Download 1 Lecture Pharmacology Dr. nahlah Pharmacology of the Autonomic

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Lecture Pharmacology
Pharmacology of the Autonomic Nervous System
Lecture Outline
Dr. nahlah
16-10-2016
I. Introduction
II. Anatomy
III. Biochemistry
a. Neurotransmitters
b. Synthesis and storage
c. Release of acetylcholine
d. Termination of action of acetylcholine
IV. Acetylcholine Receptors
a. Muscarinic receptors
b. Nicotinic receptor
V. Cholinergic Agonists
a. Direct-acting cholinergic agonists.
b. Indirect-acting cholinergic agonists
VI. Cholinergic Antagonists
VII. Skeletal Muscle Relaxants
Learning Objectives:
1) An understanding of the clinical physiology of the cholinergic nervous system
a. Neurotransmitters involved in major central and peripheral neuronal pathways
b. Synthesis and metabolism of acetylcholine (Ach)
2) An understanding of muscarinic agonists and antagonists, and cholinesterase inhibitors
3) An understanding of agents that stimulate or relax skeletal muscle, including the
cholinergic neuromuscular agonists and antagonists.
I. Introduction
The nervous system controls all the major functions of the body. It is divided into
central and peripheral nervous systems. The peripheral nervous system includes the somatic
and autonomic nervous systems which control voluntary and involuntary functions
respectively. The ANS controls the vegetative functions of the body. These include functions
like circulation, respiration, digestion and the maintenance of body temperature.
Organization of the nervous system.
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II. Anatomy
Parasympathetic neurons: The parasympathetic preganglionic fibers arise
from cranial nerves III (oculomotor), VII (facial), IX (glossopharyngeal), and X (vagus),
as well as from the sacral region (S2 to S4) of the spinal cord and synapse in ganglia
near or on the effector organs. [Note: The vagus nerve accounts for 90% of
preganglionic parasympathetic fibers in the body. Postganglionic neurons from this
nerve innervate most of the organs in the thoracic and abdominal
cavity.
Schematic diagram of the sympathetic and parasympathetic divisions of the peripheral
autonomic nervous system
III. Biochemistry
a. Neurotransmitters
Acetylcholine (ACh) is the primary transmitter in all autonomic ganglia and at
the synapses between parasympathetic postganglionic neurons and their effector
cells. It is the transmitter at postganglionic sympathetic neurons to the
thermoregulatory sweat glands. It is also the primary transmitter at the somatic
(voluntary) skeletal muscle neuromuscular junction.
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Simplified summary of parasympathetic, sympathetic somatic innervations
b.
Synthesis and storage
Acetylcholine is synthesized in the nerve terminal by the enzyme choline
acetyltransferase (ChAT) from acetyl-CoA and choline ( rate-limiting step). ACh is
actively transported into its vesicles for storage.
c.
Release of acetylcholine—Release of transmitter stores from vesicles
requires the entry of calcium through calcium channels This interaction results in
fusion of the membranes of the vesicles with the nerve-ending membranes, the
opening of a pore to the extracellular space, and the release of the stored
transmitter.
d.
Termination of action of acetylcholine—
The action of acetylcholine in the synapse is normally terminated by
metabolism to acetate and choline by the enzyme acetylcholinesterase in the
synaptic cleft. Inhibition of acetylcholinesterase is an important therapeutic (and
potentially toxic) effect of several drugs.
Characteristics of transmitter synthesis, storage, release, and termination of action
at cholinergic nerve terminals
IV. Acetylcholine Receptors(cholinergic)
The most important classification depends on their responsiveness to the agonist drugs,
muscarine and nicotine.
a. Muscarinic receptors(M)
There are at least 5 subtypes of muscarinic receptors, referred to as M1, M2, M3, M4
and M5. However, only M1, M2, and M3 receptors have been functionally characterized
They mediate their effects through G proteins coupled to phospholipase C,or to potassium
channels.
b. Nicotinic receptor(N)
There are at least two subtypes of nicotinic receptors, referred to as NM and NN. The
NM receptor mediates skeletal muscle stimulation, while the NN receptor mediates
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stimulation of the ganglia of the autonomic nervous system.The nicotinic receptor
functions as a ligand-gated ion channel.
