ANS Pharmacology - Parasympathetics Flashcards
Sites of action of acetylcholine in peripheral nervous system
Preganglionic fibers to ANS ganglia
Preganglionic fibers to adrenal medulla
Parasympathetic postganglionic fibers
Sympathetic postganglionic fibers innervating sweat glands (anomaly!)
NMJ
Muscarine
Parasympthomimetic
Nicotine
Acts as stimulant —> desensitizes sympathetic/parasympathetic
Acetylcholine
Both sympathetic / parasympathetic
Nicotinic vs muscarinic action
Acetylcholine biosynthesis
Addition of acetyl CoA to choline > ChAT choline acetyltransferase (cytoplasmic enzyme)
Pre-formed ACh transported into vesicles, no intracellular metabolizing enzymes
Choline from diet/protein metabolism (from serine)
RLS = Transport of choline into nerve terminal
Drugs affecting ACh synthesis / release
Hemicholinium : blocks choline uptake
Vesamicol : blocks transport into vesicles
Cholineacetyltransferase : none to date
Botulinus toxin
Bind to cell membrane + internalized > Block fusion of vesicles with plasma membrane (cleaves synaptobrevin) > block transmission
From Clostridium botulinum
Flaccid paralysis of muscles; death by paralysis of respiratory muscles
Mechanism of synaptic transmitter release
Nerve depolarization > voltage gated Na/Ca channels > Ca depended vesicle fusion and exocytosis > diffusion into synaptic cleft > receptor binding and activation > transmitter breakdown
Termination of acetylcholine action
Enzymatic breakdown of ACh by acetylcholinesterase
Acetylcholinesterase
Terminates ACh action at nerve terminals
Attached on pre/post-synaptic membrane by collagen-like filaments
Very rapid action, 150 microsec turnover
Cleaves bond to form Acetate/choline - choline re-uptake (RLS)
Pseudocholinesterase
Synthesized in liver, found in plasma
Function unclear
Nicotinic sites in PNS
Preganglionic fibers to all ANS ganglia
Preganglionic fibers to adrenal medulla
NMJ
Muscarinic sites in PNS
Parasympathetic post-ganglionic fibers
Sympathetic postganglionic fibers innervating sweat glands
Nicotinic receptors
Nicotinic neuronal - Nn
Nicotinic muscle - Nm
Ligand-gated ion channels “ionotropic receptors”
Muscarinic receptors
GPCR
“Metabotropic receptors”
Activation of Nicotinic ACh receptors
ANS ganglion stimulation - both sympathetic and parasympathetic
Release of EPI/NE from adrenal gland
Contractions of skeletal muscle
CNS - tremor, anxiety, sleep disturbances, resp/circ center effects
Nicotinic receptor structure/ activation
Pentameric structure; a, b, y, d subunits
Two a subunits —> each bind ACh to open channel —> Na moves in, K moves out
Muscarinic receptor structure/activation
7TM GPCR receptor
- gland secretion (sweat, salivary, mucous, lacrimal)
- contract smooth muscle (airway, GI, gall bladder, urinary, ureters)
- pupillary constriction
- relax sphincters (GI, urinary, biliary)
- show HR
SLUMD (salivation, lacrimation, urination, defecation, miosis)
M2 - muscarinic type II receptor
Heart, smooth muscle, autonomic ganglia
Inhibitory
M3 - muscarinic type III receptor
Exocrine glands, smooth muscle, blood vessels (endothelium)
Excitatory
Action of M2 receptors
Inhibitory in cardiac muscle
Inhibition of adenyl ate cyclase + activation of K+ channels (decreases potential > harder to depolarize)
Action of M3 receptors
Excitatory in smooth muscle
Opening of plasma membrane and intracellular Ca channels
Parasympathomimetic drugs
Therapeutic uses (agonists): ophthalmology (glaucoma), urinary tract disorders, GI tract disorders
Side effects: Salivation-lacrimation-urination-defecation-miosis; abdominal pain; severe hypotension
Examples of parasympathomimetic drugs
Acetylcholine (no significant therapeutic applications, broad spectrum, poorly absorbed orally/subq, rapidly hydrolzyed by IV admin)
MEthacholine
Carbachol
Bethanecol
Methacholine
Synthetic analog of acetylcholine
Reduced susceptibility to hydrolysis, more selective for Muscarinic
Used for diagnosis of asthma
CV side effects - limited clinical use
Carbachol
Carbamylated ACh
Resistant to AChE
Both muscarinic + nicotinic activity
Limited clinical use due to ganglionic stimulation
Used to induce miosis, treatment of glaucoma
Bethanecol
Methylated + carbamylated ACh
Resistant to AChE
Very selective for muscarinic over nicotinic
Used to test pancreatic function, treat urinary retention (stimulate bladder contraction)
Naturally occuring Cholinergic alkaloids
Pilocarpine - S Am shrub pilocarpus; mainly muscarinic, 100x potency of ACh; pronounced action on salivary/sweat glands; opthalmologocial use; can inc BP/tachycardia
Arecoline - from “betel nut”, no therapeutic uses, previously de-wormer
Muscarine - from mushroom; high dose —> death; atropine = antidote
Atropine
Anti muscarinic agent
