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Volume 1
Neuromuscular Physiology and Pharmacology
| Question | Answer |
|---|---|
| An action potential travels along the motor nerve axon and ultimately invades the ____ ____ _____. | presynaptic nerve terminal |
| Depolarization of the presynaptic nerve terminal causes what channels to open? | voltage gated calcium channels |
| Calcium travels from where to where? | from outside the nerve terminal, down a concentration gradient into the nerve terminal |
| What occurs due to the influx of calcium in the nerve terminal? | Release pool vesicles fuse with the nerve cell membrane and open to the exterior. |
| What is this process called? | Quantal release |
| What is it called quantal release? | each vesicle contains a quantum of acetylcholine |
| How many quanta are released by each action potential arriving at a presynaptic nerve terminal? | 125 |
| ACh spills out into the synaptic cleft via ___. | exocytosis |
| How many ACh molecules are released per quantum (vesicle)? | 10,000 |
| How does the presynaptic nicotinic receptor responds to ACh in the cleft? | By increasing the synthesis of ACh and mobilizing ACh containing vesicles (storage pool) |
| What type of feedback loop is this? | Positive feedback |
| What is the purpose of this positive feedback system? | prevents the depletion of ACh at the neuromuscular junction and also accounts for the phenomenon of fade seen with nondepolarizing muscle relaxants, and phase II block with succinylcholine. |
| Where do motor neurons to skeletal muscle originate? | anterior, ventral horn of the spinal cord |
| Sensory neurons from skeletal muscle carry action potentials to the spinal cord via what? | the dorsal horn |
| Motor and sensory nerves are __ nerves. | somatic |
| Which are more important for anesthetists to know about-motor or sensory nerves? | motor nerves to skeletal muscle |
| Motor neurons are what type of fiber? | A alpha |
| Describe A alpha fibers. | largest, most heavily myelinated fibers, thus have the fastest conduction velocity. |
| What is a motor unit? | a single A alpha motor nerve and all o the skeletal muscle fibers it innervates |
| What do SAME, DAVE, and SAD stand for? | Sensory Afferent Motor Efferent; Dorsal Afferent Ventral Efferent; Sensory Afferent Dorsal |
| The presynaptic terminal of the motor nerve releases ___ to the motor end plate. | ACh |
| What are embedded in the membrane of the presynaptic nerve terminal? | voltage gated calcium channels and nicotinic receptors |
| Where else are nicotinic receptors found? | post-synaptically in the membrane of the motor end-plate |
| Where are acetylcholinesterase molecules found? | in close proximity to the postsynaptic nicotinic receptors; they extend into the synaptic cleft in order to metabolize ACh |
| How wide is the synaptic cleft? | 20-50 nm wide |
| What clinical effect does the number of ACh molecules released by the presynaptic membrane have? | The immense quantity of ACh transiently in the cleft may account for the larger initial doses of muscle relaxants, compared to maintenance doses |
| Describe the steps that occur at the postsynaptic membrane with ACh? | ACh combines with nAChR on the motor end plate and the channel allows Na, Ca, and K ions to diffuse across, causing depolarization. At threshold, an AP is initiated in the perijunctional area which sweeps across skeletal muscle and triggers contraction |
| What part of the nicotinic receptor must ACh attach to open the channel? | both alpha subunits |
| What direction do Na, Ca, and K travel through the nicotinic receptor channel? | NA and Ca diffuse into the cell, and K diffuses out into the extracellular space |
| What part of the neuron depolarizes when the ions travel through the channel? | motor end plate |
| What is this depolarization called? | End plate potential |
| What is the entire process of events from the presynaptic membrane to the muscle fiber contraction called? | excitation contraction coupling |
| What is acetylcholinesterase also known as? | true, specific, genuine, or type 1 cholinesterase |
| What does acetylcholinesterase break down ACh into? | choline and acetate |
| What happens to the motor end plate when ACh is metabolized? | the motor end plate repolarizes and the muscle becomes ready for another squirt of ACh from the nerve terminal |
| What happens to the choline byproduct? | it is transported back into the nerve terminal where it is used to re-synthesize ACh |
