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NMBAs
Neuromuscular Blocking Agents
| Question | Answer |
|---|---|
| What type of muscle fibers innervate the NMJ? What is their origin? | Myelinated, fast-conducting Group A fibers. They originate in the anterior horn of the spinal cord gray matter. |
| What type of receptors are found at the NMJ? | Nicotinic Acetylcholine receptors |
| Where does depolarization begin? What is the general pathway? | In the brain. Brain-nerve nerve-nerve nerve-muscle. |
| What is responsible for breaking down ACh? What are the products? | Acetylcholinesterase. Acetate and choline. |
| What happens when a nerve potential reaches the nerve terminal. | ACh is released into the synaptic cleft near nAChRs. |
| How is ACh produced? How is it stored? | Synthesized from acetylcoenzyme-A and choline in the presence of choline acetylase. 80% is stored in synaptic vessicles and 20% remains as non-vesicular reserve |
| What happens after ACh is released? | It binds to nAChRs and generates a MEPP. |
| What is a MEPP? | Mini End-Plate Potential; it results from the binding of ACh to the nAChR. the sum of MEPPs produces en-plate potential. |
| Aside from the action potential, what other factors are required for ACh release? | Calcium and cAMP. |
| As a result of stimulation, about how much ACh is released from the nerve terminal? | About 5 times as much as is needed to generate an action potential |
| How is ACh broken down? What happens to the products? | It is immediately exposed to acetylcholinesterase and hydrolyzed. Choline is taken back up into the nerve terminal (recycled) and acetate diffuses away from the synapse. |
| What type of receptor is the nAChR? What happens after it opens? | It is a ligand gated receptor, the endogenous ligand of which is Na. After it opens, Na enters the cell and (if enough enters) causes depolarization. |
| Describe the nAChR. | It is a pentameric transmembrane protein. It has the following subunits: 2 alpha, 1 beta, 1 delta, and 1 epsilon. |
| Describe the action of the nAChR. | An agonist must bind to each alpha sub-unit for the protein to open. This allows Na to enter the cell. After the cell fires its action potential, Ca is released from the sarcoplasmic reticulum. |
| How do DMRs and NDMRs differ in terms of their effects on nAChRs? | DMRs = agonists. NDMRs = antagonists. |
| What is required to trigger the action of the nAChR? | 2 agonists. This can be 2 ACh molecules, 2 SCh molecule, or 1 ACh molecule and 1 SCh molecule. |
| How do NDMRs work? | A molecule of NDMR occupies an alpha receptor. This prevents ACh/SCH from binding to the subunit and causing the pore to open. There is no ion flux or depolarization. They may also block the receptor pore (esp after large doses) preventing ion flux. |
| How can the termination of NDMRs be enhanced? | Increase the agonist (ACh, SCh) by inhibiting its breakdown. |
| How is SCh broken down? | Hydrolyzed by plasma cholinesterase (aka psuedo-, butyrocholinesterase), which is not present at the NMJ. |
| What is responsible for termination of SCh activity? | Diffusion of the drug away from the NMJ. |
| What is the first step of SCh diffusion? Why is this difficult? | Detachment from the aplha-subunit. SCh has a higher affinity for the nAChR than ACh so it is based on concentrations. |
| Why does blockade occur with SCh use? Why is this concerning? | The cell depolarizes, but does not repolarize because the SCh has not detached (produces depolarization followed by flaccid paralysis). Ions are still able to flow (i.e. K+) |
| What are the types of channel blockade and how do they differ? | Open (drug blocks pore, impeding ion flow) and closed (drug acts around pore mouth and prevents ion passage) |
| Generally, how do NDMRs prevent muscle contraction? | They occupy one alpha subunit on the nAChR. It does not produce an action (bc it is an atagonist), but it also means that at most only one alpha receptor can be stimulated. Therefore, the muscle will not contract. |
| What is the idea behind the concept of extrajunctional receptors? How is this different from receptor upregulation or down regulation? | Not normally present in large numbers, they proliferate if neural activity is decreased (ie trauma, sepsis, PROLONGED BED REST, burn, SC injury, etc). They are a different type of cell from the nAChR. |
| How are extrajunctional receptors different from nAChRs? | They stay open longer after depol (allowing inc K out). They are spread across the entire muscle (not only at the NMJ). They are highly sensitive to agaonists, but LESS sensitive to antagonists. |
| What are prejunction receptors? What do they do? | They are nAChRs found on prejunctional membranes. They are believed to regulate ACh release. Stimulation inhibits ACh release from the presynaptic membrane and stimulates production of more ACh in the terminal. |
| How does post-tetanic facilitation differ with DMR and NDMRs? | There is NO PTF with DMR (conductino is simply weaker, assuming there is any). NDMR: weak twitches, tetany (which fades), stronger (but FADING) twitches. |
