ACh serves as the synaptic
transmitter at:
CHOLINERGIC
AND
NEUROMUSCULAR
PHARMACOLOGY
2 families of cholinoceptors
muscarinic receptors
nicotinic receptors
Responses
to cholinergic
activation
Subtypes and characteristic of
muscarinic receptors
Receptor
subtype
Other
names
Location
Postreceptor
Mechanism
M1
M1a,
neuronal
Nerves, stomach
IP3, DAG cascade
M2
M2a,
cardiac M2
Heart, nerves,
smooth muscle
cAMP, activation
of K+channels
M3
M2b,
glandular
M2
Glands, smooth
muscle,
endothelium
IP3, DAG cascade
all autonomic ganglia, SNS & PNS
postganglionic parasympathetic nerve
endings
postganglionic SNS endings to sweat
glands
neuromuscular junction
CNS
Subtypes and characteristic of
nicotinic receptors
Recept
or
subtyp
Ne
M
m4
?CNS
cAMP
m5
?CNS
IP3, DAG cascade
NN
Other names
Location
Structural Postrec.m
features
echanism
Muscle type,
end plate
receptor
Skeletal
Pentamer
muscle
(α2, β, γ, δ)2 Na+, K+
neuromuscu
depolarizi
lar junction
ng
Neuronal type, Postganglio
α and β
ion
ganglion
nic cell
subunits
channel
receptor
body,
only as α 2 β
dendrites
2 or α 3 β 3
1
Parasympathetic transmission
Cholinergic drugs
Directly acting cholinomimetics
Drugs affecting the PS
system
Parasympathetic transmission path
Drugs affecting the PS
system
ACh
preganglionic neuron
N
ACh
M
Direct acting
postganglionic neuron
ganglion near
target tissue
Direct acting
effector tissue
or organ
Cholinergic
agonists (+)
– TA: ophtalmology miosis intraocular
pressure (glaucoma)
Betanechol not hydrolyzed by AChE
– TA: stimulation of atonic bladder postpartum/postoperational nonobstructive urinary
retention
– ADE: sweating, salivation, flushing, BP, nausea,
abdominal pain, diarrhea, bronchospasm
Muscarinic
agonists (+)
ACh-esterase
inhibitors (+)
Esters of choline
Alkaloids
Esters of choline
Acetylcholine too unstable in plasma to be
used as a drug
Carbachol not hydrolyzed by AChE
Cholinergic
antagonists (-)
Indirect acting
Muscarine
Pilocarpine – alkaloid, tertiary amine, not degraded
by AChE
– quick onset of action
– TA: ophtalmology emergency and chronic lowering of
intraocular pressure (IOP) in open-angle and closed-angle
glaucoma
– TA: xerostomia (that follows head and neck radiation TMTs
or is associated with Sjorgen syndrome)
Muscarinic
antagonists (-)
Indirect acting
ACh-esterase
inhibitors (+)
Alkaloids
Muscarinic agonists
Pharmacokinetics
Ach – rapidly destroyed
Carbachol, bethanecol – not affected by
the cholinoseterases longer duration
of action
Pilocarpine – well absorbed after p.o.,
s.c. or topical adm., access to CNS
– ADE:
• lipid soluble enters CNS disturbances
• stimulates profuse sweating and salivaton
2
Muscarinic agonists
Adverse effects
SLUD, which is
–
–
–
–
Salivation
Lacrimation
Urination
Defecation
Muscarinic agonists
Major contraindications
asthma
ischaemic heart disease
hyperthyroidism
peptic ulcer
AChE cleavage of ACh into Ch and
acetate
Ø of AChE ACh in synaptic space
PS transmission (both M and N
receptors)
Types:
– reversible (therapeutic)
