[PHARMACOLOGY]
They act as
CHOLINOCEPTOR-ACTIVATING, CHOLINESTERASE-
INHIBITING DRUGS and CHOLINOCEPTOR-BLOCKING DRUGS
Dr. Elizabeth R. Telado | October 18, 2018
Acetylcholine (Ach)
- Endogenous NT (Baeyer, 1867)
- No therapeutic application; diffuse action
- Rapid hyrdrolysis
o Acetylcholinesterase (AchE)
o Plasma butyrylcholinesterase
- 2 types of activity (1914)
o Muscarinic
o Nicotinic
PARASYMPATHOMIMETICS
- also called Cholinomimetics / Cholinergic agonists
PARASYMPATHOLYTICS
- also called Cholinergic antagonists
CHOLINERGIC AGONISTS
- drugs that influence activity of cholinergic receptors
- drugs that mimic/copy the action of Ach
NOTES:
Classified by their spectrum of action and mechanism of action
SPECTRUM OF ACTION
Muscarine Receptors: mediate effects of acetylcholine and of
other cholinomimetic drugs at neuroeffector junctions
(parasympathomimetics effects)
o Muscarine: mimicked effects of parasympathetic
discharge (parasympathomimetic)  occurred
through an action on receptors at effector cells, not
those in ganglia
o Member of G protein-linked families
o Agonist selectivity: determined by subtypes of
muscarinic receptors and G proteins present in a cell
o Location: plasma membranes of cells in CNS, in organs
innervated by parasympathetic nerves, endothelial
cells, in tissues innervated by postganglionic
sympathetic cholinergic nerves.
Nicotinic Receptors: ganglion & skeletal muscle receptors
o Nicotine: stimulate autonomic ganglia and skeletal
muscle NMJs but not autonomic effector cells
o Member of Ion channel families
o Location: plasma membranes of postganglionic cells
in all autonomic ganglia, of muscles innervated by
somatic motor fibers, and of some CNS neurons
MECHANISM OF ACTION
Direct-acting agonists: receptor-mediated, bind directly to
postsynaptic cholinergic (muscarinic or nicotinic) receptors
Indirect-acting agonists: aka anticholinesterases; produce
primary effects by inhibiting acetylcholinesterase, which
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hydrolyzes acetylcholine to choline and acetic acid.
amplifiers of endogenous acetylcholine
Structure-activity relationships among choline esters
A. METHYLATION (CH3 )
- Muscarinic selectivity
- Slight cholinesterase resistance
B. CARBAMYL SUBSTITUTION (O=CNH2 )
- Cholinesterase resistance
Notes:
Tertiary compounds – lipid soluble, non-polar, non-ionized;
can traverse BBB; ex. Pilocarpine, Physostygmine
o In treatment of atropine poisoning (antimuscarinics),
[atropine can traverse the CNS and produce
manifestations] as an antidote, a cholimimetic drug that
can also traverse CNS should be given  Physostigmine,
if only necessary
Quaternary compounds – lipid insoluble, water soluble,
positively charged, polar, ionized; poorly absorbed, poorly
distributed in body membranes
DIRECT-ACTING
MUSCARINIC RECEPTOR AGONISTS
I. CHOLINE ESTERS – Acetylcholine, Methacoline,
Carbachol, Bethanecol
II. NATURALLY-OCCURING ALKALOIDS – Pilocarpine,
Muscarine, Arecoline, Lobeline, Nicotine, Varenicline
 Muscarine – poison mushrooms, selective for
muscarinic receptors
 Pilocarpine – from pilocarpus plant; not a substrate
for AchE, selective for musc. receptors
 Arecoline – from betel nut, not a substrate for AchE,
selective for musc. receptors
Muscarine
- From Amanita muscaria
- ONLY MUSCARINIC actions
- No clinical use
- Cause mushroom poisoning due to ingestion of
poisonous mushroom (*late onset mushroom psg. Is
NEUROGENIC)
Pilocarpine
- Chewing of leaves; salivation
- 1874 – Brazilian physician Coutinhou 1 st experiment
- 1875 – alkaloid isolated
- (Weber) – acts on pupils, sweat and salivary glands
Pharmacologic Properties of Choline Esters & Natural
Alkaloids
1
 CHOLINE ESTERS
Quaternary amines
Poorly absorbed ff. oral
absorption
Poor ability to cross blood
brain barrier (BBB)
Short half-life due to fast
elimination by the kidney
NATURAL ALKALOIDS
Tertiary amines
Readily absorbed
Cross the BBB
Primarily eliminated by the
kidney, enhanced with
acidification
Muscarine – quaternary
amines but can still be toxic
with CNS effects
Pilocarpine – decrease
clearance with hepati c
impairment

