NT transmitters
Cholinergic transmission Adrenergic transmission
About Ach= primary transmitter in all
autonomic ganglia
- btw parasymp postganglia & their
effector
- somatic = skeletal muscle
neuromuscular junction
Synthesis & - in neve terminal by enzyme
storage ChAT from acetyl CoA (made in
mito) & choline (transported across
CM)
- RL step= transport of choline to
terminal= inhibited by
hemicholinium
- into vesicles by VAT= actively=
inhibited by vesamicol
Release - require Ca2+ through Ca channels
& triggering btw SNARE
- v-SNARE, t-SNARE= docking
of vesicle to nerve ending & w/
influx of Ca2+= opens & release
Ach= inhibited by botulism toxins
Termination - via metabolism=
acetylcholinesterase in synaptic
cleft = products are recycled in
body
Drug effects - drugs above= not selective & can
on block PANS & SANS & somatic
synthesis, neuromuscular junctions
storage, - but botulism= very slow acting
Co-transmitters
NE= primary= @ sympa postganglia - most/ if not all=
neuron effector cell synapses in most autonomic have
tissues transmitter vesicle
- sympa to thermoregulatory other transmitters
(eccrine) sweat glands and - can be localized i
vasodilator in skeletal m., which same vesicle as pri
release Ach or separately
- dopamine= vasodilator in renal - function= modula
vessels but NE is vasoconstrictor of of synaptic transm
these
- tyr transported across C< the - are ATP (adenosi
hydroxylated by tyr-hydroxylase = triphosphate),
RL step to DOPA= inhibited by enkephalins, vasoa
metyrosine intestinal peptide,
- NE & D= into vesicle by VMAT & neuropeptide Y,
stored there substance P,
- MAO= in mito in adrenergic nerve neurotensin,
endings & inactivates some NE & D somatostatin, and o
in cytoplasm= hence MAO
inhibitors= increase store of them
- VMAT=inhibited by reserpine=
results =depletion of transmitter store
- need Ca2+ like Ach
- noradrenergic and dopaminergic
neurons lack receptors for
botulinum and do not transport this
toxin into the nerve terminal
- release is blocked by guanethidine
- not via metabolism
- diffusion & reuptake via NET,
DAT to reduce conc in synaptic cleft
- outside cleft= metabolized by
MAO & COMT= products are
excreted
- 24-h excretion of metanephrine,
normetanephrine, VMA= provide
total measure of catecholamine in us
- above drugs= used for diseases like
hypertension cuz they block sympa
not parasymp
- Other drugs promote catecholamine
 release, due to large size hence can be used release (eg, the amphetamines) and
termination for selective local effects predictably cause sympathomimetic
of action effects.

ANS receptors:
Cholinoceptors
Most respond to Ach & analogues
=subs=divided to
Muscarinic – respond to muscarine
(alkaloid) & Ach
- like postganglia cholinergic nerve
stimulation
- location= autonomic effector cells=
heart, vascular endoth., smooth m.,
presynaptic term, exocrine gl.
- 5 subtypes= 3 important for PNS
All 5 are= G-pr. Coupled receptors
Nicotinic – located in Na-K ion channels
- respond to Ach, nicotine (Ach
mimic=no response to M)
- 2 mjr subtypes= in ganglia & skeletal
end plates
Adrenoceptors
Activated by NE, epi, D= subtypes
are=
Alpha receptors= on vascular
smooth m., presynaptic, blood
platelets, fat cells (lipocytes,
adipocytes), neurons in brain
- subdivided to 2 mjr types= diff.
fam of G-coupling pr.
Beta receptors= on most smooth m.,
cardiac, some presynaptic, lipocytes
- subdivided to 3 = all Gs pr.
Dopamine receptors
It’s a subclass of adrenoceptors
but / diff distribution & function
- in renal and splanchnic vessels
and in the brain
- 5 subtypes but D1 most
important in peripheral effector
cells
- D2= found in presynaptic
- D1, D2 & other= lots in CNS

