NMJ Agents (Week 1--Melega) Flashcards Preview

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Flashcards in NMJ Agents (Week 1--Melega) Deck (35)
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Where do we have cholinergic (ACh) nerve terminals?




Synthesis and breakdown of ACh

ChAT turns Choline + Acetyl CoA into ACh

AChE breaks down ACh into Acetate and Choline

Specifics: choline is brought into the presynaptic terminal (along with Na+) by a choline transporter --> Acetyl CoA from mitochondria combines with Choline and Choline Acetyltransferase (ChAT) creates ACh --> ACh packaged into vesicles, fuses with membrane and is released into synaptic cleft --> AChE on postsynaptic terminal degrades ACh into Choline and Acetate


ACh nicotinic receptor

Ligand-gated ion channel

Nonselective cation channel (primarily Na+, but K+ too, and Ca2+ very little)

Pentamer (5 diff subunits)

In autonomic ganglia (symp and para), NMJ, brain

Note: antagonists effective at ganglia do not block at NMJ

Note: when ACh nicotinic receptor activated at NMJ, Na+ flows in mostly because large driving force (low driving force for K+ because resting potential is -80 which is close to K+'s potential, and large driving force for Ca2+ but receptor has very low permeability to Ca2+)


Where are the cell bodies of the motor neurons of the NMJ?

In the spinal cord (ventral horn)!

These motor neurons project uninterruptedly to NMJ, where neuron "invades" the muscle



Located at cholinergic synapses (postsynaptic membrane) and in erythrocytes

Specific for ACh hydrolysis (does not hydrolyze succinylcholine)



AKA plasma cholinesterase, butyrylcholinesterase

Occurs mainly in plasma, liver and glia

Hydrolyzes esters, no specificity (hydrolyzes succinylcholine)


Classes of cholinesterase inhibitor drugs

Reversible (edrophonium)

Carbamate: slowly reversible, carbamylates AChE (neostigmine, physostigmine, pyridiostigmine)

Organophosphate: irreversible, phosphorylates AChE (isoflurophate)


How many NMJ receptors do you have to block to get a decrease in muscle contraction?

Have to block 70% of ACh receptors to decrease muscle contraction

When 95% of receptors occupied, get full blockade


Lambert-Eaton Myasthenic Syndrome

Autoimmune neuromuscular disorder

Antibodies against presynaptic voltage-gated Ca2+ channel proteins --> reduction in Ca2+ entry during nerve terminal depolarization --> synaptic vesicles can't bind presynaptic membrane --> decreased ACh release

Most common initial complaint is proximal muscle weakness involving lower extremities more than upper extremities


Myasthenia Gravis

Autoimmune neuromuscular disorder

Antibodies against nicotinic receptors (postsynaptic) at NMJ --> decrease in functional ACh activity --> muscle weakness and fatigability

Variable weakness and fatigability of voluntary muscles; often improves with rest and worsens with activity; first symptoms often ocular-related (diplopia and ptosis) later extending to limbs and other muscle groups

Note: antibodies that bind to muscle-specific protein kinase have been described in patients with MG who do not have antibody against ACh receptors (MuSK needed to create clustering of receptors which is necessary for proper functioning!)


Pharmacotherapy for Myasthenia Gravis

AChE inhibitors: pyridostigmine (long-acting, 3-6h, used for maintenance therapy; peripheral AChE inhibitor, so no effect in CNS!)

Corticosteroids: prednisone (for moderate to severe cases, if inadequate response to AChE inhibitors)

Immunosuppressants: azathioprine (inhibitor of DNA and RNA synthesis, metabolized to 6-mercaptopurine (6-MP), reserved for steroid failure or unacceptable effects from prolonged steroid use, slow onset of action (3-12 months)


IVIG therapy for Myasthenia Gravis

Immunotherapy, or intravenous gamma globulin (IVIG)

IVIGs are sterile, purified IgG products manufactured from pooled human plasma and typically contain more than 95% unmodified IgG which has intact Fc-dependent effector functions; can affect all components of immune regulatory network

Effective short-term tx for acute exacerbations of MG, but clinical improvement takes several days to occur and effects only last 6-8 weeks

Features that may be relevant to efficacy: neutralization of circulating antibodies through anti-idiotypic antibodies, down-regulation of proinflammatory cytokines (IFN-gamma), blockade of Fc receptors on macrophages, suppression of inducer T and B cells and augmentation of suppressor T cells, blockade of complement cascade


Non-pharmacologic/drug therapy for Myasthenia Gravis

Immunotherapy: intravenous gamma globulin (IVIG, only effective short-term for acute exacerbations of MG, takes a few days to start working and only lasts 6-8 weeks)

Plasmapheresis: removes circulating antibodies including the autoimmune antibodies responsible for the disease

Thymectomy: important tx option especially if thymoma is present (thymic abnormalities found in ~75% of patients with MG)


Neuromuscular blockers

Block transmission from motor nerve to motor end plate

Used during surgical procedures, primarily as adjuncts to general anesthesia and for surgical procedures to be conducted without having to achieve deep anesthesia

Have no effect on CNS processes because do not cross BBB


Two classes of neuromuscular blocking drugs

Two ways to block transmission from motor nerve to motor end plate:

1) Competitive antagonists (non-depolarizing)

2) Non-competitive (depolarizing)


Competitive (non-depolarizing) neuromuscular blocking agents

To obtain better muscle relaxation in surgical anesthesia (note that only blocks movement, sensation is NOT affected, patient still conscious, so must use anesthesia!); used for skeletal muscle relaxation to facilitate tracheal intubation

