Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Natural opium alkaloids, ATC Code: N02AA01 
Morphine is a narcotic analgesic obtained from opium, which acts mainly on the central nervous system and smooth muscle.

Morphine is a potent analgesic with competitive agonist actions at the μ- receptor, which is thought to mediate many of its other actions of respiratory depression, euphoria, inhibition of gut motility and physical dependence. It is possible that analgesia, euphoria and dependence may be due to the effects of morphine on a μ-1 receptor subtype, while respiratory depression and inhibition of gut motility may be due to actions on a μ-2 receptor subtype.

Morphine is also a competitive agonist at the κ-receptor that mediates spinal analgesia, miosis and sedation. Morphine has no significant actions at the other two major opioid receptors, the δ- and the σ- receptors.
Morphine directly suppresses cough by an effect on the cough centre in the medulla. Morphine also produces nausea and vomiting by directly stimulating the chemoreceptor trigger zone in the area postrema of the medulla. Morphine provokes the release of histamine.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetics of morphine is not dose dependent.
Absorption
Maximum blood concentration is reached within 10-20 minutes.

Distribution
The volume of distribution of morphine is approximately 3 L/kg with a plasma protein binding of about 35 %. Morphine is widely distributed throughout the body, mainly in the kidneys, liver, lungs and spleen: lower concentrations appear in the brain and the muscles. Morphine crosses the placenta and is excreted into the breast milk (see section 4.6).

Biotransformation
Morphine is metabolised in the liver to the two main metabolites morphine-3-glucuronide (lacks analgesic effect but can contribute with excitatory effects) and morphine-6-glucuronide (M6G) (more potent than morphine itself). Small amounts of morphine-3,6-diglucuronide can also be formed.
Morphine and its metabolites undergo enterohepatic circulation.

Elimination
Morphine is primarily eliminated via glucuronidation, and the excretion of unchanged morphine in the urine is 5-10 %. Clearance is approximately 24 mL/min*kg and the half-life is about 2-3 hours.
Up to 10 % of a dose may be excreted via the bile into the faeces.
M6G is excreted via urine, which causes M6G accumulation in renal impairment.

Special population
The morphine bioavailability can increase in liver cancer patients.

Hepatic impairment
Impaired hepatic function influence the elimination of morphine.
Renal impairment
Impaired renal function influence the elimination of morphine. M6G is excreted via the urine.
Accumulation of the active metabolite M6G occurs in patients with renal impairment.