Mkgrady8 Neuro 3 Cholinergic Path

acts at nicotinic and muscarinic receptors

hydrolysis of ACh

a drug that inhibits acetylcholinesterase (AChE)

in the synaptic junction peripherally and in the synaptic cleft centrally

in the plasma and glial cells; this is similar to cholinesterase in its actions

inhibit AChE

organophosphate compounds that are irreversible AChE inhibitors; pseudocholinesterase is more sensitive to inhibition by organophosphate compounds than AChE

anionic site on AChE binds positively charged choline moiety; esteratic site is the active site on AChE and binds carbonyl carbon of ACh; ACh breakdown by AChE is extremely rapid (microseconds); drugs that compete with ACh for binding to either or both of these sites can inhibit AChE and buildup ACh at receptor site

neostigmine; edrophonium; pyridostigmine; physostigmine; donepezil

echothiophate; parathion (insecticide); sarin (nerve gas)

compete with ACh for binding to anionic or esteratic sites by carbamylating the esteratic site; they form a stronger bond with esteratic site than ACh and thus time required for their breakdown is much longer (i.e. 60-120 min)

phosphorylate esteratic site for 2 weeks so new AChE must be synthesized to break ACh down; can alter structure of AChE so that it won't hydrolyze ACh as well ('aging' of AChE); extremely dangerous compounds and should bot be taken parenterally; kill by causing respiratory arrest because they paralyze the diaphragm and intercostal muscles by building up ACh at nicotinic receptors to high enough levels that nicotinic receptors are desensitized

some irreversible AChE inhibitors (aka organophosphates) can cause delayed neurotoxicity but mechanism is unknown (unrelated to inhibition of AChE); involves ataxia, muscle paralysis, and demyelination and appears 8-14 days after drug exposure

treatment of GI tract or bladder atony; glaucoma (wide and narrow angle); myasthenia gravis (treatment and diagnosis); to terminate the effect of an overdose of a curare like competitive blocker; to terminate attack of supraventricular tachycardia

reversible AChE inhibitor; due to positive charge will NOT cross BBB readily and does not cause CNS effects; is hydrolyzed to edrophonium by SChE; duration of action 2-4 hrs; good drug for treatment of paralytic ileus of bladder atony

now considered DOC for treatment of myasthenia gravis (MG); positively charged and has a longer duration of action than neostigmine; duration of action 3-6 hrs; absorbed better than neostigmine; fewer side effects than neostigmine (i.e. diarrhea)

competitively binds to both the esteratic and anionic sites; very short acting (5 mins); not hydrolyzed by AChE; rapidly cleared by kidneys; DOC for DIAGNOSIS of myasthenia gravis; causes an immediate improvement in muscle strength upon IV injection; can be used to treat supraventricular tachycardia; can be used to treat overdose of d-tubocurarine like drug

not charged so will cross BBB and cause CNS effects; mainly used in the eye in conjunction with pilocarpine for treatment of narrow angle glaucoma until iridectomy can be done; can be used as an antidote for atropine intoxication

second drug to be approved for treatment of Alzheimer's disease; exhibits less hepatotoxicity than tacrine

irreversible AChE inhibitor; organophosphate; positively charged and long acting; only used topically in the eye mainly for side angle glaucoma, but better drugs available

irreversible; an organophosphate compound; a potent insecticide and acaricide; highly toxic to humans and some wild life; does not cause delayed neurotoxicity

also an organophosphate; chemical warfare agent (a nerve gas); most toxic and rapidly acting (i.e. much more potent than organophosphate pesticides); clear odorless liquid but evaporates quickly into vapor (gas) and spreads into environment; usually can be lethal even at very small concentrations due to suffocation (asphyxia) unless antidote quickly administered; causes moderate level of delayed neurotoxicity 8-14 days after drug exposure; no drug antidote for delayed neurotoxicity

pralidoxime and atropine

pulls organophosphate off esteric site of AChE; must be given rapidly to prevent aging of AChE; works especially well at the NMJ (drug active at muscarinic and nicotinic sites)

an effective muscarinic antagonist; not charged and thus will cross the BBB; controls signs of muscarinic excess, it blocks muscarinic effects of excess salivation, miosis, bronchocontriction, bronchiole secretions, and sweating caused by inhibition of AChE at muscarinic receptor sites

most prevalent and thoroughly studied disease that affects synaptic transmission; an autoimmune disorder of function at the synapse between cholinergic motor neurons and skeletal muscle; antibodies against the nicotinic acetylchoine (ACh) receptor are produced which interfere with synaptic transmission by reducing the number of functional receptors

severe drooping of the eyelids (ptosis); since ACh is the transmitter at NMJ the skeletal muscles (often cranial muscles, as well as limb muscles) become weakened with no known clinical signs of denervation of muscle atrophy