No CNS activity

All neuromuscular blocking drugs except succinylcholine

Acts at nicotinic receptor site at NMJ by competing with ACh (reversible)

Tubocurarine was prototypical drug, but no longer used

Ex: pancuronium, rocuronium


Pharmacokinetics of competitive (non-depolarizing) neuromuscular blocking agents

Highly polar, quaternary compounds (do not enter CNS)

Poor bioavailability

Administered IV

Not metabolized at synapse

Some metabolized by liver and have short half lives and duration of action <1hr

Some excreted by kidney and have longer half lives and duration of action >1hr

Some side effects due to binding at nicotinic receptors at ganglia and to mast cells


Autonomic side effects of competitive (non-depolarizing) neuromuscular blockers

These side effects are minor in newer drugs, but present in tubocurarine

Block autonomic ganglia and compromise ability of sympathetic nervous system to increase heart contractility and rate in response to hypotension


Side effects regarding histamine release of competitive (non-depolarizing) neuromuscular blockers

Can cause histamine release from mast cells which can cause bronchospasm, skin flushing, hypotension, peripheral vasodilation


How are different competitive (non-depolarizing) drugs cleared from the system?

Pancuronium and vecuronium metabolized by liver

Vecuronium and rocuronium depend on biliary excretion

Atracurium, cisatracurium and mivacurium are extensively metabolized but also depend on extrahepatic mechanisms


Antibiotics and competitive (non-depolarizing) neuromuscular blockers

Using the two together enhances neuromuscular blockade because antibiotics reduce ACh release (ex: aminoglycosides act presynaptically to block Ca2+ channels)


What do AChE inhibitors do to the effects of competitive (non-depolarizing) neuromuscular blockers?

AChE inhibitors (neostigmine, pyridostigmine) increase ACh availability at NMJ, so they reverse the effect of competitive (non-depolarizing) neuromuscular blockers

Used during spontaneous neuromuscular-blockade recovery


Why would a muscarinic antagonist be administered with AChEIs during reversal of neuromuscular blockade?

Muscarinic antagonist minimizes effects of increased ACh at muscarinic synapses


Non-competitive (depolarizing) neuromuscular blocking agents

Succinylcholine (2 ACh molecules linked end to end!)

Short half-life (5-10 min) because rapidly hydrolyzed by plasma cholinesterase (in liver and plasma)

Reacts with nicotinic receptor to open the channel and cause sustained depolarization of the motor end plate so that it is unresponsive to subsequent impulses, resulting in flaccid paralysis/relaxation (fasciculations and muscular contractions occur first though)

Remember, for excitation-contraction coupling to continue, end plate repolarization must occur to produce repetitive firing that maintains muscle tension

After initial excitation and opening, Na+ channels close and cannot reopen until end-plate repolarizes

Anesthetic of choice for laryngospasm, endotracheal intubation, electroconvulsive shock therapy


Succinylcholine pharmacokinetics

Rapid onset of action (30-60sec)

Short duration of action (<10min)

Metabolized by pseudocholinesterase (not AChE) into succinylmonocholine

Only a small fraction reaches NMJ, and as drug plasma levels fall, succinylcholine molecules diffuse away and limit its duration of action


Effects of genetic variation on duration of succinylcholine action

Some people have low pseudocholinesterase levels --> modest prolongation of succinylcholine's actions

Some people have genetically aberrant pseudocholinesterase with low activity --> 1/50 have one abnormal gene and get 20-30 min block; 1/3,000 have 2 abnormal genes and have 4-8 hr blockade after adnimistration of succinylcholine!


Precautions when using succinylcholine

Hyperkalemia: normal muscle releases enough K+ during succinylcholine-induced depolarization to raise serum K+ by 0.5mEq/L, which is usually insignificant in normal patients, but if patient has burn, nerve damage or neuromuscular disease, closed head injury, can cause too much K+ release into blood and occasionally cause cardiac arrest

Increased intragastric pressure: in heavily muscled patients, fasiculations associated with succinylcholine may cause increase in intragastric pressure

Muscle pain: myalgias common post-op complaint of heavily muscled patients or those who receive large doses


Which muscle groups are most and least sensitive to muscle relaxants?

Most sensitive: ocular muscles, then jaw, neck, limbs, intercostals and abdomen

Least sensitive: diaphragm (which is why patients undergoing surgery hiccup or breathe as early sign that relaxants are wearing off)



One component of upper motor neuron syndrome (CNS)

Increased muscle tone, exagerrated deep tendon reflexes, abnormal reflexes, Babinski's sign

Manifestations of excessive involuntary motor activity

Most common causes are traumatic brain injury, stroke, MS, cerebral palsy, spinal cord injury

Characterized increases in tonic stretch reflexes and flexor muscle activity along with muscle weakness

Hyperexcitability of stretch reflex

Often have abnormal bowel and bladder function as well as skeletal muscle

Mechanisms involve stretch reflex arc itself and higher centers in CNS (upper motor neuron lesions), with net loss of descending inhibitory influences on spinal cord stretch reflex of the motor unit, resulting in hyperexcitability of alpha motoneurons in cord

Drug therapy designed to "replace" aspects of the cortical modulation/inhibition of the stretch reflex or interfere directly with skeletal muscle (ie E-C coupling)


GABA receptors

GABAA receptor: ligand-gated Cl- channel, so Cl- influx hyperpolarizes membrane resulting in neuronal inhibition

GABAB receptor: G protein coupled receptor increases conductance of K+ channel and inhibits cAMP production to hyperpolarize the neuron

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