Morphine

[SH4:p93-p102]

Quick summary

 

 

Usage

• Analgesia

Structure

[Opioids]

• Morphine is the prototype of all the opioid agonists
• Phenanthrene nucleus consists of 3 benzene rings (14 carbons)
• Most opioid agonists also has a 4th carbon ring (piperidine, a 5 carbon + 1 nitrogen ring)
  --> N in the piperidine ring is a tertiary amine
  * At pH 7.4, tertiary amine is highly ionised --> More water solubility
• Levorotatory isomer is the active form

Pharmacodynamics

[Pharmacodynamics of opioids]

Main actions

• Analgesia
• Hypotension
• Drug tolerance and dependence
• Respiratory depression

Mechanisms of action

• Agonists at MOP and KOP
  * [SS3:p260]

Pharmacokinetics (PK)

Absorption

IV, IM, subcutaneous, inhalation, oral

Distribution

• Vd (steady state)
  = 224 L [SH4:p93]
  = 3-5 L/kg [RDM6:p401]
• Vd (central compartment)
  = 0.1-0.4 L/kg [RDM6:p401]
• Protein-binding
  = 35% [SH4:p93]
  = 20-40% [RDM6:p401]

Distribution into CNS

• Plasma morphine concentration after IV does NOT correlate closely with opioid's pharmacologic activity
  --> May reflect the delay in morphine penetrating the BBB
• But only small amount of morphine enters the CNS
  * <0.1% of morphine administered IV has entered CNS at the time of peak plasma concentration
• CSF concentration of morphine peaks 15-30 minutes after IV
  * Then decays more slowly than plasma concentration
• Poor penetration of morphine into CNS is due to:
  * Relatively poor lipid solubility
  * High degree of ionisation at physiological pH
  * Protein binding
  * Rapid conjugation with glucuronic acid

Distribution to other tissues

• Morphine accumulates quickly in kidneys, liver, and skeletal muscles
• Morphine, unlike fantanyl, does NOT undergo significant first-pass uptake into the lungs

Effects of acid-base

• Alkalosis increases nonionized fraction of morphine
• Acidosis decreases non-ionised fraction of morphine
  * But increase pCO2 increases CBF and delivery
  --> More than compensate for the decreased nonionized fraction
  --> Acidosis results in higher plasma and brain concentration

Metabolism

• Principle metabolic pathway of morphine
  = Conjugation with glucuronic acid
• Location
  = Hepatic and extrahepatic (especially kidney)
• High hepatic extraction ratio
  = 0.6-0.8 [RDM6:p401]

Metabolites

• Morphine-3-glucuronide
  * 75-85%
  * Inactive
  * Elimination takes slightly longer than morphine (Morphine-3-glucuronide detectable in urine for up to 72 hours)
• Morphine-6-glucuronide
  * 5-10%
  * Some effects (analgesia, respiratory depression via agonism at mu receptors)
  * Similar impairment of hypercapnic drive as morphine
  * [RDM6:p402] M6G is stronger MOP agonist than morphine, with similar duration of action
  * [SH4:p102] Analgesic potency of M6G is 650 times that of morphine, but affinity to MOP is similar
• Normorphine
  * 5%
  * Formed when morphine demethylated
• Codeine
  * Small amounts

NB:

• Ratio of M3G:M6G = 9:1
  * [SH4:p95]

Location

• Renal metabolism
  * Significant contribution
  * Reason for lack of impairment in clearance in hepatic cirrhosis
  * May even increase when hepatic metabolism is impaired

Elimination

• Clearance
  = 1050 mL/min [SH4:p93]
  = 15-30 mL/kg/min [RDM6:p401]
• Small fraction (1-2%) excreted unchanged in urine
• Most metabolites eliminated in urine
  * 7-10% eliminated in bile