Actions of sympathetic and parasympathetic nervous systems on effector organs
V. Cholinergic Agonists
Drugs with acetylcholine-like effects (cholinomimetics) consist of 2 major subgroups
on the basis of their mode of action (ie, whether they act directly at the acetylcholine
receptor or indirectly through inhibition of cholinesterase). Drugs in the direct-acting
subgroup are further subdivided on the basis of their spectrum of action (ie, whether they
act on muscarinic or nicotinic cholinoceptors).
Subgroups of cholinomimetic drugs.
a. Direct-acting cholinergic agonists.
Cholinergic agonists mimic the effects of ACh by binding directly to cholinoceptors
(muscarinic or nicotinic). These agents may be broadly classified into two groups:
1) Choline esters, which include ACh and synthetic esters of choline, such as carbachol
and bethanechol.
2) naturally occurring alkaloids, such as nicotineand pilocarpine
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1) Choline esters
 Acetylcholine may be considered the prototype that acts directly at both muscarinic and
nicotinic receptors. . it lacks therapeutic importance because of its multiplicity of
actions (leading to diffuse effects) and its rapid inactivation by the cholinesterases. ACh
has both muscarinic and nicotinic activity
The pharmacological effects of acetylcholine.

Bethanechol
Is structurally related to ACh. It is not hydrolyzed by AChE due to the esterification of
carbamic acid. It lacks nicotinic actions but does have strong muscarinic activity. It has about
a 1-hour duration of action.
Therapeutic applications:
1) In urologic treatment, to stimulate the atonic bladder, particularly in
postpartum or postoperative, nonobstructive urinary retention.
2) Bethanechol may also be used to treat neurogenic atony as well as megacolon.
Adverse effects: Bethanechol causes the effects of generalized cholinergic stimulation
These include sweating, salivation, flushing, decreased blood pressure, nausea, abdominal
pain, diarrhea, and bronchospasm.

Carbachol (carbamylcholine)
Is an ester of carbamic acid Has both muscarinic and nicotinic actions. It is poor
substrate for AChE. It is biotransformed by other esterases, but at a much slower rate.
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.
Adverse effects: At doses used ophthalmologically, little or no side effects occur due to lack
of systemic penetration (quaternary amine)
2) naturally occurring alkaloids:
 Pilocarpine
The alkaloid pilocarpineis 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 can penetrate the CNS
at therapeutic doses. It exhibits muscarinic activity
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Therapeutic uses:
1- In glaucoma:
- Pilocarpine is the drug of choice in the emergency lowering of intraocular pressure
of both narrow-angle and wide-angle glaucoma.
2- Pilocarpine available as tablet used for treatment of xerostomia (dry mouth),
a- After irradiation of head & neck.
b- Sjogren's syndrome.
Actions of pilocarpine and atropine on the iris and ciliary muscle of the eye.
Adverse effects:
 blurred vision
 night blindness
 brow ache.
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
b.
Indirect-acting cholinergic agonists (Anticholinesterase Agents)
AChE is an enzyme that specifically cleaves ACh to acetate and choline. Inhibitors of
AChE (anticholinesterase agents or cholinesterase inhibitors) indirectly provide a cholinergic
action by preventing the degradation of ACh. This results in an accumulation of ACh in the
synaptic space.
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a- Indirect acting Cholinesterase inhibitor, Reversible:
1- Short acting:
Edrophonium: Used parentrally ( by injection).
- Short duration of action (10-20 minutes).
Therapeutic uses:
1- Drug of choice for diagnosing Myasthenia gravis (MG).
2- Used to differentiate M.G (which is weakness due to sever disease or inadequate
anticholinesterase treatment) from cholinergic crisis (which is weakness due to over
treatment with anticholinesterase).
2- Intermediate & long acting:
 Physostigmine
Its duration of action is about 30 minutes to 2 hours, and it is considered an
intermediate-acting agent. Physostigminecan enter and stimulate the cholinergic sites in the
CNS.
Therapeutic uses:
1) The drug increases intestinal and bladder motility, which serves as its therapeutic
action in atony of either organ.