– irreversible (toxic, therapeutic)
Drugs affecting the PS
system
Direct acting
Bronchospasm
Hypotension
Arrhythmias
AChE inhibitors
Indirectly acting cholinomimetics
Muscarinic
agonists (+)
AChE inhibitors – reversible
Edrophonium
Physostigmine
Neostigmine
Piridostygmine
Muscarinic
antagonists (-)
Indirect acting
ACh-esterase
inhibitors (+)
AChE inhibitors – reversible
Edrophonium – ultra-short duration of action
(5-10-20 min)
– TA: diagnostics of myasthenia gravis (myastenic
crisis vs. cholinergic crisis)
Physostigmine – tertiary amine substrate
for AChE
–
–
–
–
–
A: 2-4 h
PK: CNS penetration
TA: intestinal and bladder motility in atony
TA: glaucoma
TA: atropine overdose
3
AChE inhibitors – reversible
Neostigmine – more polar than
physostigmine – doesn’t enter CNS
–
–
–
–
A: 2-4 hours
TA: atony
TA: tubocurarine antidote
TA: myasthenia gravis (autoimmune disease muscular weakness)
AChE inhibitors – irreversible
Echothiophate, isoflurophate
Nerve gases – sarin, soman, tabun
Insecticides – malathion, parathion,
paraoxon
Pyridostigmine – longer duration (3-6 h)
– TA: myasthenia gravis
AChE inhibitors - irreversible
Echothiopate/Isoflurophate
– TA: topically – chronic TMT of open-angle
glaucoma
– ADE: few after topical administration
AChE inhibitors in Alzheimer Disease
A: brain AChE, BuChE
TA: Alzheimer Disease
Tacrine – withdrawn (hepatotoxicity)
Donepezil
Galantamine
Rivastigmine!! : BuChE>AchE, no
metabolism, no tolerance
Irreversible AChE inhibitors
Organic phosphates – irreversibly bind to AChE
– toxic after systemic application (toxic military gases,
insecticides)
– A: generalized cholinergic stimulation, paralysis of motor
function (problems with breathing), convulsions, miosis
• CNS: coma, respiratory depression, seizures
• Muscarinic: nausea, vomiting, diarrhea, blurring of vision,
sveating, salivation
• Nicotinic: mscle twiching, fasciculations, weakness, flaccid
paralysis
– antidote cholinoesterase regenerator pralidoxime (PAM)reactivation of AChE ineffective after aging (loss of
phosphonate alkyl group)
– Atropine – having an anticholinergic action
– Emesis, lavage, catharsis, charcoal
Therapeutic use of
AChE inhibitors
Use
TMT of glaucoma
Drugs
physostigmine
echothiophate
isoflurophate
Diagnosis of myasthenia gravis edrophonium
TMT of myasthenia gravis
neostigmine
pyridostygmine
TMT of Alzheimer’s disease
donepezil
rivastigmine
tacrine
Reversal of nondepolarizing
muscle relaxants
edrophonium
Neostigmine
pyridostygmine
4
Therapeutic uses of
cholinomimetics - SUMMARY
Myasthenia gravis – TMT, diagnosis
Reversal of nondepolarizing muscle
relaxants
Xerostomia
Glaucoma
Alzheimer’s disease
Antidote for atropine poisoning
Tubocurarine anidote
Bladder atony
GI disorders: postoperative abdominal
Muscarinic antagonists
Atropine - actions
Atropine
– Belladonna alkaloid
– competitive M antagonist
– A: mydriasis, cycloplegia
– A: gastric and intestinal motility, antispasmodic
(pirenzepine – M1 antagonist – better at HCl
production), motility of urinary bladder
