Cholinergic transmission Adrenergic transmission Co-transmitters

About Ach= primary transmitter in all
autonomic ganglia
- btw parasymp postganglia & their
effector
- somatic = skeletal muscle
neuromuscular junction
NE= primary= @ sympa postganglia
neuron effector cell synapses in most
tissues
- sympa to thermoregulatory
(eccrine) sweat glands and
vasodilator in skeletal m., which
release Ach
- dopamine= vasodilator in renal
vessels but NE is vasoconstrictor of
these
- most/ if not all=
autonomic have
transmitter vesicles w/
other transmitters
- can be localized in
same vesicle as primary
or separately
- function= modulation
of synaptic transmission

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
- tyr transported across C< the - are ATP (adenosine
hydroxylated by tyr-hydroxylase = triphosphate),
RL step to DOPA= inhibited by enkephalins, vasoactive
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 others
in cytoplasm= hence MAO
inhibitors= increase store of them
- VMAT=inhibited by reserpine=
results =depletion of transmitter store

Release - require Ca2+ through Ca channels - need Ca2+ like Ach

& triggering btw SNARE
- v-SNARE, t-SNARE= docking
of vesicle to nerve ending & w/
influx of Ca2+= opens & release
Ach= inhibited by botulism toxins
- noradrenergic and dopaminergic
neurons lack receptors for
botulinum and do not transport this
toxin into the nerve terminal
- release is blocked by guanethidine

Termination - via metabolism= - not 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
release, due to large size hence can be used
- 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 (eg, the amphetamines) and
termination for selective local effects
of action
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
predictably cause sympathomimetic
effects.
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 (AKA causes
vasodilation that can be blocked by atropine)
- 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
- 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=
 - 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)
- 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
- 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
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
- after hydrolysis= carbamate=released by
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
- 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

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
- in small doses= very addicting = vaping= inhaling
nicotine
- CNS effects = same as tobacco smokers
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 edrophonium can improve
muscle strength myasthenia crisis but weakens
cholinergic crisis
- esp. oragnoph.= clinical importance due to
accidental exposure to toxic amounts of
pesticides
- most like parathion= can rapidly fatal if not
recog. & treated immediately
- antidote= atropine= antimuscarinic/ inverse
agonist= 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
- 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)
 Muscarinic antagonist
Classification - Can be subdivided to their spc M- receptors or lack of selectivity
& - only 2 distinctly receptor selective M1 antagonist has clinical trials= pirenzepine &
pharmacokinetics telenzepine= not used in USA
- some M3 subtypes used in USA
- most are non-selective
- can be subdivided basis on primary clinical target organs= CNS, eye, bronchi,
gastrointestinal, genitourinary
- CNS or eye= lipid solu to cross lipid barriers = mjr determinant= presence/absence of
permanently charged (quaternary) amine grp in drug cuz charged are less lipid sol.

- atropine= non-selective= found in Atropa belladonna & other plants

- tertiary amine= relative; lipid-sol= can cross mem.
- in CNS, eye. Etc.
- eliminated by metabolism partially in liver & partially unchanged in urine
- ½ life= 2 hrs
- duration of action= 4-8 hrs except in eye its >72 hrs

- ability to cross lipids= essential for drugs used in Parkinson’s

- drugs used for antisecretory or antispastic actions in gut, bladder, bronchi= selected for
min CNS activity= may have quaternary amine to limit penetrating BBB/ lipid barriers

Mech. Of action - competitive (surmountable) antagonist

- can be overcome by increased conc. Of M agonists
- Km= increased= AKA need higher conc to reach Vmax
- Vmax= unchanged

Effects - predictable derived from cholinergic blockade= like ocular, bronchial, gastrointestinal,
genitourinary, and secretory effects
- CNS= less predictable = seen @ therapeutic conc. Like sedation, reduction of motion sickness,
reduction of sign of parkinsonism
- cardiovas. Effects= initial slowing of heart rate caused by central effects or blockade of
inhibitory presynaptic muscarinic receptors on vagus nerve endings= followed by tachycardia &
decreased atrioventricular conduction time
- M1= can be selective for gastrointes.
-
Clinical uses - used in CNS, eye, bronchi, gut, and urinary bladder
- CNS= scopolamine= standard for motion sickness= 1 of most effective
- Benztropine, biperiden, and trihexyphenidyl are representative of several antimuscarinic
agents used in parkinsonism= esp. when ppl become unresponsive to levodopa (more effective)
- Benztropine= sometimes parenterally to treat acute dystonia caused by 1st generation
antipsychotic medications

