Analgesic Drugs
OPIOIDS
Dose conversion between different opioids is an inexact science, with equi-analgesic doses being based on relative potencies, often derived from studies that are not designed for dose equivalence calculation. Table 5.1 shows suggested equi-analgesic doses for some opioids.
Mechanism of Action
Opioid receptors were originally classified by pharmacological activity in animal preparations, and later by molecular sequence. The three main receptors were classified as μ (mu) or OP3, κ (kappa) or OP1 and δ (delta) or OP2. Another opioid-like receptor has been identified recently; it is termed the nociceptin orphanin FQ peptide receptor. Receptor nomenclature has changed several times in the last few years; the current International Union of Pharmacology (IUPHAR) classification is MOP (mu), KOP (kappa), DOP (delta) and NOP for the nociceptin orphanin FQ peptide receptor (Table 5.2).
Opioid receptors are distributed widely in both central and peripheral nervous systems. The different effects of currently available opioids are dependent on complex interactions at various receptors. There is a range of endogenous neuropeptide ligands active at these receptors (Table 5.2); they function as neurotransmitters, neuromodulators and neurohormones. The endogenous tetrapeptide endomorphins 1 and 2 are potent agonists acting specifically at the MOP receptor; they play a role in modulating inflammatory pain.
Pharmacodynamic Effects of Opioids
Analgesic Action
supraspinal effects in the brainstem, thalamus and cortex, in addition to modulating descending systems in the midbrain periaqueductal grey matter, nucleus raphe magnus and the rostral ventral medulla
inhibitory effects within the dorsal horn of the spinal cord both pre- and postsynaptically
a peripheral action in inflammatory states, where MOP receptors modulate immune function and nociceptors are important in regulating peripheral sensitization.
Opioid Structure
The structures of opioid analgesics are diverse, although for most opioids it is usually the laevorotatory (laevo) stereoisomer that is the active compound. The structures of some of the common agents are shown in Figures 5.1 and 5.2. Agents in current use include phenanthrenes (e.g. morphine – Fig. 5.1), phenylpiperidines (e.g. meperidine (pethidine), fentanyl – Fig. 5.2) and diphenylpropylamines (e.g. methadone, dextropropoxyphene). Structural modification affects agonist activity and alters physicochemical properties such as lipid solubility. A tertiary nitrogen is necessary for activity separated from a quaternary carbon by an ethylene chain. Chemical modifications that produce a quaternary nitrogen significantly reduce potency as a result of decreased CNS penetration. If the methyl group on the nitrogen is changed, antagonism of analgesia may be produced.
Other important positions for activity and metabolism, as seen on the morphine molecule (Fig. 5.1), include the C-3 phenol group (the distance of this from the nitrogen affects activity) and the C-6 alcohol group. Potency may be increased by hydroxylation of the C-3 phenol; oxidation of C-6 (e.g. hydromorphone); double acetylation at C-3 and C-6 (e.g. diamorphine); hydroxylation of C-14 and reducing the double bond at C-7/8. Further additions at the C-3 OH group reduce activity. A short-chain alkyl substitution is found in mixed agonist-antagonists, hydroxylation or bromination of C-14 produces full antagonists and removal or substitution of the methyl group reduces agonist activity.
Pharmacokinetics and Physicochemical Properties
After prolonged infusion, significant sequestration in fat stores and other body tissues occurs for highly lipid-soluble opioids. This is reflected in the ‘context-sensitive t½’ i.e. the time taken for the plasma concentration to reduce by 50% after an infusion designed to maintain constant plasma concentrations has been stopped (see Chapter 1). The context-sensitive t½ is increased after prolonged infusion for most opioids apart from remifentanil. For example, the elimination t½ for fentanyl after bolus administration is 3–5 h, but increases to 7–12 h after prolonged infusion.
Most opioid metabolism occurs in the liver (phase I and II reactions) with the hydrophilic metabolites predominantly excreted renally, although a small amount may be excreted in the bile or unchanged in the urine. As a result, hepatic blood flow is one of the major determinants of plasma clearance. Metabolism of individual drugs is shown in Table 5.3. Enterohepatic recirculation may occur when water-soluble metabolites excreted in the gut may be metabolized by gut flora to the parent opioid and then reabsorbed. Lipid-soluble opioids may diffuse into the stomach, become ionized because of the low pH and then be reabsorbed in the small intestine; this results in a secondary peak in plasma concentration.
TABLE 5.3
Metabolism and Excretion of Some Opioids
EDDP; 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine
A summary of physicochemical and pharmacokinetic properties of some opioids is shown in Table 5.4. Metabolism (including production of active metabolites), distribution between different tissues and elimination all interact within individual subjects to produce clinically important actions at receptor sites.
Factors affecting pharmacokinetics include:
Age. Systemic dose is often calculated on body weight, although there is little evidence to support this in adult clinical practice. Age is often more important because of both pharmacokinetic and pharmacodynamic factors. Metabolism and volume of distribution are often reduced in the elderly, leading to increased free drug concentrations in the plasma. Hepatic blood flow may have declined by 40–50% by age 75 years, with reduced clearance of opioids. Increased CNS sensitivity to opioid effects is also found in the elderly.