Morphine

3.6.12.1.1 Pharmacology

Morphine and other opioids produce their pharmacological effects by binding to opioid receptors located throughout the body. At least four distinct opioid receptor classes have been described within the CNS in addition to several subtypes. Members of each class of opioid receptor have been cloned by cDNA and the predicted amino acid sequences described. Receptor binding studies have elucidated distinct selectivity profiles for four receptor types, namely, |i (mu), k (kappa), a (sigma), and 8 (delta), whereas functional studies have revealed unique pharmacological profiles.7 Morphine and other opioids produce analgesia primarily through interaction with mu receptors. In addition, binding with | -receptors produces respiratory depression, miosis, reduced gastrointestinal activity, and euphoria. Drugs that bind selectively to kappa receptors also produce analgesia but act principally in the spinal cord and result in less intense miosis or respiratory depression compared with mu agonists.7 Kappa agonists produce spinal analgesia, sedation, and miosis whereas sigma agonists produce dys-phoric psychomimetic effects. The effects produced by binding to delta opioid receptors are unclear. The enkephalins are the endogenous ligands for these receptors. Binding to this receptor type also produces spinal and supraspinal analgesia. The highest concentrations of opioid receptors are found in the limbic system, thalamus, hypothalamus, striatum, mid brain, and spinal cord.8 Morphine possesses greater agonist activity at mu rather than kappa receptors, some activity at delta receptors, and minimal activity at sigma receptors.

At least three mechanisms have been proposed to account for opioid-induced analgesia. Opioid receptors on the terminals of primary afferent nerves mediate inhibition of the release of neurotransmitters. Morphine also exerts postsynaptic inhibitory actions on interneurons and on the output neurons of the spinothalmic tract that transports nociceptive information to higher centers in the brain.7 Morphine causes constriction of the pupil by an excitatory action on the parasympathetic nerve innervating the pupil. Morphine also causes respiratory depression, due to a direct effect on the respiratory centers of the brainstem by reducing the responsiveness to carbon dioxide. Opioids depress the pontine and medullary centers involved in regulating the rhythmicity of breathing.7 Nausea and vomiting caused by morphine and other opioids is due to direct stimulation of the chemoreceptor trigger zone in the medulla oblongata.

3.6.12.1.2 Absorption

Morphine may be administered orally, by subcutaneous or intramuscular injection, or by intravenous or epidural dosing or continuous infusion. The oral bioavailability of morphine is low due to extensive first pass hepatic metabolism. After epidural administration, morphine is completely absorbed with 7% of the dose reaching the cerebrospinal fluid and spinal cord.9 Peak concentrations of morphine in plasma were achieved approximately 30 min after a single dose. After continuous epidural infusion of 0.75 mg/h, plasma concentrations of 5 ng/mL were consistently measured.9

Intermittent intravenous administration of morphine may result in wide variations in morphine concentrations. For example, variations of 200 ng/mL may be observed after the administration of 5 mg every 4 h (peak concentrations of approximately 200 ng/mL within minutes of administration declining to less than 20 ng/mL by 1 h).9 However, if morphine is infused at a rate of 1.5 mg/h, then plasma concentrations are maintained at approximately 20 ng/mL after 1 h of accumulation. Assuming pain relief is achieved when plasma morphine concentrations are in the range 15 to 50 ng/mL, effective pain relief would be achieved by continuous intravenous infusion rather than intermittent intravenous dosing in the scenarios outlined above. These actions of morphine are explained by the pharmacokinetic characteristics such as a small central compartment volume, a large volume of distribution, and a rapid clearance.

A single intravenous dose of 0.125 mg/kg of morphine to adults resulted in a peak serum concentration at 0.5 min of 440 ng/mL, declining to 20 ng/mL by 2 h.10 Intramuscular injection of the same dose resulted in an average peak serum concentration of 70 ng/mL, 10 to 20 min after administration, declining to 20 ng/mL after 4 h. Epidural administration of a single dose of 0.1 mg/kg of morphine to surgical patients produced an average peak serum concentration of 80 ng/mL after 10 min, declining to approximately 10 ng/mL after 4 h (N=9).11 The oral bioavailability of morphine is approximately 38% with a reported range of 15 to 64%.12 Oral doses of 20 to 30 mg of morphine administered to adult terminally ill cancer patients maintained morphine serum concentrations above 20 ng/mL for 4 to 6 h.13

3.6.12.1.3 Distribution

The volume of distribution of morphine ranges from 2 to 5 L/kg in humans.12 Plasma protein binding of morphine in healthy humans ranges from 12 to 35% and appears to be independent of concentration over approximately a 1000-fold range although a slight decrease (24 to 20% bound) was observed when the concentration was increased from therapeutic by 60-fold.14 Morphine is bound mainly to albumin with approximately 5% bound to y-globulin and 5% to a1-acid glycoprotein. The blood/plasma concentration ratio for morphine in healthy humans averages 1.02.12 This ratio was found to be consistent in the concentration range 35-140 nM.14 The plasma half-life averaged 1.8 h and 2.9 h in female and male surgical patients, respectively.15 Aitkenhead et al.10 found no increase in half-life in patients with renal failure but it is doubled in cirrhotic patients.16

Morphine is relatively hydrophilic and therefore distributes slowly into tissues and does not persist. In the adult, small amounts cross the blood-brain barrier, with more lipophilic opioids such as heroin and methadone crossing rapidly.7 Morphine administered epidurally or directly into the spinal canal is effective in producing prolonged analgesia. However, there is rostral spread of the drug in the spinal fluid which may result in respiratory depression and other adverse effects later.

3.6.12.1.4 Metabolism and Excretion

The major pathway for the metabolism of morphine is by conjugation with glucuronic acid (Figure 3.6.12.1). The free phenolic hydroxyl group undergoes glucuronidation to produce morphine-3-glucuronide, a highly water soluble inactive metabolite. The metabolite, morphine-6-glucuronide is pharmacologically active and when administered systemically was found to be twice as potent as morphine. However, when administered intrathecally or intracerebroventricularly to rodents, morphine 6-glucuronide was approximately 100-fold more potent than the parent compound. Higher blood concentrations of this metabolite are measured in patients undergoing chronic oral dosing, suggesting a significant role in producing analgesia in such individuals.

CH3COO O 'OCOCH3

Heroin

HO CT 'OCOCH3

6-Acetylmorphine ch3

CH3COO O 'OCOCH3

Heroin

HO CT 'OCOCH3

6-Acetylmorphine

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