weakness is revered by intravenous injection inhibitors of acetylcholinesterase (AChE) so EDROPHONIUM (DIAGNOSTIC), neostigmine, PYRIDOSTIGMINE (DOC), and physostigmine; pyridostigmine (or neostigmine) increases the duration of action of ACh and therefore compensate for the reduced ACh activity in myasthenia

model created by repeated injection of pt serum or purified ACh receptor protein; observe reproduction of electrophysiological abnormalities in such animals by reducing the number of ACh receptors in skeletal muscle; inhibitors of cholinesterase reverses the myasthenia like symptoms

remove the thymus (if there is a benign tumor there); draining lymph from thoracic lymph ducts improve symptoms; return of lymph fluid to the pt recreates symptoms but not when lymphocytes are replaced; plasmapheresis procedure also improves symptoms

the geometry of the end plate is also distributed and normal infolding is reduced and synaptic cleft is enlarged all of which reduce synaptic transmission likelihood; therefore transmission is blocked even though the process of ACh release is normal

it is not clear what initiates production of circulating antibodies to the ACh receptor that cause myasthenia but 2 possibilities= persistent viral infection may alter the properties of the surface membrane making it immunogenic or bacterial and viral antigens may share epitopes with ACh receptor thus antibodies produced against foreign organism may recognize and interfere with function of ACh receptor

due to an increase in degradation or turnover of the receptors; the cross linking of ACh receptors by the antibody triggers and facilitates the normal endocytosis and phagocytic destruction of the receptors (causing 2-3 fold increase in receptor turnover rate); the circulating antibodies are not found in all pts and there is no consistent correlation between concentration of antibodies and the severity of symptoms

an acquired autoimmune form in older children and adults with ACh receptor antibodies; a non immune heritable congenital form without ACh receptor antibodies, this is a heterogenous syndrome where some pts have abnormalities in presynaptic terminals (with abnormal ACh release) and others with apparent postsynaptic disorders (e.g. congenital lack of cholinesterase or low numbers of ACh receptors)

some pts with lung cancer have a neuromuscluar disorder called presynaptic (facilitating) neuromuscular block (aka lambert eaton); physiological response is opposite of myasthenia showing gradual increase to repetitive stimulation so that the final summated action potential is 2-4 times the amplitude of the first potential; disorder probably due to the presence of antibodies to voltage gated calcium channels in the presynaptic terminals (loss of calcium channels will impair release of ACh when nerve terminals are depolarized); symptoms in pts often improve after plasmapheresis or immunosuppressive drug therapy supporting the notion that circulating antibodies are responsible for the disorder; CALCIUM GLUCONATE OR GUANIDINE (agents that enhance the release of ACh) are the treatments

botulism toxin is found to be associated with impaired ACh release; treated with CALCIUM GLUCONATE OR GUANIDINE (agents that enhance the release of ACh)

in classical autoimmune MG circulating antibodies directed against nicotinic ACh receptors interfere with function of the receptor and neuromuscular synaptic transmission; there is a reduction in the number of ACh receptors at the NMJ due to increased rate of receptor turnover; the symptoms are improved by inhibitors of cholinesterase and by other therapy such as thyrmectomy; animal models of the disease have been created; immunological changes cause the physiological abnormalities; MG is more than one disease= there is an autoimmune form and a non immune congenital form

has physiological response opposite of myasthenia; circulating antibodies directed to presynaptic terminals appear to be responsible for the symptoms; pts are treated by plasmapheresis and drugs that enhance release of ACh

an action potential sweeps down motor nerve terminal and its propagation is dependent on Na influx; arrival of action potential at nerve terminal enhances Ca2+ influx through channels which triggers ACh release from synaptic vesicles; ACh diffuses across synaptic junction and acts on a nicotinic receptor to open channels to positively charged ions; an increased influx of Na and K leads to muscle action potential; excitation in muscle tissue spreads via a transverse tubular system (actin and myosin slide together with the help of Ca released from the sarcoplasmic reticulum to cause muscle contraction)

to produce skeletal muscle relaxation during general anesthesia so less anesthetic is required

non depolarizing neuromuscular blockers that compete with ACh at nicotinic receptor and act strictly as ACh antagonists when producing skeletal muscle relaxation (prototype= d-tubocurarine); depolarizing neuromuscular blockers that are agonists which initially cause persistent depolarization followed by receptor desensitization and when used clinically they initially produce muscle fasiculations prior to muscle relaxation (prototype= succinylcholine)

d-tubocurarine, pancuronium, doxacurium, vecuronium, atracurium, rocuronium, and mivacurium

