4.cholinergic agonists + antagonists

 Dr. Mahmoud H. Taleb
Assistant Professor of Pharmacology and Toxicology
Department of Pharmacology and Medical Sciences,
Faculty of Pharmacy- Al-azhar University
1Dr. Mahmoud H. Taleb

 Central Nervous System (CNS) - Brain and
spinal cord
 Peripheral Nervous System (PNS) - Located
outside the brain & spinal cord
* Autonomic Nervous System (ANS) &
the somatic
 The PNS receives stimuli from the CNS &
initiates responses to the stimuli after it’s
interpreted by the brain
4
Dr. Mahmoud H. Taleb

 ANS acts on smooth muscles & glands
- Controls & regulation of the heart, respiratory.
system, GI tract, bladder, eyes & glands
- Involuntary - person has little or no control
 Somatic - voluntary - person has control (skeletal
muscle)

 ANS has 2 sets of neurons:
1. Afferent (sensory) - sends impulses to the CNS
for interpretation
2. Efferent - receives impulses (info.) from the brain
& transmits from the spinal cord to the effector
organ cells
- 2 branches - sympathetic &
parasympathetic nervous system

Two families of cholinoceptors, designated
muscarinic and nicotinic receptors, can be
distinguished from each other on the basis of
their different affinities for agents that mimic the
action of ACh (cholinomimetic agents or
parasympathomimetics).
Dr. Mahmoud H. Taleb 14

 A. Muscarinic receptors
 Muscarinic receptors belong to the class of G
protein–coupled receptors. These receptors, in
addition to binding ACh, also recognize muscarine,
an alkaloid that is present in certain poisonous
mushrooms. By contrast, the muscarinic receptors
show only a weak affinity for nicotine, five
subclasses of muscarinic receptors: M1, M2,
M3, M4, and M5. Although five muscarinic
receptors have been identified by gene
cloning, only M1, M2, and M3 receptors have
been functionally characterized

 Locations of muscarinic receptors:
These receptors have been found on ganglia of the
peripheral nervous system and on the autonomic
effector organs, such as the heart, smooth muscle,
brain, and exocrine glands ,Specifically, although all
five subtypes have been found on neurons,
M1receptors are also found on gastric parietal cells,
M2receptors on cardiac cells and smooth muscle,
and M3receptors on the bladder, exocrine glands,
and smooth muscle.

 Mechanisms of acetylcholine signal
transduction: when the M1 or M3 receptors are
activated, the receptor undergoes a conformational
change and interacts with a G protein, designated
Gq, that in turn activates phospholipase C.
This leads to the hydrolysis phosphatidylinositol-(4,5)-
bisphosphate to yield diacylglycerol and inositol
(1,4,5)-trisphosphate. Both inositol (1,4,5)-
trisphosphate and diacylglycerol are second
messengers. Inositol (1,4,5)-trisphosphate causes an
increase in intracellular Ca2+ This cation can then
interact to stimulate or inhibit enzymes or to cause
hyperpolarization, secretion, or contraction.

 Diacylglycerol activates protein kinase C. This
enzyme phosphorylates numerous
 proteins within the cell. In contrast, activation of the
M2subtype on the cardiac muscle stimulates a G
protein, designated Gi, which inhibits adenylyl
cyclase and increases K conductance. The heart
responds with a decrease in rate and force of
contraction

 Muscarinic agonists and antagonists:Attempts are currently
underway to develop muscarinic agonists and antagonists
that are directed against specifi c receptor subtypes. For
example, pirenzepine, a tricyclic anticholinergic drug, has a
greater selectivity for inhibiting M1muscarinic receptors,
such as in the gastric mucosa. At therapeutic doses,
pirenzepinedoes not cause many of the side effects seen
with the non-subtype-specifi c drugs; however, it does
produce a refl ex tachycardia on rapid infusion due to
blockade of M2receptors in the heart. Therefore, the
usefulness of pirenzepineas an alternative to proton pump
inhibitors in the treatment of gastric and duodenal ulcers is
questionable. Darifenacin is a competitive muscarinic
receptor antagonist with a greater affi nity for the
M3receptor than for the other muscarinic receptors. The
drug is used in the treatment of overactive bladder. [Note:
At present, no clinically important agents interact solely with
the M4and M5receptors.] Dr. Mahmoud H. Taleb 19

 These receptors, in addition to binding ACh, also
recognize nicotine but show only a weak affi nity for
muscarine The nicotinic receptor is composed of five
subunits and it functions as a ligand-gated ion
channel .Binding of two ACh molecules elicits a
conformational change that allows the entry of sodium
ions, resulting in the depolarization of the effector cell.
Nicotine at low concentration stimulates the receptor,
and at high concentration blocks the receptor. urarine.

