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87 Cards in this Set
- Front
- Back
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What are some Functions of nervous system? 4 things
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Gathers information from outside and inside body (sensory function)
Transmits information to processing area of brain and spinal cord Processes information to determine best response (integrative function) Sends information to muscles, glands, and organs so they can respond (motor function) |
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What are the 2 divisions of the nervous system?
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Central and Peripheral
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What are the 2 divisions of the peripheral nervous system? What are the functions?
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Autonomic – regulates internal environment through involuntary control
Sympathetic & Parasympathetic Somatic – motor and sensory pathways that regulate voluntary motor control of skeletal muscle |
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T or F:
Somatic nervous system regulates activities that are under conscious control |
True
Lift finger, wiggle toes – uses motor neurons of somatic nervous system Many nerves in somatic system part of reflexes and act automatically From sensory receptor in periphery to spinal cord to motor neuron causing motor response |
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Nerve fibers are adrenergic or cholinergic
Adrenergic fibers contain __________ Cholinergic fibers contain _________ |
norepi, acetycholine
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What are cholinergic receptors, agonists, and antagonists?
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Cholinergic receptors -
Proteins in cell membranes that react with ACh Cholinergic agonists - Drugs that act like ACh on cholinergic receptors Cholinergic antagonists - Drugs that react with cholinergic receptors and block acces to ACh |
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Where are cholinergic fibers found?
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All presynaptic nerve fibers of autonomic nervous system (sympathetic and parasympathetic)
All post-synaptic nerve fibers of parasympathetic nervous system Post-synaptic sympathetic nerve fibers to sweat glands (stimulated) and skeletal muscle blood vessels (dilated) During exercise Motor nerve fibers to skeletal muscles in somatic nervous system Central cholinergic neurons and preganglionic sympathetic neurons that innervate the adrenal medulla |
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What kind of drugs effect the cholinergic receptor?
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Cholinergic and anticholinesterase
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What are the 2 types of cholinergic receptors?
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Muscarinic -
Primarily on effector cells in visceral organs Nicotinic - Parasympathetic and sympathetic ganglia Skeletal muscle |
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Muscarinic receptors belong to which family of receptors? How many types are there?
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Belong to superfamily of G protein receptors
Five types – M1-M5: Odd number (M1, M3, M5) receptors work through release of intracellular Ca++ Even number (M2, M4) work through inhibition of adenylate cyclase M1 neuronal M2 cardiac M3 glandular |
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Massive parasympathetic response (ACh receptor response) would leave
pt doing what? |
Helplessly salivating, weeping, wheezing, vomiting, urinating, defecating, and seizing organism
ACtions are the same as a vagal response. |
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Muscarinic eye effects?
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Contraction of smooth muscle of iris sphincter (miosis) and contraction of ciliary muscle
Allows anterior chamber to drain |
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Muscarinic heart effects?
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SA node – decrease in rate (neg. chronotropy)
Atria – decrease in contractility (neg. inotropy) AV node – decrease in conduction velocity (neg. dromotropy) Ventricles – small decrease in contractility |
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Muscarinic blood vessel effects?
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Arteries – dilatation (constriction high dose direct effect)
Veins – dilatation (constriction high dose direct effect) |
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Muscarinic effect on lungs?
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Bronchiole muscle – contraction (bronchoconstriction)
Bronchial glands - stimulation |
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Muscarinic effect on GI tract?
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Motility – increased
Sphincters – relaxation Secretion – stimulation |
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Muscarinic effect on glands?
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Sweat, salivary, lacrimal, nasopharyngeal – secretion
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Muscarinic effect on bladder?
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Detrusor – contraction
Trigone & sphincter – relaxation |
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Nicotinic receptors belong to which family? What membrane proteins are present? They are designated as what?
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Belong to superfamily of ligand-gated ion channels
Membrane proteins: 2 alpha subunits Beta Epsilon Delta Designated as N1 or N2 N1 at autonomic ganglia N2 at NMJ Two receptors blocked by different antagonists |
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Nicotinic receptors on ganglia and motor end plates differ and are blocked by different drugs...explain.
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N1 receptors blocked by ganglionic blocking drugs
No IV ganglionic blocking agent for use in US today N2 receptors blocked by neuromuscular blocking agents |
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What are the Nicotinic Receptors Effects at the NMJ?
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Binds to and activates acetylcholine (nicotinic/cholinergic) receptor on postsynaptic muscle cell:
Binds to alpha subunits -- Both alpha subunit sites occupied, channel opens, action potential occurs, ions flow, muscle contraction occurs May be occupied by ACh or antagonist Only one alpha subunit occupied, channel remains closed |
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Acetylcholine (ACh) Synthesis happens where?
