OPIOIDS

Drug

Agent

Morphine

Pethidine

Tramadol

Naloxone

Class

Phenanthrene

Atropine-like Phenylpiperidine

Phenylpiperidine analogue of codeine

Thebaine derivative

Structure

Formulation

Iv

Syrup

tablet

Iv

Intranasal

Oral

epidural

50mg tab

100mg/2ml

crystalline white powder

iv

Isomers

Levo active

Levo active

R+ mu, ↑5HT

S- ↑NA

P/kin

pKa

7.9 (weak base)

8.5

9.4

% unionised @ pH 7.4

23%

7%

Lipid solubility

Poor

1

40 x morphine

po absorption

Variable

Good

Good (peak 2hr)

good

Bioavailability

25% (lung uptake 7%)

50%

70% (100% rpt doses)

20% (1^st pass)

PPB (%)

35% (albumin)

60%

minimal

V_dss (L/kg)

3

4.4

2.1

CL(ml/kg/min)

14

10

22

Metabolism

HHER (liver, kidney)

M3G 75% inactive

M6G10% active

Demethylation, hydrolysis

Norpethidine – (90%)

½ potency, CNS stim

t_1/2 15-40hr

toxic dose 10-15mg/kg/24hr

cytP450 (CYP2D6) → desmethyl tramadol (M1) (6xpotency)

HHER

conjugation

Excretion

90% renal

10% bile

Urine pH<5>

renal

bile

t½α (min)

t½β (hr)

2hr

3-4hr

5hr (9hr M1)

1-1.5hr

CSHT 4hr ivi

Admin

Potency

1

1/10 morphine

1/10 morphine

Dose

0.15mg/kg iv/im/sc

0.5mg/kg po

0.05mg/kg epi (1/3 iv)

0.015mg/kg it (1/3 epi)

1.5mg/kg iv/im

sc → stinging

0.5mg/kg epi

1mg/kg it sole agent

1-4mcg/kg

5mcg/kg/min ivi

Hepatic failure

CL unchanged (↑renal)

No change ?why not

Accumulate

Renal failure

Glucuronides accum → prolonged effects

accumulation

accumulate

Target level

0.05mcg/ml mod analg

0.7mcg/ml

Onset

IM 15-30min

Epi 1hr

Effect site equilibration

IV 15-30min

IM 45-90min

Duration

IM 4hr

Epi 18hr

IT >24hr

2-4hrs

30-40min

Offset

redistribution

Other

Glucuronidation impaired by MAOI → prolonged action