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Pharmacology: Relaxants and Local Anaesthetics
Which of the following relaxants are likely to be potentiated in a patient on cyclophosphamide?(10)
1. Suxamethonium.
2. Cisatracurium.
3. Mivacurium.
4. Rapacuronium.
Ans:1,3
Cyclophosphamide inhibits the activity of numerous cholinesterases and has been reported to potentiate the effects of both suxamethonium
and mivacurium.
Cisatracurium is largely hydrolysed by non-enzymatic (Hofmann) degradation.
Rapacuronium is an aminosteroid, nondepolarising neuromuscular blocking agent and is not hydrolysed by cholinesterases.
Which of the following statements are true with regard to local anaesthetic toxicity?(86)
1.A predictable relationship between plasma concentration and toxic effect exists for both lignocaine and bupivacaine.
2. Bretylium is a useful antiarrhythmic in bupivacaine-induced ventricular tachycardia.
3. Lignocaine potentiates the cardiotoxicity of bupivacaine.
4. Convulsions can be expected with lignocaine at 10-12 ug/ml.
Ans:2,4
Toxicity associated with the systemic uptake of LA's predominantly involves CNS and CVS effects. For Lignocaine a reasonably predictable
relationship exists between signs and symptoms of toxicity and plasma concentration (ug/ml) (perioral numbness-4; convulsions-10-12;
coma-16; respiratory arrest-20; CVS collapse-25).The ratio between CVS collapse and convulsions (CC/CNS ratio) is a useful index of the
safety of the agent. Bupivacaine is considered a more toxic agent because it has a lower CC/CNS ratio as compared with Lignocaine (3.6 v
1.6 ) and it is less predictable. Moreover, toxicity parallels anaesthetic potency which is related to lipid solubility.
Cardiotoxicity is a greater threat with Bupivacaine than Lignocaine. VT/VF is a real possibility with the former and is notoriously difficult to
treat especially in the parturient. Bretylium has a role because of this, but is in itself not reliable. Lignocaine induced VT/VF has not been
described in humans. Hypercarbia decreases protein binding, hence more drug is available to cross the BBB.
WOOD, A. & WOOD, M; Drugs and Anesthesia, 2nd Ed.,1990.
COUSINS ,M & BRIDENBOUGH; Neural Blockade, pp 121-8.
With regard to prilocaine:(174)
1. It is a tertiary amine.
2. It has a shorter duration of action than lignocaine.
3. Its duration of action is increased with adrenaline.
4. Clinically detectable cyanosis can be expected in doses greater than 600 mg.
Ans: 4
Prilocaine is an amide type local anaesthetic agent. Hence, it has structural similarities to lignocaine and mepivacaine; however, it is a
secondary amine. It has a significantly decreased potential for producing systemic toxicity which is partly attributed to this. It requires no
preliminary dealkylation, undergoing immediate enzymatic hydrolysis to ortho-toluidine and N-propylalamine. Recall that lignocaine
undergoes N-dealkylation to yield monoethylglycinexylidide (MEGX) which, in turn, is followed by secondary N-dealkylation to give
glycinexylidide (GX) before hydrolysis. Prilocaine also has larger volume of distribution. Its rapid metabolism and redistribution result in
lower serum levels after intravenous anaesthesia or accidental intravascular injection.
Prilocaine has a clinical profile which is similar to lignocaine. It has a relatively rapid onset of action, a moderate duration of action, and
causes a profound depth of conduction blockade. In contrast, it causes significantly less vasodilation than lignocaine. As a result its duration
of action is not increased by adrenaline. The duration of action of prilocaine without adrenaline is similar to that of lignocaine with
adrenaline.
The major problem associated with the use of prilocaine is its tendency to cause methaemoglobinaemia. Minor degrees of
methaemoglobinaemia occasionally follow lignocaine, however, prilocaine is unique amongst the local anaesthetic agents for its ability to
reduce the blood's oxygen carrying capacity to cause clinically detectable cyanosis. Methaemoglobin (metHb) exists physiologically in a
concentration of about 1% of total haemoglobin. This is because the ferrous porphyrin component of haem is continuously being oxidized to
the ferric form. However, a specific reductase continuously reduces it back to the functional ferrous form. Cyanosis does not become
clinically detectable until 5-6% of the patient's haemoglobin is in the ferric state.
A total dose of 300 mg of prilocaine will produce a metHb of 1.9%, while a dose of 600 mg will produce a level of 5.3%. Thus, by limiting
the total dose to 600 mg, cyanosis can be avoided. Note that in healthy individuals, enough to cause any compromise in oxygenation, but
this may occur in patients whose oxygen carrying capacity is already reduced. It is not recommended in obstetrics, as the cyanosis caused by
prilocaine may make exclusion of neonatal cyanosis from other causes difficult.
The following is the abstract ( Bartholomew) from an editorial entitled:
Prilocaine for Bier's block: how safe is safe?
" Prilocaine has become the agent of choice for Bier's block (or intravenous regional anaesthesia--IVRA), since 1983 when the product
licence of bupivacaine was withdrawn for this purpose owing to fatal or serious complications. No serious complications have been
documented in the literature relating to prilocaine in IVRA and we have conducted a survey within the U.K. which indicates that about
45,000 Bier's blocks have been carried out with prilocaine without convulsion, arrhythmia or fatality. This includes cases of accidental cuff
deflation or even failure to inflate the cuff, resulting in bolus doses to the circulation. Prilocaine has now been in use since 1964 and the
Committee for Safety of Medicines has no deaths on record over a 25-year period. (This includes other types of regional anaesthesia). We
suggest that intravenous regional anaesthesia using prilocaine is a safe technique. It is highly unlikely that fatalities will occur, provided
present guidelines are adhered to. We can find no reason to limit its use to trained anaesthetists only, but would recommend that a strict
protocol is adhered to. "
WINNIE, A.P.; Plexus Anesthesia, vol 1, Churchill Livingstone, 1984, p 224.
COUSINS & BRIDENBAUGH; Neural Blockade, p138.
WOOD, M. & WOOD, A.J.J.; Drugs and Anesthesia, 2nd Ed.,1990, p 332
BARTHOLOMEW, K. & SLOAN, J.P; Arch. Emerg. Med., vol7, no 3, 1990 Sep, pp 189-95.
With regard to EMLA* (Eutectic Mixture of Local Anaesthetics):(175)
1. The melting point of a eutectic mixture is greater than that of the individual components
2. The components are lignocaine and prilocaine
3. The components are lignocaine and bupivacaine
4. It requires a minimum of 60 minutes to work
Ans:2,4
EMLA* is a 5% cream consisting of a eutectic mixture of 2.5% lignocaine and 2.5% prilocaine. A eutectic mixture is one which has a
melting point lower than that of the individual components. When lignocaine and prilocaine are mixed together in base form, the crystalline
powders interact to form a liquid at room temperature. This is important in the preparation of oil-in-water emulsions as it obviates the need
for dissolving the local anaesthetic base in an oil before the addition of an emulsifier. Thus, it is possible to increase the concentration of
local anaesthetic in the emulsion droplets from approximately 20% (lignocaine) to 80% (lignocaine-prilocaine) in eutectic formulations,
while still keeping the total concentration of local anaesthetic low (5%).