| What does the release of NT from all nerve terminals, including the motor nerve terminals, depends on? | the entry into the terminal of CA++; "Calcium comes in, neurotransmitter goes out" |
| Hypocalcemia is associated with a(n) (increase/decrease) in the amount of neurotransmitter released, and hypercalcemia is associated with a(n) (increase/decrease) in the amount released. | hypo- decrease; hyper-increase |
| Hypomagnesemia is associated with a(n) (increase/decrease) in the amount of neurotransmitter release, and hypermagnesemia is associated with a(n) (increase/decrease) in the amount of neurotransmitter released. | Hypo-increase; hyper-decrease |
| Calcium and magnesium are _____ at presynaptic nerve terminals | antagonistic |
| The nicotinic acetylcholine receptor has how many subunits? | 5 |
| The nicotinic acetylcholine receptor has a number of protein variations known as what? | isoforms |
| What is the adult isoform? fetal isoform? | Adult: 2aiBye (2 alpha i beta gamma epsilon; fetal 2aiByo (2 alpha i beta gamma delta) |
| In adult skeletal muscle, what type of isoform are located at extrajunctional and prejunctional receptors | extra-junctional: fetal isoform; prejunctional: a3B2 (alpha 3 Beta 2) |
| Two of the five subunits are ___. | identical |
| Which subunits are identical ? | alpha subunits |
| Where is AChE located? | anchored to the extracellular surface of the cell membrane |
| What is the significance of two identical alpha subunits? | 2 ACh molecules are needed to open each nicotinic acetylcholine receptor; an ACh molecule must attach to each of theses two identical subunits where the nicotinic receptors are located in order to open the channel |
| In addition to ACh, acetylcholinesterase also degrades what substances? (5) | ester local anesthetics, neostigmine, edrophonium, remifentanil, and esmolol |
| Nondepolarizing drugs are _____ inhibitors. | competitive |
| Describe an overview of a nondepolarizing block. | When a nondepolarizing agent binds to either ACh binding site on a nicotinic receptor, ACh cannot attach to the receptor and the channel cannot open |
| Describe an overview of a depolarizing block. | Succinylcholine binds to nAChR and opens channels in the same way ACh does. Because, however, succinylcholine is not metabolized by true acetylcholinesterase, voltage gated Na channels in the perijunctional area become and remain inactivated. |
| What does it mean that Na channels in the perijunctional area become and remain inactivated? | they do not reset to the closed, resting conformation, in the face of persistent depolarization |
| How common are fasciculations after succinylcholine administration? | 60-90% |
| When does myalgia occur? | 24-48 hours after administration |
| After IV administration, a nondepolarizing neuromuscular blocker circulates where? | to all tissues, including skeletal muscle |
| The nondepolarizing neuromuscular relaxant diffuses from the ____ compartment into the ____ ____ of the neuromuscular junction. | vascular, synaptic cleft |
| What effect does the nondepolarizing agent have on the nAChR? | none- the ion channel does not open |
| What happens when a nondepolarizer causes a channel to stay closed? | the postsynaptic membrane remains polarizes, and thus a nondepolarizing neuromuscular blockade is established |
| Describe 5 characteristics of a nondepolarizing block. | MOA is competitive inhibition; fade follows high frequency stimulation (>0.1 Hz); exhibits post-tetanic facilitation; antagonized by anticholinesterases; no fasciculations |
| Is a nondepolarizing block a Phase I or Phase II block? | Phase II |
| what is succinylcholine composed of? | 2 acetylcholine molecules linked together |
| Whats another name for succinylcholine? | diacetylcholine |
| Succinylcholine, after it is administered intravenously, diffuses into ___ from __. | tissues from blood |
| What happens when succinylcholine molecules reach the motor nerve terminal? | the succinylcholine molecules that reach the motor nerve terminal of skeletal muscle combine with nicotinic receptors and cause the channels of the motor end plate to open; the motor end plate depolarizes and a single contraction occurs |
| Action potentials cannot be initiated in the skeletal muscle until the cell ____. | repolarizes |
| An AP cannot be initiated in the skeletal muscle because the sodium gates are what? | in the inactivated state |
| What cannot happen as long as the motor end plate does not repolarize? | additional action potentials and hence contractions cannot be initiated |
| What is the result of the inability for additional action potentials to be propagated? | muscle paralysis |