Direct acting Indirect acting

 - Group of choline ester=Ach, methacholine,
carbachol, bethanechol
- grp of naturally occurring alkaloids= muscarine,
pilocarpine, nicotine, lobeline
- new drugs= neonicotinoids clothianidin,
imidacloprid, and others as insecticide
- differs in their spectrum of action= amount of N vs
M & pharmacokinetics
Classificatio M agonist= parasympathomimetic; = mimic
n parasymp nerve stimulation w/ other effects
- 5 subgroups
- but it activates non-selectively
N agonist= both ganglionic and neuromuscular
Cholinoceptors
- selectivity= limited
- slightly selective M antagonist
- slightly selective N antagonist
Molecular M mech= G-coupled= GPCRs
mech. Of - M1,M3= Gq= phospholipase- C= mem. bound
action enzy= release of 2nd messenger= DAG & IP3
- DAG= modulate PKC
- IP3= release of Ca2+ from intracell storage= w/in preventing binding & hydrolysis of endogenous
smooth m.= result in contraction
- M2= Gi= also K+ channel in heart & elsewhere=
opening of them
- M4, M5= role in CNS
N mech= channel pr of Na/K
- when activated= channel opens & depol.= direct
influx of Na= excitatory postsyn. Potential (EPSP) - after hydrolysis= carbamate=s released by
- if large enough= EPSP= propagate to surrounding
mem.
- Nn= sympa & parasymp
- Nm= neuromuscular. End plates
Tissue & - vasodilation is not a parasympathomimetic
organ effects response= it is not evoked by parasympathetic nerve synapse where its released
discharge, even though directly acting
cholinomimetics cause vasodilation
- this vasodilation= due to release of
EDRF=mediated by uninnervated M receptors on
endothelial cells
- decreased BP= evoke baroreceptors= strong
compensatory sympa. Discharge to heart = cause
tachycardia
- inhibits AchE= hence indirect = amplify its
effects
2 mjr types= these are AchE inhibitors
Carbamic acid esters= carbamates=
- neostigmine= prototype carbamate
Phosphoric acid esters= organophosphates=
- parathion= important insecticide= prototype
of this
3rd class= alcohol (not an ester) =
edrophonium= very short duration action
Both bind to AchE & hydrolysis
- alcohol portion is then released
- acidic part= carbamate or phosphate ion=
released slowly from enzyme active site=
Ach
- hence amplify AchE effects when transmitter
is released
- edrophonium= not ester but enough affinity to
bind active site & prevent Ach binding for 5-15
mins
AChE = 2-8 hrs
- organophosphates= long lasting= due to
forming very stable complex w/ enzyme= after
initial hydrolysis= phosphoric acid is released
over days- weeks
- Recovery= by syn of new enzy.
- increase conc., ½ life & action of Ach in
- both N & M effects= dom. Effects vary by
organs
- not much role in uninnervated sites where
Ach isnt released normally like endothelial
cells
 - parasymp= vagal stimul.= bradycardia
- only sympa= stimul. Thermoregulatory = eccrine,
sweating = no parasymp.
- blood vessels are dominated by sympathetic= N
activation results in vasoconstriction = mediated by
postgangl. Noradrenergic n. discharge
- gut= dom. By parasymp.
Clinical use - increasing cholinergic= benefits= in glaucoma,
Sjögren’s syndrome, and loss of normal cholinergic
activity in the bowel and bladder
- used to assist smoking cessation = varenicline=
partial agonist of nicotine= reduce craving on ppl
addicted to nicotine by non-autonomic action
- produce skeletal m. paralysis= succinylcholine
- N & related neonicotinoids= used as insecticides
even though theres toxic effects
Toxicity Overdose of Ach= signs/symptoms= predicted=
M toxicity= CNS stimul, miosis, spasm o
accommodation, bronchoconstriction, excessive
gastrointestinal & genitourinary smooth m. activity,
increased secretory activity (sweat gl., airway,
gastrointes., lacrimal) & vasodilation
- bradycardia= followed by reflex tachycardia= if
drug given as IV bolus= where reflex occur
otherwise
- M in mushrooms= positioning= short term =
nausea, vomiting, diarrhea= some are lethal
N toxicity= include ganglionic stimulation and
block and neuromuscular end plate depolarization
leading to fasciculations and then paralysis
- convulsion followed by depression
- indirect= when increased N activation is
needed @ neuromuscular junction
- predictable & can benefit
- carbamates= neostigmine, physostigmine,
pyridostigmine, and ambenonium= used
more therapeutically than organophosphates =
esp. for myasthenia= an autoimm. Disease
- rivastigmine= carbamate= exclusively for
Alzheimer’s= some actions are unknown
- carbaryl= carbamates= used in agriculture as
insecticide
- oragnoph.= in medicine = malathion (a
scabicide) and metrifonate (an anthelminthic
agent)
- edrophonium= for rapid reversal of non-
depol. Neuromuscular blockade= in diagnosing
myasthenia
- cholinergic crisis can result in muscle
weakness like that of myasthenic crisis,
distinguishing the 2 conditions may be difficult
= hence giving this can improve muscle
strength myasthenia crisis but weakens
cholinergic crisis
- esp. oragnoph.= clinical importance due to
accidental exposure to toxic amounts f
pesticides
- most like parathion= can rapidly fatal if not
recog. & treated immediately
- antidote= atropine= antimuscarinic= no
effect on nicotinic toxicity
- nicotinic toxicity= treated by respiratory
support & regenerating active AchE
- oragnoph. Inhibitors= removed for enzy by
use of regenerator compounds like
pralidoxime= can reverse N & M signs
- if enzy. -phosphate binding is allowed to
persist= aging occurs= regenerator drugs cant
remove inhibitor
- in small doses= very addicting = vaping= inhaling
nicotine
- CNS effects = same as tobacco smokers
- organophosphates are used extensively in
agriculture as insecticides and anthelminthic
agents= like malathion, parathion
- some like malathion, dichlorvos are
relatively safe in humans because they are
metabolized rapidly to inactive products in
mammals (and birds) but not in insects
- some are prodrugs= like malathion,
parathion= have to metabolized to the active
product (malaoxon from malathion, paraoxon
from parathion
- toxic effects= same as direct acting but w/
vasodilation is late & uncommon, bradycardia
more than tachycardia, CNS = common with
organophosphate and physostigmine
overdosage and includes convulsions, followed
by respiratory and cardiovascular depression
- DUMBBELSS (diarrhea, urination, miosis,
bronchoconstriction, bradycardia, excitation [of
skeletal muscle and CNS], lacrimation, and
salivation and sweating)