3. Pharmacology
          3.5. Opioids
              3.5.3. Opioid agonists
 3.5.3.3. Morphine

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]

 



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