Tramadol Flashcards
What is the mechanism of action of tramadol?
- μ-opioid receptors in the CNS
- tramadol itself is a prodrug and shows relatively weak affinity for opioid receptors
BUT:
- tramadol is metabolized by cytochrome P450 enzymes in the liver to O-desmethyltramadol (M1; = active analgesic metabolite) –> 200-times higher affinity for the μ-opioid receptor
Others:
- norepinephrine and serotonin reuptake inhibition
Tramadol is a racemic mixture. Discuss where the different compounds exert it’s mechanism of action and their potency?
(+)-tramadol.: 4 times more potent than (-)-tramadol on μ- receptors
- opioid receptors
- a2-adrenergic receptors
- serotonin receptors
(-)-tramadol:
- a2-adrenergic receptors
metabolite also exists as two stereoisomers:
- (+)-M1 acts on μ-opioid receptors
- (-)-M1 interacts with a2-adrenergic receptors
Discuss the pharmacokinetic properties of tramadol?
- tramadol (oral) was detected in the plasma in about 9.5 minutes
- peak tramadol plasma concentration at 1.5 hours
- detectable for 5–10 hours
- Low concentrations of M1 in plasma, but high concentra- tions of M2 + M5
- M3, and M5 were detected in urine, but no M
Discuss the difference of tramadol’s pharmacokinetics in cats compared to dogs?
Cats:
- IV and oral administration resulted in a slower clearance than observed in dogs, with good bioavailability (93%; but might be erroneously high)
- Time to reach peak concentration after oral administration is similar to that found in dogs
- M1 is the principal product in the metabolism
Name the metabolites of tramadol and their properties?
- O-desmethyltramadol (M1) = analgesic metabolite –> 200 times more potent than (+) or (-)-tramadol
- N- desmethyltramadol (M2) = inactive
- inactive N-N didesmethyltramadol (M3; metabolised from M2)
- N-NO tridesmethyltramadol (M4; metabolised from M2)
- N,O- didesmethyltramadol (M5; metabolised from M1 + M2)
What is the major metabolite of tramadol found in plasma and urine?
N,O- didesmethyltramadol (M5)
M1 production is considered to be low in dogs
Why does M5 (N,O- didesmethyltramadol) not work in the brain despite having affinity for μ-opioid receptor?
Does not effectively cross blood-brain-barrier
Discuss the difference of tramadol’s efficacy as an analgesic in dogs and cats?
- multiple studies have failed to demonstrate significant analgesic effects in dogs (produce more M2 than M1)
- studies of tramadol in cats have consistently demonstrated analgesic efficacy (produce more M1 than M2)
- cats are more prone to side effects
What is the reason for the lack of analgesic property of tramadol in dogs?
- low circulating concentrations of M1 (active analgesic metabolite) in dogs
- much higher plasma M1 concentrations in cats
What is the rational of co-administration of tramadol and fluconazole?
- decrease first pass metabolism + increase systemic availability
- increasing plasma M1 concentrations (e.g. through selective inhibition of tramadol + M1 metabolic pathways)
How is tramadol metabolised to M1 in dogs?
- in liver mcrosomes
- CYP2D15: tramadol to M1 + M2 to M5
- CYP2B11: tramadol to M2
- CYP3A12: tramadol to M2
- CYP2C21: M1 to M5
What is the tramadol dosage regime used in dogs?
PO: 2-5 mg/kg q8-12 hr
highest dose for maximum analgesic effect: 10 mg/kg q8hr
What is the tramadol dosage regime used in cats?
- PO: 1-3 mg/kg PO eq12-24hr
- 4 mg/kg q6hr was recommended to maintain analgesic effects in cats
- IV : 2 mg/kg
How long can it take for tramadol to exert it’s maximum effect in chronic conditions (cancer, degnerative joint disease)?
- up to 14 days