EMLA* requires a minimum of 60 minutes of application under an occlusive bandage for anaesthetic effect.
POWELL, D.M. ET AL; "Damage to Tissue Defenses by EMLA* Cream", The Journal of Emergency Medicine, vol 9, 1991, pp 205-9.
The constant infusion of Vecuronium for a period of more than 48 hours has been implicated in:(182)
1. The persistence of residual weakness which may last 3-6 months.
2. An acute myopathy which becomes apparent as the neuromuscular junction (NMJ) returns to normal.
3. A cardiomyopathy in asthmatics who have received high dose steroids.
4. Prolonged NMJ failure in patients with renal failure.
Ans: 1,2,3,4
Myopathy complicating the therapy of severe asthma has been recently described in several case reports. Twenty-five consecutive patients
admitted to the intensive care unit (ICU) at the hospital cited in the reference below, for mechanical ventilation for severe asthma were
studied for the incidence of creatine kinase (CK) enzyme rise and for the development of clinical myopathy. Pharmacologic therapy was
standardized, every patient receiving corticosteroids and aminophylline intravenously and salbutamol both nebulized and intravenously.
Twenty-two patients received muscle relaxant therapy with vecuronium. In 19 of 25 (76%) of patients there was elevation of CK levels to a
median of 1,575 U/L (range, 66 to 7,430) occurring 3.6 +/- 1.5 days after admission. In nine patients there was clinically detectable
myopathy. The presence of either myopathy or CK enzyme rise was associated with a significant prolongation of ventilation time. Arterial
blood gas measurements on admission to the ICU revealed a pH (mean +/- SD) of 7.07 +/- 0.21, a PaCO2 of 87.2 +/- 32.7, and a PaO2 (with
a high FIO2) of 129 +/- 97 mm Hg; however, no correlation was found between the severity of initial metabolic disturbance and the
subsequent development of myopathy.
There was no association between the type of corticosteroid administered and the subsequent development of myopathy. Patients with
myopathy had received a significantly higher total dose of vecuronium when compared with those who did not develop myopathy (p <
0.001, Kruskal Wallis test). The authors have therefore found a surprisingly high incidence of CK enzyme rise and myopathy in this group of
mechanically ventilated patients with severe asthma.
DOUGLASS, J.A. ET AL; Am Rev Respir Dis., vol 146, no 2, Aug 1992 , pp 517-9 .
Suxamethonium:(184)
1. Is unlikely to cause muscle pains in a young, ambulant woman.
2. Causes a rise in serum potassium typically of the order of 0.5-1.0 mmol/L.
3. Causes an atypically large rise in serum potassium in patients with renal failure.
4. Causes a rise in serum potassium which is not prevented by pretreatment with a non-depolarizing muscle relaxant.
Ans:2,4
Suxamethonium typically causes an increase in the serum potassium of 0.5-1.0 mmol/L ( and sometimes 2 mmol/L). An atypically large rise
in serum potassium occurs in patients who have developed " extra-junctional" acetylcholine receptors at the muscle motor end-plate. Patients
with renal failure have disorders of potassium regulation, but do not have " extra-junctional " receptors. A typical rise in serum potassium
should be expected in these patients, however, if they already have hyperkalemia, a further rise of 1-2 mmol/L may be enough to cause
serious complications.
Muscle pain associated with suxamethonium typically occur in young women following minor procedures. This is partly explained on the
basis of a greater muscle mass in the young; and earlier ambulation following minor procedures, which " betrays " the condition. Longer
periods of bed rest associated with major procedures are felt to conceal the potential for pain. It is interesting to note that it is not commonly
reported in patients undergoing electroconvulsive therapy.
The pathogenesis is unclear. Theories include:
-muscle damage caused by the asynchronous contraction of muscle during fasciculation.
-release of lactic acid subsequent to muscle fasciculation.
-fascial damage caused by synchronous muscle fasciculation, and
-the rise in serum potassium.
Muscle pain may be prevented or reduced by " pre-treatment " with 10% of the standard intubating dose of a non-depolarizing muscle
relaxant. Greatest protection is afforded when the interval between administration of the intravenous induction agent and suxamethonium is
small.
The " normal " rise in serum potassium associated with suxamethonium is postulated to occur secondary to opening of outward potassium
channels on depolarization of the motor end-plate. Muscle fibre damage associated with fasciculations may also contribute. It typically lasts
for a period of 15 minutes, but may not return to normal values for 1 hour after the administration of suxamethonium.
Anaesthetic agents have been implicated in modifying this effect. This evoked release may be greater after N2O and halothane, for example.
In contrast, the evoked release may be attenuated by " pre-treatment " with gallamine. d-tubo-curarine, pancuronium, Mg, dantrolene,
diazapam, lignocaine, calcium gluconate, and salbutamol. " Self-taming " by pre-treatment with suxamethonium may also occur. These are
experimental findings and apply to the " normal " response only.
Certain groups of patients experience proliferation of " extra-junctional" acetylcholine receptors which occur outside the margins of the
motor end-plate. Suxamethonium causes a larger than usual rise in serum potassium. This rise is of the order of 2-3 mmol/L, but has been
reported as higher. It varies with the nature of the condition involved, its age, and severity. The conditions in which it has been described
include:
(1)BURNS. A 10-60 day rule has been described subsequent to reports of the phenomenon between days 14 -66 after burns. As in other
conditions, a latent phase occurs; " extra-junctional " receptors do not appear immediately after injury.
(2)ACUTE UPPER MOTOR NEURON LESIONS & STRUCTURAL BRAIN DAMAGE. These include spinal cord injury, anoxic
brain damage, encephalitis, subarachnoid haemorrhage, and cerebrovascular accidents.
(3)PROGRESSIVE NEUROLOGICAL CONDITIONS. Demyelinating diseases, and brain tumours may be associated with the
response. Again this will be greater if the disease is rapidly progressive, and in general, the potential for evoked release of potassium is of a
lower magnitude and occurs over a longer period of time. The relationship in Parkinson's disease is not clear.
(4)CHRONIC STABLE NEUROLOGICAL CONDITIONS. These are generally associated with a " normal " response only, including
cerebral palsy.
(5)LOWER MOTOR NEURON DISEASE. The phenomenom has been described betwen days 42-192 following acute peripheral nerve
damage, and cardiac arrest has been reported follwing suxamethonium with diffuse neuropathies.
(6)MUSCULAR DYSTROPHIES. Hyperkalemia has been reported in patients with Duchenne's muscular dystrophy, however, this was
ascribed to Malignant Hyperpyrexia.
(7)TRAUMA. As with burns, this occurs in manner influenced by the time from injury, and the extent of nerve and muscle damage.
(8)INFECTION. Again, this response has been seen in severe infection including osteomyelitis and gangrene.
GIBB, D.B; Anaesth Intens Care, 1, 109, 1973 & 1, 183, 1974. (The last word on suxamethonium in two parts!)
