ANATOMY, PHYSIOLOGY OF
ANATOMY OF THE
MOTOR UNIT: a motor neuron innervates a muscle
dividing into many nerve fibers each of which supplies 1
muscle fiber. the combination of motor neuron & the
muscle fiber it innervates is a motor unit.
SYNAPSE: is the area on the nerve lying closets to the
muscle cell, situated opposite a specialized area of the
muscle cell called endplate. The synaptic cleft is only
MOTOR ENDPLATE: is a small specialized area of the
muscle that is rich in Ach receptors. The surface of the
muscle at the endplate is deeply folded with many
ridges & secondary clefts. The ridges have high
concentration of Ach receptors on the crest of their folds.
There are 1-10 million receptors at the endplate.
The NMJ consists of prejunctional motar nerve
ending separated from a highly folded
postjunctional membrane of the skeletal muscle
fiber by a synaptic cleft that is 20-30 nm wide &
filled with extracellular fluid.
The nonmyelinated nerve endings contains
mitochondria,endoplasmic reticulum, and synaptic
vesicles necessary to synthesize the
The resting membrane potential of approx -90 mv
across nerve and skeletal muscle membranes is
maintained by the unequal distribution of potassium
and sodium ions across the membrane.
ANATOMY OF NMJ (CONT..)
The NMJ contains 3 types of nicotinic cholinergic
receptors:- 2 are postsynaptic on the skeletal
muscle surface, 1 junctional and the other
extrajunctional-and one is presynaptic on the nerve
The extrajunctional are not involved in the normal
neurotransmission but may proliferate if the skeletal
muscle is diseased, damaged, or denervated.
The postsynaptic receptors are concentrated on the
junctional folds, immediately opposite the sites on
the nerve endings where Ach is released.
The neurotransmitter at the NMJ is quaternary
ammonium ester acetylcholine. Ach in motor nerve
ending is synthesized by the acetylation of choline under
the control of enzyme choline acetylase.
Ach is stored in synaptic vesicles in the motor nerve
endings and released into the synaptic clefts as packets
(quanta) each of which contain atleast 1000 molecules
The amount of acetylcholine released by each nerve
impulse is large, at least 200 quanta of about 5000
molecules each, and the number of AChRs activated by
transmitter released by a nerve impulse is also large,
about 500,000 molecules.
There seem to be two pools of vesicles that release
acetylcholine, a readily releasable pool and a
reserve pool, sometimes called VP2 and VP1,
Arrival of nerve impulse causes the opening of
calcium channels & Ca enters the nerve terminal &
there is Ca dependant synchronous release of
hundreds of quantas of Ach that bind to nicotinic
cholinergic receptors on the postsynaptic
membrane causing a change in the membrane
permeability to ions.
Ach receptors bind to the pentameric complex & induce a
conformational change in the proteins of the alpha subunits
which open the channel & K ion leaks outside whereas Na
ion moves inside.
Inside the cell the resting membrane potential is -90mv.Na
ions are attracted to the inside of the cell which induces
depolerization. Once the threshold of -50mv is reached
voltage gated Na channels on the sarcolemma are opened
& allow the flow of Na ions into the muscle. This increases
the rate of depolerization forming AP that passes around the
whole sarcolemma causing muscle contraction.
In the absence of AP, quanta of Ach are released randomly
producing miniature endplate potentials of <1mv that are
insufficient to trigger depolerization of the skeletal muscle
NERVE ACTION POTENTIAL
Nerve signals are transmitted by action potentials which
are rapid changes in the membrane potential.
Resting stage: before the action potential. The
membrane is said to be polerised because of large
negative memb potential that is present.
Depolerization stage: the memb becomes permeable to
Na ions allowing a large no of positively charged Na
ions to flow into the interior of the axon.The normal
polerised state of -90mv is lost & potential rises rapidly
in the positive direction, this is called depolerisation.
NERVE ACTION POTENTIAL
Repolerization stage: within a few seconds after the
membrane has become permeable to Na ions the
Na channel begins to close& K channel open more
than they normally do. The rapid diffusion of K ions
to the exterior re-establishes the normal negative
resting membrane potential.
. A, THE
ION CHANNEL IS INACTIVE AND DOES NOT OPEN IN THE ABSENCE OF ACETYLCHOLINE.
