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pharmacology
1/15/98

Dr Kotlikoff: more 
receptor/effector stuff

We talked before about differential signalling, 
and how the same innervation results in contraction in one area, 
relaxation in another, and so forth. there are a number of areas of 
differential signalling.

sometimes, nerves release the same NT but the 
effector has different types of receptors, eg in the heart adrenergic 
signals interact w/B1 receptor and are excitatory, and in [other] muscle, 
there is the B2 receptor and it's inhibitory.
Or, ACH can bind to the 
same receptors, but have different effector mechanisms.
In heart, K+ 
opens after ACH binds M2 receptor; in smooth muscle, K+ channel closeees 
after ACH binds M2 receptor. Or, you can have ACH released in one area - 
eg tubular area of gut, and VIP in another area - sphincters of gut - 
resulting in two different signals due to firing of one nerve.

so, 
moving to specifics of muscarinic receptor 2nd messenger coupling - 

M1: 
expressed in nerve, CNS, glands
   coupled to Gq/11 which signals through 
IP3

M2: expressed on heart, smooth muscle - presynaptically on axons
    
coupling is through Gi, which affects K+ channels (opens them in the 
heart, closes them in smooth muscle), inhibits cyclase (in all systems), 
and can open cation channels

M3: expressed in smooth muscle, glands; 
	
coupled to Gq/11 which signals through IP3

M1 and M3 are often talked 
about as one group; very similar.

Looking at it more 
physiologically...what is muscarinic receptor signalling actually doing?


Muscarinic stimulation results in: stimulation of sweat and salivary 
glands, mucous production, and lacrimal glands; contraction in most 
smooth muscles (a couple of exceptions are the sphincters in the GI 
tract, where muscarinic receptors are not really found, and in the 
vessels, where as you recall the nerve goes into the endothelium, causing 
release of NO, which relaxes the NO). so muscarinic signalling is 
indirectly inhibitory in those two cases of smooth muscle. It's important 
to remember the general rule - in the airways, GI tract, bladder - 
muscarinic stimulation, vagal stimulation, results in smooth muscle 
contraction. In the pupil, narrowing of the pupil via contraction of the 
iris occurs. There is relaxation of GI sphincters. There is a slowing of 
the heart - prominent inhibitory effect on the heart. This constellation 
of muscarinic signs was noted very early - overstimulation of 
parasympathetic system/ muscarinic receptors results in salivation, 
lacrimation, urination, defectation - SLUD. See handout - table of 
sympathetic and parasympathetic effects on various effector organs. 
usually opposite effects. note that the blood vessel dilation is 
indirect. in the lung, the airway caliber is under vagal control - vagal 
stimulation causes bronchoconstriction, and muscarinic antagonists relax 
the airways. when you think about drugs in these systems, think about 
preexisting tone and how to modify it. in heart, there is preexisting 
vagal control - if you give atropine, or muscarinic antagonist, you will 
speed up the heart, by inhibiting the vagal stimulation.

Muscarinic 
Agonists: [moving into the drug section!]

also called 
parasympathomimetic drugs (based on the effects they have). these can be 
classified in terms of their susceptibility to ACHesterase and their 
specificity for muscarinic or nicotinic receptors. right now, all the 
muscarinic agonists we're discussing have equal potency at M1, M2, and 
M3. we do not have useful compounds to differentiate b/w these subtypes, 
but they will likely be developed while we're in practice. ideally, we'd 
like to affect M3 without affecting M2 and vice versa. but these 4 have 
equal affinity for all muscarinic receptors.

1. methacholine - a 
selective muscarinic agonist, used clinically to treat GI/urinary 
disorders where you want to promote bladder contraction or gut motility. 
the problem is that this drug is least resistant to ACHesterase so has 
the shortest duration of action. cardiovascular effects limit clinical 
use
2. carbachol - has more nicotinic affinity than the others - not 
fully muscarinic selective. too much ganglionic stimulation. 
3. 
bethanechol - most clinically useful - fewest nicotinic effects, more 
resistance to ACHesterase than methacholine
4. pilocarpine - has some 
nicotinic effects. 100 x more potent than ACH. mainly a muscarinic 
agonist. tx glaucoma esp in patients with narrow filtration 
angle...produces miosis, narrowing the pupil, opening the filtration 
angle, decreasing intraocular pressure - but also increase BP due to 
nicotinic effects.

non-pharmaceuticals:

5. arecoline - in betel nuts 
chewed by "native populations" - addictive. muscarinic activity. no 
therapeutic use.

6. muscarine - toxic alkaloid in mushrooms that causes 
mushroom toxicity and SLUD. found in amanita muscaria. 

Muscarinic 
antagonists:

these are all not subtype specific - will block M1, M2, and 
M3.