2) Physostigmineis also used in the treatment of overdoses of drugs with
anticholinergic actions, such as atropine.
Adverse effects:
 on 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.

Neostigmine
It is more polar, is absorbed poorly from the GI tract, and does not enter the CNS. Its
effect on skeletal muscle is greater than that of physostigmine.
Therapeutic uses:
1) To stimulate the bladder and GI tract.
2) Antidote for competitive neuromuscular-blocking agents.
3) To manage symptoms of myasthenia gravis.
Adverse effects:




salivation, flushing, decreased blood pressure
nausea, abdominal pain, diarrhea
Bronchospasm
Neostigmineis contraindicated when intestinal or urinary bladder obstruction is
present.
 Pyridostigmine and ambenonium
Used in the chronic management of myasthenia gravis. Their durations of action are
intermediate (3 to 6 hours and 4 to 8 hours, respectively)
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- Indirect acting Cholinesterase inhibitor, Reversible used to treat Alzheimer’s disease :
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 others
because of its hepatotoxicity.
Donepezi, Rivastigmine, and galantamine: Despite the ability to delay the
progression of Alzheimer’s disease, none can stop its progression.
adverse effect: GI distress.
b- Indirect acting Cholinesterase inhibitor, Irreversible (Very long acting):

Isoflurophate & Echothiophate - These drugs are used topically in the eye for the
chronic treatment of open-angle glaucoma. The effects may last for up to one week
after a single administration.

A number of synthetic organophosphate compounds. Used in agriculture or pesticides
& insecticides.
Many of these drugs are extremely toxic & were developed by the military as nerve
gases. Of these substances GA (Tabun); GB (Sarin) and GD (Soman) called Nerve gases,
although they are volatile liquids.

Poisoning with Cholinesterase inhibitors
(Organophosphorous poisoning)
Mechanism of action:
- An organophosphate that covalently binds to a serine-OH at the active site of Achesterase.
Once this occurs, the enzyme is permanently inactivated, and restoration of Achesterase
activity (recovery) requires the synthesis of new enzyme molecules, this process may take
weeks, although clinical recovery is usually evident within days.
Clinical Features of Organophosphorous poisoning:
1- Excessive salivation, nausea, vomiting. abdominal cramps, diarrhea & lacrimation.
2. Excessive bronchial secretion, bronchoconstriction, cough, wheezing and dyspnea.
3. Bradycardia.
4. Involuntary micturation.
5. Sweating .
6. Muscle weakness, twitching.
7. Meiosis (small size pupil) , anxiety, headache, convulsion, respiration failure.
- Death is due to actions on CNS, paralysis of respiratory m. and excessive bronchial
secretion & constriction.
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Treatment of Organophosphorous poisoning:
1. Maintenance of vital respiration sings .
2. Decontamination to prevent further absorption by removal of the clothes , washing of the
skin .
3. Atropine (antimuscarinic drug) parenterally in large doses (atropine dose is l-2mg I.V.
every 15-60 min , until sings of effect appear: (dry mouth & heart rate in excess of' 70
beats/min).
4. Because atropine has antimuscarinic effect only, so not block N-M junction which has
nicotinic receptors, therefore Mechanical ventilation may be needed to assist respiratory
muscle.
5. Diazepam for convulsions if present.
6. Atropine eye drops may relieve headache caused by meiosis.
7. Reactivation of acetylcholinesterase:
- Pralidoxime (PAM) this can reactivate the inhibited Achesterase, because it has a very high
affinity for the phosphorus atom, that allows it to displace the organophosphate ( so it
hydrolyze the phosphorylated Achesterase enzyme) and regenerates the this enzyme.
-These substances hasten the destruction of accumulated Ach and unlike atropine, they have
both antimuscarinic and antinicotinic effects.
- The best result obtained if received within 12 hours of the poisoning, but muscle power
may improve within 30 minutes.
VI. Cholinergic Antagonists
Classifications of Anticholinergic Drugs;
Antimuscarinic Drugs:
They are divided into:
I- Tertiary amine: Alkaloid esters of tropic acid.
