Lecture notes on ANS Cholinergic Drugs.

1. Autonomic Nervous System
Cholinergic Drugs
Gelenta Salopuka
Pharmacology, BMS
13th March, 2023

2. Learning Outcomes
▪ The student should be able to:
▪ Know what cholinergic drugs are; the specific drug
examples for the different groups.
▪ Briefly describe their mechanisms of action and
adverse effects associated with their uses;
▪ Attain knowledge on the important pharmacokinetic
features;
▪ and the therapeutic uses of these drugs.

3. Cholinergic (cholinomimetic) Drugs
▪ Drugs that act on receptors @ all sites in the body
where ACh is transmitter of the nerve impulse.
▪ They act directly on peripheral blood vessels to dilate
them.
▪ Cholinergics include ACh receptor stimulants plus
cholinesterase inhibitors cholinomimetic agents
(mimic ACh).
▪ Cholinoceptor stimulants are classified by:
1. type of receptor that is activated
muscarinic or nicotinic agents
2. MOA
– drugs that bind directly to (& activate) cholinoceptors &
– drugs that act indirectly by inhibiting hydrolysis of
endogenous ACh.

4. Cont…
▪ Cholinergic drugs include:
(a) choline esters, e.g. carbachol, bethanecol
(b) alkaloids, e.g. pilocarpine, muscarine
(c) cholinesterase inhibitors, e.g. physostigmine, neostigmine
▪ Sites of action include:
(1) Autonomic nervous system
(a) Parasympathetic division
▪ Ganglia
▪ Post-ganglionic endings (all)
(b) Sympathetic division
▪ Ganglia
▪ A minority of post-ganglionic endings (e. g. sweat glands)
(2) Neuromuscular junction
(3) Central nervous system
(4) Blood vessels, mainly arterioles

5. Fig 1.Major Groups of Cholinomimetics
Source: Katzung, 7th ed., p 91

6. Mode of action of cholinergics
▪ Direct-acting cholinergic agents bind to & activate
muscarinic or nicotinic receptors.
▪ Indirect-acting agents elicit primary effects through
inhibition of acetylcholinesterase (AChE), which
hydrolyzes ACh to choline & acetic acid.
▪ Inhibition of AChE →↑endog ACh conc in synaptic clefts &
neuroeffector junctions. Xs ACh then stimulates
cholinoceptors to induce ↑ed responses.
▪ These drugs act primarily where ACh is physiologically
released & are thus amplifiers of endog ACh.

7. MOA:-Direct stimulants of muscarinic
receptors
▪ Activate parasympathetic nervous system &
modify organ function through muscarinic
receptors by two major mechanisms:
1. ACh released from parasympathetic nerves
activates muscarinic receptors on effector cells
to alter organ function directly.
2. ACh released from parasympathetic nerves
interacts with muscarinic receptors on nerve
terminals to inhibit release of their
neurotransmitter.

8. MOA:- Direct stimulants of nicotinic receptors
▪ Nicotinic agonist occupies nicotinic receptor → ion
(Na-K) channels open; allowing Na+ & K+ to diffuse
rapidly down their concentration gradients.
▪ Receptor activation → depolarization of nerve cell or
neuromuscular end plate membrane.
▪ Prolonged agonist occupancy of nicotinic receptor:
• impedes effector response, i.e. postganglionic neuron
stops firing (ganglionic effect) & skeletal muscle cell relaxes
(neuromuscular end plate effect).
• prevents electrical recovery of postjunctional membrane
→ induction of a state of "depolarizing blockade“.
• (further discussions in future lectures in this series)

9. Chemistry of choline
esters
▪ Have a permanently
charged quaternary
NH4
+ group →
relatively insoluble in
lipids.
▪ ACh & methacholine
are acetic acid esters
of choline and b-
methylcholine,
respectively.
▪ Carbachol &
bethanechol are
carbamic acid esters of
the same alcohols.
Source: Fig 7.2, chpt 7; Katzung 10th ed.,

10. Choline esters
Pharmacokinetics
▪ Poorly absorbed & poorly distributed into CNS
(hydrophilic).
▪ All are hydrolyzed in GIT ( less active by oral
route) BUT
▪ They have marked differences in susceptibility to
hydrolysis by cholinesterase.
▪ Acetylcholine is very rapidly hydrolyzed;
▪ large amounts req’d through IVI to produce detectable
effects.
▪ large IV bolus injection has brief effect ( 5-20 secs),
▪ IM & SC inj produce only local effects.