| Which nerve stimulation method is better to observe fades? | Double burst. |
| Where are nAChRs located? Where are mAChRs located? | Pregang-postgang synapse in PSNS, pregang-postgang synapse in SNS, NMJ. Postgsng-end organ synapse in PSNS. See Diagram. |
| What is important to remember regarding the activity of DMRs and NDMRs? How is this demonstrated? | Any drug with nAChR affinity will also have mAChR affinity. This is demonstrated through the many side effects of the drugs. |
| What is the functional group common to all NMBAs? What pharmacokinetic properties does this produce? pharmacodynamic? | Quarternary ammonium groups. Ionized, water-soluble, limited lipid solubility. Limited Vd (14L), no BBB/placenta, no PO, no CNS effects, minimal renal reabsorption |
| What are the two ways of classifying NDMRs? | By length of action and by structure. |
| What are the clinically relevant long, intermediate, and short acting NDMRs? | L: Pancuronium; I: Roc, Vec, Atra, Cistra; S: NONE! |
| With which anesthetic agents do NMBAs interact? How? | Volatile agents (x N2O). VA's potentiate the effects of NDMRs via Ca channels necessitating smaller doses. |
| What are the clinucal uses of NMBAs? | Facilitate intubation, enhance surgical conditions, dec O2 utilization in critically ill pt's w/ limited reserve, treat laryngospasm (sm. SCh dose), treat trunkal rigidity of opioids. CANNOT TREAT BRONCHOSPASM (autonomic NS)! |
| Why must laryngospasm be treated swiftly? | Large breath against the closed larynx can cause pulmonary edema. |
| Why is the NMBA ED95 unique compared to other drug profiles? | This is where the drug causes 95% supression of a single twitch via peripheral nerve stimulator NOT to produce muscle relaxation in 95% of people. |
| What is the recommendation for NDMR doses? What is special about this recommendation? | 2x the ED95. 90% muscle relaxation is adequate for surgical relaxation. |
| What factors determine NMBA choice? | Speed of onset, duration of action, side effect profile, patient health history. |
| We were told about a specific indication for the use of succinylcholine. What is it? | Full stomach. |
| What are some signs of inadequate return of function after NMBA administration? | Difficulty focusing/diplopia, inability to swallow/dysphagia, ptosis, mandibular weakness, low VT, "FLOPPY". |
| What have NMBAs earned the title of? Which 2 are most responsible? | Causing the most allergic reactions in anesthesia. Biggest offenders are SCh and Roc. |
| What are the 2 structural classifications of NDMRs? How are they distinguished? | Benzylisoquinoliniums (-uriums; more likely to release histamine) and Aminosteroids (-uroniums). |
| How does the chemical structure of NMBAs affect receptors and side effect profile? | Ammonium (+) is attracted to n&mAChRs (-) potentially causing cardiac side effects. Carbon chain length are more specific to nAChRs (autonomic block makes at 6 C's, NM blockade maxes at 10 C's). |
| What are the doses for SCh? | Norm: 0.5-1 mg/kg RSI: 1-1.5 mg/kg (more likely 1.5) |
| What does phase I blockade refer to? What might this cause? | Sustained depolarization in which the depolarized membrane and receptors cannot respond to additional agonist. It may cause fasciculations. |
| What are fasciculations the result of? | Uncoordinated muscle contraction during DMR blockade. |
| By how much does serum K normally rise with SCh administration? What is important about this in terms of dose? When should SCh not be given? | 0.5 mEq/L. It is NOT dose dependent. Do not give if K is > 5.0 |
| What might happen with SCh overdose? | Phase II blockade: Fade on TOF or after tetany? |
| What is the difference between Phase I and Phase II blockade? | I: Decreased tetany, TOF ratio > 0.7, no PTFacil, fasciculations, AUGMENTED w/ anti-AChEase. II: tetanic FADE, TOF ratio < 0.7, no fasciculations, reversible. |
| How does abrupt onset of a Phase II blockade manifest? | As tachyphylaxis and increased dose requirements. |
| What are the products of SCh metabolism? What are the fates of te products? | SCh -> S-MONO-CH + choline -> succinic acid + choline. They are likely not taken back up. |
| What is SCh termination of action due to? How do we know? | Diffusion away from the site of action. Plasma cholinesterase does not reach the NMJ. |
| What might prolong the action of SCh? | Decreased plasma cholinesterase (decreased synthesis(pregnancy), drug induced inhibiton(metoclopramide), or genetic conditions(atypical cholinesterase)). |
| When is atypical cholinesterase often discovered? | After prolonged effect from 1st dose. |
| What test permits the Dx of atypical cholinesterase? What do the results demonstrate? | Dibucaine test. 80=normal; 40-60=hetrozygosity (1:480, modest inc DOA); 20=homozygous (1:3200, NMB may last hours). |
| How does myasthenia gravis affect NMBAs? | Resistance to SCh may be seen d/t a decrease in function nAChRs. |