1- Atropine (hyoscyamine) is found in the plant (Atropa belladonna).
prototype.
2- Hemoatropine: Semi synthetic.
3- Scopolamine.
II- quaternary amine: Semi synthetic & synthetic.
- They have been developed to produce more peripheral effects with decrease CNS effect.
Include: Propantheline , Ipratropium , Clidinium bromide.
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Pharmacokinetic of antimuscarinic drugs:
- It is absorbed from GIT, mucus membrane , skin and eye . Belladonna alkaloid cross blood
brain barrier (BBB) .
- Scopolamine has greater effect on CNS & eye than atropine.
- Atropine has greater effect on heart, intestine, bronchi and urinary tissue than scopolamine
when absorbed.
Mechanism of Action of Atropine:
- Atropine has a high affinity for muscarinic receptors, where it binds competitively &
reversiblely, preventing Ach from binding to that site.
- It is stimulating or depressing depend on target organs and dose. Also depend on disease.
- Atropine is both a central and peripheral muscarinic blocker.
- Its general actions last about 4 hours except when placed topically in the eye, where the
action may last for days.
Actions of Atropine:
1- CNS:
- Normal dose has minimal stimulant effect and slow sedation.
Notes:
- Atropine opposes the effects of all cholinergic drug on the CNS, at postganglionic
cholinergic N-endings & on the peripheral blood vessels.
- It does not oppose cholinergic effects at the N-m junction or significantly at the autonomic
ganglia.
a- Mydriasis (dilated pupil): By blocking the MR in papillary muscle.
b- Cycloplegia: By weakening the contraction of ciliary M
loss of ability to
accommodate for near vision.
c- Reduction of lachrymal secretion (dry or sandy eyes).
d- Increase intraocular pressure (IOP) ? due to dilated iris blocking drainage of IO fluid from
angle of anterior chamber (serious in elderly).
3- On CVS :
- Atropine produces divergent effects on the CVS, depending on the dose.
a- At low doses the predominant effect is a decreased cardiac rate (bradycardia) due to central
vagal nerve activation.
b- At higher doses, the cardiac receptors on the SA node are blocked, and the cardiac rate
increases modestly (tachycardia).
Note: Atropine has no significant effect on peripheral blood vessels in therapeutic dose but
with poisoning, there is marked vasodilatation.
4- On Respiratory : bronchial dilatation , decrease secretion.
5- Gastrointestinal (GlT):
a- Antispasmodic to reduce activity of the GlT.
b- Block salivary gland leading to drying of oral mucosa (xerostomia).
6- On GUT: smooth muscle of ureter , bladder wall are relaxed and urination is slowed.
7- Exocrine glands secretions: All decrease (except Milk), causing dry mouth, dry eyes, dry
skin (inhibit sweating), bronchial secretion decrease & become viscid.
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Poisoning with Atropine:
Features:
- Dry mouth with dysphasia.
- Mydriasis, blurred vision.
- Hot flushes , dry skin with hyperthermia (CNS effect - absence of sweating).
- Restlessness ,anxiety, excitement hallucinations, delirium, mania.
- The cerebral excitation is followed by depression and coma.
Treatment:
- By giving activated charcoal to adsorb the drug, diazepam for excitement.
Clinical uses of antimuscarinic agents:
1. On CNS:
a- Benzhexol ,orpheradrine, against rigidity and tremor in parkinsonism.
b- Hyoscine, promethazine, as antiemetic.
c- Hyoscine prevent or reduce motion sickness.
2. Ophthalmologic disorders:
- Antimuscarinic used in cases that need mydriasis with cycloplagia or prolonged action
(Atropine, Homotropine, and Cyclopentolate) .
-Tropicamide is the short acting mydriatic drug.
3. Respiratory disorder:
a. Preoperative: To decrease bronchial secretion & spasm by preanesthetic injection of
atropine or scopolamine (scopolamine cause amnesia for events associated with surgery).
b- Ipratropium is useful in the treatment of asthma and COAD in patients unable to take
adrenergic agonists.
- New drug (Tiotropium) a long acting quaternary aerosol (by inhalation) antimuscarinic
drug.
