Handbook of Drug Interactions

3. Opioids and Opiates 125
Because of this, easy transport of opioids through the placenta, and the low conjugating
capacity in neonates, opioids used in obstetrics analgesia have a much longer duration
of action and can easily cause respiratory depression in neonates (3).
Hepatic metabolism is the main mode of inactivation, usually by conjugation with
glucuronide. Esters (e.g., heroin) are rapidly hydrolyzed by common tissue esterases.
Heroin is hydrolyzed to monoacetylmorphine and finally to morphine, which is then
conjugated with glucuronic acid. These metabolites were originally thought to be inactive,
but it is now believed that morphine-6-glucuronide is more active as analgesic than
morphine. Accumulation of these active metabolites may occur in patients in renal failure
and may lead to prolonged and more profound analgesia even though central nervous
system (CNS) entry is limited (2).
Some opioids are also N-demethylated by CYP3A and O-demethylated by CYP2D6
in the liver but these are minor pathways. Codeine, oxycodone, and hydrocodone are
converted to metabolites of increased activity by CYP2D6. Genetic variability of CYP2D6
and other CYP isozymes may have clinical consequences in patients taking these compounds.
Accumulation of a demethylated metabolite of meperidine, normeperidine, may
occur in patients with decreased renal function or those receiving multiple high doses
of the drug. In sufficiently high concentrations, the metabolite may cause seizures,
especially in children. However, these are exceptions, and opioid metabolism usually
results in compounds with little or no pharmacologic activity (2).
Hepatic oxidative metabolism, mainly N-dealkylation by CYP3A4, is the primary
route of degradation of the phenylpiperidine opioids (e.g., fentanyl) and eventually leaves
only small quantities of the parent compound unchanged for excretion (2).
3. PHARMACODYNAMICS
Morphine and most other opioids elicit a mixture of stimulatory and inhibitory
effects, with the major sites of action being the brain and the gastrointestinal tract. Areas
of the brain receiving input from the ascending spinal pain-transmitting pathways are
rich in opioid receptors.
3.1. Opioid Receptors
Three major classes of opioid receptors have been identified in various nervous
system sites and in other tissues. They are mu (µ), delta (), and kappa (). The newly
discovered N/OFQ receptor, initially called the opioid-receptor-like 1 (ORL-1) receptor
or “orphan” opioid receptor has added a new dimension to the study of opioids.
Each major opioid receptor has a unique anatomical distribution in brain, spinal cord,
and the periphery. These distinctive patterns of localization suggest specific possible
functions. There is little agreement regarding the exact classification of opioid receptor
subtypes. Pharmacological studies have suggested the existence of multiple subtypes
of each receptor. Behavioral and pharmacological studies suggested the presence
of µ 1 and µ 2 subtypes. The µ 1 site is proposed to be a very high affinity receptor with
little discrimination between µ and ligands. The data supporting the existing of opioid
receptor subtypes are derived mainly from behavioral studies. In the case of
receptor, numerous reports indicate the presence at least one additional subtype (3).