 Nicotinic receptors are located in the CNS,
adrenal medulla, autonomic ganglia, and the
neuromuscular junction (NMJ). Those at the NMJ
are sometimes designated NM, and theothers,
NN. The nicotinic receptors of autonomic ganglia
differ from those of the NMJ. For example,
ganglionic receptors are selectively blocked by
hexamethonium, whereas NMJ receptors are
specifically blocked by tubocurarine.

 NM-cholinoceptors
◦ Location: neuromuscular junction
◦ Function: depolarization of muscle end
◦ plate and contraction of skeletal muscle
 NN-cholinoceptors
 Location: autonomic ganglia
 Function: depolarization
 postganglonic membrane
 (in adrenal medula –
 catecholamine release)

 Direct acting - act on the receptors to activate a
tissue response
 Indirect acting - inhibit the action of the enzyme
cholinesterase (acetylcholinesterase - ACH)
 Major uses = Stimulate bladder & GI tone,
constrict pupils (miosis), neuro-
muscular transmission


Is the neurotransmitter of the parasympathetic
N.S and cholinergic nerves, it is therapeutically of
no importance due to:
1. Multiplicity of actions.
2. Rapid inactivation by acetyl-cholinesterase.
3. Has both muscarinic and nicotinic activity.

 A. Neurotransmission at cholinergic
neurons
1. Synthesis of acetylcholine
 ACh is highly concentrated in synaptic storage
vesicles present in the axoplasm of the terminal.
ACh is formed from choline and activated acetate
acetylcoenzyme A, a reaction catalyzed by the
enzyme choline acetyltransferase. The highly
polar choline is actively transported into the
axoplasm.
 2. Storage of acetylcholine in vesicles:
The specific choline transporter is localized
exclusively to membranes of cholinergic axons
and terminals

3. Release of acetylcholine
During activation of the nerve membrane, Ca2+
enters into the axoplasm through voltage-gated
channels to activate protein kinases. As a result,
vesicles close to the presynaptic membrane and
fuse with this membrane.
During fusion, vesicles discharge their contents
into the synaptic gap. ACh quickly diffuses
through the synaptic gap. The molecule of ACh is
a little longer than 0.5 nm. The synaptic gap is as
narrow as 30–40 nm.

 4. Binding to the receptor:
 At the postsynaptic effector cell membrane, ACh reacts
with its receptors. Because these receptors can also be
activated by the alkaloid muscarine, they are referred to
as muscarinic (M-) cholinoceptors. In contrast, at
ganglionic and motor endplate cholinoceptors, the action
of ACh is mimicked by nicotine and they are,
 therefore, said to be nicotinic (N-) cholinoceptors.
 5. Degradation of acetylcholine:
 Released ACh is rapidly hydrolyzed and inactivated by a
specific acetylcholine esterase, present on pre- and
postjunctional membranes, or by a less specific serum
choline esterase (butyryl choline esterase), a soluble
enzyme present in serum and interstitial fluid.

 (1) Choline ester
◦ (stimulants of M- and N-receptors):
◦ Acetylcholine, Carbachol, methacholine, and Bethanechol
 (2) Alkaloids
◦ a) stimulants of M-receptors:
 Pilocarpine, Cevimeline Musacarine,
 b) stimulants of N-receptors:
 Nicotine, and Lobeline
DIRECT-ACTING CHOLINERGIC DRUGS

 1) Reversible drugs (most are carbamates)
 a) With N3+
(cross BBB)
 Alkaloids: Galantamine, Physostigmine
 Synthetic drugs:
 Donepezil, Rivastigmine, Tacrine
 b) With N4+
(do not cross BBB)
 Demecarium, Edrophonium (Tensilon®
)
 Neostigmine, Pyridostigmine