Results of Loew and Dale’s experiment on Ach

 Muscarinic action closely resembles stimulation of
parasympathetic nerves
 Blocking of muscarinic effects by atropine; larger
doses of Ach produces nicotine-like effects:
o Stimulation of ALL autonomic ganglica
o Stimulation of voluntary muscles
o Secretion of adrenaline
Site of actions of cholinergic agonists in autonomic and
somatic nervous system
Muscarinic Receptors Subtypes:
M1 (neural)
o Sites: CNS and peripheral neurons, gastric parietal
cells
o Mediates excitatory effects produced by decrease in
K+ conductance  membrane depolarization
o Deficiency associated with dementia
o Increase gastric acid secretion following vagal
stimulation

M2 (cardiac)
o Sites: Heart, presynaptic terminal of peripheral and
central neurons
o Exert INHIBITORY effects mainly by:
- Increasing K + conductance
- Inhibiting Ca 2+ channels
o Co-expressed with M3 in the visceral smooth muscle
and contribute to the smooth muscle-stimulating
effect of muscarinic agonist drugs
Affinity to cholinergic receptors
M3 (glands/smooth muscles)
o Sites: exocrine glands, smooth muscles (visceral),
specific location in the CNS
o Exert EXCITATORY effects
- Stimulation of salivary, bronchial and sweat
- Contraction of visceral smooth muscles
o Relaxation of smooth muscle (mainly vascular) which
releases nitric oxide from neighboring cells

Acetylcholine Receptors
NICOTINIC
Muscle – skeletal
neuromuscular junction
Ganglionic – transmission at
sympathetic and
parasympathetic ganglia
CNS – widespread in brain
M4 and 5
o Sites: primarily CNS
o Functional role not well understood
MUSCARINIC
*Mice lacking receptor  behavioural changes
Typical G-protein coupled
o Recent findings: M4 and M2 affects cell proliferation
receptor
5 molecular subtypes (M1 to
M5 )
Odd numbers – M1,3,5 + Gq
activate inositol phosphate
pathway
Even numbers – M2, 4 + Gi
inhibits adenylyl cyclase 
reduce cAMP