Naturally occuring - in Belladona
M»»»N receptor antagonist
Tachycardia, dec intestinal contraction/motility, drying airway/sinuses/bronchodilation; pupillary dilation, tremor, CNS delusion/excitment
Therapeutic uses of atropine
Preanesthetic - decrease respiratory secretions
OTC cold medications - dec lacrimal/nasal secretions
Anti-asthmatic medication
Ophthalmology - mydriasis
Cough suppression in vet med with hydrocodone
Homoatropine
Anti muscarinic
More rapid onset that atropine
Shorter duration of action
Less potent
Scopolamine
Antimuscarinic
Pre-anesthesia to decrease resp secretions
OTC motion sickness
Same peripheral action as atropine, but pronounced sedative action
Sedate mentally ill patients
Propantheline
Synthetic antimuscarinic
No BBB penetration - no CNS unless high dose
Mitigate GI spasm/secretions (spasmodic colic in horses)
Reduce rectal tearing risk in rectal exam
Reduce spasm/promote relaxation of esophagus during choke in horses
Tropicamide
Short duration of action
Used in ophthalmology > mydriasis
Short recovery time (preferred over atropine)
Iris/lens innervation
Parasympathetic —> miosis (contract); muscarinic agonist same effect
Sympathetic —> mydriasis (dilate); muscarinic antagonists same effect
Mydriasis
Radial (dilator) muscle - contraction causes pupil dilation, innervated by sympathetic
Muscarinic antagonists
Miosis
Circular (sphincter) muscle - constriction of pupil, innervated by parasympathetic
Muscarinic agonist
Ciliary muscle
Contraction —> lens bulges - near vision accommodated
Relaxation - lens flattens - far vision accommodated
Innervated by parasympathetic system (ACh mediated)
Cyclopelgia
Paralysis of ciliary muscle - lack ability to accommodate
Can happen with too much or too little ACh
Paralysis of Accomodation
Muscarinic antagonist —> simulates too little ACh present
Absence of contraction —> lungs flatted; far-sightedness
Spasm of accomodation
Muscarinic agonists of AChE inhibitors —> simulate too much ACh
Ciliary muscle constant maximal contraction > lens budged; near sightedness
Treatment of narrow angle (acute congestive) glaucoma
Miosis with pilocarpine and physostigmine > inc drainage
Reduce pressure until surgery
Muscarinic antagonists can precipitate an attack
Treatment of wide angle (open angle, chronic, simple) glaucoma
Surgery!
Mechanism of drug action unclear
Use pilocarpine/physostigmine
B-blockers in the eye
Decrease production of aqueous humor
Synthetic nicotinic agents
Directly or indirectly modify Nicotinic Cholinergic receptor activity
Ganglionic stimulants
Ganglionic blockers
AChE inhibitors
Ganglionic stimulants
Nicotine - complex often unpredictable physiological responses, stimulation + desensitization; CNS effects; stimulates adrenal medulla to release NE/EPI, Nicotinic receptor in skeletal muscle (no significant therapeutic uses)
Ganglionic blockers
Hexamethonium - blocks ganglionic nicotinic receptors (Nn) not Nm; limited use - both sympathetic/parasympathetic
Trimethaphan - has been used in vet med to lower BP during surgery
AChE inhibitors
Inhibit breakdown of ACh —> parasympathomimetic
Side effects: muscarinic actions at autonomic effector organs, nicotinic action at ANS ganglia, nicotinic stim at NMJ (followed by desensitization > flaccid paralysis), CNS effects
Classes of AChE inhibitors
Reversible inhibitors - reversible
Carbamylating inhibitors - prolonged
Phosphorylation inhibitors - irreversible
Reversible AChE inhibitor
Edrophonium
Competitive inhibitor, no covalent attachment
Rapidly reversible, short acting
Used to diagnosis Myasthenia gravis (weakness of contraction due to decrease in receptor density at NMJ)
Carbamylated inhibitors of AChE
Breakdown produces carbamate vs acetate —> much slower to release
Physostigmine
Plant derived alkaloid
AChE inhibitor
Absorbed well from GI, crosses BBB
Originally used in myasthenia gravis to inc ACh at NMJ
Used in glaucoma
Used in atropine poisoning
Other carbamylating AChE inhibitors
Neostigmine (only peripheral effects - used currently to treat myasthenia gravis, no BBB cross)
Pyridostigmine (shorter half life)
Demecarium
Phosphorylation inhibitors of AChE
Organophosphate
Diisopropyl fluorophosphoric acid
used in insecticide products
synthesis of new AChE required to recover
Nerve gases, Sarin, VX gas
Toxicology of O-P poisoning
- Overstimulation of muscarinic / nicotinic ACh receptors (SLUMD)
- Overstimulation of ACh receptors at NMJ in skeletal muscle
- Paralysis of diaphragm / thoracic muscles > resp failure
- CNS effect
O-P poisoning antidote
Pralidoxime (2-PAM)
Phosphate acceptor
Only effective before “aging” process (1-3 h)
Therapeutic uses of anticholinesterases
Glaucoma
During Anethesia
Myasthenia gravis
Atropine poisoning