BINDING OF ONE ACETYLCHOLINE MOLECULE (FILLED CIRCLE) TO ONE OF TWO BINDING
SITES DOES NOT OPEN THE CHANNEL.
SITES OF BOTH Α-SUBUNITS
C, WHEN ACETYLCHOLINE
SIMULTANEOUSLY (FILLED CIRCLES),
BINDS TO THE RECOGNITION
A CONFORMATION CHANGE IS
TRIGGERED THAT OPENS THE CHANNEL AND ALLOWS IONS TO FLOW ACROSS THE MEMBRANE
It is speculated that nerve AP activates adenylate cyclase in
membranes of nerve terminals leading to formation of cyclic
adenosine monophosphate (cAMP).cAMP subsequently
opens Ca ion channels causing synaptic vesicles to fuse with
nerve membrane & release Ach.
Situated in close proximity is enzyme acetylcholinesterase.
Acetylcholinesterase at the junction is the asymmetric or A12form protein made in the muscle, under the end plate. It is a
type B carboxylesterase enzyme. There is a smaller
concentration of it in the extrajunctional area.
The enzyme is secreted from the muscle but remains attached
to it by thin stalks of collagen fastened to the basement
membrane This enzyme is responsible for the rapid hydrolysis
of Ach in <1ms to acetic acid & choline.
Choline then re-enters motor nerve endings to again
participate in the synthesis of new Ach.
Postjunctional membranes contain 2types of
receptors- junctional and extrajunctional , nicotinic
cholinergic receptors are largely present on the
Postjunctional nicotinic cholinergic receptors are
glycoproteins with mol.wt of 25,0000 daltons. Each
receptor consists of 5 subunits that are arranged
concentrically and designated alpha, beta, gamma
,delta & e.There are 2 alpha subunits and these
receptors are concentrated on the shoulders of
postjunctional membrane folds which places them
precisely opposite prejunctional release sites for
NICOTINIC RECEPTORS CONT..
Nicotinic cholinergic receptors extend throughout
the skeletal muscle membrane and approx 2nm into
the cytoplasm. The subunits of the receptor are
assembled like barrel staves into cylindrical
receptors which has a central funnel shaped core,
so as to form a channel to allow the flow of ions
along a concentration gradient.
Each NMJ contains millions of postjunctional
receptors & a burst of Ach from the nerve ending
open atleast 400,000 recptors. As a result sufficient
flow through these receptors to depolarize the
endplate to create AP.
EXTRAJUNCTIONAL & PREJUNCTIONAL
They are not present in large numbers as their
synthesis is supressed by neural activity. Whenever
motor nerve are less active due to trauma or
denervation they proliferate
The prejunctional receptors differ from the
postjunctional nicotinic receptors in 1) chemical
binding characteristics 2) the nature of the ion
channel they control 3) their preferential blockade
during high frequency stimulation.
ACTIONS OF DPMR & NDMR
Classic Actions of Nondepolarizing Muscle Relaxants :
Neurotransmission occurs when acetylcholine released by the
nerve action potential binds to AChRs. All NDMRs impair or
block neurotransmission by competitively preventing the
binding of acetylcholine to its receptor. The final outcome (i.e.,
block or transmission) depends on the relative concentrations
of the chemicals and their comparative affinities for the
Classic Actions of Depolarizing Muscle Relaxants
Depolarizing relaxants, at least initially, simulate the effect of
acetylcholine and can therefore be considered agonists
despite the fact that they block neurotransmission after initial
stimulation. Structurally, succinylcholine is two molecules of
acetylcholine bound together. It binds to the receptor , open
the channel, pass current, and depolarize the end plate.
It is an NM disorder affecting the NMJ & it is characterized by
impaired neuromuscular transmission & muscle
weakness.Prevalence is 1/20000-30000. F/M ratio is 6:4.
Age: any age Most patients have circulating autoantibodies
to the postsynaptic nicotinic Ach receptors. A thymoma is
found in approx 10% of patients & hyperplasia of the thymus
is found in young patients, although the precise etiology is
Features : weakness on exertion that improves with rest.
Ocular, bulbar & facial muscles are commonly involvedptosis, reduced facial expression,dysarthria & dysphagia.