 2) Irreversible anticholinesterase agents
 (most of them are organophosphates)
 a) Thiophosphate insecticides
◦ Parathion and Malathion
 b) Nerve paralytic gases
 for chemical warfare
◦ Tabun
◦ Sarin
◦ Soman

 Lipid insoluble antiChEs (neostigmine and
 other quaternary ammonium compounds)
 produce more marked effect on the skeletal
 muscles (direct action on muscle end-plate
 NN-cholinoceptors as well).
 Stimulate ganglia but muscarinic effects
 are less prominent.
 They do not penetrate in CNS and
 have no central effects

Eyes: contraction of ciliary muscle and smooth muscle of
the iris sphincter (miosis) – aqueous humor outflow,
drainage of the anterior chamber
- Cardiovascular: Bradycardia (possibly preceded by
tachycardia), vasodilation (all vascular beds including
pulmonary and coronary – M3) and hypotension,
reduction of the contraction strength (atrial and
ventricular cells, IK+ , ICa2+ diastolic depolarization , NO-
inhibitable ATP?), negative chronotropic effect (inhibition
of adrenergic activation).

GI - increases in tone, amplitude of contractions, and peristaltic
activity of the stomach and intestines, enhances secretory activity
of the gastrointestinal tract.
- Urinary bladder - increase ureteral peristalsis, contract the
detrusor muscle of the urinary bladder, increase the maximal
voluntary voiding pressure, and decrease the capacity of the
bladder.
- Respiratory system It cause Bronchoconstriction and increase
bronchial secretions.
- Other effects – Increased secretion from all glands that receive
parasymphatetic enervation (salivary, lacrimal, tracheobronchial,
digestive and exocrine sweat glands)

“SLUDGE”
 Salivation
 Lacrimation
 Urinary incontinence
 Diarrhea
 Gastrointestinal cramps
 Emesis

 Cholinergic agonists (also known as
parasympathomimetics) mimic the effects of
acetylcholine by binding directly to cholinoceptors.
These agents may be broadly classified into two groups:
choline esters, which include acetylcholine
 and synthetic esters of choline, such as carbachol and
bethanechol.Naturally occurring alkaloids, such as
pilocarpine constitue the second group. All of the direct-
acting cholinergic drugs have longer durations of action
than acetylcholine.

 B. Bethanechol
 Bethanechol is an unsubstituted carbamoyl ester,
structurally related to ACh, in which the acetate is
replaced by carbamate, and the choline is methylated
.Hence, it is nothydrolyzed by AChE (due to the
esterifi cation of carbamic acid), although it is
inactivated through hydrolysis by other esterases. It
lacks nicotinic
 actions (due to the addition of the methyl group) but
does have strong muscarinic activity. Its major
actions are on the smooth musculature of
 the bladder and GI tract. It has about a 1-hour
duration of action.

 1. Actions: Bethanechol directly stimulates muscarinic
receptors, causing increased intestinal motility and tone.
It also stimulates the detrusor muscle of the bladder,
whereas the trigone and sphincter are relaxed. These
effects increase voiding pressure and decrease bladder
capacity to cause expulsion of urine.
 2. Therapeutic applications: In urologic treatment,
bethanechol is used to stimulate the atonic bladder,
particularly in postpartum or postoperative,
nonobstructive urinary retention. Bethanechol may
also be used to treat neurogenic atony as well as
megacolon.
 3. Adverse effects: Bethanechol causes the effects of
generalized cholinergic stimulation These include
sweating, salivation, flushing, decreased blood
pressure, nausea, abdominal pain, diarrhea, andDr. Mahmoud H. Taleb 43

 C. Carbachol
 Carbachol has both muscarinic as well as nicotinic actions. It lacks
the methyl group present in bethanechol Like bethanechol, carbacholis
an ester of carbamic acid and a poor substrate for AChE. It is
biotransformed by other esterases
 but at a much slower rate.
 1. Actions:
Carbacholhas profound effects on both the cardiovascular
 and GI systems because of its ganglion-stimulating activity, and it may
first stimulate and then depress these systems. It can cause release of
epinephrine from the adrenal medulla by its nicotinic action. Locally
instilled into the eye, it mimics the effects of ACh, causing miosis
and a spasm of accommodation in which the ciliary muscle of the eye
remains in a constant state of contraction

 2. Therapeutic uses: Because of its high potency,
receptor nonselectivity, and relatively long duration of
action, carbacholis rarely used therapeutically except in
the eye as a miotic agent to treat glaucoma by causing
pupillary contraction and a decrease in intraocular
pressure. Onset of action for miosis is 10 to 20 minutes.
Intraocular pressure is reduced for 4 to 8 hours.
 3. Adverse effects: At doses used
ophthalmologically, little or no side effects occur due
to lack of systemic penetration (quaternary amine).