– A: low dose bradycardia (blockade of inhibitory
prejunctional neurons), high dose tachycardia
(vagal blockade at the SA&AV nodes), dilution of
cutaneous vasculature (reduction in BP)
– A: blockade of salivary (xerostomia), sweat (
body temperature) and lacrimal glands, inhibits
secretion in the pharynx, trachea and bronchi,
relaxes bronchial smooth muscles, decrease
airway resistance
Muscarinic antagonists
Drugs affecting the PS
system
Direct acting
Muscarinic
agonists (+)
Muscarinic
antagonists (-)
Indirect acting
ACh-esterase
inhibitors (+)
Muscarinic antagonists
Atropine – therapeutic actions
ophthalmologic diagnostics mydriasis (fundus
examination – more often tropicamide,
homatropine), cycloplegia (refractive errors
measurement)
antispasmodic agent (GI tract, bladder)
antidote (penetrates CNS): insecticides
(irreversible AChE inhibitors), mushroom poisoning
(muscarine)
antisecretory agent (respiratory tract; before
surgery)
Bradycardia
GU – TMT of cramping and urgent bladder in mild
cystitis
Muscarinic receptor antagonists
The naturally occurring alkaloids:
atropine and scopolamine
Semisynthetic derivatives of these
alkaloids: hyoscine butylbromide
Synthetic congeneres: homatropine,
tropicamide,cyclopentolate, ipratropium,
tiotropium
Muscarinic antagonists
Atropine – adverse effects
dry mouth, blurred vision, „sandy eyes”,
tachycardia, constipation, attack of
glaucoma (elderly)
restlessness, confusion, hallucinations,
delirium
high doses depression, collapse of
circulatory and respiratory system death
5
Effects of atropine in relation to dose
(Goodman & Gilman’s)
DOSE (mg)
(mnemonic device)
EFFECTS
Slight cardiac slowing; some dryness of mouth; inhibition
(therapeutic of sweating
0,5
dose)
1
Definite dryness of mouth; thirst; acceleration of heart;
sometimes preceded by slowing; mild dilation of pupils
2
Rapid heart rate; palpitation; marked dryness of mouth;
dilated pupils; some blurring of near vision
5
All the above symptoms marked; difficulty in speaking
and swallowing; restlessness and fatigue; headache, dry,
hot skin; difficulty in micturion; reduced intestinal
peristalsis
10 and
more
Above symptoms more marked; pulse rapid and weak; iris
practically obliterated, vision blurred; skin flushed, hot,
dry, and scarlet; ataxia, restlessnes, and excitement;
hallucinations and delirium; coma
Muscarinic antagonists
(semisynthetic)
Hyoscine butylbromide
TA: relieve bladder or intestinal spasms
Muscarinic antagonists
Scopolamine
Atropine poisioning
Mad as a hatter.
Blind as a bat.
Dry as a bone.
Red as a beet.
Hot as a pistol.
Muscarinic antagonists
(synthetic)
Homatropine, tropicamide, cyclopentolate: mydriasis: produce
mydriasis and cycloplegia
Mebeverine, TA: antispasmodic
Propantheline, TA: antispasmodic, urinary incontinence, peptic ulcer
disease and nervous stomach
Ipratropium (aerosol, dry powder, nasal spray)
– quarternary derivative of atropine
– TA: asthma slow onset of action
• first choice β2-adrenergic agonists
– TA: COPD!!