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Occurs in cytoplasm from acetyl-CoA and choline
Enzyme choline acetyltransferase catalyzes reaction Acetyl-CoA- Synthesized in mitochondria which are present in large numbers in nerve ending Choline- Transported into cell from extracellular fluid |
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Ach is Transported into & stored vesicles in ________
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cytoplasm
Rapid process Usually 1000-50,000 molecules of ACh in each vesicle >100 vesicles of ACh open after action potential reached |
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Release depends on extracellular ____
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Ca++
Occurs when action potential reaches terminal and sufficient influx of Ca++ Fusion of vesicular membrane with terminal membrane Exocytosis of large quantity of ACh into synaptic cleft at somatic motor nerve terminal |
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How is ach metabolized?
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Effect usually <1ms
Rapidly hydrolyzed by acetylcholinesterase: True cholinesterase Found in cholinergic synapse in high amounts Plasma cholinesterase (pseudocholinesterase) : Present in low concentrations around cholinergic receptors High concentrations in plasma Not important in hydrolysis of ACh IMPORTANT in hydrolysis of SCh and Mivacurium |
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Brief duration of SCh due to hydrolysis by ____ _________
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plasma cholinesterase
Only small part of IV dose of SCh reaches NMJ |
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Plasma Cholinesterase is synthesized where?
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in liver
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Can get Decreased plasma cholinesterase activity from
what? |
Severe liver disease
Drug-induced Genetics |
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Explain Atypical Plasma Cholinesterase..what causes it?
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Usually unknown until SCh
Single cholinesterase gene: Nucleotide alterations cause numerous variants in gene Dibucaine a Local amide anesthetic may Inhibit normal plasma cholinesterase by 80% Inhibits atypical enzyme by 20% |
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What does Dibucaine number of 80 mean?
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(80% inhibition) = normal enzyme
20 = homozygous patient 1 in 3200 Recovery may take up to 3 hours 40-60 = heterozygous patient 1 in 480 Recovery may take up to 30 minutes Reflects quality of cholinesterase not quantity Plasma cholinesterase gives quantity – may still be atypical |
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What is the difference between Plasma Cholinesterase and Acetylcholinesterase
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Plasma cholinesterase (pseudo cholinesterase)
In plasma Hydrolyzes SCh Atypical when prolonged block after SCh No other physiological function Acetylcholinesterase (true cholinesterase) In synaptic cleft of NMJ Hydrolyzes ACh One of most efficient enzymes known Hydrolyzes 300,000 molecules of ACh every minute |
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Anticholinesterase Drugs are cholinergic agonists or antagonists? What are they used for?
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Cholinergic agonists----
Reversal of NM blockade Inhibition of acetylcholinesterase increases amount of ACh ACh competes with and displaces NDMR Treatment of myasthenia gravis Caused by autoimmune destruction of ACh receptors Increased amounts of ACh present when these drugs given may improve symptoms Treatment of certain tachyarrhythmias PSVT, WPW |
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What are the 3 classifications of anticholinesterases?
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Carbamates -
Physostigmine - Antilirium (first one) Neostigmine - Prostigmin Pyridostigmine – Regonol, Mestinon Quaternary ammonium alcohols- Edrophonium – Enlon, Tensilon Organophosphates- Echothiophate iodide (Phospholine) eye drops for glaucoma Insecticides (parathion, Malathion, soman, sarin) |
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Anticholinesterase mechanism of action?
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Enzyme inhibition
Inhibit acetylcholinesterase End result – more ACh Presynaptic effects If given in absence of NDMRs may produce fasciculations of skeletal muscle Direct effect on NMJ May produce block but at very high doses |
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What are Cholinesterase Inhibitors used for?
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Primary use—reverse NMB. Has been used to treat myasthenia gravis, urinary bladder atony.
NM transmission blocked when nondepolarizers compete with ACh to bind to nicotinic ACh cholinergic receptors. Cholinesterase inhibitors indirectly increase the amount Ach available to compete with the nondepolarizer, therefore reestablishing NM transmission Can paradoxically potentiate NMB in excessive doses. Can prolong depolarization block of SCh. |
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Time required to fully reverse nondepolarizing NMB depends on:
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Choice of cholinesterase inhibitors
Dose of cholinesterase inhibitors NMB being antagonized Extent NMB before reversal |
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What are some Commonly used Anticholinesterase Drugs and the Pharmacokinetics?
