pharma lecture 5

What neurotransmitter is released by all parasympathetic neurons (both pre- and post-ganglionic)?

Acetylcholine (ACh)

What are the two main types of acetylcholine receptors?

Ligand-gated ion channels (nicotinic) and G-protein coupled receptors (muscarinic)

Where are nicotinic receptors mainly found in the autonomic nervous system?

At ganglionic junctions (on post-ganglionic neurons)

What are the three "restorative" functions of the parasympathetic nervous system?

Rest and restore, rest and digest, feed and breed

What enzyme synthesizes acetylcholine?

Choline acetyltransferase (CAT)

What are the two precursors required for ACh synthesis?

Choline and Acetyl co-enzyme A (AcCoA)

How is choline taken up into the cholinergic nerve ending?

Choline transporter (sodium-dependent)

How is ACh stored in vesicles?

Via an ACh carrier (vesicular transporter)

What triggers ACh release from vesicles?

Calcium influx through N-type voltage-operated calcium channels (VOCC)

What is the process of ACh release called?

Exocytosis

What enzyme degrades acetylcholine in the synaptic cleft?

Acetylcholinesterase (AChE)

What are the breakdown products of ACh after AChE action?

Acetate and choline

How is ACh release regulated via autoinhibition?

ACh acts on presynaptic M2 receptors → inhibits adenylyl cyclase → reduces cAMP → ↓Ca²⁺ influx → ↓ACh release

What are the five muscarinic receptor subtypes?

M1, M2, M3, M4, M5

Which muscarinic receptors are Gq/11-coupled?

M1, M3, M5

Which muscarinic receptors are Gi-coupled?

M2 and M4

What second messenger system do Gq-coupled muscarinic receptors activate?

PLC → PIP2 → IP3 + DAG → ↑ intracellular Ca²⁺

What second messenger system do Gi-coupled muscarinic receptors inhibit?

Adenylyl cyclase → ↓ cAMP → ↓ PKA

Where are M1 receptors mainly located and what is their effect?

CNS and glands (↑IP3/DAG, ↑Ca²⁺)

Where are M3 receptors mainly located and what is their effect?

Smooth muscle and glands (↑IP3/DAG, ↑Ca²⁺ → contraction/secretion)

Where are M2 receptors mainly located and what is their effect?

Heart and CNS (↓cAMP, ↓Ca²⁺ → ↓ heart rate)

What effect does parasympathetic stimulation have on heart rate and via which receptor?

Bradycardia (decreased heart rate) via M2 receptors

What are the two mechanisms by which M2 receptor activation causes bradycardia?

↑ K⁺ channel conductance (hyperpolarization), 2) ↓ Ca²⁺ channel conductance (slower depolarization)

Do parasympathetic nerves have a large effect on ventricular contractile force? Why?

No, because ventricles have little parasympathetic innervation

What is the direct vascular effect of ACh on blood vessels?

Vasodilation (via M3 receptors on endothelium)

Is vasodilation a major physiological effect of parasympathetic activation?

No, because blood vessels have very little parasympathetic innervation

What effect does parasympathetic stimulation have on the circular muscle of the iris?

Contraction → pupil constriction (miosis)

What effect does parasympathetic stimulation have on ciliary muscle?

Contraction → accommodation for near vision

What effect does parasympathetic stimulation have on bronchial smooth muscle?

Constriction (M3-mediated)

What effect does parasympathetic stimulation have on GI smooth muscle?

Constriction (increased motility)

What effect does parasympathetic stimulation have on exocrine glands?

Increased secretion (e.g., salivary, lacrimal, bronchial, gastric)

Is sweating parasympathetic or sympathetic?

Sweating is sympathetic (but uses ACh as neurotransmitter)

What effect does parasympathetic stimulation have on the eye's drainage angle?

Pupil constriction improves drainage angle, reducing intraocular pressure

What is the main clinical use of muscarinic agonists?

Treatment of glaucoma (pilocarpine eye drops)

How does pilocarpine reduce intraocular pressure?

Contracts circular muscle of iris → pupil constriction → improves aqueous humour drainage

What are side effects of muscarinic agonists?

Slow heart rate, low BP, excess sweating/tearing, flushing, urinary frequency, diarrhea, visual disturbances

Name two naturally occurring non-selective muscarinic antagonists.

Atropine (from deadly nightshade) and Hyoscine (from thorn apple)

What are the cardiac effects of atropine?

Tachycardia (mild, 80-90 bpm) – blocks M2 receptors on SA node

What are the ocular effects of atropine?

Mydriasis (pupil dilation) and cycloplegia (paralysis of accommodation)

Why is atropine dangerous in glaucoma?

Pupil dilation narrows the drainage angle, increasing intraocular pressure

What are the GI effects of atropine?

Reduced motility and some inhibition of gastric secretion

What are the CNS effects of high-dose atropine?

Excitation, restlessness, agitation, disorientation

What is the clinical use of atropine in cardiovascular medicine?

Intravenous atropine for sinus bradycardia (<60 bpm)

Name two muscarinic antagonists used in respiratory disease (COPD/asthma).

Ipratropium (Atrovent) and Tiotropium (Spiriva)

Why do inhaled muscarinic antagonists have few systemic side effects?

Poorly absorbed into circulation; do not cross blood-brain barrier