 D. Pilocarpine
 The alkaloid pilocarpine is a tertiary amine and is stable to
hydrolysis by AChE .Compared with ACh and its derivatives, it
is far less potent but is uncharged and will penetrate the CNS
at therapeutic doses. Pilocarpine exhibits muscarinic activity
and is used primarily in ophthalmology.
 1. Actions: Applied topically to the cornea,
pilocarpineproduces rapid miosis and contraction of the ciliary
muscle. When the eye undergoes this miosis, it experiences a
spasm of accommodation. The vision becomes fixed at some
particular distance, making it impossible to focus .[Note the
opposing effects of atropine, a muscarinic blocker, on the eye.
 Pilocarpineis one of the most potent stimulators of secretions
(secretagogue) such as sweat, tears, and saliva, but its use
for producing these effects has been
 limited due to its lack of selectivity. The drug is beneficial in
promoting salivation in patients with xerostomia resulting from
irradiation Dr. Mahmoud H. Taleb 46

 2. Therapeutic use in glaucoma:
 ***** Pilocarpineis used to treat glaucoma and is the
drug of choice in the emergency lowering of
intraocular pressure of both narrow-angle (or closed-
angle) and wide-angle (also called open-angle)
glaucoma. Pilocarpine is extremely effective in opening
the trabecular meshwork around Schlemm’s canal,
causing an immediate drop in intraocular pressure as a
result of the increased drainage of aqueous humor. This
action occurs within a few minutes, lasts 4 to 8 hours,
and can be repeated. The miotic action of pilocarpineis
also useful in reversing mydriasis due to atropine.
Dr. Mahmoud H. Taleb
47

 3. Adverse effects:
 Pilocarpinecan enter the brain and cause CNS
disturbances. Poisoning with this agent is characterized
by exaggeration of various parasympathetic effects,
including profuse sweating (diaphoresis) and salivation.
Parenteral atropine, at doses that can cross the
blood-brain barrier, is administered to counteract the
toxicity of pilocarpine

 Acetylcholinesterase is an enzyme that specifically cleaves
acetylcholine to acetate and choline and, thus, terminates its
actions. It is located both pre- and postsynaptically in the
nerve terminal, where it is membrane bound. Inhibitors
acetylcholinesterase indirectly provide a cholinergic action
by prolonging the lifetime of acetylcholine produced
endogenously at the cholinergic nerve endings. This results
in the accumulation of acetylcholine in the synaptic space
,These drugs can thus provoke a response at all
cholinoceptors in the body, including both muscarinic and
nicotinic receptors of the autonomic nervous system, as well
as at neuromuscular junctions and in the brain.

 A. Edrophonium
 Edrophonium is the prototype short-acting AChE
 inhibitor. Edrophonium binds reversibly to the active
center of AChE, preventing hydrolysis of ACh. It is
rapidly absorbed and has a short
 duration of action of 10 to 20 minutes due to rapid renal
elimination. Edrophoniumis a quaternary amine, and its
actions are limited to the
 periphery. It is used in the diagnosis of myasthenia gravis,
which is an autoimmune disease caused by antibodies
to the nicotinic receptor
 at NMJs. This causes their degradation, making fewer
receptors available for interaction with the neurotransmitter.
Intravenous injection of
 edrophoniumleads to a rapid increase in muscle strength.
Care must be taken, because excess drug may provoke a
cholinergic crisis (atropineis Dr. Mahmoud H. Taleb 50