| What metabolizes succinylcholine? | plasma cholinesterase |
| Where is plasma cholinesterase located? | plasma |
| Where is acetylcholinesterase located? | at the motor end plate |
| What are other names for plasma cholinesterase? | pseudocholinesterase, butyro-, benzoyl-, false, non-specific, and type II cholinesterase. |
| Is succinylcholine metabolism in the plasma slow or fast? | fast |
| How is the succinylcholine attached on the motor end plate terminated? | As circulating succinylcholine is metabolized, a gradient develops for succinylcholine to diffuse from the skeletal muscle motor-end plate back into the plasma, and the effect of succinylcholine is terminated |
| Describe 6 characteristics of a depolarizing block. | decreased single twitch height, response to high frequency stimulation is maintained, minimal or no fade after TOF, antagonized by nondepolarizers, potentiated by anticholinesterase, muscle fasciculations precede block |
| Is a depolarizing block from succinylcholine a Phase I or II block? | Phase I |
| Describe the relationship between succinylcholine and voltage gated sodium channels. | When motor end plate depolarizes in response to SCh voltge gated Na chnls in the membrane adjacent to motor end plate snap into the inactivated state. As long as SCh maintains the depolarized state the Na chnls remain inactivated nd AP cannot be elicited |
| When the gated sodium channel is in the inactivated state, another action potential cannot be fired no matter how intense the stimulus. The absolute refractory period corresponds to the time when the fast voltage gated sodium channels... | are in the inactivated state. Depolarization of the motor end plate by succinylcholine causes the voltage gated sodium channels to become inactivated, thereby electrically arresting the skeletal muscle. |
| At the neuromuscular junction, does the presynaptic action of succinylcholine enhance or antagonize its postsynaptic action? | Succinylcholine, by stimulating the presynaptic nAChR, augments the release of ACh. Sine the released ACh opens channels and depolarizes the motor end plate like SCh, the presynaptic action of SCh enhances its postsynaptic action. |
| What is the brand name for succinylcholine? | Anectine |
| Define Potency. | the relationship between twitch depression and dose. ED 95 represents 95% block of a single twitch, compared to a control single twitch. |
| Define onset time. | time to maximum blockade after administration of agent; usually compared at 2x ED 95 |
| Define duration of action. | time from injection to return of 25% twitch height; Nagelhout defines "total duration of action" as the time from drug administration to 90% recovery of twitch response. |
| Define recovery index. | time interval between 25% to 75% twitch height |
| Are quarternary ammonium compounds ionized or non-ionized? | ionized |
| Nondepolarizing agents can be classified in two categories based on structure. What are they? | aminosteroids and benzylisoquinolones |
| How can you tell the difference between the two? | aminosteroid: curonium;benzylisoquinolones: curium |
| Name the monoquarternary aminosteroids | vecuronium, rocuronium |
| Name the bisquarternary aminosteroids. | pancuronium |
| Name the bisquarternary benzylisoquinolones. | atracurium and cisatracurium |
| Name 5 Physiologic properties of neurmuscular relaxants. | 100% ionized at physiologic pH; very highly protein bound; do not cross the blood brain barrier; do not cross placental barrier; trapped in the renal tubule after filtration because of high degree of ionization |
| Why don't neuromuscular blockers cross the blood brain or placental barrier? | they are ions so they do not cross lipid barriers |
| All muscle relaxants can be excreted by _____ if other routes are unavailable. | the kidneys |
| Metabolism is the primary route of elimination for what 4 NMBs? | succinylcholine, atracurium, cisatracurium, and mivacurium |
| Biliary excretion is the primary route of elimination for what two NMBs? | vecuronium and rocuronium |
| Renal excretion is the primary route of elimination for what 6 NMBs? | d-tubocurarine, metocurine, pancuronium, gallamine, doxacurium, and pipercuronium |
| The termination of atracurium, cisatracurium, vec and roc is by ____. | redistribution |
| How is atracurium metabolized? | 2/3 by ester hydrolysis and 1/3 by Hoffman elimination |
| Ester hydrolysis: | nonspecific esterases, biologic elimination |
| What is Hoffman elimination? | pH and temperature dependent degradation; chemical elimination |
| How is cisatracurium eliminated? | Hoffman elimination |