– ADE: none
Scopolamine
– Belladonna alkaloid
– PK: longer duration of action than atropine,
better CNS penetration
– TA : anti-motion sickness
– TA : blocks short-term memory (anesthetic
procedures)
– AE : sedation, predictable autonomic
adverse effects with increase of dose
Muscarinic antagonists used in
Parkinson Disease
Benztropine, trihexphenidyl, biperiden
–
–
–
–
–
MoA: antimuscarinic agents
FK : penetrate to the CNS
A: tremor
TA: Parkinson’s
ADE: mood changes, hallucinations, xerostomia,
accomodation problems, GI tract and urinary
bladder motility
Oxitropium (aerosol): TA :COPD
Tiotropium (aerosol): TA :COPD
Glycopyrrolate
– TA: marked antisialogogue action (long duration, potency relative to
atropine 2:1)
– TA: premedicant
6
Therapeutic uses of
muscarinic antagonists
Ophthalmology: examination of the retina and optic disc
Respiratory tract – COPD, asthma
GI, biliary and genitourinary tracts - antispasmodic action
CNS
– motion sickness
– Parkinson’s Disease
Anticholinergic Drugs
Ganglionic blockers
1. Antimuscarinic drugs
2. Ganglionic blocking drugs
3. Neuromuscular blocking drugs
Antidote to Anticholinesterase
Antidote to poisoning by mushrooms containing muscarine
Preanesthetic medication
Cholinergic antagonists
Muscarinic
antagonists
OF LIMITED CLINICAL APPLICATION:
GI tract – once the most widely used drugs for the management
of peptic ulcer
CVS – AMI in patients whom excessive vagal tone causes sinus or
nodal bradycardia
Ganglionic blockers
Nicotinic
antagonists
Competitive
neuromuscular
blockers
Ganglionic
blockers
Ganglionic blockers
Neuromuscular blockers
Nicotine
– small doses ganglionic excitation
• heart rate, blood pressure
• peristalsis and secretions
• appetite
– high doses ganglionic blockade
• heart rate, blood pressure
• activity of GI tract and bladder
• neuromuscular blockade
TA: aid smoking cessation by easing nicotine craving
ADE: tolerance and dependance
Trimethaphan
– short acting
– TA: IV infusion emergency lowering of blood
pressure (pulmonary edema, dissecting aortic
aneurysm) when other agents cannot be used
(sodium nitroprusside + β-blocker treatment
of choice for aortic dissection, IV
nitroglycerine acute pulmonary edema)
– TA: lowering of blood pressure in surgery
Cholinergic antagonists
Muscarinic
antagonists
Ganglionic
blockers
Cholinergic agonists
Nicotinic
antagonists
Competitive
(nondepolarizing)
neuromuscular
blockers
Nicotinic
agonists
Noncompetitive
(depolarizing)
neuromuscular
blockers
7
Neuromuscular blockers
Block the nicotinic transmission at the
neuromuscular end-plate
– nondepolarizing classical antagonists of N
receptors
– depolarizing desensitization of N receptors
Use of neuromuscular blockers
Surgical relaxation
Control of ventilation
TMT of convulsions
Nondepolarizing neuromuscular blockers
Adverse drug effects
Cardiovascular Effects
Hyperkaliemia
Increased Intraocular pressure
Increased intragastric pressure
Muscle pain
Nondepolarizing neuromuscular blockers
Classification
Isoquinoline
derivatives
–
–
–
–
–
–
Tubocurarine
Atracurium
Cisatracurium
Metocurine
Mivacurium
Doxacurium
Nondepolarizing neuromuscular blockers
Tubocurarine, … (-curium, -curonium, -
Steroid derivatives
-
Pancuronium
Vecuronium (liver)
Pipecuronium
Rocuronium (liver)
curine)
– action can be overcome by ACh concentration
in synaptic gap (AChE inhibitors)
– sensitivity: small muscles (face, eye) > fingers >
libs, neck, trunk > intercostal muscles >
diaphragm
– TA: IV surgery relaxation of skeletal
muscles
– TA: mivacurium quick recovery (short surgical
procedures)
– ADE: muscle weakness, myopathy
– ADE: histamine release (bronchoconstriction in
asthmatics), ganglionic blockade, blood
pressure
Depolarizing neuromuscular agents
Succinylcholine
– Phase I: excitation fasciculations
– Phase II: flaccid paralysis (desensitization)
– short duration (degradation by AChE) and quick
onset of action
– TA: IV endotracheal intubation prior to
surgery
– TA: IV electroconvulsive shock treatment
– ADE: malignant hyperthermia (with halothane)
– ADE: apnea (genetically related deficiency of
AChE)
– ADE: muscle pain and stiffness (12 to 24 h
later)
8