Binds primarily to inhibitory G-Protein Coupled μ-opioid receptors→ ↑adenylyl cyclase→ ↓cAMP→ hyperpolarization of cell→↓neurotransmitter release

mod affinity for μ receptors, weak κ, δ
-in spinal desc inh pathways by inh of neuronal reuptake of norad&serotonin
-presynaptic stim of seritonin release

CNS:
Opioid receptors present in cerebral cortex, periaqueductal grey, nucleus accumbens, area postrema, thalamus and NTS
- Analgesia
- Sedation
- Respiratory depression
- Nausea
- Euphoria
- Psychotomimetics
Seizures (due to M6G metabolite)

PNS Excitatory action
Histamine release

CNS:
- Analgesia
- Hallucinations
- Confusion
- Delirium
- Agitation
- Seizures
- Coma (Serotonin syndrome)

Respiratory depression and
constipation

PO/IV/IM/SC/SL/IT
Poor bioavailability 30% (good abs but high 1st pass metab)
onset / duration Oral ~30 minutes; I.V.: 5-10 minutes

Bioavailability- 75% PO

relative lipid sol 1

but crosses BBB

pKa 8.0 (25% unionised)
slow redistribution

Crosses placenta
Lipid soluble-crosses BBB

prot bind 20-40% (Alb)

Low plasma protein binding, approximately 20%.

mod Vd 3-4L/kg

2.9-4.37 L/kg.

Metabolised to morphine-3-glucuronide (70%)
and morphine-6-glucuronide (10%) by gut wall and liver.
M6G is 10-20 times potent, may accumulate in renal failure

Extensively hepatic via demethylation ,
glucuronidation, and sulfation; active metabolite by CYP2D6 (M1; O-desmethyl tramadol)

Excreted mainly in urine as conjugates with 10% in faeces

Urine 90% (30% unchanged), 10% faeces.

Half time 2-4hrs (large interpatient Variability)

T1/2: ~6-8 hrs;
Act metab:7-9hrs;
old, hepatic/renal imp.