Autonomic Pharmacology

Autonomic Pharmacology

• The nervous system comprises the central nervous system (CNS) and the peripheral nervous system (PNS).
• The CNS includes the brain and spinal cord.
• The PNS includes motor and sensory neurons.
• The somatic nervous system controls voluntary movements.
• The autonomic nervous system controls involuntary responses.
• The autonomic nervous system has sympathetic ("fight or flight") and parasympathetic ("rest or digest") divisions.
• The enteric nervous system primarily affects digestive organs.

Anatomic Differences of the ANS & SNS

• Parasympathetic nerves emerge from the craniosacral regions.
• Sympathetic nerves emerge from the thoracolumbar regions.
• Both parasympathetic and sympathetic nerves use acetylcholine (ACh) at the first synapse.
• Parasympathetic postganglionic neurons also use ACh.
• Sympathetic postganglionic neurons use norepinephrine (NE), epinephrine (Epi), or dopamine (D).

Cholinergic Transmission

• Cholinergic transmission involves the neurotransmitter acetylcholine (ACh).
• There are five key target processes for pharmacologic therapy: neurotransmitter biosynthesis, storage, release, termination of action, and receptor effects.

Biosynthesis

• ACh is synthesized in the cytoplasm.
• The process involves acetyl-CoA and choline.
• Choline acetyltransferase (ChAT) catalyses the reaction.
• Acetyl-CoA is synthesized in mitochondria within nerve endings.
• Choline is transported from the ECF into neuron terminals by the sodium-dependent membrane choline transporter (CHT).
• Hemicholiniums block the (CHT) symporter.

Storage

• After synthesis, ACh is transported into vesicles via the Vesicle-Associated Transporter (VAT).
• Vesamicol blocks VAT.
• Each vesicle can store 1,000-50,000 ACh molecules.

Release

• Fusion proteins are required for vesicle-membrane fusion and release.
• VAMPs (vesicle-associated membrane proteins) align vesicles with release sites and trigger neurotransmitter release.
• SNAPs (synaptosomal nerve-associated proteins) are also found at release sites and interact with VAMPs.
• Action potentials trigger an influx of calcium ions, leading to the fusion of vesicles with the terminal membrane and exocytotic release of acetylcholine.
• Botulinum Toxin blocks the ACh vesicle release process.

Termination of Action

• After release from the presynaptic nerve terminal, ACh may bind to and activate cholinoceptors.
• Acetylcholinesterase (AChE) metabolizes ACh, splitting it into acetate and choline.

Cholinergic Agonists

• Parasympathomimetics/"Cholinomimetics"
• Cholinergic agonists and anticholinesterases
• Cholinergic agonists include choline esters and cholinomimetic alkaloids.
• They act through muscarinic and nicotinic receptors also

Direct-Acting Cholinergic Agonists (Choline Esters)

• Poorly absorbed/distributed to the CNS due to being hydrophilic.
• Structural modifications lead to resistance from hydrolysis by AChE, potentially prolonging the duration of action.
• Methyl groups reduce potency at N receptors.

Direct Acting Cholinergic Agonists (Cholinomimetic Alkaloids)

• Muscarine is a quaternary amine.
• Nicotine is liquid, lipid-soluble, and well-absorbed.
• Pilocarpine and lobeline are also included in this category.
• Urinary acidification increases clearance.

Indirect Acting Cholinomimetics

• AChE inhibitors/anti-cholinesterases increase ACh concentration by preventing its breakdown.
• These fall into three chemical groups: simple alcohols with quaternary ammonium groups, carbamic esters of alcohol with quaternary/tertiary ammonium groups, and organic derivatives of phosphoric acid.

Cholinergic Antagonists

• Divided into subgroups based on receptor affinities: antimuscarinic and antinicotinic agents.
• Antinicotinic agents include ganglionic blockers and neuromuscular blockers.

Basic Pharmacology of Antimuscarinic Drugs

• Atropine (prototype) blocks muscarinic receptors.
• These are naturally occurring compounds (alkaloids) with antimuscarinic effects.
• Atropine, hyoscyamine is derived from Atropa belladonna, aka deadly nightshade, and Datura stramonium, aka Jimson/Jamestown weed or thorn apple with the levo-stereoisomer being more potent.
• Absorbed well from the gut or conjunctival membranes; quaternary derivatives have lower absorption.
• Widely distributed in the body.
• Atropine elimination includes a rapid phase (t1/2 = 2 hrs) and a slow phase (t1/2 = 13 hrs).
• Blocks muscarinic receptors.

Pharmacodynamics: Mechanism of Action

• Atropine causes reversible muscarinic receptor blockade.
• Larger ACh concentrations can reverse Atropine effects.
• It decreases the second messenger IP3 and prevents the inhibition of adenylyl cyclase.
• Certain antimuscarinic agents act as inverse agonists, shifting receptors to an inactive state.

Effects of Muscarinic Blocking Agents

• CNS: Sedation, anti-motion sickness, antiparkinson action, amnesia, delirium.
• Eye: Cycloplegia, mydriasis.
• Bronchi: Bronchodilation, especially if constricted.
• Gastrointestinal tract: Relaxation, slowed peristalsis, reduced salivation.
• Genitourinary tract: Relaxation of bladder wall, urinary retention.
• Heart: Initial bradycardia, then tachycardia.
• Blood vessels: Blocks muscarinic vasodilation.
• Glands: Reduces salivation, lacrimation, and gastric secretion.

Clinical Applications

• CNS Disorders: Parkinson's Disease (benztropine, biperiden, trihexyphenidyl), motion sickness (scopolamine).
• Ophthalmology: Retinal examination (atropine, homatropine, cyclopentolate, tropicamide).
• Respiratory Disorders: Asthma/COPD (ipratropium, tiotropium, aclidinium).
• GIT Disorders: Hypermotility (dicyclomine, glycopyrrolate, hyoscine).
• Urinary Disorders: Bladder spasm and urge incontinence (oxybutynin, darifenacin, solifenacin, tolteridine, fesoterodine, trospium, propiverine).
• Cholinergic Poisoning e.g due to pesticides and insecticides is countered with the administration of antimuscarinic drugs IV.

Basic Pharmacology of Ganglion-Blocking Drugs

• Competitively block ACh and similar agonists at nicotinic receptors in both parasympathetic and sympathetic autonomic ganglia.
• Also block the ion channel gated by nicotinic cholinoceptors.
• Non-selective, leading to clinical use.

Ganglion Blockers

• Organ effects include CNS sedation, prominent cycloplegia/mydriasis, hypotension, tachycardia.

Neuromuscular-Blocking Drugs

• Structural analogs of ACh that act either as antagonists or agonists.
• They can be be non-depolarizing (competitive) or depolarizing
• Tubocurarine, Pancuronium, atracurium cisatracurium Vecuronium, Rocuronium are used

Neuromuscular (NM) Nondepolarizing (competitive) Blockers

• Interact with nicotinic receptors to prevent the binding of ACh.
• Prevent the depolarization of the muscle cell membrane and inhibit muscular contraction.

Neuromuscular: Depolarizing Blockers

• Phase I, membrane depolarizes
• Succinylcholine is used when rapid endotracheal intubation is required during the induction of anesthesia