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Neostigmine, pyridostigmine, edrophonium most commonly used drugs for reversal of NDMRs
No significant difference among three if normal kidneys & liver Plasma concentrations peak and decline in first 5-10 minutes Vd – 0.7-1.4 L/kg T ½ β – 60-120 minutes Clearance – 8-16 mL/kg/min |
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Edrophonium, neostigmine, & pyridostigmine are part of which group? What is the significance of this?
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Quaternary ammonium group
Poorly lipid soluble Don’t cross GI tract or BBB |
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Physostigmine & organophosphates are part of which group? What is the significance of this?
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Tertiary amines
Lipid soluble Absorbed from GI tract Cross BBB – predictable effects on CNS |
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Why do Anticholinesterases have a Large Vd?
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Usually due to lipid solubility
Due to extensive storage in liver and kidneys with these drugs |
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What is the renal clearance for the anticholinesterases? What clinical significance is this?
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50% of neostigmine
75% of edrophonium & pyridostigmine Renal failure = prolonged elimination half time ****clinical significance – more prolonged than NDMR so not apt to see recurarization |
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Where are anticholinesterase drugs metabolized?
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Liver:
50% of neostigmine 30% of edrophonium 25% of pyridostigmine Metabolites don’t contribute significantly to drug effects (mostly inactive) Duration of action longer in elderly Dose requirements less in infants and children |
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Anticholinesterase Pharmacodynamics
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Acetylcholinesterase has anionic and esteratic site
Sites complement acetylcholine Anionic site binds to quaternary nitrogen of acetylcholine Esteratic site binds to ester link |
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Neostigmine:
Doses, duration, peak effect, solubility, side effect |
Lipid insoluble—can’t pass through blood-brain barrier
Effects at 5-10 min. Peaks at 10 minutes. Lasts > 1 hour. Pediatric and geriatric patients more sensitive: more rapid onset and require smaller dose. Dose—0.04 mg/kg Maximum dose 0.08 mg/kg (Adults 5 mg) Muscarinic side effects minimized by prior or concomitant administration of anticholinergic. Side effects: N, V, fecal incontinence, delayed PACU stay, atropine-resistant bradycardia at higher doses (200 ug) |
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What is a benefit of using glyco over atropine with Neostigmine?
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Onset of glycopyrrolate (0.2 mg glyco per 1 mg neostigmine) similar to neostigmine and has less tachycardia than atropine (0.4 mg per 1 mg neostigmine)
BUT Has been reported that neostigmine crossed the placenta resulting in fetal bradycardia. Atropine may be a better choice in pregnant patients receiving neostigmine. |
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Pharmacodynamics of Edrophonium
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Presynaptic site of action
Muscarinic effects mild compared to others Reversible inhibition : Attaches to anionic site on acetylcholinesterase (AChE) H+ bonds at esteratic site Forms new complex - Prevents binding of AChE with ACh |
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Edrophonium duration, dosing, potency, solubility, concentration
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Limited lipid solubility.
< 10% as potent as neostigmine. Dose: 0.5-1 mg/kg. Solution has 10 mg/cc Also available as Enlon-Plus which has 10 mg edrophonium and 0.14 mg atropine. Most rapid onset 1-2 minutes. Shortest duration |
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Why use Atropine with Edrophonium?
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Rapid onset well matched to atropine 0.14 mg atropine per 1 mg edroophonium.
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Compare Edrophonium to Neostigmine?
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Extreme age patients are not more sensitive to edrophonium reversal.
May not be as effective as neostigmine at reversing intense NMB, but may be more effective in reversing a mivacurium blockade. Less muscarinic effects, requiring only half the amount of anticholinergic agent. |
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Physostigmine dosing, solubility, concentration, group
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Tertiary amine.
Lipid soluble Only clinically available cholinesterase inhibitor that passes blood-brain barrier. Dose: 0.01-0.03 mg/kg Solution 1 mg/ml |
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What limits physostigmine as a NMB reversal?
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Lipid solubility and CNS penetration limit usefulness as reversal for nondepolarizers, but make it effective in treating central anticholinergic toxicity caused by OD atropine or scopolamine.
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Other than NMB reversals, what else can physostigmine help with?
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Reverses some of CNS depression and delirium associated with use of benzodiazepines and volatile anesthetics
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T or F:
Physostigmine is Effective in preventing postop shivering. |
True
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T or F: physostigmine is Metabolized by plasma esterases almost completely.
