Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties

Pharmacotherapeutic group: Glucocorticoids, ATC Code: H02AB04
Pharmacotherapeutic group: Anaesthetics, ATC Code: N01BB02

Methylprednisolone
Methylprednisolone acetate is a synthetic glucocorticoid with the actions and use of natural corticosteroids. It has greater anti-inflammatory potency than prednisolone and less tendency than prednisolone to induce sodium and water retention. However the slower metabolism of the synthetic corticosteroid with their lower protein-binding affinity may account for their increased potency compared with the natural corticosteroids.

Lidocaine
Lidocaine has the actions of a local anaesthetic which reversibly blocks nerve conduction near the site of application or injection.

Pharmacokinetic Properties

5.2      Pharmacokinetic properties

No pharmacokinetic studies have been performed with the combination product of methylprednisolone and lidocaine, however, data are provided from pharmacokinetic studies performed with the individual product components methylprednisolone and lidocaine.

Absorption:

Methylprednisolone:
One in-house study of eight volunteers determined the pharmacokinetics of a single 40 mg intramuscular dose of Depo-Medrol. The average of the individual peak plasma concentrations was 14.8 ± 8.6 ng/mL, the average of the individual peak times (tmax) was 7.25 ± 1.04 hours, and the average area under the curve (AUC) was 1354.2 ± 424.1 ng/mL x hrs (Day 1-21).

Lidocaine:
Pharmacokinetics of lidocaine after synovial absorption following intra-articular bolus injection in patients with knee joint arthroscopy was studied with different maximum concentration (Cmax) values reported. The Cmax values are 2.18 µg/mL at 1 hour (serum) and 0.63 µg/mL at 0.5 hour (plasma) following administration of lidocaine doses of 7 mg/kg and 400 mg, respectively. Other reported serum Cmax values are 0.69 µg/mL at 5 minutes and
0.278 µg/mL at 2 hours following administration of lidocaine doses of 25 mL of 1% and 20 mL of 1.5%, respectively.

Pharmacokinetic data of lidocaine after intra-bursa and intra-cyst administrations for local effect are not available.

Distribution:

Methylprednisolone:
Methylprednisolone is widely distributed into the tissues, crosses the blood-brain barrier, and is secreted in breast milk. Its apparent volume of distribution is approximately 1.4 L/kg. The plasma protein binding of methylprednisolone in humans is approximately 77%.

Lidocaine:
The plasma protein binding of lidocaine is concentration-dependent, and binding decreases as concentration increases. At concentrations of 1 to 5 µg/mL, 60%-80% lidocaine is protein bound. Binding is also dependent on the plasma concentration of the α1-acid glycoprotein.

Lidocaine has a volume of distribution at steady state of 91 L.

Lidocaine readily crosses the placenta, and equilibrium of unbound drug concentration is rapidly reached. The degree of plasma protein binding in the foetus is less than in the mother, which results in lower total plasma concentrations in the foetus.

Metabolism:

Methylprednisolone:
In humans, methylprednisolone is metabolized in the liver to inactive metabolites; the major ones are 20α-hydroxymethylprednisolone and 20β-hydroxymethylprednisolone. Metabolism in the liver occurs primarily via the CYP3A4. (For a list of drug interactions based on CYP3A4-mediated metabolism, see section 4.5.)

Methylprednisolone, like many CYP3A4 substrates, may also be a substrate for the ATP- binding cassette (ABC) transport protein p-glycoprotein, influencing tissue distribution and interactions with other medicines modulated by P-gp.

Lidocaine:
Lidocaine is mainly metabolized by the liver. The main metabolites of lidocaine are monoethylglycine xylidide, glycinexylidide, 2,6-dimethylaniline, and 4-hydroxy-2,6- dimethylaniline. The lidocaine N-dealkylation to monoethylglycine xylidide is considered to be mediated by both CYP1A2 and CYP3A4. The metabolite 2,6-dimethylaniline is converted to 4-hydroxy-2,6-dimethylaniline by CYP2A6 and CYP2E1.

Elimination:

Methylprednisolone:
The mean elimination half-life for total methylprednisolone is in the range of 1.8 to 5.2 hours.
Total clearance is approximately 5 to 6 mL/min/kg.
Lidocaine:
The clearance of lidocaine in plasma following intravenous bolus administration is 9 to 10 mL/min/kg.

The elimination half-life of lidocaine following intravenous bolus injection is typically 1.5 to 2 hours.

The pharmacological actions of monoethylglycine xylidide and glycinexylidide are similar to but less potent than those of lidocaine. Monoethylglycine xylidide has a half-life of approximately 2.3 hours and glycinexylidide has a half-life of about 10 hours and may accumulate after long-term administration.

Only 3% of lidocaine is excreted unchanged by the kidneys. About 73% of lidocaine appears in the urine as 4-hydroxy-2,6-dimethylaniline metabolite.

Special Population

Methylprednisolone:
No pharmacokinetic studies have been performed for methylprednisolone in special populations.


Lidocaine:
Hepatic impairment
Following intravenous administration, the half-life of lidocaine has approximately 3-fold increase in patients with liver impairment. Pharmacokinetic data of lidocaine after intra- articular, intra-bursa and intra-cyst administrations for local effect are not available in hepatic impairment.

Renal impairment
Mild to moderate renal impairment (CLcr 30-60 mL/min) does not affect lidocaine pharmacokinetics but may increase the accumulation of glycinexylidide metabolite following intravenous administration. However, lidocaine clearance decreases about half and its half-life is approximately doubled with increased accumulation of glycinexylidide metabolite in patients with severe renal impairment (Clcr <30 mL/min).

The pharmacokinetics of lidocaine and its main metabolite of monoethylglycine xylidide are not altered significantly in haemodialysis patients who receive an intravenous dose of lidocaine.

Pharmacokinetic data of lidocaine after intra-articular, intra-bursa and intra-cyst administrations for local effect are not available in renal impairment.

No dosing adjustments are necessary in renal failure. Methylprednisolone is haemodialysable.