Limb weakness, when present is usually proximal,
& weakness of the small muscles of the hand may
Myasthenia may be unmasked by anesthesia
which may result in hypoventilation or apnoea
Treatment: *oral anticholinesterases-pyridostigmine
*Immunosupression-corticosteriods or azathioprine
*Thymectomy – young onset, Ab positive pt,
IMPLICATIONS FOR ANESTHESIA:
Increased sensitivity to non-depolerizing muscle
Resistance to depolerizing muscle relaxants
Increased sensitivity to neuromuscular effects of
Risk of aspiration with bulbar weakness
Risk of postop resp failure with resp muscle wkn
Risk of cholinergic crisis with excessive doses of
Effects of immunosupressant therapy.
Anaesthesia : the management of anesthesia depends on
severity of disease, type of surgery & need of muscle
relaxants. A short acting non-depolerizing muscle relaxant
administered in increments or by infusion with careful
monitoring of the neuromuscular blockade is advised for
patients in whome muscle relaxation is deemed necessary.
Many surgical procedures like thymectomy may be
performed without the use of muscle relaxants & this may
facilitate early extubation.
Volatile agents specially isoflurane,decrease the availability
of Ach at the NMJ & potentiate the effects of nondepolerising muscle relaxants.sevoflurane is rapidly
eliminated & is probably the volatile agent of choice.
NMJ- MYASTHENIA GRAVIS
Maintenance of anesthesia with propofol has the
advantage of avoiding the neuromuscular effects of
volatile agents,& in combination with thoracic
epidural analgesia has been reported to reduce the
requirement of post-op ventilatory support after
Cautious use of other respiratory depressants like
opiates is recomended. Non-opiate analgesics &
local analgesic should be used wherever
possible.Neostigmine should be used cautiously
because of its risk of precipitating cholinergic crises
.All patients of MG should be monitered closely &
some may require ventilatory support post-op.
NMD- MULTIPLE SCLEROSIS..
Multiple sclerosis (MS) is an autoimmune disorder
characterized by T-cell–mediated autoantibodies
against myelin and a subsequent inflammatory
response within the central nervous system (CNS:
brain and spinal cord). Thus, MS is a disorder of the
myelinated part of the axon that leads to secondary
nerve conduction failure. The disease affects mainly
women, primarily between 20 and 40 or 45 and 60
years of age. Although the etiology is unknown, it
has been speculated that MS is caused by
environmental factors combined with a genetic
Patients with MS frequently report paresthesias, muscle
weakness, and sensory disturbances. Typically, there is a
localized or, late in the course of disease, generalized
muscle weakness with the legs affected more than the
In severe cases, respiration may be involved with the
development of hypoxemia. Diplopia and other cranial
nerve–dependent impairments are early and frequent
signs, along with sensory abnormalities and sometimes
disturbed bowel and bladder function.
As a rule, symptoms are closely related to the site
affected within the CNS, and the amount of symptoms is
related to the extent of sclerosing CNS plaque. Notably,
MS can be associated with impaired autonomic function,
which may lead to adverse reactions to sympathomimetic
Diagnosis of MS is currently based on a combination of
clinical and laboratory tests, including cerebrospinal fluid
(CSF) antibody analysis and radiology (detection of CNS
plaque by magnetic resonance imaging). Medication
consists of various combinations of immunosuppression
Its speculated that general anesthesia& surgery may
increase the risk for aggravation of MS. Patients should
therefore be informed of the potential for aggravated
symptoms in the postoperative period. In general,
preoperative chronic immunosuppressive medication
should be continued during the perioperative period.
Patients with MS are sensitive to physical (pain, fever,
infection) and emotional stress, which makes it more
likely that symptoms will be intensified in the
Great care must be exercised to minimize changes in
body temperature, fluid homeostasis, and central
hemodynamics (preload, afterload) and to maintain
respiration. Although intravenous induction agents
and volatile anesthetics have been used safely, it is
wise to avoid administering depolarizing
neuromuscular blocking drugs to MS patients. MSinduced denervation or misuse myopathy may lead to
a risk for succinylcholine-induced hyperkalemia,
which can result in fatal cardiac arrhythmias
Use of nondepolarizing NM blockers appears to be
safe. Regional anesthesia, including epidural
application of low concentrations of local anesthetics,
has been used in MS patients. Spinal anesthesia
exacerbates symptoms in MS and is therefore not
recommended for MS patients by most authorities.