When used in conjunction with amide local anaesthetics (LA's):(200)
1. Lipid carrier solutions prolong the duration of effect.
2. IV Clonidine reduces the incidence of epidural shivering.
3. Clonidine potentiates membrane stabilisation produced by LA's
4. Alkalinisation of solutions increases the rate of onset and efficacy of LA's.
Ans:1,2,3
Both lipids and clonidine have potentially useful interactions with local anaesthetic compounds. A lipid carrier (such as iophendylate) can
effectively double the duration of effect of most local anaesthetics. Clonidine exerts complex effects at various sites - These include:antinociception at a spinal cord level, (as do other Alpha 2 agonists), membrane stabilisation and abolition of shivering. . Alkalinisation of LA's
consistently increases their rate of onset of the local anaesthetics (whatever their route of administration), but usually has not been found to
affect their efficacy.
Prolongation of epidural anesthesia using a lipid drug carrier with procaine, lidocaine, and tetracaine.
Langerman L; Grant GJ; Zakowski M; Golomb E; Ramanathan S; Turndorf H Anesthesia Analgesia. 1992 Dec; 75(6): 900-5
This study evaluated the effect of a lipid drug carrier (iophendylate) on epidural anesthesia. The intensity and duration of motor blockade
produced by aqueous and lipid preparations of local anesthetics were assessed in rabbits with long-term indwelling catheters in the epidural
space. Motor blockades produced by procaine (1%, 2%, and 4%), lidocaine (1%, 2%, and 4%), and tetracaine (0.5%, 1%, and 2%) in normal
saline solution were compared with the effects produced by equimolar amounts of the drug solutions in iophendylate. Procaine (4%) in
aqueous solution produced motor blockade lasting 30 +/- 3.54 min (mean +/- SD) versus 84 +/- 4.18 min in lipid solution. Lidocaine (2%
and 4%) in aqueous solution produced motor blockade lasting 41 +/- 4.18 and 65 +/- 6.12 min versus 39 +/- 4.18 and 118 +/- 10.1 min,
respectively, in lipid solution. Aqueous tetracaine (0.5%, 1%, and 2%) produced motor blockade of 106 +/- 9.62, 189 +/- 6.52, and 273 +/26.8 min versus 284 +/- 14.7, 335 +/- 15.8, and 365 +/- 26.9 min, respectively, in their lipid counterparts. A control group of animals that
received normal saline solution or iophendylate alone did not exhibit motor blockade. These results may be attributed to sustained release of
local anesthetics from the lipid vehicle. Hence, lipid drug carriers may be effective in prolonging epidural anesthesia.
Low dose i.v. clonidine reduces shivering after epidural anaesthesia
Tagariello V, Bertini L, Alcione AM, Molino FM, Rossignoli L. ALR 1991; 1: 38-43.
Forty-one male patients who had received epidural anaesthesia with 2 % mepivacaine and who had experienced shivering following epidural
block were enrolled in this randomized, double-blind, crossover study.
Patients were divided into two groups to receive either i.v. clonidine (group A, n : 21) or saline as placebo (group B, n: 20) to control
postepidural shivering. i.v. fluids were warmed to body temperature (37øC) and local anaesthetic solution was administered at room
temperature. ECG, blood pressure and oxygen saturation body temperature were recorded. Hypotension was promptly treated by i.v.
ephedrine. Shivering was noted and graded according to a fourpoint scale (0-- no shivering; 1 = moderate shivering, patient comfortable; 2 =
mild shivering, subjective cold sensation; 3= generalized shivering, patient uncomfortable, intolerable subjective cold sensation).
According to the study protocol, patients with grade-2 shivering were given 50 p.g i.v. clonidine every 4 minutes up to 150 pg, or saline at
the same time intervals and bolus dosages. After 12 minutes, if no effects on shivering were noted, the protocol was repeated changing the
study solutions. In the group A patients (n= 19, 90%) a dramatic reduction in shivering was observed (P <0.001), while in the placebo group
90% of patients worsened. Group B patients improved when they received clonidine (P <0.005). No significant differences were noted in
sensory level of analgesia, hypotension and ephedrine administration, oxygen saturation and body temperature between the groups.
Hypotension was related to the epidura| block, which was not worsened by the administration of clonidine.
Comment
Although the mechanism of action of clonidine on shivering is unknown, its clinical effects seem surprising. The rapidity of action and the
lack of hypotensive effects at such low doses suggest that further larger studies are needed to investigate the possibility of its routine use in
controlling postepidural shivering.
Clonidine enhances the effects of lidocaine on C-fiber action potential.
Gaumann DM; Brunet PC; Jirounek P Anesthesia Analgesia. 1992 May; 74(5): 719-25
We examined local anesthetic effects of clonidine and its interaction with lidocaine with regard to tonic inhibition of the C-fiber action
potential (AP) on the isolated, desheathed rabbit vagus nerve by the sucrose gap method. Clonidine and lidocaine at 500 microM
concentrations caused a comparable degree of C-fiber inhibition, corresponding to an AP area under the curve of 75.8% +/- 9.4% (mean +/SE) and 82.2% +/- 5.9% of control, respectively. Concentrations of clonidine less than 500 microM did not inhibit C-fiber AP. Clonidine,
added in concentrations of 500 nM, 500 microM, and 5 mM to a 500 microM lidocaine perfusion, caused a significant decrease in fiber
blockade of 18%, 20%, and 54%, respectively, as compared with clonidine added to Locke perfusion (P less than 0.05). The sodium channel
blocker tetrodotoxin (3 microM) decreased the AP area to 9.3% +/- 1.3% of control. The remaining tetrodotoxin-resistant AP was almost
completely blocked by clonidine (500 microM) and lidocaine (500 microM), indicating a higher susceptibility of tetrodotoxin-resistant fibers
to the two drugs than the C-fiber population as a whole. The enhancing effect of a low dose of clonidine (500 nM) on lidocaine-induced (500
microM) inhibition of C-fiber AP might explain the clinical observation that clonidine, at approximately 1000-fold lower concentrations than
lidocaine, prolongs the action of lidocaine in peripheral nerve block.
Comparison of plain and alkalinized local anaesthetic mixtures of lignocaine and bupivacaine for elective extradural caesarean section.
Fernando R; Jones HM Br. J. Anaesth. 1991 Dec; 67(6): 699-703
We have examined a local anaesthetic mixture of 0.5% bupivacaine 10 ml and 2% lignocaine 10 ml with adrenaline 1 in 200,000, to which
8.4% sodium bicarbonate 2 ml was added, for extradural Caesarean section. The alkalinized mixture of local anaesthetics produced a block
of more rapid onset and density than a mixture of bupivacaine and lignocaine alone (P less than 0.001).
Comparison between clonidine and epinephrine admixture to lidocaine in brachial plexus block.