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Neurotransmission at cholinergic neurons
Direct Effect of Muscarinic Stimulants
EYES Contraction of iris sphincter = miosis
Contraction of ciliary muscles =
accomodation
CVS Increase in K + current
Decrease in slow, inward Ca 2+ current
Reduction in hyperpolarization activated
current that underlies diastolic
depolarization
= hyperpolarization, reduce action
potential duration, decrease contractility
 decrease HR and force of contraction
Respiratory Contracts the smooth muscles of bronchial
System tree
Increase secretions of the gland and
tracheobronchial mucosa
 wheezing, noisy breathing
GIT Increase secretory and motor activity
Salivary and gastric glands strongly
stimulated (intestinal and pancreatic
glands less stimulated)
 depolarization of smooth muscle cell
membrane and increase Ca 2+ influx
Genitourinary Stimulate detrusor muscle
Relaxes trigone and sphincter muscle of
bladder
 voiding
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Therapeutic Uses
Acetylcholine – topically for induction of miosis during eye
surgery
Methacoline – administered by inhalation for the diagnosis of
bronchial hyperactivity
Bethanecol – urinary retention postoperatively and other
causes; stimulation of peristalsis postoperatively gastric atony
Carbachol – topically in ophthalmology: treatment of
glaucoma; induction of miosis during eye surgery
Pilocarpine – topically for treatment of glaucoma; orally for
treatment of xerostomia (5-10 mg TID)
Cevimeline – Quinuclidine derivative of Ach; high affinity to M 3
on lacrimal and salivary gland; long acting sialogogic action
with fewer side effects; enhances lacrimal secretion in Sjorgen
syndrome
General Therapeutic Uses of Muscarinic Receptor Agonist:
o Treatment of urinary bladder disorders
o Xerostomia
o Diagnosis of bronchial hyperactivity
o Treatment of glaucoma
INDIRECT-ACTING
CHOLINESTERASE INHIBITORS
Notes:
Normally:
Ach + Enzyme (AchE) → A-E complex → hydrolysis → choline
+ acetylated E → split of acetyl-E bond + H2 0
 In the initial catalytic step, Ach binds to the enzyme’s
active site and is hydrolyzed yielding free choline and
acetylated enzyme.
 In the second step, the covalent acetyl bond is split,
with the addition of water (hydration).
 The entire process takes place approximately 150
microseconds.
With the action of Indirect-acting drugs:
Ach + Inhibitors (I) → I-E complex → hydrolysis of E → ↑Ach
 With Ach release, the indirect-acting cholinomimetic
drugs form complex with AchE, and then hydrolyze
this enzyme; therefore, Ach is spared from being
degraded.
Cholinesterases
1. Acetylcholinesterase
 Localized within junctions and synapses
 Primarily responsible for inactivation of released
acetylcholine
2. Butyrylcholinesterase
 Found in plasma and platelets
 Substrate: circulating choline esters
General Mechanism of Action:
1. Prolongation of acetylcholine’s effects
a. Muscarinic sites
b. Neuromuscular nicotinic sites
c. Autonomic ganglia
Examples of anticholinesterases:
REVERSIBLE (Carbamates) IRREVERSIBLE
3
 Natural: Physostigmine Organophosphorus o Parathion, Malathion
Synthetic: Neostigmine, compounds (OPC): o Lipid soluble, well absorbed by all routes
distigmine, rivastigmine, Disopropyl o Converted to oxygen analog in the body
donepezil, gallantamine, fluorophosphates (DFP); o Malathion is rapidly metabolized in birds and
edrophonium, ambenonium, ecothiophate, parathion, mammals but not insects. Fish cannot detoxify
demecarium malathion, diazinon o Parathion is not effectively detoxified in vertebrates.
(insecticides and
pesticides) Pharmacologic Effects
Nerve gases in war: Tabun,  Result from increased Ach concentration in junctions
sarin, soman and synapses
Carbamate: Carbaryl and  Muscarinic effects: same as for muscarinic agonists in
propoxur (Baygon ® ) eyes, heart, GIT, bladder, lung and so on
 Ganglionic effects: Hypertension
Physostigmine  Skeletal muscle effects: Facilitation of muscle,
- Alkaloid, from calabar bean voluntary contract, tremor
- West Africa, “Ordeal poison”
- (1864) Jobst and Hesse Uses
- (1877) glaucoma treatment – Laqueur  Myasthenia gravis
 Glaucoma
Chemical groups:  Bladder atony
Edrophonium – simple alcohol (ROH) bearing a quaternary  Alzheimer’s disease (Rivastigmine, Donepezil, Gallantamine)
ammonium group  Belladonna poisoning
Carbamates: Neostigmine – with quaternary ammonium group
Organophosphates: Echothiophate - organic derivative of CONTRAINDICATIONS
phosphoric acid
1. Bronchial asthma: induction of bronchospasms and
Duration of Action mucus secretions
Group Duration of Action (Approx) 2. Acid peptic disease (Duodenal ulcer): exocrine
ALCOHOL secretions leading to increase gastric secretions  gastric
o Edrophonium 5-15 minutes ulcerations
CARBAMATES 3. Coronary insufficiency: coronary slowing, AV conduction
o Neostigmine 0.5-4 hours slowing
o Pyridostigmine 4-6 hours 4. Hyperthyroidism: ↑ sensitivity to circulating
o Physostigmine 0.5-2 hours catecholamine which may stimulate the adrenal medulla
ORGANOPHOSPHATE increasing aggregate sympathetic effects
o Echothiophate 100 hours 5. Intestinal or Bladder obstruction: Due to intense
contraction  rupture or perforation
Indirect-acting Cholinomimetics 6. Parkinsonism
A. Quaternary carbamates
o Conjunctiva, skin, lungs – poor absorption ADVERSE EFFECTS
o CNS distribution – negligible
o Relatively stable in aqueous solution  Mimic effect that would occur during exaggerated
o Metabolized by nonspecific esterases and parasympathetic activity
cholinesterase  Extension of primary effects:
o Duration of effect: depends on inhibitor-enzyme o GI distress: nausea, vomiting, diarrhea,
complex formation abdominal cramps
B. Synthetic quaternary ammonium agents o Increased secretions: salivation, hyperhidrosis
o Edrophonium, neostigmine, pyridostigmine (increased sweating), lacrimation
C. Physostigmine o Heart: bradycardia  arrest
o Naturally occurring tertiary amine o Eyes: difficulty in visual accommodation
o Well-absorbed from ALL sites (topically: eyes) (cyclospasm)
o Distributed in CNS o Blood Vessels: Cutaneous vasodilation (Flushing)
o More toxic than polar quaternary carbamates o Lungs: bronchoconstriction
D. Organophosphate (except echothiophate) o Type A ADR
o Well-absorbed: skin, lungs, gut, conjunctiva  Carbamate and Organophosphate inhibitors –
o Highly effective as insecticides “DUMBELS”- diarrhea, urinary frequency, miosis, muscle
o Less stable in water than carbamates weakness, bronchospasm, excitation, lacrimation,
o Limited half-life in environment seizure, sweating, salivation
E. Thiophosphate insecticides