11. Cont…
▪ Methacholine is more resistant to AChE
hydrolysis.
▪ Carbamic acid esters, carbachol &
bethanechol are even more resistant to
hydrolysis by cholinesterase.
❖ have correspondingly longer durations of action.
▪ The b-methyl gp (methacholine, bethanechol)
↓ potency of these drugs at nicotinic
receptors.

12. Alkaloids (Source: Fig 7.3, chpt 7; Katzung 10th ed.,)
•Pilocarpine, nicotine &
lobeline: tertiary natural
cholinergic alkaloids; well
absorbed from most sites of
admin.
• Nicotine (liquid), lipid-
soluble - absorbed across the
skin.
•Lobeline similar to nicotine.
•Muscarine, a quaternary
amine, oral absorption less
than tertiary amines; toxic
when ingested, e.g., via
mushrooms & can enter BBB.
•Excreted mainly by kidneys

13. Indirect-acting cholinomimetics
▪ These drugs are also known as anti-
cholinesterase (anti-CHE) agents / cholinesterase
inhibitors.
▪ Commonly used agents fall into three chemical
gps:
1. Simple alcohols (ROHs) bearing a quaternary NH4+
gp e.g. edrophonium
2. Carbamic acid esters of ROHs bearing a quaternary
or tertiary NH4+ gps (carbamates, e.g. neostigmine)
3. Organic derivatives of phosphoric acid
(organophosphates, e.g. isoflurophate)

14. Variation in MOA of anti-CHE agents based on
chemical subgroup
▪ Quartenary ROHs (edrophonium)
▪ reversibly bind electrostatically by hydrogen bonds to active
site preventing access of ACh.
▪ Carbamate esters (neostigmine & physostigmine)
▪ undergo a two-step hydrolysis sequence similar to ACh BUT
covalent bond of the carbamoylated enzyme is > resistant to
the 2nd step, hence the process is prolonged .
▪ Organophosphates
▪ undergo initial binding & hydrolysis by AChE → a
phosphorylated active site; the covalent phosphorus-enzyme
bond is very stable & hydrolyzes in water @ v slow rate
(hundreds of hours).
▪ after initial binding-hydrolysis step, phosphorylated enzyme
complex undergoes a process called aging.

15. Chemistry of cholinesterase
inhibitors
▪ Neostigmine - a typical
comp’d that is an ester of
carbamic acid (1) & a
phenol with a quaternary
NH4+ gp (2).
▪ Physostigmine – a
naturally occurring
carbamate & a tertiary
amine.
▪ Edrophonium – not an
ester but binds to active
site of the enzyme.
▪ Carbaryl – example of a
large gp of carbamate
insecticides; v ↑ lipid
solubility so v rapid
absorptn into insect &
distribution to CNS .
Source: Fig 7-5, p97 of Katzung 7th ed.

16. Quartenary carbamates
PHARMACOKINETICS
• Absorption of quaternary carbamates from conjunctiva,
skin & lungs is poor (permanent charge on molec → lipid
insoluble).
• Oral doses higher than parenteral.
• Distribution into CNS is negligible.
• Physostigmine, well absorbed from all sites & hence used
topically in the eye;
• distributed into CNS & is > toxic than more polar
quaternary carbamates.

17. Cont…
▪ Neostigmine & pyridostigmine, poor oral
absorption thus larger doses needed.
▪ Carbamates, relatively stable in aq. solution;
metabolized by non-specific esterases in the
body plus cholinesterase.
▪ Duration of action dependent on stability of
inhibitor-enzyme complex (not metabolism/
excretion).

18. Organophosphate cholinesterase inhibitors
Pharmacokinetics
• Very lipid-soluble liquids, highest risk of toxicity & ↑ vapor
pressures.
• Less volatile agents & common agents such as insecticides
(e.g., diazinon, malathion in agric); dispersed as aerosols/ as
dusts adsorbed to an inert, finely particulate material.
• Rapidly absorbed from skin, lung, gut & conjunctiva (toxic to
humans).
• Aq solutions relatively < stable than carbamates & thus have
limited t1/2 in environment (compared w other major class of
insecticides, halogenated hydrocarbons like DDT).