- Eye= used for mydriasis= “beautiful lady”= from Atropa belladonna= dilate pupils
- also cause cycloplegia and prevent accommodation
 - atropine (>72 h), homatropine (24 h), cyclopentolate (2–12 h), and tropicamide (0.5–4 h)
- Bronchi=used to reduce airway secretions in general anesthesia
- ipratropium= quaternary agent= via inhalation= bronchodilation in asthma & COPD= less
likely to cause tachycardia and cardiac arrhythmias in sensitive patients= few antimuscarinic
effects outside the lungs because it is poorly absorbed and rapidly metabolized
- Tiotropium is an analog with a longer duration of action
- Aclidinium & umeclidinium are newer long-acting antimuscarinic drugs available in
combination with long-acting β2-adrenoceptor agonists= via inhalation= for COPD

- Gut= Atropine, methscopolamine, & propantheline were used in the past to reduce acid
secretion in acid-peptic disease, but no we used H2 blockers= more effective, frequent
- M1 selective inhibitor= pirenzepine= for peptic ulcers
- M blockers= for reducing cramps, hypermotility in transient diarrhea but diphenoxylate &
loperamide= more effective

- Bladder= similar for urgency in mild cystitis & reduce bladder spasms after surgery
- Tolterodine, darifenacin, solifenacin, fesoterodine, & propiverine are slightly selective for
M3 receptors= for stress

- Cholinesterase inhibitor intoxication= atropine= given in large doses parenterally= reduce

M signs of poisoning w/ AchE inhibitors
- Pralidoxime= regenerate active AchE

Toxicity - atropine toxicity= “Dry as a bone, hot as a pistol, red as a beet, mad as a hatter.”
(1) Predictable toxicities= blockade of thermoreg. Sweating= cause hyperthermia or atropine
fever= “hot as a pistol”= lethal in infants & bad for kids
- sweating, salivation, lacrimation= reduced or stopped= “dry as a bone”
- Moderate tachycardia is common, and severe tachycardia or arrhythmias= common w/ large
doses
- elder ppl=acute angle-closure glaucoma and urinary retention, especially in men with prostatic
hyperplasia
- constipation & blurred vision= all ages

(2) Other toxicities= unpredictable from PANS, CNS & cardiovas.

- CNS= cause sedation, amnesia, and delirium or hallucinations “mad as a hatter”= convulsions
- tricyclic antidepressants, may cause hallucinations or delirium in the elderly
- @ high doses= cardiac IV conduction= blocked= hard to treat
- dilation of cutaneous vessel of arm, head, neck, trunk= atropine flush= “red as beet” =
diagnostic of drug overdose= mech. Unknown

(3) Treatment of toxicity= symptomatic

- Severe tachycardia may require cautious administration of small doses of physostigmine
- Hyperthermia can usually be managed with cooling blankets or evaporative cooling

Contraindication - used w/ caution for infants due to hyperthermia

s - contraindicated in persons with glaucoma, especially the closed angle form, and in men with
= not used prostatic hyperplasia
Nicotinic antagonist Cholinesterase regenerators
Ganglion- - act like competitive antagonists but some can block - Pralidoxime is the prototype
blocking drugs itself cholinesterase regenerator
- 1st few to treat hypertension= now outdated - chemical antagonist= w/ oxime grp=
- Hexamethonium (C6, a prototype), mecamylamine, extreme high affinity for phosphorus in
etc. oragnoph.
- but parasym & symp= effect too severe to tolerate for - affinity exceeds of enzyme active site=
long time so it binds to inhibitor & displace
- Trimethaphan= recent but unused now= lipid sol, enzyme if aging doesn’t occur
inactive orally, short ½ life= used IV for severe - hence active enzyme is regenerated
hypertension (malignant hypertension) - treat patient exposed to high doses of
- nicotine (in the form of nicotine gum or patches), organophosphate AChE inhibitor
varenicline (a partial agonist given by mouth), and insecticides, such as parathion, or to
mecamylamine= enters the CNS= good in smoking nerve gases
cessation - not for carbamate overdose
- interrupt sympa= hence, venous pooling; postural
hypotension is a major manifestation of this effect
- toxicities= dry mouth, blurred vision, constipation, and
severe sexual dysfunction= hence rarely used

Neuromuscular - useful for muscle relaxing for surgery & mech.

blocking drugs Ventilation