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True
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T or F:
If correct dose of NMB used and neuromuscular block is monitored, and anticholinesterase given only when 3rd twitch of TOF response detectable, then residual block should never be seen. |
False, 2nd twitch of TOF
No rationale for using excessive doses of NMB drugs. PNS must always be used. Even if partial reversal is achieved, paralysis may worsen in PACU if patient hypoventilates. |
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Pyridostigmine: max dose, conc, onset, duration,
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20% as potent as neostigmine
May be given is doses up to 0.4 mg/kg Max adult dose 20 mg. Solution has 5 mg/ml. Onset of action slower than neostigmine (10-15 minutes) Duration of action longer (> 2 hours) Glycopyrrolate 0.05 mg per 1 mg pyridostigmine or atropine 0.1 mg per 1 mg pyridostigmine must be given to prevent bradycardia. Glyco preferred due to its slower onset of action matches better |
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Organophosphates...how are they different?
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Special class of cholinesterase inhibitors
Form stable irreversible bonds to enzyme. Used in ophthalmology and pesticides. Clinical duration of cholinesterase inhibitors used in anesthesia is most influenced by the rate of drug disappearing from plasma. Difference in duration of action can be overcome by dosage adjustments. So a normally short duration of action of edrophonium can be partially overcome by increasing the dose. |
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Pharmacodynamics of organophosphates?
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Irreversible inactivation
Combine with AChE at esteratic site to form stable inactive complex Inactivates AChE for life Echothiophate only organophosphate used clinically today |
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Pharmacodynamics of Neostigmine & Pyridostigmine
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Reversible inhibition
Form carbamyl ester complex at esteratic site of AChE Substitutes for ACh Newly formed carbamylated AChE has half-time of 15-30 min |
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______stimulates autonomic ganglia and skeletal muscle receptors.
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Nicotine
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T or F:
CNS has both nicotinic and muscarinic receptors. |
True
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T or F
Nicotinic receptors are blocked by NMB. Muscarinic receptors are blocked by anticholinergics. (Atropine) |
True
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Normal NM transmission depends on Ach binding to nicotinic cholinergic receptors on motor end plate.
Nondepolarizers act by competing with Ach for binding sites. Reversal of NMB depends on spontaneous means of? |
gradual diffusion
Redistribution Metabolism Excretion |
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Stability of the anticholinesterase bond influences duration of action
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Electrostatic attraction and H+ bonding of Edrophonium are short lived.
Covalent bonds of Neostigmine and Pyridostigmine hold longer |
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CV effects of anticholinesterases?
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CV—predominant muscarinic effect on the heart is vagal-like bradycardia. Can progress to sinus arrest. Has been reported in newly transplanted (denervated) heart, but more likely in transplanted heart after 6 months (reinnervated).
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Pulmonary and Cerebral effects of anticholinesterases?
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Pulmonary receptors—can result in bronchospasm (smooth muscle contraction) and increased respiratory tract secretions.
Cerebral receptors—Physostigmine is cholinesterase inhibitor that crosses blood-brain barrier and can cause diffuse activation of EEG by stimulating muscarinic and nicotinic receptors within the CNS. |
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GI and gland effects of anticholinesterases?
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GI receptors—muscarinic stimulation increases peristaltic activity (esophagus, gastric, intestinal)
And glandular secretion (salivary, parietal). Periop bowel anastomotic leak, nausea, vomiting, fecal incontinence have been attributed to cholinesterase inhibitors. |
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Unwanted muscarinic side effects are decreased by prior or concomitant administration of __________such as atropine or glycopyrrolate.
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anticholinergic
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Compare the duration of action of anticholinesterases and anticholinergics?
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Duration of action of cholinesterase inhibitors are similar.
Clearance--hepatic (25 – 50%) renal (50-75%) Any prolongation of nondepolarizer NMB from renal or hepatic insufficiency will probably have corresponding increase in duration of action of cholinesterase inhibitor. |
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Reversal should be given unless full reversal demonstrated or planned vent.
What warrants full reversal? |
ST x 5 sec.
Sustained head lift x 5 sec if awake. |
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Dose of cholinesterase inhibitor depends on the degree of NMB. How?
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Usually estimated by response to nerve stimulator.
No amount of cholinesterase inhibitor can immediately reverse a block with no response to ST. Absence of any palpable single twitch after 5 sec ST @ 50 Hz implies very intense block that can’t be reversed. Excessive doses of cholinesterase inhibitor may prolong recovery. Some evidence of spontaneous recovery must be present before reversal is attempted. |
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Post-tetanic count correlates with time of return of first twitch of TOF and ability to reverse intense paralysis. How?