4. CVS disorders:
a. Atropine used parenterally in Myocardial infarction (MI) because it block reflex
vagal stimulation (bradycardia) accompany pain (of inferior MI) .
b. Atropine used to treat sinus bradycardia and particularly useful when the arrhythmias
result from anesthetic , cholinesters and succinyl choline.
5. GIT disturbances:
a. Antispasmodic for treatment of spastic condition of the GIT because it lead to relaxation of
smooth muscle, propantheline,
- Hyosine butyl bromide (Buscopan) effective relaxant of the sm.m .
b- Peptic ulcer : M1 inhibitor (Pirenzepine, Telenzepine).
c- In preanesthesia they reduce salivation and gastric secretion.
d- Hyoscine, promethazine, as antiemetic.
6. Urinary disorders:
- Flavoxate, propantheline & oxybutynin, are used to relievesmooth muscle-spasm
accompanying infection in cystitis and for detrusor instability.
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7. Atropine used as antidotes to cholinergic and anticholinesterase agent, it is drug of
choice to treat poisoning from organophosphate pesticides.
- Its also used to block muscarinic effects due to cholinergic drugs such a Neostigmine are
used.
II- quaternary amine: Semi synthetic & synthetic drugs.
- They have been developed to produce more peripheral effects with decrease CNS effect.
1- Clidinium bromide: It is derivative of belladonna alkaloid used in treatment of gastric
disorders.
- Sometimes combine with chlordiazepoxide (librax).
2- Propantheline (Duspataline):
a. Used to relief from symptoms in patients with
irritable bowel syndrome (IBS),
pancreatitis, gastritis, diverticulitis, colitis .
b. As antispasmodic for ureter and urinary bladder.
3- Ipratropium: It is useful in the treatment of asthma and COAD in patients unable to take
adrenergic agonists.
Adverse effect of antimuscarinic drugs:
In the infants even ordinary dose could result in antimuscarinic fever, while in adults it
depends on the dose :
1. Small dose: decrease salivation , decreased bronchial secretion, decrease sweating .
2. medium dose: pupil dilation visual accommodation decreased and heart rate is increased.
3. Largest dose: inhibition to the urination and intestinal motility and this is followed by
decrease in gastric section and motility.
4. over dose: all above are exaggerated , with CNS excitation , restlessness , irritability and
hallucination.
Contraindication of antimuscarinic agents:
1. glaucoma.
2. In elderly men should be used in caution and should be avoided in those have history of
prostatic hyperplasia .
3. Because atropine slow gastric empting , they increase symptoms in patient with peptic
ulcer .
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Nicotinic antagonists
1- Ganglion blocking agent: Trimethaphan
2- Neuromuscular Blocking Drugs:
a- Non Depolarizing Competitive N-M blocking agents:
Tubocurarine, Pancuronium, Atracurium,
b- Depolarizing Non competitive N-M blocking agents
Suxamethonium (Succinylcholine).
1- Ganglion blocking agent:
- Hexamethionin, mecamylamine and other ganglion-blockers were extensively used in the
treatment of hypertension.
- But unfortunately, the adverse effect of ganglion blocked are so sever (both sympathetic and
parasympathetic divisions are blocked), that patients are unable to tolerate long term
treatment with them
Trimethaphan:
- It is the only Ganglion-blocker still in clinical use. Its poorly lipid soluble.
Inactive orally
and has a short half-life.
- It is used I.V to treat sever accelerated hypertension (malignant hypertension).
Note: As ganglion-blocking agents interrupts sympathetic control of venous-pooling, postural
hypotension is the result.
2- Neuromuscular Blocking Drugs:
- These drugs are important for producing complete sk-m relaxation in surgery, by specific
blockade of the N-M junction.
-They enable light level of anesthesia to be employed with adequate relaxation of the muscles
of the abdomen and diaphragm.
- They also relax the vocal cords and allow the passage of a tracheal tube.
Note: Patients who have received a M-relaxant should always have their respiration assisted
or controlled until the drug have been inactivated or antagonized.
a. Non Depolarizing competitive N-M blocking agents
Action:
- Drugs of this group cause N-M block by competing with Ach at the receptor site at the N-M
junction so prevent depolarization of muscle cell membrane and inhibit muscle contraction so
causing complete SK- M relaxation.
