Core pharmacology

Class Group

Opiate Analgesic

Legacy Cicm Level

Level 2

Introduction

Potent synthetic analgesic

Indications Uses

- Management of severe pain not responsive to alternative treatments
- Pain syndromes: neuropathic, cancer pain
- Detoxification and maintenance treatment of opioid addiction

Presentation

Tablet, PO solution, Inj

Main Action

Full µ agonist &
NMDA antagonist

Mechanism of action

µ:
Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release

- agonist of κ- and σ-opioid receptors
- antagonist of NMDA receptor (hence improved analgesic efficacy and reduced opioid tolerance)
- inhibitor of serotonin and norepinephrine uptake.

Onset Peak Duration

Peak 1-7.5hrs

Physiological effects

analgesia, suppression of opioid withdrawal symptoms,

Adverse Effects Toxicity

sedation, miosis, sweating, hypotension, bradycardia, nausea and vomiting (via binding within the CTZ), and constipation.

Arrhythmias, QT prolongation

Dependence, tolerance

At higher doses, methadone use can result in respiratory depression, overdose, and death

Absorption

PO BA 36-100%

Distribution

Highly lipid soluble (less than fentanyl)

Protein binding

85-90% (α1-acid glycoprotein)

Volume of distribution

1-8 L/kg
(variation with gender and weight)

Metabolism

Extensive first pass by CYP450

Excretion

Renal and Faecal after extensive biotransformation

Half-life

7-59hrs

Special Points

- Lower neuropsychiatric toxicity due to lack of active metabolites
- minimal accumulation in renal failure
- good BA
- low cost
- longer duration of action

Route And Dose

PO dose range 10-225mg

(relative potency 1)