The need for postoperative care is dependent on the
preoperative symptoms, type of surgery, and status of
the patient at the end of the surgical procedure. In this
context, MS patients with severe weakness and
respiratory distress, including pharyngeal dysfunction,
may need extended postoperative care, such as
respiratory support and intense physiotherapy.
MOTOR NEURON DISORDERS
Motor Neuron Disorders
Motor neuron disorders involve either the upper or
the lower motor neurons of the cerebral cortex,
brainstem, and spinal cord. Some forms are mixed,
whereas others have predominately upper or lower
motor neuron involvement. Amyotrophic lateral
sclerosis (ALS) is the most common disease within
this group and involves both upper and lower motor
neurons. Other examples of motor neuron disease
are Kennedy's disease (spinobulbar muscular
atrophy), Friedreich's ataxia (mixed upper and lower
motor neurons), and spinal muscular atrophy (lower
MOTOR NEURON DISORDERS
ALS is characterized by progressive and variable
loss of motor neurons within the cerebral cortex,
medullary nuclei of cranial nerves, and nuclei of the
ventral horn in the spinal cord. Degenerative loss of
these neurons leads to progressive muscle
weakness, muscle atrophy, and loss of neuronal
mass in these locations. Sensory functions,
including intellectual capacity and cognition, as well
as bowel and bladder function, are not usually
affected in ALS.
ALS has an incidence of about 2 in 100,000, and
onset of the disease is around 40 to 50 years of
age, with males affected more than females
MOTOR NEURON DISORDERS
Most cases are sporadic, but rare familial forms) do exist.
The underlying mechanism of motor neuronal death are
unclear, but it has recently been suggested that
superoxide dismutase mutations may have a key role in
the increased formation of free radicals seen in subsets
The diagnosis is made by electrophysiology
(electromyography [EMG] and electroneurography) and
by neurologic examination, which demonstrates early
spastic weakness of the upper and lower extremities,
typical subcutaneous muscle fasciculations, and bulbar
involvement affecting pharyngeal function, speech, and
the facial muscles. No curative treatment is currently
available, and patients are therefore treated
MOTOR NEURON DISOREDERS
Bulbar involvement in combination with respiratory
muscle weakness leads to a risk for aspiration &
pulmonary complications. Notably, these patients may
have increased sensitivity to the respiratory
depressant effects of sedatives and hypnotics.
Succinylcholine should be avoided because of the risk
for hyperkalemia as a result of denervation and
Nondepolarizing NM blocking agents may cause
prolonged and pronounced NM blockade & hence
should be used with great caution.
General anesthesia combined with epidural anesthesia
has been used without complications
GUILLAIN BARRE SYNDROME
Guillain-Barré syndrome (GBS) is an acute
inflammatory polyneuritis caused by an immunologic
reaction.The etiology is unknown, in many cases a
timely association with a viral (influenza-like) or
bacterial infection or even lymphomatous disease
can be demonstrated.
Symmetric peripheral flaccid muscle weakness and
sensory loss develop. The lower extremities are
affected first, after which the disease progresses to
the upper extremities and cranial nerve–innervated
muscles in some cases. Importantly, patients may
also have autonomic involvement that could lead to
sudden fatal cardiac and circulatory collapse
GUILLIAN BARRE SYNDROME
The diagnosis is made after careful neurologic
examination, clinical electrophysiology, and
CSF analysis may show a typical increase in
CSF protein in combination with a normal cell
count, which is a classic sign of the disease.
Treatment focuses on respiratory support,
nutritional support, and early initiation of
GUILLIAN BARRE SYNDROME
Succinylcholine should not be used because of
the risk of hyperkalemia. Nondepolarizing
muscle relaxants are not contraindicated but
should be avoided as a result of the increased
sensitivity and risk for prolonged muscle
weakness in the postoperative period. The risk
for autonomic dysfunction, respiratory failure,
and aspiration may require assisted or
mechanical ventilation, even in the
GUILLIAN BARRE SYNDROME
Great care should be taken to maintain
circulatory stability, including adequate cardiac
preload and afterload. Careful hemodynamic
monitoring is therefore essential in these
General anesthesia can be used; however, the
combination of general anesthesia and epidural
anesthesia is more controversial. Although
regional anesthesia is not contraindicated, there
are reports of an association between GBS and
DUCHENNE MUSCLE DYSTROPHY
It is the commonest & severest muscular
dystrophies. it is a X linked recessive condition that
presents in the early childhood with weakness of
the lower limbs & pelvic muscles.