19. Cont..
• Echothiophate highly polar & more stable than
other organophosphates;
• Aq preparation for ophthalmic use has long
activity (weeks).
• All (except echothiophate)distributed to all parts
of body + CNS.
• Poisoning may include CNS toxicity.

20. Therapeutic uses
▪ Major uses of cholinomimetics include diseases of the:
1. Eye (glaucoma, accommodative esotropia),
2. GI & urinary tracts (postoperative atony, neurogenic
bladder),
3. Neuromuscular junction (myasthenia gravis, curare-
induced neuromuscular paralysis) &
4. Very rarely heart (certain atrial arrhythmias).
▪ Anti-CHE agents used in treatment of atropine
overdose.
▪ Newer cholinesterase inhibitors used in Alzheimer's
disease.

21. Specific uses & duration of action of
cholinesterase inhibitors (Source: Tbl 7-4, p98 of Katzung 7th ed.)
Drug group Uses Approx duration of action
Alcohols, e.g.
edrophonium
Myasthenia gravis, ileus,
arrhythmias
5 – 15 mins
Carbamates & related,
neostigmine
Myasthenia gravis, ileus 0.5 – 2 hrs
pyridostigmine Myasthenia gravis, ileus 3 – 6 hrs
physostigmine Glaucoma 0.5 – 2hrs
ambenonium Myasthenia gravis 4 – 8 hrs
demecarium Glaucoma 4 – 6 hrs
Organophosphates, e.g.
ecothiophate
Glaucoma 100 hrs

22. Toxicity
▪ Toxic effects of cholinoceptor stimulants is
influenced by their:
▪ absorption,
▪ access to CNS,
▪ & metabolism
▪ Direct-acting muscarinic stimulants (e.g.,
pilocarpine & choline esters) cause predictable
signs of muscarinic excess in over-dosage.
▪ Effects include nausea, vomiting, diarrhea, urinary
urgency, salivation, sweating, cutaneous vasodilation &
bronchial constriction.
▪ They are all blocked competitively by atropine & its
congeners.

23. Direct-acting nicotinic stimulants (e.g. nicotine)
Acute toxicity
▪ Fatal dose, approx 40 mg ( 1 drop of pure liquid = amount
in 2 regular cigarettes).
▪ Ingestion of nicotine insecticides/ tobacco by infants &
children causes vomiting
▪ Large doses:
– CNS stimulation → convulsions → coma & respiratory arrest
– muscle end plate depolarization, which may lead to
depolarization blockade and respiratory paralysis
– hypertension & cardiac arrhythmias
Chronic nicotine toxicity
▪ Addiction to cigarettes (directly related to nicotine content).
▪ Increased risk of vascular disease & sudden coronary death
(associated with smoking).
▪ Contributes to ↑ incidence of ulcer recurrences in smokers with
peptic ulcer.

24. Cholinesterase inhibitors
▪ Dominant initial signs of acute effects:
▪ miosis, salivation, sweating, bronchial
constriction, vomiting & diarrhoea
▪ then CNS effects soon after, accompanied by
peripheral nicotinic effects, esp. depolarizing
neuromuscular blockade.
▪ Parenteral atropine given in large doses to
control signs of muscarinic excess.

25. Summary
▪ Cholinergic drugs act on receptors at all sites in
the body where ACh is transmitter of the nerve
impulse.
▪ These drugs can directly activate cholinoceptors
(nicotinic & muscarinic receptors) ultimately
causing increased effector response;
▪ Or they can indirectly increase levels of
endogenous acetylcholine by inhibiting
acetylcholinesterase, enzyme responsible for
breakdown of ACh.

26. References
1. Katzung, Basic & Clinical Pharmacology 10th
ed., e-book
2. Laurence & Bennett, Clinical Pharmacology
6th ed. 1987
3. Goodman’s & Gilman’s The Pharmacological
Basis of Therapeutics 11th ed., 2006