Gaumann D; Forster A; Griessen M; Habre W; Poinsot O; Della-Santa D Anesthesia Analgesia. 1992 Jul; 75(1): 69-74
The admixture of clonidine or epinephrine to lidocaine for brachial plexus block was studied with regard to duration of block, postoperative
analgesia, and plasma concentrations of lidocaine. Thirty-three patients of ASA physical status I and II received an admixture of either
clonidine (150 micrograms; n = 15) or epinephrine (200 micrograms; n = 18) to 40 mL of 1% lidocaine in a randomized, double-blind
fashion. Bone surgery predominated in those patients receiving clonidine and soft-tissue surgery in those receiving epinephrine (P less than
0.05). Onset and duration of block were not different between the groups. With the admixture of clonidine, fewer patients were completely
pain free for greater than 12 h (13.3%) and pain scores (visual analogue scale 0-10) were higher 6 h after the block (median 4; range 0-6)
than with epinephrine (61.1%; median 2; range 0-7, respectively; P less than 0.05). In patients who had received clonidine, peak plasma
concentrations of lidocaine were higher (10.29 +/- 2.96 mumol/L) and occurred earlier (23.7 +/- 9.3 min; mean +/- SD) than in those treated
with epinephrine (6.9 +/- 1.71 mumol/L; 72.5 +/- 56.2 min; P less than 0.05). This indicates the absence of a local vasoconstrictor effect of
clonidine and implies a reduced margin of safety with regard to local anesthetic toxicity. Although clonidine does not offer advantages
compared with epinephrine, it may be a useful adjunct to local anesthetics in those patients in whom the administration of epinephrine is
contraindicated.
With regard to Ropivacaine:(227)
1. It is a pure S-stereoisomer.
2. It is slightly less potent than bupivacaine (1:1.3 to 1:1.5).
3. Reversal of myocardial Na+ channel blockade is considerably faster with ropivacaine than with bupivacaine.
4. It has a butyl group on the piperidine ring.
Ans:1,2,3
The butyl group on the piperidine ring of bupivacaine has been replaced by a propyl group in ropivacaine. Commercial bupivacaine is a
racemic mixture of the R and S stereoisomers, whereas ropivacaine is a pure S isomer.
Na+ channel blockade by bupivacaine is notoriously slow to reverse and is much more rapid in the case of ropivacaine. Slow Na+ channel
reversal has been associated with persistent conduction defects, re-entry disorders and the development of major ventricular arrhythmias.
The combination of easy reversal of Na+ channel blockade together with a relative lack of negative inotropic effect leads to a significant
reduction in cardiotoxic effects of ropivacaine as compared to bupivacaine.
With regard to cardiotoxicity of bupivacaine and ropivacaine:(228)
1. The cardiotoxic profile of these drugs is similar.
2. QRS prolongation parallels the local anaesthetic potency of these drugs on the isolated nerve.
3. Myocardial Na+ channel blockade is less marked with R-isomers
4. Myocardial depression parallels the local anaesthetic potency of these drugs on the isolated nerve.
Ans: 4
Ropivacaine is generally less cardiotoxic than bupivacaine. Myocardial depression of these (and other) local anaesthetics parallels the local
anaesthetic potency of the drugs on the isolated nerve. However, conduction disorders are far less marked with ropivacaine than with
bupivacaine. - This may be a reflection of the fact that R-stereoisomers are far more potent at blocking myocardial Na+ channels than the
corresponding S-isomers.
With regard to the placental transfer of ropivacaine:(235)
1. It is more likely to reach the fetus than chloroprocaine.
2. It is facilitated by fetal acidosis.
3. It is less transferable than mepivacaine.
4. All of the above.
Ans:4
Ester-linked local anaesthetic agents undergo such rapid hydrolysis in the maternal plasma that minimal amounts are transferred to the fetus.
– The plasma half-life of chloroprocaine in the presence of a normal pseudocholinesterase is about 20 seconds.
In contrast, the amide-linked agents have relatively long half-lives. - Thus, in combination with their low molecular weights and high lipid
solubilities, they can all transverse the placenta to a greater or lesser degree.
The ease of transfer is determined, in part, by the degree of ionisation at physiological pH. This, in turn, is determined by the pKa of the
agent. Drugs with a low pKa have a greater proportion of the un-ionised species and are therefore more likely to be transferred.
The five amide agents can be ranked in order of PKa and diffusibility as follows:
Mepivacaine (pKa 7.65) Etidocaine (pKa 7.76) Lidocaine (pKa 7.85) Ropivacaine (pKa 8.1) Bupivacaine (pKa 8.16). On this basis,
mepivacaine is likely to show the greatest degree of placental transfer and bupivacaine the least.
The phenomenon of ‘ion trapping’ may facilitate transfer of the amide-linked agents to the acidotic fetus.
Shnider, S, Anesthesia for Obstetrics, 3rd Edition, pp. 86-90.
A 2 mg/ml solution of ropivacaine:(236)
1. Is vasoconstrictive when given intradermally.
2. May reasonably be used for brachial plexus anaesthesia.
3. May reasonably be used for obstetric analgesia.
4. Is likely to prove cardiotoxic if 15ml (30mgs) are given intravenously to an adult.
Ans:1,3
In common with all amide-linked local anaesthetics, vasoconstriction occurs at low concentrations and vasodilatation at high concentrations.
Plexus anaesthesia should be performed using at least 5 mg/ml ropivacaine and is unlikely to be successful if a 2 mg/ml solution is used.
Sensory-motor splitting is a prominent feature of the drug. This may be used to advantage in the area of obstetric analgesia when ropivacaine
2 mg/ml can provide satisfactory analgesia with little motor impairment.
Symptoms of neurotoxicity generally appear before those of cardiotoxicity. In adult human volunteers, symptoms consistent with mild CNS
toxicity appeared after an average (intravenous) total dose of ~ 125 mg. It should be noted that ropivacaine is not approved for intravenous
use.
A 3mg/ml solution of ropivacaine infused by the mid-thoracic epidural route:(237)
1. Is unlikely to produce motor blockade if infused at 10ml (30mg) /hr.
2. Is roughly equivalent to 0.5% bupivacaine in terms of its potency.
3. Is unlikely to cause CNS toxicity if infused at 10ml/hr for 24 hours.
4. Will produce less effective postoperative analgesia than a 5mg/ml solution given at 6 ml / hr.
Ans: 1,3
A 3mg/ml solution of ropivacaine infused at this rate is very unlikely to produce significant motor blockade, neither will it produce the
plasma concentrations which are associated with CNS toxicity if epidurally administered to a 70kg adult.
5mg/ml ropivacaine is an unnecessarily concentrated solution to use for postoperative analgesia. – Solutions in the range 2-3mg/ml (0.2 –
0.3%) having been generally found to be appropriate for this application.
A recent study by Schug SA et al in the British Journal of Anaesthesia is typical of the results of research into the use of ropivacaine for
postoperative analgesia. These results (reproduced from “The International Monitor”) are summarised below.
Postoperative analgesia by continuous extradural infusion of ropivacaine after upper abdominal surgery
Schug SA, Scott DA, Payne J, Mooney PH, Haeggloef B. Br J Anaesth 1996; 76 (4): 487-491.
