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