PK: Most non depolarizing agent have relatively long t1/2 ranging from 20 min to several
hours.
- These drugs are given parentally (by injection).
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Tubocurarine
- Is the prototype it produces a competitive block at the endplate causing flaccid paralysis
lasts 30-60 min.
- Tubocurarine blocks autonomic ganglia and causes an initial transient drop in blood pressure
and cause histamine release which may induce bronchospasm.
Note: The action of competitive N-M blocking agent is antagonized by anticholinesterases,
Neostigmine is usually given I.V , preceded by atropine to prevent the parasympathetic
autonomic effect of Neostigmine (bradycardia and salivation).
b. Depolarizing Non competitive N-M blocking agents
Suxamethonium (Succinylcholine)
Mechanism of action:
- It attaches to the nicotinic receptors and acts like Ach to depolarize the N-M junction.
- Unlike acetylcholine, which is instantly destroyed by Achesterase, the depolarizing agent
persists at high concentrations in the synaptic cleft, remaining attached to the receptor for a
relatively long time, & providing a constant stimulation of the receptor.
- Initially produces short-lasting muscle fasciculation, followed within a few minutes by
paralysis.
- The drug does not produce a ganglionic block, except in high doses, although it does have
weak histamine-releasing action.
- Normally, the duration of action of succinylcholine is extremely short (Total paralysis last
up to 4 min)
*It is particularly useful (used) for brief procedures such as tracheal intubations or
electroconvulsive therapy (ECT).
PK of Suxamethonium (succinylcholine):
- Succinylcholine is injected intravenously.
- Unlike the non depolarizing muscle relaxants its action cannot be reversed.
- Its brief duration of action (several minutes) results from rapid hydrolysis by plasma pseudo
cholinesterase.
- It is hydrolyzed by plasma pseudo cholinesterase and its persistence in the body is increased
by :
1- Neostigmine, which inactivate that enzyme.
2- In patient with hepatic disease or sever malnutrition, whose plasma concentration of
enzyme may be lower than normal.
3- Procaine and amethocaine also are destroyed by this enzyme and so by competing with
suxamethonium for the enzyme, may prolong its action.
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4- There are persons with hereditary defects in amount or kind of enzyme, who cannot
destroy the drug as rapidly as normal, so paralysis (Apnea) then lasts for hours.
- Here treatment consist of ventilation until recovery, and may need fresh blood
transfusion.
Adverse effects of Succinylcholine:
1- Hyperthermia: When halothane is used as an anesthetic, administration of
succinylcholine has occasionally caused malignant hyperthermia (with muscular rigidity and
hyperpyrexia) in genetically susceptible people.
- Treated by rapidly cooling the patient and by administration of dantrolene ?..
2- Apnea: A genetically related deficiency of plasma cholinesterase or presence of an
atypical form of the enzyme can lead to apnea due to paralysis of the diaphragm.
3- Cardiovascular:
a- Repeated injections of suxamethonium can cause bradycardia and even cardiac arrest these
probably due to activation of cholinoceptors in the heart and this can be prevented by
atropine.
b- It causes release of K from muscle which can be enough to cause cardiac arrest in patients
with already hyperthermia.
4- Muscle pain lasting 1-3 days due to muscle fasciculation preceded the paralysis by
Suxamethonium.
- The pain can largely prevented by preceding succinylcholine with a small dose of a
competitive N-M blocking agent (tubocurarine).
5- High dose can stimulate the uterus and can cause premature labor in pregnant.
Contraindication of succinylcholine:
1- Hypersensitivity to suxamethonium,
2- Severe liver disease.
3- Burned patient.
4- Pregnancy.
Uses of N-M blocking Drugs:
- These drugs are important for producing complete skeletal muscle relaxation in surgery
(main use).
Other uses:
1- Control Ventilation:
- In respiratory failure due to obstructive airway disease.
2- Treatment of convulsion:
- By decrease peripheral manifestation of convulsion (As these drugs not cross BBB so has no
effect on the central processes involved).