Ropivacaine is a new local anaesthetic with advantages that suggest an important role in the provision of postoperative analgesia. The main
aim of this study was to investigate the dose-response relationship of extradural infusion of ropiva-caine. We studied 36 ASA I-III patients
undergoing upper abdominal surgery during general anaesthesia and extradural block (catheter insertion at T6-9) using 0.5% ropivacaine in a
randomized, double-blind study. After surgery nine patients each received an extradural infusion of either ropivacaine 0.1%, 0.2%, 0.3% or
saline at a rate of 10 ml.h-l for 21 h.
All patients had access to i.v. morphine via a PCA device. The ropivacaine groups consumed significantly less morphine over the 21h
infusion period than the saline group (medians: saline 75 mg; 0.1% ropivacaine 32 mg; 0.2% ropivacaine 39 mg; 0.3% ropivacaine 13 mg)
(P < 0.05). Pain (VAS scores) at rest was significantly lower in all ropivacaine groups than in the saline group after 4 h of infusion (medians:
saline 45 mm; 0.1% ropivacaine 15 mm; 0.2% ropivacaine 12 mm; 0.3% ropivacaine 0 mm). Pain on coughing was significantly less in all
ropivacaine groups than in the saline group after 4 h infusion (medians: saline 67 mm; 0.1% ropivacaine 44 mm; 0.2% ropivacaine 33 mm;
0.3% ropivacaine 0 mm) and for 0.2% and 0.3% ropivacaine at later times. Motor block was negligible throughout the infusion. Patient
satisfaction was higher in the 0.2% and 0.3% ropivacaine groups than the two other groups.
Ropivacaine is appropriate for use in:(238)
1. A patient with proven allergy to procaine.
2. Intravenous Regional Anaesthesia (Bier’s blocks).
3. A patient with dialysis-dependent renal failure.
4. Spinal anaesthesia.
Ans:1,3
Ropivacaine is not approved for use in either intravenous regional anaesthesia (IVRA) or spinal anaesthesia. Cross-reactivity between the
ester-linked (eg procaine) and amide-linked (eg ropivacaine) local anaesthetics probably does not occur.
Although not yet approved for IVRA the use of the drug in this manner has recently been described by Hartmannsgruber et al.
Mivacurium:(422)
1. Is metabolised by plasma cholinesterase.
2. Has an elimination half-life of about 20 minutes.
3. Will lower systemic vascular resistance by about 1/3 when given at a dose of 0.2 mg/kg.
4. Does not cause significant histamine release.
Ans:1,3
Mivacurium is a relatively new nondepolarising diester neuromuscular blocking agent. It is metabolised in vitro by human plasma
cholinesterase at 70% the rate of succinylcholine and undergoes ester hydrolysis in the liver. Its duration of action is twice that of
succinylcholine but only one third to one half the duration of action of atracurium and vecuronium. It has an elimination half-life of 8 to 10
minutes. Thus it shows significant clinical potential for maintenance of blockade by continuous infusion.
Mivacurium 0.15 mg mg/kg produces changes of only small changes in mean arterial pressure (12%) and systemic vascular resistance
index(16%). However, mivacurium 0.2 mg/kg produces a 25% reduction in mean arterial pressure, a 14% increase in cardiac index and a
35% decrease in systemic vascular resistance index.
Comparison of the haemodynamic effects of mivacurium and atracurium during fentanyl anaesthesia.
Loan PB; Elliott P; Mirakhur RK; Bunting HF; Bhanumurthy S; McMurray TJ.
The drug causes significant histamine release which can be prevented with H1 antagonists.
Effect of oral antihistamine premedication on mivacurium-induced histamine release and side effects.
Doenicke A; Moss J; Lorenz W; Mayer M; Rau J; Jedrzejewski A; Ostwald P
Cisatracurium:(428)
1. Releases histamine when given at a dose of 0.1 mg/kg.
2. Is metabolised primarily by Hofmann degradation.
3. Is an aminosteroid compound.
4. Is metabolised to largely inactive compounds.
Ans:2,4
Even at 8 times the ED95 dose, Cisatracurium is not a histamine releasing drug. It is a benzylisoquinolinium compound unlike, for example,
vecuronium which is an aminosteroid.
Cisatracurium is an intermediate-duration, non-depolarizing neuromuscular-blocking agent, the purified form of one of the 10 stereoisomers
of atracurium which is cleared primarily by Hofmann elimination. It produces minimal cardiovascular changes and does not release
histamine even at up to eight times the dose that produced 95% of the maximum response (ED95) for neuromuscular bloclc At twice the
ED95, the pharrnacodynamic profile of cisatracurium is similar to that of an equipotent dose of atracurium apart from a slightly slower onset
of action. A more rapid onset is produced when the dose is increased. The clinically effective duration of action, as assessed by the twitch
response of the abductor policis muscle to a train of four stimulations, increases with increasing doses; however, doubling the dose only adds
approximately 23 min to the duration of clinically effective block The clinically effective duration of action ranges from 45 min after twice
the ED95 (0.1 mg/kg) to approximately 90 min after eight times the ED95 (0.4 mg/kg).
Neuromuscular block can be maintained with incremental or repeat bolus doses or continuous infusions of cisatracurium without any
cumulative neuromuscular~blocking effect. Neuromuscular block induced with cisatracurium can be readily reversed using
anticholinesterase agents. Cisatracurium has a predictable and rapid rate of spontaneous recovery (5-95% recovery about 30 min)
irrespective of the initial dose administered or the duration of maintenance dosing.
The pharmacodynamics of cisatracurium in healthy adults. Savarese JJ et al. Current Opinion in Anaesthesiology; Vol 9, Suppl 1 April 1996.
Pancuronium:(429)
1. Is excreted largely unchanged in the urine.
2. Has an active metabolite that retains 50% of the activity of pancuronium.
3. Can cause a myopathy if used for prolonged periods.
4. Is a benzylquinolinium compound.
Ans:1,2,3
Pancuronium is excreted largely unchanged in the urine, and a small percentage is metabolized, most significantly to 3hydroxypancuronium. The metabolite has 50% of the neuromuscular-blocking activity of pancuronium, is excreted in the urine and bile, and
may reach significant concentrations when large doses of Pancuronium are administered. In common with vecuronium, which is also steroidbased, there have been reports of myopathy following prolonged use of pancuronium. Pancuronium may be associated with undesirable
vagolytic effects.
Structurally pancuronium is an aminosteroid.
Current Opinion in Anaesthesiology; Vol 9, Suppl 1 April 1996 p S48.
Which of the following statements are true regarding atracurium:(431)
1. It theoretically has 16 stereo-isomers.
2. More than 50% of its neuromuscular blocking activity is due to cisatracurium in the preparation.
3. It does not need to be given in modified dosage to a patient in renal failure.
4. It is a benzylisoquinolinium.
Ans:1,2,3,4
Atracurium has four chiral centres, but because of molecular symmetry, the 16 theoretically possible isomers are reduced to 10.
Six of the 10 isomers have been prepared and evaluated for neuromuscular, autonomic and cardiovascular effects. All of the isomers exhibit
neuromuscular-blocking activity with a 10-fold range of potency, and with the exception of cisatracurium, produce autonomic and
cardiovascular effects at doses similar to those of atracurium.
