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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