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 Physostigmine Neostigmine Belladona
Source Natural Synthetic - Atropine and Scopolamine
Chemistry Tertiary amine Quaternary - Roman empire: obscure poisoning
ammonium - India: roots and leaves for asthma
compound - (Bezold and Bloebaurn, 1867): blocked cardiac effect
Oral Good Poor of vagal stimulation
absorption - (Heidanhain, 1872): prevents salivary secretion
CNS action Present Absent produced by stimulation of chorda tympani
Eye Penetrates mucosa Poor penetration
Effector Ganglia Muscle Atropine
Uses Miotic (for glaucoma) Myasthenia - Source: Atropa belladonna, Datura stramonium
Atropine poisoning gravis - Chemistry: Alkaloid, racemic mixture (dl -
Curare poisoning hyoscyamine); Tertiary amine – L isomers are 100x
Dose 0.5-1 mg 0.5-2.5mg IM/SC more potent than D isomers
oral/parenteral 15-30mg oral - Structure: Organic ester of tropic acid (aromatic acid)
and tropine (organic base)
Duration of 4-6 hours 3-4 hours
action - Uses: For management of organophosphate
poisoning (Atropine sulphate: 1 to 2 mg IV every 5-15
min until signs of reversal such as dry mouth, pupil
Toxicity: Direct-Acting Nicotinic Stimulants
dilation, increase heart rate --- May have to be
ACUTE TOXICITY
repeated for 24-48 hrs or longer ---- 1 g per dose for
 Nicotine 40 mg (1 drop of pure liquid)
1 month may be required)
 CNS stimulation
 Skeletal muscle end plate depolarization
Muscarinic-receptor antagonists
 Respiratory paralysis
A. Quaternary amines with GIT application
 Hypertension and cardiac arrhythmia
(PUD/Hypermotility)
 Treatment: symptomatic
o Propantheline, Glycopyrrolate
CHRONIC TOXICITY  Addiction
B. Quaternary amines for use in Asthma
Major source: Insecticides
o Ipatropium, Benztropine
s/s: exaggeration of Ach effects
C. Tertiary amines with peripheral applications
Management: maintenance of vital signs; decontamination;
o Pirenzepine for PUD
antidote – atropine, pralidoxime
o Dicyclomine for PUD/hypermotility)
o Tropicaminde – mydriatic, cycloplegic
CHOLINERGIC RECEPTOR ANTAGONISTS
D. For Urinary disorders
(Cholinoceptor blockers, muscarinic antagonists/blockers,
o Oxybutin, Trospium, Darifenacin, Solifenacin,
parasympatholytics)
Tolterodine
o divided in accordance with their specifi c targets in the
central/peripheral nervous system:
Antimuscarinic drugs used in Ophthalmology
1. Antimuscarinic drugs
Drugs Duration of Usual concentration (%)
2. Antinicotinic drugs
- Ganglion blockers effect
- Neuromuscular junction blockers \ Atropine 5-6 days 0.5 - 1
Scopolamine 3-7 days 0.25
Classification of antimuscarinic drugs Homatropine 12-24 hours 2-5
1. Chemical Cyclopentolate 3-6 hours 0.5 – 2
2. Therapeutic Tropicamide 15-60 min 0.5- 1

A. Natural Belladonna alkaloids Pharmacologic Actions

o Atropine (dl-hyoscyamine) o CNS: minimal stimulant effect
o Hyoscine (scopolamine) o Eye: unopposed sympathethic dilator activity 
B. Semisynthetic and synthetic substitutes mydriasis
o Tertiary amines: Benztropine, Dicyclomine, o CVS: tachycardia
Homatropine, Oxyphencyclamine, Pirenzepine, o GIT: decrease motility
Tropicamide, Propiverine, Oxybutyn, Darifenacin, o Genitourinary: hesistancy in urination
Solifenacin, Tolterodine o Respiratory: bronchodilation
o Quaternary amines: Anistropine, Clidinium, o Sweat glands: suppression
Gkycopyrrolate, Ipratropium, Isopropamide,
Methscopolamine, Propantheline, Trospium,
Mepenzolate, Tridihexethyl

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 Therapeutic applications of Antimuscarinics

Mechanism of Action:
 Competitive antagonism of the muscarinic receptors
 Pharmacologic effects:
- Blockade of parasympathetic signals
- Blockade of sympathetic signal mediated by
muscarinic receptors
ABSORPTION
o Well absorbed from GIT and conjunctival membrane
o Bioavailability: 25%
o 10-30% absorption of quaternary antimuscarinic drug
after oral admin.
DISTRIBUTION
o Wide distribution for atropine and other tertiary agts.
o Significant levels achieved in CNS within 30min to 1hr
o Scopolamine is rapidly and fully distributed into CNS
where it has greater effects than most other
antimuscarinic drugs
o Quaternary drugs are poorly taken up by brain
EXCRETION
o 60% of dose excreted unchanged in urine
o The rest appears as hydrolysis and conjugation
products
Dose: 0.4 mg, 3x to 4x a day
Route: oral, IM, IV, Eye drops, Eye ointment

Atropine effects in relation to dose

-/-/-END-/-/-

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