1 Pharmacology of the Parasympathetic Nervous System Edward JN Ishac Department of Pharmacology and Toxicology Medical College of Virginia Campus of Virginia Commonwealth University Richmond, Virginia, USA Smith Building, Room 742 [email protected]8-2127 8-2126 Autonomic Nervous System ANS Diagram Key Points Division – Anatomical Usually dual innervation Usually antagonistic Usually one dominates Usually some ANS “tone” Neurons of the ANS Key Points Preganglionic fibers – mylinated Postganglionic fibers – non mylinated SNS pre : post 1:20 PNS pre : post 1:1 (exception 1:10,000 Auerbachs plexus) Key role of Ach Motor fiber not part of ANS Cholinoceptors Muscarinic M 1 - Ganglia cells M2- Cardiac muscle M3- Sweat glands M 4 /M 5 Nicotinic N N - Ganglia cells N M - Neuromuscular junction Cholinergic Neurotransmission Rate limiting step Uptake of cholineinto nerve terminal Termination Enzymatic by acetylcholinesterase (AchE)
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Pharmacology of the Parasympathetic Nervous System
Edward JN Ishac
Department of Pharmacology and ToxicologyMedical College of VirginiaCampus of Virginia Commonwealth University Richmond, Virginia, USA
• Choline esters- ACH (muscarinic & nicotinic action)- bethanechol (oral or sc, never iv or im → cardiac arrest)- methacholine (not common)- carbachol (direct/indirect; muscarinic & nicotinic)
• Alkaloids:- muscarine (mushrooms)- pilocarpine (DOC, used in glaucoma emergence)- oxotremorine (synthetic) CNS action (basal ganglia)
• Toxicity:dry mouth, mydriasis, tachycardia, hot flushed skin, agitation and delirium.
High concentrations may cause ganglionic-blockade leading to hypotension
• Treatment:- quaternary cholinesterase inhibitor eg. neostigmine or physostigmine (cns action)- for hypotension: sympathomimetics (α-agonist, eg.methoxamine)
Toxicity and treatment
• mad as a hatter: CNS, delirium• red as a beet: direct vasodilation
• blind as a bat: cycloplegia• hot as hell (a hare): ↓sweat, thermoregulation• dry as a bone: decreased secretions
Symptoms of Antimuscarinic Toxicity
Belladonna (beautiful lady) poisoning
Mad as a Hatter
Mercury was used to treat hats. It was applied on to the fur to roughen the fibres and make them mat more easily
Mercury is a cumulative poison that causes kidney and brain damage. Physical symptoms include trembling (known at the time as hatter's shakes ), loosening of teeth, loss of co-ordination, and slurred speech; mental ones include irritability, loss of memory, depression, anxiety, and other personality changes. This was called mad hatter syndrome.
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T y p e M e m b e r s Ef fects
A g o n i s t s 1 . A c h 2 . B e t h a n e c o l 3 . P i l o c a r p i n e 4 . M e t h a c h o l i n e
1 . h e a r t ⇒⇒ b radycard ia , ↓↓ contracti l i ty, ↓↓ c o n d u c t i o n v e l o c i t y i n t h e A V n o d e
2 . v a s c u l a t u r e ⇒⇒ med ia te vasod i la t ion v i a s y n t h e s i s o f N O b y e n d o t h e l i a l cel ls
3 . s m o o t h m u s c l e ⇒⇒ ↑↑ tone in in test in e & b l a d d e r ; ↓↓ tone in sph inc te rs
4 . e y e ⇒⇒ c o n t r a c t i o n o f s p h i n c t e r ( m i o s i s ) & c i l i a r y m u s c l e f o r n e a r v i s i o n
5 . e x o c r i n e g l a n d s ⇒⇒ ↑↑ s w e a t i n g ( S N S ) , s a l i v a t i o n & g a s t r i c a c i d s e c r e t i o n
A n t a g o n i s t s 1 . a t r o p i n e - n o n -
se lec t ive , long las t ing 2 . s c o p o l a m i n e –
centra l ly a c t i n g 3 . h o m a t r o p i n e –
s h o r t e r a c t i n g 4 . p i r e n z e p i n e - M 1
r e c e p t o r s e l e c t i v e ( an t i-ulcer)
1 . h e a r t ⇒⇒ t achycard ia , ↑↑ A V n o d e c o n d u c t i o n
2 . v a s c u l a t u r e ⇒⇒ n o e f f e c t ( n o c h o l i n e r g i c i n n e r v a t i o n )
3 . s m o o t h m u s c l e ⇒⇒ re laxat ion in GI & u r ina ry t rac t
4 . e y e ⇒⇒ m y d r i a s i s & c y c l o p l e g ia 5 . e x o c r i n e g l a n d s ⇒⇒ d r y m o u t h , d r y
s k i n , & ↓↓ g a s t r i c a c i d s e c r e t i o n 6 . C N S e f f e c t s ⇒⇒ be l l adonna tox ic i ty
( m a d a s a h a t t e r , r e d a s a b e e t , b l i n d a s a b a t , h o t a s h e l l )
Parasympathetic Summary
Rapidly reversible (competitive)
Edrophonium ⇒⇒ used for myasthenia gravis (aka Tensilon)