 B. Physostigmine
 is a nitrogenous carbamic acid ester found naturally
in plants and is a tertiary amine. It is a substrate for
AChE, and it forms a relatively stable carbamoylated
intermediate with
 the enzyme, which then becomes reversibly
inactivated. The result is potentiation of cholinergic
activity throughout the body.
 1. Actions: Physostigminehas a wide range of
effects as a result of its action, and stimulates not only
the muscarinic and nicotinic sites of
 the ANS but also the nicotinic receptors of the NMJ. Its
duration of action is about 2 to 4 hours, and it is
considered to be a intermediate-acting agent.
Physostigminecan enter and stimulate the cholinergic
sites in the CNS Dr. Mahmoud H. Taleb 51

 2. Therapeutic uses: The drug increases intestinal
and bladder motility, which serve as its therapeutic action in
atony of either organ Placed topically in the eye, it produces
miosis and spasm of accommodation, as well as a lowering of
intraocular pressure. It is used to treat glaucoma, but pilocarpineis
more effective. Physostigmine is also used in the treatment of
overdoses of drugs
 with anticholinergic actions, such as atropine, phenothiazines,
and tricyclic antidepressants.
 3. Adverse effects:
 The effects of physostigmineon the CNS may lead
 to convulsions when high doses are used. Bradycardia and a fall
in cardiac output may also occur. Inhibition of AChE at the
skeletal NMJ causes the accumulation of ACh and, ultimately,
results in paralysis of skeletal muscle. However, these effects are
rarely seen with therapeutic doses

C. Neostigmine
Synthetic compound reversibly inhibits acetylcholinesterase, it does not
enter CNS, it has greater effect on skeletal muscle that can increase
contractility then paralysis.
Uses:
1.stimulate atonic bladder and intestine.
2.Antidote for neuromuscular blocking agents like tubocurarine.
3.Symptomatic treatment in myasthenia gravis.
Side effects:
Salivation, flushing, hypotension, nausea, abdominal pain, diarrhea,
and bronchospasm.

 Pyridostigmine and ambenomium are other
cholinesterase inhibitors that are used in the chronic
management of myasthenia gravis. Their durations of
action are intermediate (3 to 6 hours and 4 to 8 hours,
respectively), but longer than that of neostigmine. Adverse
effects of these agents are similar to those of neostigmine.

 Patients with Alzheimer's disease have a deficiency of
cholinergic neurons in the CNS. This observation led to
the development of anticholinesterases as possible
remedies for the loss of cognitive function.
 Tacrine [was the first to become available, but it has
been replaced by the others because of its
 hepatotoxicity. Despite the ability of donepezil
rivastigmine and galantamine to delay the progression
of the disease, none can stop its progression.
Gastrointestinal distress is their primary adverse effect.

Indirect-Acting Agents
 Cause skeletal muscle contractions
 Used for diagnosis and treatment of
myasthenia gravis
 Used to reverse neuromuscular blocking agents
 Used to reverse anticholinergic poisoning (antidote)
Examples: physostigmine, pyridostigmine

 A number of synthetic organophosphate
compounds have the capacity to bind covalently to
acetylcholinesterase.
 The result is a long-lasting increase in
acetylcholine at all sites where it is released.
Many of these drugs are extremely toxic and were
developed by the military as nerve agents.
Related compounds, such as parathion, are
employed as insecticides.

1. Mechanism of action: is an organophosphate that
covalently binds via its phosphate group to the
serine-OH group at the active site of AChE. Once this occurs,
the enzyme is permanently inactivated, and restoration of AChE
activity requires the synthesis of new enzyme molecules.
Following covalent modification of AChE, the phosphorylated
enzyme slowly releases one of its ethyl groups. The loss of an
alkyl group, which is called aging, makes it impossible for
chemical reactivators, such as pralidoxime, to break the bond
between the remaining drug and the
enzyme.

 2. Actions: Actions include generalized cholinergic
stimulation, paralysis of motor function (causing breathing
diffi culties), and convulsions. Echothiophate produces
intense miosis and, thus, has found therapeutic use.
Intraocular pressure falls from the facilitation of outfl ow
of aqueous humor. Atropine in high dosages can
reverse many of the muscarinic and some of the central eff
ects of
 echothiophate.
 3. Therapeutic uses: An ophthalmic solution of the
drug is applied
 topically to the eye for the chronic treatment of open-angle
glaucoma. Echothiophateis not a first-line agent in the
treatment of glaucoma. In addition to its other side effects,
the potential risk for causing cataracts limits its use

Acute intoxication must be recognized and
treated promptly . The dominant initial signs
are those of muscarinic excess: miosis,
salivation, sweating, bronchial constriction,
vomiting, and diarrhea. Central nervous
system involvement (cognitive disturbances,
convulsions, and coma) usually follows
rapidly, accompanied by peripheral nicotinic
effects resulted im muscle twitch and
convulsion.