Cisatracurium is more potent than atracurium and, unlike atracurium and all the other isomers, bolus injections of high multiples of the 95%
effective neuromuscular-blocking dose does not produce histamine-like cardiovascular effects or increase plasma histamine concentration.
Lignocaine:(470)
1. Is a Vaughan-Williams Class 1B anti-arrhythmic.
2. Is given in the dose range 1-1.5 mg.kg as an initial bolus dose.
3. Increases the fibrillation threshhold of the heart.
4. Increases the defibrillation threshhold of the heart.
Ans: 1,2,3,4
All of the are correct. An interesting study has recently been published which questions the role of such drugs in 'in-hospital cardiac arrest' see below.
Do advanced cardiac life support drugs increase resuscitation rates from in-hospital cardiac arrest? The OTAC Study Group.
Ann Emerg Med 1998 Nov;32(5):544-53
van Walraven C, Stiell IG, Wells GA, Hebert PC, Vandemheen K
STUDY OBJECTIVE: The benefit of Advanced Cardiac Life Support (ACLS) medications during cardiac resuscitation is uncertain. The
objective of this study was to determine whether the use of these medications increased resuscitation from in-hospital cardiac arrest.
METHODS: A prospective cohort of patients undergoing cardiac arrest in 1 of 5 academic hospitals was studied. Patient and arrest factors
related to resuscitation outcome were recorded. We determined the association of the administration of ACLS drugs (epinephrine, atropine,
bicarbonate, calcium, lidocaine, and bretylium) with survival at 1 hour after resuscitation.
RESULTS: Seven hundred seventy-three patients underwent cardiac resuscitation, with 269 (34. 8%) surviving for 1 hour. Use of
epinephrine, atropine, bicarbonate, calcium, and lidocaine was associated with a decreased chance of successful resuscitation (P <.001 for all
except lidocaine, P <.01). While controlling for significant patient factors (age, gender, and previous cardiac or respiratory disease) and
arrest factors (initial cardiac rhythm, and cause of arrest), multivariate logistic regression demonstrated a significant association between
unsuccessful resuscitation and the use of epinephrine (odds ratio . 08 [95% confidence interval .04-.14]), atropine (.24 [.17-.35]), bicarbonate
(.31 [.21-.44]), calcium (.32 [.18-.55]), and lidocaine (.48 [.33-.71]). Drug effects did not improve when patients were grouped by their initial
cardiac rhythm. Cox proportional hazards models that controlled for significant confounders demonstrated that survivors were significantly
less likely to receive epinephrine (P <. 001) or atropine (P <.001) throughout the arrest.
CONCLUSION: We found no association between standard ACLS medications and improved resuscitation from in-hospital cardiac arrest.
Randomized clinical trials are needed to determine whether other therapies can improve resuscitation from cardiac arrest when compared
with the presently used ACLS drugs.
Which of the following concentrations of ropivacaine will provide effective wound-infiltration analgesia after hernia repair?(472)
1. 0.75%
2. 0.125%
3. 0.5%
4. 0.0625%
Ans: 1,3
Mulroy et al found that ropivacaine 0.25% and 0.5% was adequate for pain relief after outpatient hernia repair, whereas the 0.125% solution
was no more effective than saline.
Reg Anesth Pain Med 1999 Mar-Apr;24(2):136-41 Mulroy MF, Burgess FW, Emanuelsson BM
Ropivacaine 0.25% and 0.5%, but not 0.125%, provide effective wound infiltration analgesia after outpatient hernia repair, but with
sustained plasma drug levels.
Histamine release is a feature of administration of which of the following relaxants?(489)
1. Rocuronium.
2. Mivacurium.
3. Vecuronium.
4. Atracurium.
Ans:2,4
Br J Anaesth 1995 Nov;75(5):588-92 Naguib M, Samarkandi AH, Bakhamees HS, Magboul MA, el-Bakry AK
Histamine-release haemodynamic changes produced by rocuronium, vecuronium, mivacurium, atracurium and tubocurarine.
We have examined the effects of different benzyl-isoquinolinium and steroidal neuromuscular blocking compounds on plasma
concentrations of histamine, heart rate and arterial pressure in surgical patients. A single, rapid (5-s) bolus of mivacurium 0.2 mg kg-1,
atracurium 0.6 mg kg-1, tubocurarine 0.5 mg kg-1, vecuronium 0.1 mg kg-1 or rocuronium 0.6 mg kg-1 was administered to 75 patients (n =
15 in each group). Anaesthesia was induced with thiopentone 6 mg kg-1 i.v. and maintained with isoflurane and 70% nitrous oxide in
oxygen. Venous blood samples were obtained before induction, 1 min after thiopentone and 1, 3 and 5 min after administration of the
neuromuscular blocking drug.
Mivacurium, atracurium and tubocurarine caused 370%, 234% and 252% increases in plasma histamine concentrations at 1 min,
respectively. Corresponding values at 3 min were 223%, 148% and 157%, respectively. These changes were significant (P < 0.01) at 1 and 3
min.
In contrast, the rocuronium and vecuronium groups had no significant changes in either plasma histamine concentrations or haemodynamic
variables.
Concomitant use of an anticonvulsant drug such as phenytoin will:(490)
A. Potentiate the action of both rocuronium and suxamethonium.
B. Diminish the action of both rocuronium and suxamethonium.
C. Potentiate the action of rocuronium but diminish that of suxamethonium.
D. Potentiate the action of suxamethonium but diminish that of rocuronium.
E. None of the above.
Ans: D
J Neurosurg Anesthesiol 1999 Apr;11(2):86-9 Koenig HM, Hoffman WE
The effect of anticonvulsant therapy on two doses of rocuronium-induced neuromuscular blockade.
Larger and more frequent doses of steroidal neuromuscular blocking agents are required to paralyze patients taking anticonvulsants
(carbamazepine and phenytoin). We compared the effects of rocuronium on onset, duration, and speed of recovery from neuromuscular
blockade (NMB) in anticonvulsant-treated (Tx) and untreated (C or control) patients. Thirty-eight neurosurgical patients were enrolled: 11
Tx and 8 C patients received 0.6 mg/kg rocuronium; 9 Tx and 10 C patients received 1.2 mg/kg rocuronium. Anesthesia was induced with
midazolam, fentanyl, and thiopental, and maintained with N2O and isoflurane in O2. The evoked compound electromyograph (EMG) of the
hypothenar eminence was recorded (train-of-four supramaximal stimulus at 2 Hz every 20 seconds). Rocuronium was administered after
baseline EMG was recorded. Data = mean +/- SD. Rocuronium 1.2 mg/kg significantly shortened onset time [depression of baseline height
of first twitch (T1) to 10% of baseline] of NMB versus rocuronium 0.6 mg/kg in both Tx (2.5+/-2 versus 3.3+/-2 minutes) and C (1.3+/-1
versus 2.8+/-1 minute) patients. Duration (recovery to 25% of T1) of NMB was significantly shorter in the Tx patients than in the C patients
who received rocuronium 0.6 mg/kg (21+/-9 versus 45+/-20 minutes), but similar in Tx and C patients who received 1.2 mg/kg rocuronium
(56+/-24 versus 69+/-21 minutes). The speed of recovery (time from 10 to 25% recovery of T1) was significantly slower in Tx patients who
received 1.2 mg/kg rocuronium (9+/-5 minutes) than in those who received 0.6 mg/kg (5+/-3 minutes) and not different from controls who
received 0.6 (9+/-4 minutes) or 1.2 mg/kg (12+/-7 minutes) rocuronium. We recommend the use of rocuronium 1.2 mg/kg and very frequent
monitoring of NMB in anticonvulsant-treated patients to avoid premature and extremely rapid recovery after the standard 0.6 mg/kg
rocuronium.