1. atropine - naturally occuring belladonna plant alkaloid. very 
commonly used. "belladonna" means beautiful woman - the plant was used to 
dilate womens' eyes, to increase their attractiveness (???). simple 
competitive inhibitor for muscarinic receptor. common toxicity b/c found 
in many plants. effects at clinical doses mainly increased heart rate, 
pupillary dilation. tachycardia and ataxia occur at overdise, delirium at 
overdose - atropoine is a charged molecule which gains access to CNS at 
higher concentrations. has longterm effects - used in horses with 
cataracts to dilate the eye longterm so that animal can see around a 
central cataract - and the antagonist is also long acting - neostigmine, 
or other anticholinesterase. when you use a cholinesterase inhibitor at 
the synapse, you are competing off the atropine with ACH. atropine is a 
common preanesthetic, common OTC drying agent, bronchodilator. will 
decrease secretions and dry the airways. atropine and other shorter 
acting drugs used a lot in ophthalmology

2. scopalamine - another 
muscarinic antagonist - was included during gulf war as an antidote for 
nerve gas poisoning - turns out the nerve gases used are ACHesterase 
inhibitors which cause increased ACH concentrations at the synapses. so 
scopalamine will antagonize SLUD, and is less charged and has better 
access to CNS, so can counter neurotoxic gases. clinical uses limited - 
you don't generally want these drugs to gain CNS access for clinical 
purposes. 

3. tropicamide - rapidly reversible muscarinic antagonists - 
used as eyedrops - wears off faster.

4. homatropine
5. glycopyrrolate - 
a quaternary ammonium compound - often used as premed instead of atropine 
- charged, less CNS access. less SA block and tachycardia than atropine. 
decreases respiratory secretions which are otherwise increased in 
response to irritating anesthetic gas. 

6. probantheline - another 
antimuscarinic, more ganglionic block than atropine, limited clinical use


7. ipratropium - widely used as bronchodilator for asthmatics,directly 
inhaled. less inhibition of mucociliary clearance than atropine. 
see 
handout for others.

make sure to remember one or two of these compounds 
and their effects from each category.

M2 selective antagonists - may be 
marketed soon. will be selective for cardiac M2 receptors and useful to 
treat arrhythmias.

review of parasympathetic regulation/innervation of 
the eye and effects of specific agents on the pupil:

the radial dilator 
muscle - contraction of it causes dilation of pupil - controlled by 
norepinephrine - sympathetic innervation

sphincter muscle - contracts 
and causes constriction of pupil (miosis) - parasympathetic innervation.


pupillary diameter is a readout of the "tug of war" b/w symp and parasymp 
outflow. if you have a fight or flight response, you have sympathetic 
outflow and pupillary dilation will occur. conversely, if you stimulate 
the the parasympathetics, you constrict the pupil (by constricting the 
sphincter muscle). at the same time, there is a ciliary muscle 
controlling the refractive index of the lens - when there is no 
parasympathetic innervation, it is relaxed, and you can't accomodate for 
near vision. as you accomodate for near vision, ciliary muscle contracts, 
bending lens. ciliary muscle innervated by parasympathetics. 

when you 
do a fundic exam, one thing aside from light sensitivity that occurs is 
that also lens is paralyzed (well, ciliary muscle is) because you block 
the parasympathetic outflow. (?)

if you use a cholinesterase inhibitor, 
topically in the eye, that will cause excessive ACH accumulation at the 
synapses,resulting in contraction of the pupil and a "spasm of 
accomodation"

p 13 - drugs used in glaucoma
narrow angle glaucoma tx 
w/drugs that narrow the pupil, increasing drainage
wide angle/chronic 
simple glaucoma tx with lots of things, use anticholinesterases like 
pilocarpine, use organophosphate anticholinesterases, and use sympathetic 
agonists which decrease secretion of aqueous humor via vasoconstriction. 
you use muscarinic agonist, anticholinesterase, and sympathetic agonist 
all together. 


SUMMARY---summary---SUMMARY:

receptor/effector 
coupling:
muscarinic effector coupling - important to remember M1, M2, M3 
subtypes, know something about their distribution (M2=heart, smooth 
muscle)(M3 smooth muscle, glands)(M1 neural). M2 = G1 linked, M1 and 3 
IP3 linked.

Remember physiological effect of parasympathetic stimulation 
- SLUD or DUMBELL (salivation, lacrimation, urination, defecation) - 
smooth muscle contraction, sphincter relaxation, slow HR, decrease 
contractility of heart, narrow pupil, "rest and digest" or vegetative 
system. generalized, nonspecific effects (unlike adrenergic system). 


muscarinic agonists:

know bethanecol ** clinically most useful ** 
remember it isn't subtype selective, affects all muscarinic receptors


muscarinic antagonists:

know atropine ** belladonna alkaloid ** Hester 
Prynne was poisoned with this. 
blocks all muscarinic receptors


glycopyrrolate (premed), scopalamine (nerve gas antidote)
tropicamide, 
homatropine (ophthalmology uses)

we haven't discussed nicotinic agonists 
- some exist, but nicotinic receptor agonism isn't clinically useful b/c 
if  you open Nm you get tetany and ganglionic stimulation isn't desirable 
clinically either. similarly, nicotinic antagonists haven't been 
discussed yet - there are no specific ganglionic Nn antagonists. there 
are some Nm antagonists - neuromuscular blocking agents to be discussed 
later.

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