NMJ Agents (Week 1--Melega) Flashcards
Where do we have cholinergic (ACh) nerve terminals?
Ganglia
NMJ
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
Acetylcholinesterase
Located at cholinergic synapses (postsynaptic membrane) and in erythrocytes
Specific for ACh hydrolysis (does not hydrolyze succinylcholine)
Pseudocholinesterase
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)
Spasticity
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
Spasmolytic drugs
Diazepam: GABAA allosteric agonist (binds different site than GABA) to facilitate GABA binding to the receptor and thus potentiates GABA’s ability to inhibit (by increasing Cl- influx)
Baclofen: GABAB agonist; works on neurons in spinal cord (pre and post-synaptic); may also reduce pain by inhibiting release of substance P in spinal cord
Gabapentin: antiepileptic drug; blocks voltage-sensitive Ca2+ channels; not metabolized so entirely excreted in urine
Central-acting skeletal muscle relaxants
Tizanidine: centrally acting alpha 2 agonist to treat spasms, cramping and tightness caused by MS, back pain, spinal injuries; less muscle weakness than baclofen and benzodiazepines
Carisoprodol (Soma): CNS mechanism related to effects on GABAA receptor; less frequently used bc newer agents available
Cyclobenzaprine: related to TCA amitriptyline (antimuscarinic effects!); Na+ channel blocker; relief of muscle spasm associated with acute, painful MSK conditions (not useful for cerebral palsy, spinal cord disease, other CNS diseases)
Peripherally acting skeletal muscle relaxants
Botulinum toxin: blocks ACh release by cleaving proteins involved in exocytosis (irreversible); applied to areas of excessive muscle contraction in local muscle spasm (dystonia, strabismus, torticollis) and generalized spastic disorders
Dantrolene: reduces skeletal muscle contraction by inhibiting Ca2+ release from SR (binds RyR so Ca2+ cannot get out of the SR)
Malignant hyperthermia
Life threatening pharmacogenetic disorder that develops after or during general anesthesia
Genetic predisposition and triggering agents (volatile anesthetics and succinylcholine) necessary
Hypermetabolic state of skeletal muscle
Mutation in RyR gene causes excessive Ca2+ release from SR
Sustained elevation in myoplasmic Ca2+ concentration activates metabolic and contractile activity
Autosomal dominant
Tremor, rigidity, significant muscle contractions, hyperthermia, tachycardia
Dantrolene to treat/inhibit Ca2+ release?
Tremor effects from beta 2 agonists
Beta 2 receptors located on muscle spindle of skeletal muscles
Beta 2 stimulation increases tension generated in fast-twitch skeletal muscle fibers
Tremor caused with administration of EPI and other beta 2 agonists possibly because of increase in muscle spindle discharge coupled with effect on contraction kinetics of fibers –> instability in reflex control of muscle length