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Atracurium and Vecuronium– a palpable post-tetanic twitch appears about 10 minutes before spontaneous recovery of the first twitch of the TOF.
Pancuronium—first twitch of TOF appears about 40 minutes after a palpable post-tetanic twitch. |
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T or F:
Factors associated with faster reversal are also associated with a lower incidence of residual paralysis in PACU and lower risk of postop respiratory complications. |
True
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Anticholinergic Agents
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Antimuscarinic
Esters of aromatic acid combined with organic base. Ester linkage essential for effective binding of anticholinergics to acetylcholine receptors. This competitively blocks binding by acetylcholine and prevents receptor activation. Extent of anticholinergic effect depends on degree of baseline vagal tone. |
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CV effects of anticholinergics?
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Blockade of muscarinic receptors in SA node results in tachycardia.
Transient slowing of HR in response to low doses of anticholinergics has been reported. Facilitates conduction through AV node, shortens PR interval on EKG and often decreases heart block caused by vagal activity. Generally have little effect on ventricular function or peripheral vasculature. Large doses can cause dilation of cutaneous blood vessels. |
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Respiratory effects of anticholinergics?
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Inhibit secretions of respiratory tract mucosa, from nose to bronchi.
Relaxation of bronchial smooth musculature reduces airway resistance and increases anatomic dead space. Pronounced in patients with COPD or asthma. |
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Cerebral effects of anticholinergics?
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Depending on drug choice and dosage, effects range from stimulation to depression.
Stimulation– excitation ,restlessness, hallucinations Depression– sedation and amnesia Physostigmine reverses these actions quickly. |
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GI effects of anticholinergics?
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Reduced salivary secretions.
Decreased gastric secretions with larger doses. Prolonged gastric emptying from decreased intestinal motility and peristalsis Reduced lower esophageal sphincter pressure. May increase risk of aspiration. |
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Opthalmic effects of anticholinergics?
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Causes mydriasis (pupillary dilation)
Causes cycloplegia (inability to accommodate to near vision. |
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GU effects of anticholinergics?
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May decrease ureter and bladder tone and result of smooth muscle relaxation.
May lead to urinary retention especially in elderly men with prostatic hypertrophy |
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T or F:
Inhibition of sweat gland if give an anticholinergic may attribute to rise in body temp. (atropine fever) |
True
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Atropine: what type of drug is it, dosing?
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Tertiary amine consisting of tropic acid (aromatic acid) and tropine (organic base).
Dose 0.01-0.02 mg/kg up to usual adult dose 0.4-0.6 mg. IV or IM Doses up to 2 mg may be required to completely block cardiac vagal nerves in severe SB. Dose 0.014 mg per cc of cholinesterase inhibitor. |
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What is atropine best used for?
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Best for treating bradyarrhythmias.
Patients with CAD may not tolerate increased myocardial oxygen demand and decreased oxygen supply associated with tachycardia from atropine. Ipratropium bromide is a derivative of atropine used in inhaler for bronchospasm. Its quaternary ammonium structure limits systemic absorption. Appears effective in acute COPD when used with Beta agonist (albuterol) |
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Side effects/cautions of atropine?
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CNS effects minimal even though it can cross blood-brain barrier.
Has been associated with mild postop memory deficits. Toxic doses are usually associated with excitatory reactions. Use with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, or bladder-neck obstruction |
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Scopolamine: dosing, route of adminstration, side effects
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Differs from atropine by incorporating O2 bridge in to organic base to form scopine.
Usually given IM Solutions may have 0.3, 0.4, and 1 mg/ml. More potent antisialagogue than atropine and causes > CNS effects. Clinical dosages result in drowsiness and amnesia. |
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Scopolamine: what does it do, what pts should you avoid use with?
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Although sedative effects desirable for preop, may prolong wakeup.
Prevents motion sickness. Lipid solubility allows transdermal absorption. Avoid in patients with closed-angle glaucoma. |
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Glycopyrrolate: dose, concentration, type of anticholinergic, side effects?
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Synthetic quaternary ammonium with mandelic acid in place of tropic acid.
Usual dose is ½ that of atropine. Premed—0.005-0.01mg/kg up to 0.2-0.3 mg in adults Solution is 0.2 mg/ml. Cannot cross blood-brain barrier. No significant CNS or ophthalmic activity. Potent inhibition of salivary gland and respiratory tract secretions. HR usually increases after IV, but not IM. Longer duration of action than atropine 2-4 hours. |