(1) Maintenance of vital signs—respiration in
particular may be impaired;
 (2) Decontamination to prevent further
absorption—this may require removal of all
clothing and washing of the skin in cases of
exposure to dusts and sprays; and
 (3) Atropine parenterally in large doses, given
as often as required to control signs of
muscarinic excess.
 (4) Therapy often also includes treatment with
pralidoxime
 (5) Benzodiazepines administration of for
seizures Dr. Mahmoud H. Taleb 62

 Myasthenia gravis (MG)
 is a disease affecting skeletal muscle
 neuromuscular junctions. An autoimmune process causes
 production of antibodies that bind to the a subunits of the
 nicotinic receptor. This effect causes accelerated degradation
 of the receptor and blockade of ACh binding to receptors on
 muscle end plates. Frequent findings are ptosis, diplopia,
 difficulty in speaking and swallowing, and extremity weaknes
Severe disease may affect all the muscles, including those
necessary for respiration.

 The disease resembles the neuromuscular paralysis
produced by tubocurarine and similar nondepolarizing
neuromuscular
 blocking drugs. Patients with myasthenia are
sensitive to the action of curariform drugs and other
drugs that interfere with neuromuscular transmission
e.g., aminoglycoside antibiotics. Anti-ChEs are
extremely valuable as therapy
 for myasthenia. Almost all patients are also treated
with immunosuppressant drugs and some with
thymectomy. Edrophonium is used as a diagnostic
test in myasthenia gravis.

Cholinergic antagonists:
They are also called anticholinergic drugs or cholinergic
blockers, this group include:
1.Antimuscarinic agents ( atropine, ipratropium,
scopolamine).
2. Ganglionic blockers (mecamylamine, nicotine,
trimethaphan).
3. Neuromuscular blockers (atracutium, metocurine,
mivacurium, pancuronium, succinylcholine,
tubocurarine, and vecuronium

1-Antimuscarinic agents:
These agents block muscarinic
receptors and inhibit muscarinic
functions, they are useful in different
clinical situations, they have no
actions on skeletal neuromuscular
junctions or autonomic ganglia
because they do not block nicotinic
receptors.

A belladonna alkaloid has a high affinity for
muscarinic receptors, it is a competitive inhibito
of muscarinic receptors preventing ACH from
binding to that site.
Atropine is both central and peripheral muscarini
blocker, its action lasts about 4 hours, when use
topically in the eye its action lasts for days


1- Eye: It cause dilation of the pupil (mydriasis), unresponsiveness to light,
and cycloplegia (inability to focus for near vision), if used in patients with
glaucoma , it will cause dangerous elevation in IOP.
 2- Respiratory system: Bronchodilatation and reduce secretion.
3- CNS: Sedation, amnesia, at high doses cause agitation, hallucination,
and coma.
 4- GIT: Reduce motility so it is effective as antispasmodic.
5- Urinary system: Reduce motility and cause urine retention so used in
treatment of nocturnal enuresis in children, it dangerous to be used in
patients with benign prostatic hypertrophy due to its effect in producing
urine retention.

 6- CVS Its actions depend on the dose, at low dose
lead to bradycardia due to central activation of
vagus nerve, but recently this effect is due to
blockade of M1 receptors on the inhibitory
prejunctional neurons so increase ACH release.
At higher doses of atropine there will be blockade
of cardiac receptors on SA node and this will
increase heart rate (tachycardia), blood pressure
is not affected but at toxic doses atropine will cause
dilatation of cutaneous blood vessels.