rarely used because it lowers BP by RELEASING HISTAMINE (causing vasodilation) and by causing some blockade of ganglionic transmission through sympathetic division of ANS (i.e. removing sympathetic tone to arterioles and veins); too much d-tubocurarine causes skeletal muscle paralysis; override its blockade by giving an AChE inhibitor; is broken down if given orally so must be given by IV; only used as a surgical adjunct during general anesthesia; duration of action is 60-80 mins

fairly long acting competitive blocker; doesn't release much histamine, doesn't cause much ganglionic blockade, nor does it affect cardiovascular system much; can cause increase in BP if given rapidly also can cause tachycardia; better drug to use in asthmatics and in pts with cardiovascular problems

duration of action intermediate; no ganglionic blockade or histamine release; in rare cases it can cause tachycardia so can be dangerous in hyperthyroid pts who are sensitized to catecholamines

duration of action intermediate similar to vecuronium; it shows little effect on cardiovascular system but can cause some histamine release which will lead to hypotension

intermediate acting blocker similar to vecuronium; doesn't have much effect on cardiovascular system

is a SHORT ACTING non depolarizing blocker; it shows some effect on cardiovascular system (mediated by autonomic or HISTAMINE RELEASE); a few cases of hypotension, tachycardia, and cardiac arrhythmias have been reported

only one still used is succinylcholine; an agonist that produces skeletal muscle relaxation; succinylcholine releases vasodilator histamine and tends to slow heart rate; elevates plasma K levels; succinylcholine reduces effectiveness of digitalis so it may be unwise to use in pts taking digitalis like drugs that compete with K to increase ventricular contraction or diuretics that lower plasma K levels; very short duration of action (5 mins) due to breakdown of peudocholinesterase in the plasma; mainly used for short term procedures such as endotracheal intubation and to protect skeletal muscle during electroshock therapy; causes bradycardia by stimulating vagus; can elevate intraocular pressure so no in glaucoma pts; can cause prolonged apnea in pts with atypical pseudocholinesterase (they cannot hydrolyze succinylcholine as effectively); more prone to cause malignant hyperthermia than other skeletal muscle relaxants; no drug antidote for succinylcholine overdose

can cause respiratory paralysis by wither antagonizing action of ACh at motor end plate region of diaphragm and intercostal muscles or by causing receptor desensitization; those that release histamine such as d tubocurarine, succinylcholine, and mivacurium (cause bronchoconstriction) are dangerous to use in asthmatics

certain general anesthetics stabilize postjunctional membrane (i.e. halothane and isoflurane) and make depolarization at nicotinic receptor more difficult therefore dose of d-tubocurarine like competitive neuromuscular blocker should be reduced when using one of these anesthetics; aminoglycoside antibodies (i.e. neomycin, kanamycin) and tetracycline reduce prejunctional release of ACh by chelating Ca so less ACh arrives at nicotinic receptor for d-turbocurarine like drug to block so reduce dose of competitive blocker if used as a surgical adjunct in a pt taking more of these antibiotics

resp paralysis is caused by overdose of any of them; drug antidotes can be given to counteract the effects of d-turbocurarine, pancuronium, doxacurium, atracurium, vecuronium, rocuronium, and mivacurium; neostigmine inhibits AChE, builds up ACh in the synaptic junction, and overrides the competitive blockade (neostigmine preferable to physostigmine because neo is charged and will not cross the BBB); succinylcholine overdose (no drug antidote) and neostigmine will actually worsen the effects because succ exerts its effect by desensitizing the nicotinic reactions to ACh and an AChE inhibitor will increase the amount of ACh in the junction further desensitizing the receptors

asthma= d-tubocurarine, mivacurium, and succinylcholine; narrow angle glaucoma= succinylcholine; hyperthyroid condition= vecuronium

reduces intracellular Ca conc POSTJUNCTIONALLY in skeletal muscle by reducing Ca release from sarcoplasmic reticulum through binding and blocking ryanodine receptor channel and this inhibition causes downstream effect of muscle relaxation

used to provide muscle relaxation in pts with stoke, multiple sclerosis, or malignant hyperthermia, but dantrolene causes overall muscle weakness; malignant hyperthemia can often occur in surgical pts who are given certain general anesthetics (e.g. halothane) in conjunction with succinylcholine= an explosive release of Ca causes exaggerated skeletal muscle contraction also body temp is elevated to dangerously high levels, dantrolene helpful because it reduces Ca release and prevents explosive muscle contractions, dantrolene does not interfere with prejunctional release of ACh

drug acts centrally to produce skeletal muscle relaxation; used for muscle spasm; has advantage over valium in that it does not produce as much dependence; mechanism of action unknown but it does block the reuptake of NE; should not be taken simultaneously with an MAO inhibitor; side effects are similar to those for tricyclic antidepressants and scopolamine (dry mouth, drowsiness, tachycardia, and blurred vision)

D pralidoxime and atropine

C neostigmine because this is MG

C tubocurarine