| Are nonspecific esterases involved in the elimination of cisatracurium? | no |
| Which muscle relaxants produce autonomic ganglionic blockade? | d-tubocurarine and metocurine - block nicotinic receptors at the autonomic ganglia |
| Which muscle relaxants elicit histamine release? | succinylcholine, mivacurium, atracurium, d-tubocurarine, and metocurarine |
| Which muscle relaxants produce bradycardia? | succinylcholine |
| Why does succinylcholine produce bradycardia? | it mimics the action of acetylcholine and directly stimulates muscarinic receptors of the sinoatrial node |
| Which muscle relaxants produce tachycardia? | atracurium, d-tubocurarine, metocurine, pancuronium and gallamine |
| Why do these muscle relaxants cause tachycardia? | atracurium, d-tubocurarine, and metocurine produce reflex tachycardia; pancuronium and gallamine competitively antagonize acetylcholine, which are referred to as direct vagolytic, or more specifically antimuscarinic action |
| Which muscle relaxants produce significant hypotension? | succinylcholine, d-tubocurarine, and metocurine |
| Which muscle relaxants produce significant hypertension? | pancuronium and gallamine |
| What are 11 adverse effects associated with the use of succinylcholine. | release of K from cells; myalgia, dysrhythmias, AV conduction block, increased IOP, MH, increased ICP, prolonged respiratory paralysis; myoglobinuria; fasciculations, increased intragastric pressure |
| Why does K increase with succinylcholine administration? | K+ exits the cell through channels of the motor end plate that open in response to acetylcholine |
| How much does K increase with succinylcholine administration? | plasma K+ concentration may increase b 0.5 mEq/L in normal patients; and 5-10 mEq/L in burn, trauma, or head injury patients |
| Where does myalgia occur the most with succinylcholine administration? | subcostal, truck neck, upper abdominal region, and shoulders |
| When does myalgia usually manifest? | 24-48 hours after administration |
| What dysrhythmias may occur after succinylcholine administration? | mild tachycardia, bradycardia secondary to increased K+, especially after repeated dosing |
| How much does IOP increased after succinylcholine administration? | 5-10 mmHG |
| Why does IOP increase? | vascular mechanism of action |
| Why may prolonged respiratory paralysis occur after succinylcholine administration? | if patient has atypical plasma cholinesterase |
| What conditions may accentuate succinylcholine induced hyperkalemia? | thermal trauma (burns), spinal cord transection; paraplegia or hemiplegia; skeletal muscle trauma; upper motor neuron injury (head injury, cerebrovascular accident, Parkinson's disease); prolonged immobility |
| Each of the conditions that accentuate succinylcholine induced hyperkalemia are associated with proliferation of what? | proliferation of extrajunctional postsynaptic cholinergic nicotinic receptors |
| Why do these conditions accentuate succinylcholine induced hyperkalemia? | When nerve action potentials to skeletal muscle are interrupted, postsynaptic nicotinic receptors upregulate and spread from the NM junction to the entire muscle fiber. |
| Which of these conditions is not included in this mechanism of action? | prolonged mobility |
| If you were to use a nerve muscle stimulator on the right write of the patient with right sided hemiplegia, will the twitch be less than, the same as, or greater than the twitch on the left? | The twitch on the right will be greater than on the left. Nicotinic receptors are up regulated on the right, hemiplegic side. |
| How is malignant hyperthermia diagnosed? | unexplained signs of increased ETCO2, pyrexia, tachycardia, cyanosis, rigidity, or failure of the masseter muscle to relax (trismus) |
| What are the changes in serum composition seen in malignant hyperthermia? | increased H+, K+, Ca++, and CO2 and decreased CO2 |
| The defect in malignant hyperthermia is a mutation of the ____ ____. | ryanodine receptor (RyR1) |
| Where is the ryanodine receptor located? | embedded in the sarcoplasmic reticulum of skeletal muscle |
| The sarcoplasmic reticulum releases calcium continuously, leading to what? | sustained contraction with increased metabolism |
| What drug is used to treat malignant hyperthermia? | Dantrolene |
| How does dantrolene act? | acts on the sarcoplasmic reticulum to decrease the release of calium to contractile proteins |
| Name signs and symptoms of malignant hyperthermia? | trismus, whole body rigidity, elevation of ETCO2, tachycardia, tachypnea, increased PaCO2, cyanosis, unstable blood pressure, dysrhythmias, hyperkalemia |
