disease

Question 7

What drugs are used clinically as Nicotinic antagonists?

Answer 7

Hexamethonium

• Ganglionic receptor antagonist
• No effect on muscarinic receptor
• Clinically discontinued due to adverse drug reactions

Trimetaphan

• Ganglionic receptor antagonist
• Limited use in pulmonary oedema & hypertension

Pancuronium

• Competitive ACh antagonist at nicotinic NMJ
• Steroidal
• Used as muscle relaxant in general anaesthesia
• Also used in lethal injections in USA

Atracurium

• Competitive ACh antagonist at nicotinic NMJ
• Non-steroidal
• Used as a muscle relaxant in anaesthesia

Question 8

What is Pilocarpine and how does it work?

Answer 8

Non-selective muscarinic agonist
Used to treat Glaucoma 
- Works on M3 receptor found on iris sphincter muscle
- Causes constriction of pupil
- Improves drainage of intraocular fluid

t1/2 = 3-4 hours

Also used in dry mouth (Xerostomia)

Question 9

What drugs are used clinically as Muscarinic agonists?

Answer 9

Carbachol

• Non-selective muscarinic agent
• It’s Quaternary Ammonium salt - thus not absorbed through GI
• Does not cross BBB
• Can also administer through ocular route - Glaucoma

Xanomeline

• Selective M1 & M4 receptor agonist
• Clinical trials for schizophrenia - not in clinical use

Cevimeline

• Selective M3 receptor agonist
• Used in dry mouth

Question 10

What drugs are used clinically as Muscarinic antagonists?

Answer 10

Benztropine
- Used for PD

Scopolamine

• Treats motion sickness
• Treats Drug Addiction

Atropine

• Produces mydriasis & cycloplegia - thus widens pupil
• Non-selective muscarinic antagonist

Question 11

What are some examples of Antimuscarinic agents?

Answer 11

Incontinence treatment

• Oxybutynin
• • Urinary incontinence
• • Treatment of Transient cystitis

Anti-secretory role

• Ipratorium
• • As bronchodilator in Asthma
• • COPD - Chronic Obstructive Pulmonary Disease
• • Lowers intracellular conc of cGMP - Cyclic Guanine Monophosphate
• • local, site-specific effect
• Methylscopolamine
• • Antiulcer agent
• • Prevents secretion of gastric acid from Parietal cells