Cisatracurium Besylate (Page 6 of 9)

12.1 Mechanism of Action

Cisatracurium besylate binds competitively to cholinergic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in blockade of neuromuscular transmission. This action is antagonized by acetylcholinesterase inhibitors such as neostigmine.

12.2 Pharmacodynamics

The average ED₉₅ (dose required to produce 95% suppression of the adductor pollicis muscle twitch response to ulnar nerve stimulation) of cisatracurium is 0.05 mg/kg (range: 0.048 to 0.053) in adults receiving opioid/nitrous oxide/oxygen anesthesia.

The pharmacodynamics of various cisatracurium besylate doses administered over 5 to 10 seconds during opioid/nitrous oxide/oxygen anesthesia are summarized in Table 5. When the cisatracurium besylate dose is doubled, the clinically effective duration of blockade increases by approximately 25 minutes. Once recovery begins, the rate of recovery is independent of dose.

Isoflurane or enflurane administered with nitrous oxide/oxygen to achieve 1.25 MAC (Minimum Alveolar Concentration) prolonged the clinically effective duration of action of initial and maintenance cisatracurium besylate doses, and decreased the average infusion rate requirement of cisatracurium besylate. The magnitude of these effects depended on the duration of administration of the volatile agents:

• Fifteen to 30 minutes of exposure to 1.25 MAC isoflurane or enflurane had minimal effects on the duration of action of initial doses of cisatracurium besylate.
• In surgical procedures during enflurane or isoflurane anesthesia greater than 30 minutes, less frequent maintenance dosing, lower maintenance doses, or reduced infusion rates of cisatracurium besylate were required. The average infusion rate requirement was decreased by as much as 30% to 40% [see Drug Interactions (7.1)].

The onset, duration of action, and recovery profiles of cisatracurium besylate during propofol/oxygen or propofol/nitrous oxide/oxygen anesthesia were similar to those during opioid/nitrous oxide/oxygen anesthesia (see Table 5).

Repeated administration of maintenance cisatracurium besylate doses or a continuous cisatracurium besylate infusion for up to 3 hours was not associated with development of tachyphylaxis or cumulative neuromuscular blocking effects. The time needed to recover from successive maintenance doses did not change with the number of doses administered when partial recovery occurred between doses. The rate of spontaneous recovery of neuromuscular function after cisatracurium besylate infusion was independent of the duration of infusion and comparable to the rate of recovery following initial doses (see Table 5).

Pediatric patients including infants generally had a shorter time to maximum neuromuscular blockade and a faster recovery from neuromuscular blockade compared to adults treated with the same weight-based doses (see Table 5).

Table 5. Pharmacodynamic Dose Response^* of Cisatracurium Besylate During Opioid/Nitrous Oxide/Oxygen Anesthesia

* Values shown are the median values from the means from individual studies. Values in parentheses are ranges of individual patient values.
† Clinically effective duration of block
‡ Train-of-four ratio
§ n=the number of patients with Time to Maximum Block data
|| Propofol anesthesia
¶ Halothane anesthesia
** Thiopentone, alfentanil, N2 O/O2 anesthesia
Cisatracurium Besylate Dose	Time to 90% Block in Minutes	Time to Maximum Block in Minutes	5% Recovery in Minutes	25% Recovery † in Minutes	95% Recovery in Minutes	T 4 :T 1 Ratio ‡ ≥ 70% in Minutes	25% to 75% Recovery Index in Minutes
Adults
0.1 mg/kg(2 × ED95 )(n§ = 98)	3.3(1.0 to 8.7)	5.0(1.2 to 17.2)	33(15 to 51)	42(22 to 63)	64(25 to 93)	64(32 to 91)	13(5 to 30)
0.15|| mg/kg(3 × ED95 )(n = 39)	2.6(1.0 to 4.4)	3.5(1.6 to 6.8)	46(28 to 65)	55(44 to 74)	76(60 to 103)	75(63 to 98)	13(11 to 16)
0.2 mg/kg(4 × ED95 )(n = 30)	2.4(1.5 to 4.5)	2.9(1.9 to 5.2)	59(31 to 103)	65(43 to 103)	81(53 to 114)	85(55 to 114)	12(2 to 30)
0.25 mg/kg(5 × ED95 )(n = 15)	1.6(0.8 to 3.3)	2.0(1.2 to 3.7)	70(58 to 85)	78(66 to 86)	91(76 to 109)	97(82 to 113)	8(5 to 12)
0.4 mg/kg(8 × ED95 )(n = 15)	1.5(1.3 to 1.8)	1.9(1.4 to 2.3)	83(37 to 103)	91(59 to 107)	121(110 to 134)	126(115 to 137)	14(10 to 18)
Infants (1 to 23 months of age)
0.15 mg/kg** (n = 18 to 26)	1.5(0.7 to 3.2)	2.0(1.3 to 4.3)	36(28 to 50)	43(34 to 58)	64(54 to 84)	59(49 to 76)	11.3(7.3 to 18.3)
Pediatric Patients 2 to 12 years
0.08 mg/kg¶ (2 × ED95 )(n = 60)	2.2(1.2 to 6.8)	3.3(1.7 to 9.7)	22(11 to 38)	29(20 to 46)	52(37 to 64)	50(37 to 62)	11(7 to 15)
0.1 mg/kg(n = 16)	1.7(1.3 to 2.7)	2.8(1.8 to 6.7)	21(13 to 31)	28(21 to 38)	46(37 to 58)	44(36 to 58)	10(7 to 12)
0.15 mg/kg** (n = 23 to 24)	2.1(1.3 to 2.8)	3.0(1.5 to 8.0)	29(19 to 38)	36(29 to 46)	55(45 to 72)	54(44 to 66)	10.6(8.5 to 17.7)

Hemodynamics Profile

Cisatracurium besylate had no dose-related effects on mean arterial blood pressure (MAP) or heart rate (HR) following doses ranging from 0.1 mg/kg to 0.4 mg/kg, administered over 5 to 10 seconds, in healthy adult patients (see Figure 1) or in patients with serious cardiovascular disease (see Figure 2).

A total of 141 patients undergoing coronary artery bypass graft (CABG) surgery were administered cisatracurium besylate in three active-controlled clinical trials and received doses ranging from 0.1 mg/kg to 0.4 mg/kg. While the hemodynamic profile was comparable in both the cisatracurium besylate and active control groups, data for doses above 0.3 mg/kg in this population are limited.

Figure 1. Maximum Percent Change from Preinjection in HR and MAP During First 5 Minutes after Initial 4 × ED ₉₅ to 8 × ED ₉₅ Cisatracurium Besylate Doses in Healthy Adults Who Received Opioid/Nitrous Oxide/Oxygen Anesthesia (n = 44)

Figure 2. Percent Change from Preinjection in HR and MAP 10 Minutes After an Initial 4 × ED ₉₅ to 8 × ED ₉₅ Cisatracurium Besylate Dose in Patients Undergoing CABG Surgery Receiving Oxygen/Fentanyl/Midazolam/Anesthesia (n = 54)

No clinically significant changes in MAP or HR were observed following administration of doses up to 0.1 mg/kg cisatracurium besylate over 5 to 10 seconds in 2- to 12-year-old pediatric patients who received either halothane/nitrous oxide/oxygen or opioid/nitrous oxide/oxygen anesthesia. Doses of 0.15 mg/kg cisatracurium besylate administered over 5 seconds were not consistently associated with changes in HR and MAP in pediatric patients aged 1 month to 12 years who received opioid/nitrous oxide/oxygen or halothane/nitrous oxide/oxygen anesthesia.