Pharmacokinetics

CNS—no effect

CVS—increases heart rate, cardiac output and blood pressure slightly due to vagal blockade RS—respiratory muscle paralysis Other—no histamine release

Elimination—predominantly hepatic but also some renal elimination. Hepatic or renal failure can cause prolongation of effect

D-Tubocurarine Chloride

Structure—monoquaternary alkaloid derivative of isoquinoline. Only becomes bisquaternary at very low pH

Presentation—clear, colourless, aqueous solution of pH 4-6 (10 mg/ml 1.5 ml ampoule). Recently withdrawn from the UK

Dose—IV bolus 0.3-0.5 mg/kg. Initial dose lasts 25 min Pharmacokinetics

Protein binding Vd Cl

(mainly albumin)

CNS—increases IOP and ICP. Does not cross blood brain barrier

CVS—no direct effect on heart; histamine release and sympathetic ganglia blockade lowers systemic vascular resistance and heart rate

RS—paralysis of respiratory muscles; can cause of bronchospasm secondary to histamine release

Other—histamine release may cause wheals; increases saliva; reduced gastro-intestinal tone and motility; minimal placental transfer

Elimination—unchanged 44% in urine, 12% in bile at 24 H, 1% demethylated in liver

D-Tubocurarine has been superseded by newer agents. It was formerly popular during controlled hypotension as the ganglion blockade contributed to deliberately induced hypotension by inducing vasodilatation without causing a reflex tachycardia.

Vecuronium Bromide

Structure—monoquaternary aminosteroid, becomes bisquaternary at pH 7.4

Presentation—freeze-dried, buffered, lyophilized cake for reconstitution, containing vecuronium bromide, citric acid monohydrate, disodium hydrogen phosphate dihydrate and mannitol

Storage—avoid light and temperatures in excess of 45° C. Reconstitution with water for injections produces clear, colourless solution of pH 4.0

Dose—IV bolus 0.05-0.1 mg/kg, infusion 0.05-0.1 mg/kg/h, ED95 = 0.046 mg/kg. Initial dose lasts 30 min Pharmacokinetics

CNS—no increase in ICP

CVS—no effect

RS—respiratory muscle paralysis

Other—no increase in IOP; minimal placental transfer; no histamine release

Elimination—spontaneous de-acetylation and hepatic metabolism. Of total dose, 10-25% is excreted in urine; the rest in the bile. Most excreted unchanged. Suitable in patients with absent renal function. Hepatic failure may prolong clinical effect whereas chronic phenytoin therapy reduces the efficacy of vecuronium. There are three potential metabolites 3-hydroxy, 17-hydroxy and 3,17-dihydroxy. These have minimal neuromuscular and vagolytic activity; only 3-hydroxy is found in any significant quantity and it has 50% of the neuromuscular blocking potency of vecuronium. Vecuronium is more stable in acidic solutions and is, therefore, potentiated by respiratory acidosis

Depolarizing Agents

Suxamethonium Chloride (Succinyl Choline) Structure—dicholine ester of acetyl choline

Presentation—clear, colourless, aqueous solution of pH 3.0-5.0 with a shelf life of 2 years (100 mg in 2 ml)

Storage—in fridge at 4°C; spontaneous hydrolysis occurs in warm or alkaline conditions

Dose—IV bolus 0.3-1.1 mg/kg; children 1-2 mg/kg. Infusion 0.1% solution at 2-15 mg/min. It is effective within 30 s and lasts for several minutes

Pharmacokinetics f/2 3.5 Protein binding occurs but the extent is not known because of the transient nature of the drug

CNS—small increase in ICP which may be of relevance in the head injured patient. CVS—increased blood pressure, bradycardia RS—paralysis of respiratory muscles

Other—increases IOP, intragastric pressure and lowers oesophageal sphincter pressure (barrier pressure is increased). Increases gastric secretion and salivary production

Elimination—metabolized by plasma cholinesterase—complete recovery in 10-12 min. Of it, 2-20% is unchanged in urine. The elimination pathway is shown in Figure NJ.8.