| What is trismus? | masseter muscle spasm |
| What percept of patients who have MH exhibit trismus? | 50% |
| Whole body rigidity appears ___% of the time with MH. | 75% |
| What is tachycardia and tachypnea a result of with MH? | sympathetic stimulation secondary to underlying hypermetabolism and hypercarbia |
| With MH, PaO2 may increase > ___ mmHG and pH may decrease to less than ___. | >100, <7.0 |
| What is one of the earliest, most sensitive, and specific signs of MH? | increase ETCO2 |
| What occurs first, tachycardia or increased ETCO2? | increased ETCO2 |
| What agents trigger malignant hyperthermia? | succinylcholine and halogenated inhaltional agents: isoflurane, desflurane, halothane, enflurane, sevoflurane |
| Why isn't cardiac muscle directly involved in malignant hyperthermia? | Cardiac myocytes (muscle fibers) express the RyR2 isoform of the ryanodine receptor |
| What factors increased the degree of nondepolarizing neuromuscular block? | antibiotics, local anesthetics, VAAs, hypokalemia, hypermagnesemia, respiratory acidosis, hypothermia, antiarrhythmic agents, renal isease, hepatic disease, myasthenia gravis, elderly, obesity, lithium, diuretics, Ca Ch Blockers, |
| What antibiotics increase the degree of block with nondepolarizers? | neomycin, streptomycin, tobramycin, dihydrostreptomycin, kanamycin, gentamicin, polymixin B, colistin, lincomycin, tetracycline |
| What antibiotics is the degree of block unchanged with nondepolarizer administration? | penicillin, chloramphenicol, cephalosporins, tetracyclines, and erythromycin |
| What type of local anesthetics increase the degree of block with nondepolarizers? | amides |
| How much do LA increase the block? | dose my be reduced 1/3 to 1/2 |
| How much can the NMB dose be decreased with inhaltional agents? | 1/2 to 1/3 |
| Which antiarrhythmic agents increase the NM block? | quinidine, propanolol, and procainamide |
| WHy does old age increase the block? | in elederly >60-65 yrs because organs of elimination are less effective |
| Which two nondepolarizers are not effected by obesity? | atracurium and cisatracurium |
| What effect do corticosteroids have on the block from nondepolarizers? | block unchanged by IV administration |
| What effect do anticonvulsants have on the block from nondepolarizers? | block is decreased in patients treated chronically with anticonvulsants, however, block is increased following acute administration of phenytoin |
| What effect does thermal injury have on blocks from nondepolarizers? | block decreased; manifests 10 days after injury, peaks at 40 days, and declines after 60 days |
| What happens if 2 nondepolarizers are administered in sequence? | duration of second agent becomes that of the first agent. switching from a longer acting agent to an intermediate acting agent towards the end of the case will not provide paralysis of intermediate duration |
| What factors increase the block of succinylcholine? | antibiotics, local anesthetics, anticholinesterase agents, hypermagnesemia, atypical pseudocholinesterase, lithium, calcium channel blockers, pancuronium |
| What antibiotics increase the block from succinylcholine? | neomycin, streptomycin, dihydrostreptomycin, kanamycin, gentamicin, polymyxin A, polymyxin B, colistin, lincomycin |
| What antibiotics have no effect on the neuromuscular block after succinylcholine administration? | penicillin, chloramphenicol, cephalosporins, tetracyclines, and erythromycin |
| Which class of local anesthetics increases the neuromuscular block from succinylcholine? | amides |
| What anticholinesterase agents produce an increased block with succinylcholine administration? | edrophonium, neostigmine, physostigmine, echothiopate, |
| What other agents depress the cholinesterase enzyme and produce an increased block? | ester local anesthetics such as procaine and phenothiazines such as chlorpromazine |
| Why does pancuronium cause an increased block with succinylcholine administration? | pavulon inhibits plasma cholinesterase |
| What effect do volatile anesthetics have on the neuromuscular block produced from succinylcholine? | unchanged |
| What effect do nondepolarizers have on the block produced by succinylcholine? | decreased |
| What effect does myasthenia gravis have on the block produced by succinylcholine? | decreased |
| What is train of four? | 4 stimuli every 0.5 second = 2Hz |
| What effect do nondepolarizers have on single twitch and train of four? | they are reduced with amplitude |