| Which NMBA releases the most histamine? What might it cause? | SCh. With large/rapid doses, facial/truncal flushing, bronchospasm, dec BP leading to anaphylaxis). |
| What are the effects of SCh on the CV system? When are effects more common? How can they be prevented? What might alternatively happen? | Dysrhythmias (SB, junc, sinus arrest have been observed) d/t stimulation of cardiac postgang mAChRs. More common after a second dose or in peds. Prevent w/ NDMR or atropine. May also inc HR and BP (SNS ganglionic stimulation). |
| In what patients does hyperkalemia reliably occur? | Muscular dystrophy, 3rd degree burns, denervation injuries (mucle atrophy, trauma, sepsis, upper motor neuron injuries, prolonged bedrest, mechanical ventilation). |
| What is the mechanism behind a more exaggerated K release? | Proliferation of extrajunctional receptors? |
| What is the musculoskeletal effect of SCh administration? What is it related to? Who is likely to experience it? How can it be treated? | Myalgia. It is related to fasciculation. Young, healthy, athletic types are likely to experience it. It can be prevented with NDMRs and treated with NSAIDs as appropriate. |
| How does SCh affect the eye? Why is this important? | Increases intraocular pressure. This could cause extrusion of intraocular contents. |
| How does SCh affect the CNS? | Supposedly through and increased ICP, though this is not a consistent observation and can probably be used safely. |
| How does SCh affect the GI system? Why is this of concern? How can this be prevented? | Increases gastric pressure (presumably through abd muscle contraction). This could increase the risk for aspiration. It can be prevented with defasciculating doses of NMDRs. |
| What is trisums? Who does it affect most? What must it be differentiated from? | Sustained muscle contraction in the masseter. Common in children. Must be differentiated from MH. |
| What makes an airway an emergent airway? | Inability to ventilate said airway. For example, trismus is not an emergency unless you cannot ventilate the patient. |
| What is a major complication of SCh administration? What is the mechanism behind it? What are the symptoms? What is the treatment? | MH! Defective ryanodine receptors release excessive amounts of Ca causing a hypermetabolic state. Muscle rigidity, hyperpyrexia (late), inc O2 reqs, hypercarbia, tachycardia, metabolic acidosis, rhabdo. Treat w/ dantrolene. |
| Why is the slope of the NMBA dose-response curve important? | It is very steep so a lot (80-90%) of receptors need to be blocks before a response is seen. |
| What are the CV effects of NDMRs? | Histamine and prostacyclin release (more w/ -uriums); Also antagonizes nAChRs and mAChRs. |
| What is the autonomic margin of safety? Which has the most narrow? Widest? | The difference between the required dose of NDMR for NM blockade and the dose required for circulatory effects. Pancuronium is most narrow. Vec, Roc, Cis have widest margins. |
| What is the greatest interaction between VA's and NDMRs? | Desflurane and Rocuronium |
| What classes of drugs are known to interact with NMBAs? | ABx-NMBA (esp aminoglycosides;dec prejunc ACh release by competing w/ Ca), LocAn-NMBA, antidysrthmics-NMBA, diuretics-NMDR (inhibits cAMP which dec ACh), Mg-NDMR (esp vec), Lithium-NMBAs |
| What is the intubating dose of Pancuronium? Onset? Duration? What prolongs duration? | Dose: 0.1 mg/kg. On: 3-5 min. Dur: 60-90 min. Prolonged by: renal Dz, cirrhosis, billiary obstruction, aging |
| How is Pancuronium eliminated? Metabolized? | Elim: renal elimination (80% unchanged (unique feature)). Metab: Hepatic deacetylation (10-40%) to 3-desacetylpancuronium (50% as potent; cumulative with repeat dosing) |
| What are the CV effects of Pancuronium? | Inc HR, BP, CO (d/t antagonism mAChRs @ SA Node). This is more profound w/ AV conduction abnormalities. It also increases O2 consumption, which can contribute to ischemia. |
| How can the speed of onset for Pancuronium be hastened? | Administer a priming dose (10% of ED95, which is also the defasciculating dose). |
| Why does a higher dose of SCh need to be given after NDMR administration? | Concentrations need to be high enough to kick off the antagonist. |
| What is the Intubating dose of Vecuronium? Onset? DOA? What prolongs duration? | Dose: 0.1 mg/kg. Onset: 3-5 min. Dur: 20-35 min. Prolonged with: prolonged with renal &/or hepatic disease. |
| How is Vecuronium eliminated? | Renal and hepatic; Deacetylation to desacetylvecuronium (50-70% as potent; can cause prolongation). |
| What are some advantages of Vecuronium use? | Does not antagonize mAChRs, no histamine release. |
| What are pediatric considerations with Vecuronium? | Potency is similar to that of adults, Onset more rapid and DOA longer in infants |
| What are some elderly considerations with Vecuronium? | Prolonged DOA d/t dec clearance. |
| What are some considerations for obese patients regarding Vecuronium? | DOA is prolonged when >130% IBW. |
Created by:
mikerawley