ELIMINATION PATHWAY OP SUXAMETHONIUM

Suxometho iiiuni (îuçdnyl dicholiftefl

■ plosmo cholinesterase { (rapid)

Sutcinyl mortocholine ; choline ptosfci çholinâileroso

Succinic acid -I- thofine

Figure NJ.8

Side effects—muscle pains especially muscular, young, male and after early ambulation, malignant hyperthermia trigger. May result in trismus, histamine release and hyperkalaemia—especially if denervation, burns, trauma or renal failure co-exist.

Contra-indications—malignant hyperthermia susceptibility, burns, myotonia.

Suxamethonium is a short-acting depolarizing neuromuscular blocking agent. It is rapidly acting by virtue of rapid distribution to the neuromuscular junction and its depolarizing mode of action. Its effect is terminated by diffusion away from the neuromuscular junction followed by rapid redistribution and hydrolysis. Hydrolysis occurs in two stages each removing choline. Of suxamethonium, 80% is metabolized before reaching the neuromuscular junction.

Anti-Cholinesterases

Neostigmine Bromide

Structure—quaternary amine, alkylcarbamic acid ester

Presentation—clear, very pale yellow, aqueous solution in brown ampoule (2.5 mg in 1 ml) Storage—protect from light

Dose—IV bolus 0.05-0.08 mg/kg. Peak effect 7-11 min; duration 40 min Pharmacokinetics

Bio-availability after oral administration < 1% CNS—central hypotensive effect at high dose; miosis, blurred vision CVS—causes bradycardia and decreases cardiac output RS—bronchconstriction and reduces anatomical deadspace

Other—increases in all the following: ureteric peristalsis, gastro-intestinal peristalsis, sweating, lacrimation, gastric tone and lower oesophageal sphincter pressure

Elimination—hydrolysed by the acetyl cholinesterase that it antagonizes and by plasma cholinesterase to a quaternary alcohol. Some hepatic metabolism occurs with biliary excretion. Of it, 50-67% is excreted in the urine

Side effects—concomitant administration of anti-cholinergics is essential when used for reversal of neuromuscular blockade. The increased gastro-intestinal tone may promote anastomotic breakdown. Neostigmine inhibits the hydrolysis of suxamethonium and mivacurium and other drugs metabolized by plasma cholinesterase. High levels of neostigmine at the neuromuscular junction causes a direct blockade of the acetyl choline receptor and the raised levels of acetyl choline have a depolarizing blocking effect

PHARMACOKINETIC DATA FOR NON DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS

ED95

Dose

Vd

Clearance

Elimination t1/2 min

mg/kg

mg/kg

ml/kg

ml/kg/min

Atracurium

0.2

0.3-0.6

170

5.5

20

Doxacuirum

0.025

220

2.7

99

Mivacurium

0.08

0.07-0.25

trans-trans isomer

150-267

51-63

1.9-3.6

cis-trans isomer

290-382

93-106

1.8-2.9

cis-cis isomer

175-340

3.7-4.6

34.7-52.9

Org 9487

1.15*

1.5-2.0

293

8.5

74

Pancuronium

0.06

0.05-0.1

200

1.8

115

Pipecuronium

0.049

0.07

309

2.4

137

Rocuronium

0.3

0.6

270

4.0

131

D-Tubocurarine

0.5

0.3-0.5

450

2

120

Vecuronium

0.046

0.05-0.1

260

4.6

62

*Value quoted for ED90

Figure NJ.9

Figure NJ.9

Pharmacokinetic data for specific drugs are summarized in Figure NJ.9 and the chemical structures of atracurium, vecuronium, suxamethonium and neostigmine are shown in Figure NJ.10.

Figure NJ. 10

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