 6-Secretions: It blocks the salivary
gland secretion and produce dry
mouth (xerostomia), blocks the
Lacrimal glands secretion and
cause eye dryness (xerophthalmia),
blocks the bronchial secretion, and
blocks the secretion of sweat gland
and increase body temperature


1- Antispasmodic agent: Relax GIT and bladder.
2- Mydriatic and cycloplegic agent in the eye to
permit measurement of refractive errors.
3-Antidote for cholinergic agonists: To treat
organophsphorus poisoning (present in insecticides),
and mushroom poisoning.
4- Antisecretory agent: To block the secretion of
upper and lower respiratory tracts prior to surgery.

 Dry mouth, blurred vision, tachycardia, and
constipation. On CNS restlessness,
confusion, hallucination, and delirium, this
may progress to circulatory and respiratory
collapse and death.
It is very risky in individuals with glaucoma
and BPH so careful history is required

 A belladdona alkaloid produce peripheral effects
similar to atropine, it has greater actions on CNS
and longer duration of action.
It is one of the most effective antimotion
sickness, it is effective also in blocking short
term memory, it produce sedation but at higher
doses cause excitement.


It is inhaled derivative of atropine useful in treating
asthma and COPD in patients unable to take
adrenergic agonist.
Other agents like homatropine, cyclopentolate, and
tropicamide used mainly in ophthalmology.

D. Tropicamide and cyclopentolate These agents are used
similarly to atropine as ophthalmic solutions for mydriasis and
cycloplegia. Their duration of action is shorter than that of
atropine. Tropicamideproduces mydriasis for 6 hours, and
cyclopentolatefor 24 hours.
E. Benztropine and trihexyphenidyl
These agents are centrally acting antimuscarinic agents that have
been used for many years in the treatment of Parkinson
disease. With the advent of other drugs they have been
largely replaced. However, benztropine and trihexyphenidyl are
useful as adjuncts with other antiparkinsonian agents to treat all
types of parkinsonian syndromes, including antipsychotic-induced
extrapyramidal symptoms. These drugs may be helpful in
geriatric patients who cannot tolerate stimulants.

F. Darifenacin, fesoterodine, oxybutynin, solifenacin,
tolterodine, and trospium chloride
These synthetic atropine-like drugs are used to treat overactive
urinary bladder disease. By blocking muscarinic receptors in the
bladder, intravesicular pressure is lowered, bladder capacity is
increased, and the frequency of bladder contractions is reduced.
Side effects of these agents include dry mouth, constipation, and
blurred vision, which limit tolerability of these agents if used
continually. Oxybutyninis available as a
transdermal system (topical patch), which is better tolerated
because it causes less dry mouth than do oral formulations, and
is more widely accepted with greater patient acceptance.

They act on nicotinic receptors of the autonomic
ganglia.
- They have no selectivity toward the
parasympathetic or sympathetic ganglia .
- The effect of these drugs is complex and
unpredictable so rarely used therapeutically, used
mainly in experimental pharmacology.
-

 Ganglionic blockers specifically act on the nicotinic
receptors of both parasympathetic and sympathetic
autonomic ganglia. Some also block the ion
 channels of the autonomic ganglia. These drugs show
no selectivity toward
 the parasympathetic or sympathetic ganglia and are not
effective as neuromuscular antagonists. Thus, these
drugs block the entire output of the autonomic
nervous system at the nicotinic receptor. Except for
nicotine, the other drugs mentioned in this category are
nondepolarizing, competitive antagonists. The
responses of the nondepolarizing blockers are
complex,

 A. Nicotine
A component of cigarette smoke, is a poison with
many undesirable actions. It is without therapeutic benefit and is
deleterious to health. Depending on the dose,
nicotinedepolarizes autonomic ganglia, resulting first in
stimulation and then in paralysis of all ganglia.
The stimulatory effects are complex and result from increased
release of neurotransmitter due to effects on both sympathetic
and parasympathetic ganglia. For example, enhanced release
of dopamine and norepinephrine may be associated with
pleasure as well as appetite suppression, the latter of which
may contribute to lower body weight. The overall response of
a physiological system is a summation of the stimulatory and
inhibitory effects of nicotine. These include increased blood
pressure and cardiac rate (due to release of transmitter from
adrenergic terminals and from the adrenal medulla) and
increased peristalsis and

Short acting competitive nicotinic ganglionic
blocker that must be given by i.v infusion, it is
used for the emergency lowering of the blood
pressure in hypertension caused by pulmonary
edema or dissecting aortic aneurysm when
other agents cannot be used.


