3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.5. Opioids
                      3.1.3.5.3. Opioid agonists
 3.1.3.5.3.4. Pethidine 

Pethidine

[SH4:p102-104]

 

aka: meperidine

Use

  • Analgesia during labor and delivery and post-operatively
  • Pethidine is the only opioid considered adequate for surgery when used intrathecally
  • Suppressing postoperative shivering

 

NOT useful in:

  • Not useful for treating diarrhoea
  • Not useful as an antitussive

Structure

  • Synthetic opioid agonist at MOP and KOP receptors

Structural similarity to local anaesthetics and atropine 

  • Shares some structural features with local anaesthetics
    * A tertiary amine
    * An ester group
    * Lipophilic phenyl group
    --> Intrathecal meperidine blocks Na+ channels like lignocaine
  • Also some structural similarity with atropine
    --> Mild atropine-like antispasmodic effect

Pharmacodynamics

Potency

  • About 1/10 as potent as morphine
    --> 80-100mg of meperidine (IM) = 10 mg of morphine (IM)
  • At equal analgesic dose, similar side-effect profile as morphine

Mechanism of action

Agonist activity at

  • MOP receptors (predominant effect)
  • KOP receptors (10% of its activities)
  • Alpha2 receptors

Effects

Analgesia

May be effective in suppressing post-operative shivering
* Due to stimulation of KOP receptors and alpha2 receptors
* Also due to a drug-induced decrease in the shivering threshold (which is different from alfentanil, clonidine, propofol, or volatile AAs)

Anti-shivering

Also a potent agonist at alpha2 receptors
* May also contribute to anti-shivering effect
* Clonidine is more effective in suppressing shivering

Comparison with morphine

  • Oral absorption is better than morphine

But

  • Not useful for treating diarrhoea or coughing
  • Significant negative cardiac inotropic effect
    * Unique among opioids
  • Significant risk of histamine release
  • Greater orthostatic hypotension than morphine
  • Delirium and seizures
  • Risk of serotonin syndrome
    * Especially in patients receiving SSRIs or MAO inhibitors.

Other differences

Other differences between meperidine and morphine

  • Rarely causes bradycardia
    --> Tend to cause tachycardia (atropine-like effect)
  • Less constipation and urinary retention
  • Less biliary tract spasm
  • Does NOT cause miosis
    * Causes mydriasis instead (atropine-like effect)
  • Withdrawal symptoms are milder, faster onset and shorter duration than morphine.

 

Pharmacokinetics

Absorption

  • Well absorbed from GIT
    * Unlike moprhine
    * But still only half as effective as administered IM

Distribution

  • Vd = 305 L
  • Vd = 3-5 L/kg
    * [RDM6:p401]
  • Protein-binding = 70%

Metabolism

  • Extensive hepatic metabolism
  • Hepatic extration ratio = 0.5 - 0.7
    * [RDM6:p401]
  • Pethidine (meperidine)
    * Demethylation to norpethidine (normeperidine), OR
    * Hydrolysis to pethidinic acid (meperidinic acid)
  • Norpethidine
    --> Hydrolysis to normeperidinic acid

Norpethidine

  • Long elimination half-time = 15 hours (or <35 hours in renal failure)
    * Can still be detected in urine after 3 days
  • About 1/2the analgesic potency as pethidine
  • About twice as potent as convulsive agent as pethidine
Toxicity of norpethidine (normeperidine)
  • Myoclonus and seizures
  • May also play a role in pethidine-induced delirium (confusion, hallucination)
  • Most likely during prolonged administration (e.g. during PCA)

Elimination

  • Urinary excretion of metabolites
  • pH-dependent urinary excretion
    * Acid urine increases urinary excretion
    * pH < 5, 25% of pethidine excreted unchanged in urine
  • Clearance = 8 - 18 mL/kg/min

Action profile

  • Duration of action 2-4 hours
    * Shorter than morphine
  • Elimination half-time = 3-5 hours

Physicochemical properties

  • Weak base
  • pKa = 8.5
  • At pH 7.4
    --> 7% nonionised
  • Lipid solubility = 32 times morphine

Special considerations

Elderly

Elderly
--> Lower plasma protein binding
--> Greater concentration of free meperidine
--> Increased effect

Alcoholics

Alcoholics
--> Increased Vd
--> Lower concentration of meperidine
--> Increased tolerance to meperidine and other opioids