Cardiac muscle involvement leads to hypertrophic
cardiomyopathy, progressive respiratory weakness
leading to respiratory failure. Scoliosis is common.
Abnormal metabolic responses to suxamethonium
& volatile agents may lead to clinical syndrome of
rhabdomyolysis & hypermetabolism
DUCHNENNE MUSCLE DYSTROPHY
Perioperative cardiac events including arrhythmias,
cardiac failure & cardiac arrest may occur either due to
cardiomyopathy or metabolic disturbances, particularly
The response to non-depolerizing muscle relaxants is
variable, but the duration of action may be prolonged,
administration of incremental doses & neuromuscular
monitoring is needed.
Respiratory complications is more common late in the
disease with an increase in the incidence of postop
chest infection & respiratory failure.
Myotonic dystrophy (MD) is an inherited muscular
disorder characterized by progressive muscle
weakness. MD is caused by expansion of a CTG
trinucleotide repeat in the DMPK gene and is
inherited in an autosomal dominant manner.There
are two types MD1 & MD2
Typical signs and symptoms include muscle
weakness and wasting (most prominent in the cranial
and distal limb musculature), periodic myotonia,
progressive myopathy, insulin resistance, defects in
cardiac conduction, neuropsychiatric impairment,
cataracts, testicular atrophy, and frontal balding in
The typical cranial muscle weakness and wasting are
manifested not only in the facial, temporalis,
masseter, and sternocleidomastoid muscles but also
in the vocal cord apparatus. Mitral valve prolapse is
found in 20% of patients
During pregnancy, the symptoms may be
exacerbated. Uterine atony and retained placenta
may also complicate vaginal delivery. First-degree
atrioventricular heart block is a common finding on
the ECG before the onset of symptoms
The majority of complications were found to be
pulmonary related and significantly more frequent in
patients undergoing upper abdominal operations.The
pulmonary complications of MD are the result of
hypotonia, chronic aspiration, and central and
peripheral hypoventilation Smooth muscle atrophy,
which leads to poor gastric motility, when coupled
with a diminished cough reflex, promotes aspiration.
Succinylcholine will produce contractions lasting for
several minutes, thus making intubation and
ventilation a challenge. These contractions are not
antagonized by nondepolarizing muscle relaxants
Triggering factors, such as hypothermia,
shivering, and mechanical or electrical
stimulation, may cause a myotonic reaction.
Careful titration with relatively short-acting
anesthetic agents may be beneficial.
Close cardiac monitoring is required for MD
patients. Pacing equipments should be readily
available because a third of first-degree
atrioventricular blocks may not respond to
atropine. All patients should be treated as
though they have both cardiomyopathy and
EATON –LAMBERT SYNDROME
Eaton-Lambert myasthenic syndrome (ELMS) is
an immune-mediated channelopathy caused by
decreased release of acetylcholine as a result of
autoantibodies against presynaptic voltagegated calcium channels and other presynaptic
Patients with ELMS have muscle weakness and
fatigability, generally of the proximal limb
muscles, with the lower extremities affected
more often than the extraocular and bulbar
muscle groups. The syndrome is frequently part
of a paraneoplastic phenomenon, usually
combined with small cell lung carcinoma.
Patients with ELMS are usually worse in the
morning with gradual improvement throughout the
day. Improvement of muscle function with exercise
is due to the accumulation of presynaptic calcium
and subsequent improved release of acetylcholine.
The diagnosis of ELMS is made by careful physical
examination combined with clinical
electrophysiology showing the typical facilitation
with high-frequency nerve stimulation (30 to 50 Hz).
Anticholinesterase treatment has little effect on
patients with ELMS. Plasmapheresis,
immunoglobulin therapy, and 3,4-diaminopyridine
(DAP) result in transient improvement.
As in patients with MG, those with ELMS should
be carefully evaluated for the risk of
postoperative respiratory failure and the need
for prolonged respiratory monitoring in the
Sensitivity to depolarizing and nondepolarizing
neuromuscular blocking agents is usually
increased. In patients treated with DAP or an
anticholinesterase agent, reversal of
neuromuscular blockade may be ineffective.