 Competitive nicotinic blocker of the ganglia, the
duration of action 10 hours after single
administration.

Drugs that block cholinergic transmission between
motor nerve ending and the nicotinic receptors
on the neuromuscular end plate of the skeletal
muscle.
- They are structural analogs of ACH. They are
useful in surgery to produce complete muscle
relaxation to avoid higher anesthetic doses to
achieve similar muscular relaxation.

 They are of 2 types :
1- Antagonist (nondepolarizing type).
(isoquinoline derivative e.g. atracurium ,
tubocurarine ) or steroid derivative e.g.
pancuronium , vecuronium )
2- Agonist (depolarizing type) at the receptors
on the end plate of the NMJ ( e.g.
Succinylcholine ).

Non depolarizing ( competitive)
blockers:
mechanism of action:
At low dose: they combine with nicotinic
receptors and prevent binding with ACH so
prevent depolarization of muscle cell membrane

2. Actions: Not all muscles are equally sensitive to
blockade by competitive blockers. Small, rapidly
contracting muscles of the face and eye are most
susceptible and are paralyzed first, followed by the
fingers. Thereafter, the limbs, neck, and trunk
muscles are paralyzed. Next, the intercostal muscles
are aff ected, and, lastly, the diaphragm muscles are
paralyzed. The muscles recover in the reverse
manner,with the diaphragm muscles recovering first
and contracting muscles of the face and the eye
recovering last. Those agents that release histamine
(for example, atracurium) can produce a fall in blood
pressure, fl ushing, and bronchoconstriction.

Are adjuvant drugs in anesthesia during surgery
to relax skeletal muscles.

 Histamine release, ganglionic blockade and
hypotension.
 Postoperative muscle pain and hyperkaleamia .
 Increase IOP and intra-gastric pressure.
 Malignant hyperthermia.

◦ Cholinesterase inhibitors: They can overcome the effect
of nondepolarizing NM blockers at high doses.
◦ Haloginated hydrocarbone anesthetics: Enhance their
actions by exerting stabilizing action at the NMJ.
◦ Aminoglycoside antibiotics: Inhibit ACH release from
cholinergic nerves by competing with calcium ions, they
synergize with all competitive blockers and enhance the
blockade.
◦ Calcium channel blockers: Increase the effect of both
depolarizing and nondepolarizing agents.

Mechanism of action:
 Succinylcholine attach to nicotinic receptors and acts
like acetylcholine to depolarize NMJ.
 This drug persist at high concentration at synaptic cleft
and attach to the receptor for long time, it cause initially
opening of the sodium channel associated with the
nicotinic receptor which cause receptor depolarization
and this lead to transient twitching of the muscle
(fasciculation).
 The continuous binding of the agent to the receptor
renders the receptor incapable to transmit further
impulses, then there will be gradual repolarization as the
Na- channels will be closed and this causes resistance
to depolarization and a flaccid paralysis.

Initially produce short lasting muscle
fasciculation, followed within a few minutes by
paralysis.
The duration of action of acetylcholine is short
since it is broken rapidly by plasma
cholinesterase.

 1.Because its rapid onset of action and short
duration of action it is useful when rapid
endotracheal intubation is required during the
induction of anesthesia.
 2. Electroconvulsive shock treatment (ECT).
 Succinylcholine given by continuous i.v infusion
because of it is short duration on action ( due to
rapid hydrolysis by plasma cholinesterase).

 1- Hyperthermia: When halothane used as an
anesthetic, succinylcholine may cause malignant
hyperthermia with muscle rigidity and
hyperpyrexia in genetically susceptible individuals.
This treated by rapidly cooling the patient and by
administration of dantroline which blocks Ca
release and thus reduce heat production and
relaxing the muscle tone.
 2-Hyperkalemia: Succinylcholine increases
potassium release from intracellular stores. This
may be particularly dangerous in
 burn patients and patients with massive tissue
damage in which potassium has been rapidly lostDr. Mahmoud H. Taleb 93

3-Apnea: A genetically related
deficiency of plasma
cholinesterase or presence of an
atypical form of the enzyme can
cause apnea lasting 1-4 hours due
to paralysis of the diaphragm. It is
managed by mechanical
ventilation.

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