Can J Anaesth 1993 Oct;40(10):939-42 Melton AT, Antognini JF, Gronert GA
Prolonged duration of succinylcholine in patients receiving anticonvulsants: evidence for mild up-regulation of acetylcholine receptors?
Succinylcholine (SCh) normally causes a small increase in serum potassium concentration, but certain conditions may predispose to severe
hyperkalaemia. This is due to "up-regulation" of skeletal muscle acetylcholine receptors (AChR), which also results in resistance to nondepolarizing muscle relaxants (NDMR). Anticonvulsant therapy causes NDMR resistance because of sub-clinical blockade, and diminished
release, of acetylcholine. We studied nine patients chronically receiving anticonvulsants (phenytoin and/or carbamazepine) and nine control
patients. Anaesthesia was induced typically with thiopentone or propofol; isoflurane and N2O were used for maintenance. The ulnar nerve
was supramaximally stimulated and mechanical twitch height was measured with a force transducer at the adductor pollicis, before and after
SCh 1 mg.kg-1, until return to baseline height. Plasma potassium concentration was measured before and at three, five, and ten minutes
following SCh. Mean maximum potassium rise was 0.2 mEq.L-1 in each group. The time for return to baseline twitch height was 14.3 +/2.3 min (mean +/- SD) in the anticonvulsant group and 10.0 +/- 1.6 min in the control group, P = 0.001. The recovery index (time for 25% to
75% recovery) was 2.6 +/- 0.9 min in the anticonvulsant group and 1.4 +/- 0.3 min in the control group, P < 0.01. The normal potassium
response coupled with prolonged duration suggests a hypersensitivity to SCh that is consistent with an anticonvulsant-induced mild upregulation of AChR.
Factors which may potentiate the neuromuscular blocking activity of rocuronium include:(529)
1. Hypermagnesaemia
2. Hypokalaemia
3. Respiratory acidosis
4. Hypothermia
Ans: 1,2,3,4
Non-depolarising blockade is potentiated by: respiratory acidosis, myasthenic syndromes, metabolic alkalosis, local anaesthetics, many
antibiotics, hypermagnesaemia, hypokalaemia, hypothermia.
Generation of action potentials by muscle and nerve follow changes in the conductance of their membranes to sodium and potassium, and
normal neuromuscular function depends on the maintenance of the correct ratio between intracellular and extracellular ionic concentrations.
An acute decrease in the extracellular potassium concentration will tend to increase the endplate transmembrane potential, causing
hyperpolarisation and increased resistance to depolarisation, and consequently a greater sensitivity to the nondepolarising muscle relaxants.
Respiratory acidosis enhances rocuronium-induced neuromuscular block and opposes reversal by neostigmine. The changes observed in
metabolic acidosis and respiratory and metabolic alkalosis have yielded conflicting reports, but laboratory studies appear to indicate that in
the presence of respiratory acidosis and metabolic alkalosis the antagonism by neostigmine of rocuronium-induced neuromuscular blockade
is opposed.
For the effects of magnesium see:
Kussman B, Shorten G, Uppington J, Comunale ME Br J Anaesth 1997 Jul;79(1):122-4
Administration of magnesium sulphate before rocuronium: effects on speed of onset and duration of neuromuscular block.
The relative potency of ropivacaine in comparison to bupivacaine for analgesia in labour is:(542)
A. 1.2
B. 1.0
C. 0.8
D. 0.6
E. 0.4
Ans: D
Ropivacaine has about 60% of the potency of bupivacaine when used for analgesia in labour.
The studies by Capogna et al and Polley et al use an elegant methodology to explore this relationship.
G. Capogna, D. Celleno, P. Fusco, G. Lyons and M. Columb: BJA SA Edition Volume 5 May 1999 152-155
Relative potencies of bupivacaine and ropivacaine for analgesia in labour.
Polley LS, Columb MO, Naughton NN, Wagner DS, van de Ven CJ: Anesthesiology 1999 Apr;90(4):944-50
Relative analgesic potencies of ropivacaine and bupivacaine for epidural analgesia in labor: Implications for therapeutic indexes.
Which of the following local anaesthetics undergo significant extrahepatic metabolism?(574)
1. Prilocaine
2. Lignocaine
3. Ropivacaine
4. Procaine
Ans: 4
Amide local anaesthetics are primarily cleared from the blood stream by metabolism in the liver.
Only procaine has any significant extrahepatic metabolism - being hydrolysed by plasma cholinesterase.
With regard to Cisatracurium and atracurium:(579)
1. Cisatracurium is the major constituent by weight of atracurium.
2. Cisatracurium is three times more potent than atracurium.
3. Cisatracurium has the same onset time as atracurium when given in equipotent dosage.
4. Cisatracurium has a similar duration of effect to atracurium.
Ans: 2,4
Cisatracurium besylate is one of 10 isomers of atracurium besylate and constitutes approximately 15% of that mixture.
The neuromuscular blocking potency of Cisatracurium is approximately threefold that of atracurium besylate.
The time to maximum block is up to 2 minutes longer for equipotent doses of Cisatracurium compared to atracurium besylate.
The clinically effective duration of action and rate of spontaneous recovery from equipotent doses of Cisatracurium and atracurium besylate
are similar.
Mivacurium:(594)
1. Has a duration of effect about twice that of suxamethonium.
2. Undergoes Hofmann degradation.
3. Provokes histamine release.
4. Triggers malignant hyperthermia in susceptible swine.
Ans: 1,3
The duration of action of mivacurium is approximately twice that of suxamethonium and 30% to 40% that of atracurium.
The drug is hydrolysed by plasma cholinesterase, but does not undergo spontaneous (Hofmann) hydrolysis.
Administration of 3 times the ED 95 of mivacurium over 10 to 15 seconds evokes sufficient histamine release to lower mean arterial
pressure by about 15%.
Mivacurium does not trigger malignant hyperthermia in susceptible swine.
Rapacuronium:(595)
1. Is a depolarising muscle relaxant.
2. Is typically given in a dose of 1.5 mgs/kg.
3. Produces intubating conditions within 1 circulation time.
4. Has a duration of effect of 15 - 20 minutes if given in a dose of 1.5 mgs/kg.
Ans:2,4
Rapacuronium is a nondepolarising,aminosteroid neuromuscular blocking agent.
The recommended dose range is 1.5-2.5 mgs/kg.
