2017B15 Write brief notes on the pharmacology of tramadol.

 

List:

·     PC

·     PK

·     PD

·     Variability

 

Pharmaceutics:

Class

·  Cyclohexanol derivative

Presentation

·  Racemic mixture

·  Aqueous solution in clear glass ampoule

·  Tablet

Storage

·  Room temperature

·  Long shelf life

 

Pharmacokinetics:

Administration

·  60mg tramadol equipotent to 10mg PO morphine, 3mg IV morphine

·  PO: 50-100mg q6h or 1mg/kg q6h in children

·  IV: same

·  IM: same

Time course

·  PO peak: 2 hours

·  PO duration: 6 hours

Absorption

·  Oral bioav 80% (may increase with use)

Distribution

·  Plasma protein binding 20%

Metabolism

·  CYP2D6

·  O-demethylation

·  Activate metabolite M1 (O-desmethyltramadol) has 4x analgesic efficacy, 200x MOP affinity

·  Parent and M1 undergo glucuronidation

·  t1/2β 300 mins

Excretion

·  Renal elimination of glucuronide metabolites

 

Pharmacodynamics:

Stereoselectivity

·  +tramadol: mu opioid partial agonist (i.e. ceiling effect), SRI

·  -tramadol: NRI

·  +M1: mu opioid agonist (4x tramadol), no SRI

·  -M1: NRI

 

·  Non-competitive NMDA antagonist

Opioid effects

·  Cellular: ↓cAMP, inhibit VDCC, ↑K+ efflux

·  Supraspinal: ↑descending modulation from peri-aqueductal grey matter etc.

·  Spinal: ↓pre-synaptic release of glutamate, substance P

Monoamine effects

·  NRI: ↑NAd descending modulation of pre-synaptic 1o afferent nociceptors; ↓ afferents

·  SRI: ↑5-HT descending modulation of same; ↑ and ↓ pain afferents

NMDA effects

·  ↓Post-synaptic activation at the dorsal horn

o Short term: ↓excitability, ↓wind-up

o Long term: ↓synaptic reinforcement, ↓long term potentiation

Uses

·  Analgesia: somatic, visceral, neuropathic

·  ↓Shivering

Reversal agent

·  Naloxone 30% effective

Opioid side effects

·  PONV (5HT reuptake inhibition; may antagonize ondansetron)

·  Less euphoria, dysphoria, hallucination, tolerance, dependence

·  Less CVS and resp depression, GIT stasis

·  Less OIH

Other side effects

·  ↓Seizure threshold

·  ↑QTC -> ↑risk TdP

Drug interactions

·  Serotonin syndrome:

o Tramadol + MAOi (or SSRI)

o ↑SNS, hyperreflexia, agitation, seizures

·  Hypertensive crisis

o Tramadol + indirect acting sympathomimetic e.g. ephedrine

 

Variability: 2D6 polymorphism

Intermediate and poor metaboliser

·  Common in Hong Kong Chinese

·  ↓Analgesia, ↑5-HT effects

Ultra-rapid metaboliser

·  Common in North Africans and Arabs

·  ↑Analgesia, ↑toxicity e.g. respiratory depression

 

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