| Does fade occur with nondepolarizers during TOF? | yes |
| What is double burst stimulation? | two short bursts of 50Hz tetanic stimulation separated by 750 ms. The duration of each square wave impulse in the burst is 0.2ms |
| What is tetanic stimulation? | 50Hx, 5 seconds |
| What is post tetanic twitch? | following tetanic stimulation, there is post-tetanic facilitation (potentiation) wherein single twitches after tetany are larger than single twitches before tetany. With block by a nondepolarizing agents there is fade during and after tetany |
| Are there muscle fasciculations prior to paralysis with nondepolarizing blocks? | no |
| What is an antagonist to a nondepolarizing block? | agents that inhibit true acetylcholinesterase: edrophonium, neostigmine, pyridostigmine |
| Amplitude of single twitch contractions decreases with _____ intensity of block with nondepolarizing blocks. | increasing |
| When does fade occur with nondepolarizing blocks/ | during train of four stimulation and during tetanic stimulation |
| Is posttetanic facilitation (potentiation) present with a nondepolarizing block? | yes |
| What is the train of four ratio? | amplitude of fourth beat to amplitude of first beat |
| Describe the train of four ratio with a nondepolarizing block. | train of four ratio is less than 70% |
| The diaphragm moves when __ % of receptors are occupied. | 95 |
| Abdominal relaxation is present and adequate for most-intra-abdominal procedures when __ % of receptors are occupied. This is seen as __ twitch(s) present in TOF. | 90; one |
| __% of receptors are occupied when tidal volume returns to normal. | 75-80 |
| How many twitches are present with TOF when tidal volume returns to norma. | single twitch as strong as baseline |
| Is this a good indicator of recover? | no |
| There is no palpable fade in TOF when ___% of receptors are occupied. | 70-75 |
| There is no palpable fade in double burst stimulation when __ % of receptors are occupied. | 60-70 |
| The pt passes inspiratory pressure test, atleast -40cmH2O, head lift for 5 seconds, sustained strong hand grip, sustained bite, occurs when ___ % of receptors are occupied. | 50% |
| When is more sensitive of an indicator, OF or double burst with no fade? | double burst |
| When are conditions for intubation appropriate? (% of receptors occupied) | >95% |
| What effect does succinylcholine have on single twitch and train of four? | reduction in amplitude but no fade after TOF stimulation |
| What effect does succinylcholine have on post tetanic facilitation? | post tetanic facilitation is absent; single twitches after tetany are reduced compared to single twitches before tetany |
| Describe characteristics of Phase I Depolarizing NM blocks. (1) | fasciculations appear prior to paralysis; block is augmented by cholinesterase inhibitors; amplitude of singe twitch contractions decreases in proportion to the severity of the block; |
| Describe characteristics of Phase I Depolarizing NM blocks. (2) | fade does not occur during tetanic stimulation or TOF, although the amplitude of both are reduced; TOF ratio is greater than 70%; post tetanic facilitation is absent; block is antagonized by nondepolarizers |
| How can you reach a phase II block with succinylcholine? | treatment with higher doses of succinylcholine and/or prolonged exposure of the motor end plate to succinylcholine leads to the development of phase II, or desensitization |
| Describe a Phase II block. | Phase II block is a very complex phenomenon; ion channels of the motor end plate close for reasons that are unknown, and the motor end plate repolarizes. |
| Describe the twitch responses that you will see with a Phase II block. | Phase II block has the characteristics of a nondepolarizing block; use of a periph nerve stimulator during phase II block will show fade and post-tetanic facilitation. Higher doses of SCh inhibit presynaptic (alpha3beta2) nicotinic ACh receptors -> fade. |
| What is dual blockade? | simultaneous existence of both depolarizing (Phase I) and Phase II blockade |
| Describe the timing of reversal of nondepolarizing NM blockade. | Antagonism of NM blockade should normally not be attempted when blockade is intense because reversal will often be inadequate, regardless of the dose of antagonist administer. Reversal can be attempted when one twitch is elicited. |
| Timing of reversal of nondepolarizing NM blockade per Miller. | In general, antagonism should not be initiated before at least two, preferable three or four responses are observed |
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