Action profile

• Duration of action about 4 hours
• Peak effect after IV = 15-30 min
  * Delayed compared to fentanyl or alfentanil
• Peak effect after IM
  * Onset in 15-30 min
  * Peak effect in 45-90 min
• Half times [SH4]
  * Elimination half-time = 1.7-3.3 hours
• Half-lives [RDM6:p401]
  * Alpha phase half-life = 1-2.5 min
  * Beta phase half-life = 10-20 min
  * Gamma phase half-life = 2-4 hours

Physicochemical properties

• Weak base (alkaloid)
• Poorly lipid soluble
• pKa = 7.9
  --> At pH 7.4, 23% nonionized
• Alkalosis increase nonionized fraction of morphine, and enhance passage to CNS

Pharmaceutics

Formulation

• 50mg/5mL
  * pH 2.5 to 6.5
• Isotonic:
  * 5 mg / 1 mL
  * 10 mg / 1 mL
  * 15 mg / 1 mL
  * 30 mg / 1 mL
  * 1N HCl is used to adjust pH to 3.2 to 4.0
• Other preparations (oral, suppository)

Clinical

Administration

• Wide variability in dosage requirements
• IM or SC dose =0.1-0.2 mg/kg every 4 to 6 hours
• IV = 0.05 to 0.1mg/kg incrementally every 5 to 15 minutes
• [RDM6:p402] Oral bioavailability = 20-30%

Indications/contraindication/precautions

Head injury

• Use with caution in patients with head injury, due to
  * Associated effect on wakefulness
  * Production of miosis
  * Depressed ventilation could lead to increase PaCO2 and thus ICP
  * Possible disruption of BBB, which could increase sensitivity

Other contraindications

• Allergy
• Premature infants
• Limited respiratory reserve (e.g. emphysema, asthma)
• Others

Interactions

Monoamine oxidase inhibitors

• Formation of glucuronide conjugates may be impaired by monoamine oxidase inhibitors
  --> Exaggerated effects of opioids (especially meperidine)

Analgesia

Enhanced by

• Sympathomimetic drugs
• Physostigmine

Antagonised by

• Atropine

Respiratory depression

Exacerbated by

• Amphetamines
• Phenothiazines
• Monoamine oxidase inhibitors
• Tricyclic antidepressants

Special consideration

Renal impairment

• In renal failure
  --> Possible impairment of morphine glucuronide elimination
  --> Accumulation of metabolites (esp morphine-6-glucuronide) and unexpected ventilatory depressant effects
• In renal failure
  --> Higher plasma and CSF concentration of morphine and metabolites
  * Possible smaller Vd

Gender

• Morphine may exhibit greater analgesic potency and longer duration in women than men
• Morphine decreases the slope of ventilatory response to pCO2 in women
  * No significant change in men
• Morphine increases the apnoeic threshold in men
  * No significant change in women
• Hypoxic drive is decreased in women
  * Not in men

Lactation

• Unlikely significant amounts of drug is transferred to the breast neonates

Maternofoetal

• Foetus is vulnerable, because
  * Opioids crosses placenta easily
  * Ion trapping (due to lower pH in foetus and morphine being a weak base, similar to local anaesthetics)
  * Immaturity of neonat's BBB

Neonates

• In the first 4 days of life, clearance of morphine is reduced
  --> Neonates are more sensitive than older children to morphine's respiratory depressive effect

Elderly

• Plasma morphine concentrations are higher in the elderly than in young adults

Also,

• there is decreased sensitivity to pain, and increased analgesic response to opioids

Race

• Chinese subjects have a higher rate of clearance than white subjects due to increased partial metabolic clearance by glucuronidation
  * [PI]

Trivia

History

[Wikipedia]

• First isolated in 1804 by a German pharmacist Friedrich Serturner or a French pharmacist Barnard Courtois.
• Heroin was derived from morphine in 1874

Others

• The word "morphine" is derived from Morpheus, the god of dreams in Greek mythology. He is the son of Hypnos, god of sleep
  * [Wikipedia]