The onset time of the drug when given at a dose of 2.5 mg/kg is more than 1 circulation time, but comparable to suxamethonium.
It lasts for 15 - 20 minutes if given in
When used within the therapeutic range, which of the following drugs is most likely to potentiate neuromuscular blockade induced by
vecuronium? (675)
A. Magnesium.
B. Cyclophosphamide.
C. Lithium.
D. Phenytoin.
E. Bambuterol
Ans: A
Magnesium is a physiological calcium antagonist, and there is a correlation between the depression of neuromuscular transmission and
serum magnesium concentration.
Although overdosage of lithium causes muscle weakness, there is no real evidence that lithium potentiates neuromuscular blockade by nondepolarising relaxants if the level is within the therapeutic range.
Resistance to neuromuscular blockade in patients on long-term phenytoin has been universally observed with the aminosteroid relaxants
(pancuronium, vecuronium, pipecuronium, rocuronium).
Bambuterol is an inactive prodrug that is slowly converted in the body to its active form terbutaline. The carbonate groups that are split off
can selectively inhibit plasma cholinesterase. Thus blockade by either suxamethonium or mivacurium may be potentiated.
Cyclophosphamide inhibits the activity of numerous cholinesterases and has been reported to potentiate the effects of mivacurium.
The subject has recently been reviewed by Haywood et al. (Haywood PT, Divekar N, Karalliedde LD. Concurrent medication and the
neuromuscular junction. Eur J Anaesthesiol. 1999 Feb;16(2):77-91.)
Ion-trapping may be a clinically relevant mechanism in enhancing the placental transfer of:(720)
1. Amide local anaesthetics.
2. Salicylates.
3. Opiates.
4. Non-depolarising muscle relaxants.
Ans: 1,3
If there is a pH gradient across a membrane, drug will be trapped on the side that has the higher ionised fraction, because only the un-ionised
drug is diffusible. This phenomenon is known as 'ion trapping'.
Foetal pH is slightly lower than maternal pH. This pH gradient causes the ionised fraction of weak bases, such as opioids and local
anaesthetics, to be higher in the foetus.
In contrast, weak acids (such as salicylates) are preferentially retained on the maternal side of the placenta.
Non-depolarising muscle relaxants are very highly ionised. As a result, very small amounts are transferred to the foetus and mechanisms
such as ion-trapping are not clinically relevant.
With regard to rocuronium: (822)
1. It is an aminosteroid.
2. Biliary excretion of the unchanged drug is an important route of elimination.
3. It can provide good intubating conditions within 60 seconds of administration.
4. It is not a potent histamine releasing drug.
Ans. 1,2,3,4
Rocuronium is an aminosteroidal neuromuscular blocking agent.
The most likely severe adverse effect of rapacuronium given at a dose of 1.5 mg / kg is:(943)
A. Bradycardia.
B. Myocardial depression.
C. Transient hyperkalaemia.
D. Bronchospasm.
E. Raised intra-ocular pressure.
Ans: D
Bartkowski and Witkowski have recently reviewed this non-depolarising relaxant. These authors have commented that "Adverse effects
reported following rapacuronium are similar to those seen with several other non-depolarizing neuromuscular blocking drugs. These include
hypotension, tachycardia, bradycardia and bronchospasm. In general, these effects appear to be dose-related and are probably related to the
low potency of rapacuronium, which necessitates a higher-milligram dose. This low potency is also the probable reason for its rapid onset.
Studies employing doses greater than 1.5 mg/kg show a greater incidence of side-effects than those found with lower doses. The
recommended dose in the United States, i.e. 1.5 mg/kg, represents a compromise between rate of onset of action, reasonable duration and
minimal side-effects. In fact, the US package insert lists 1.5 mg/ kg as the only recommended dose for routine circumstances.
Overall, there has been a low reported incidence of side-effects in the United States since the approval of rapacuronium in August 1999.
Since that time at least one million patients have been treated (data on file with Organon Inc.). The side-effect that has generated the most
concern and discussion appears to be bronchospasm. The package insert lists its incidence as 3.2% in the clinical trials prior to approval.
Since that time, after the official release of the drug, the reported incidence has been just 0.005% (data on file with Organon Inc.). As is
typical of postrelease reporting, the incidence is likely to be underreported. We suspect that most of the short-lived and mild respiratory
effects detected as wheezing or increased airway pressure are probably not reported.
In spite of the low reported incidence of bronchospasm, its impact has been profound. Cases have been reported where the bronchospasm
has been severe and life-threatening, mainly in children. These prompted editorial comment about the place of rapacuronium, given these
adverse events. Further review by the regulatory agencies and manufacturer led to the voluntary withdrawal of rapacuronium from the US
marketplace in March 2001, pending revision of the package insert."
The drug is a low-potency, non-depolarising relaxant and is the 16-N-allyl-17-propionate analogue of vecuronium. It does not increase either
serum potassium or intra-ocular pressure.
See: Bartkowski RR, Witkowski TA. Rapacuronium: first experience in clinical practice. Eur J Anaesthesiol Suppl. 2001;23:90-3.
A patient on long-standing anti-convulsant therapy is UNLIKELY to exhibit resistance to which of the following muscle relaxants?(976)
A. Pipecuronium.
B. Pancuronium.
C. Vecuronium.
D. Rocuronium.
E. Mivacurium.
Ans: E
Resistance to neuromuscular blockade in patients on long-term anticonvulsant therapy has been universally observed with the aminosteroid
relaxants (pancuronium, vecuronium, pipecuronium, rocuronium). Much less commonly it has been reported with benzoyl-isoquinolones (dtubocurarine and atracurium).
This effect has been shown to be absent in the case of mivacurium, which is spontaneously hydrolysed by plasma cholinesterase.
Phenytoin and carbamazepine are potent inducers of hepatic microsomal enzymes (particularly cytochrome P450 isoenzyme III A4), which
results in the enhanced elimination of many drugs. It may be that this is the mechanism aminosteroid relaxant resistance, but this is by no
means certain. It has also been suggested that an increase in protein binding results in a decreased free fraction of the drug and that
upregulation of the ACh receptor has been induced.
The subject has recently been reviewed by Haywood et al. (Haywood PT, Divekar N, Karalliedde LD. Concurrent medication and the
neuromuscular junction. Eur J Anaesthesiol. 1999 Feb;16(2):77-91.)
Which of the following local anaesthetic drugs is NOT a chiral molecule?(995)
A. Bupivacaine
B. Mepivacaine
C. Ropivacaine
D. Lignocaine
E. Prilocaine
Ans: D
A chiral molecule is one that is not superimposable on its mirror image; it has the property of rotating the plane of polarisation of planepolarised monochromatic light that is passed through it. This phenomenon is called optical activity.
Chiral molecules all have at least one asymmetric carbon atom, i.e. an atom surrounded by four different functional groups. Threedimensionally, these optical isomers are characterised by different configurations in space and cannot be merged into one another by simple
rotation. This allows the compounds to exist in at least two forms as mirror images of each other, which are not superimposable. The
isomeric forms are totally identical regarding physiochemical properties with the exception of the rotation of plane light.