OPIOIDS

Agent Morphine Pethidine Tramadol Naloxone

Class Phenanthrene Atropine-like Phenylpiperidine Thebaine derivative
Phenylpiperidine analogue of codeine
Structure

Drug

Formulation Iv Iv 50mg tab iv

Syrup Intranasal 100mg/2ml
tablet Oral crystalline white
epidural powder
Isomers Levo active Levo active R+ mu, ↑5HT
S- ↑NA
pKa 7.9 (weak base) 8.5 9.4
% unionised 23% 7%
@ pH 7.4
Lipid Poor 40 x morphine
solubility 1
po absorption Variable Good Good (peak 2hr) good
P/kin Bioavailability 25% (lung uptake 7%) 50% 70% (100% rpt doses) 20% (1st pass)
PPB (%) 35% (albumin) 60% minimal
Vdss (L/kg) 3 4.4 2.1
CL(ml/kg/min) 14 10 22
Metabolism HHER (liver, kidney) Demethylation, hydrolysis cytP450 (CYP2D6) → HHER
Norpethidine – (90%) desmethyl tramadol (M1)
M3G 75% inactive conjugation
½ potency, CNS stim (6xpotency)
M6G10% active t1/2 15-40hr
toxic dose 10-15mg/kg/24hr
Excretion 90% renal Urine pH<5 → 25% renal bile
10% bile exreted unchanged
t½α (min)
t½β (hr) 2hr 3-4hr 5hr (9hr M1) 1-1.5hr
CSHT 4hr ivi
Potency 1 1/10 morphine 1/10 morphine
Dose 0.15mg/kg iv/im/sc 1.5mg/kg iv/im 1-4mcg/kg
0.5mg/kg po sc → stinging 5mcg/kg/min ivi
0.05mg/kg epi (1/3 iv) 0.5mg/kg epi
Admin 0.015mg/kg it (1/3 epi) 1mg/kg it sole agent
Hepatic failure CL unchanged (↑renal) No change ?why not Accumulate
Renal failure Glucuronides accum → accumulation accumulate
prolonged effects
Target level 0.05mcg/ml mod analg 0.7mcg/ml
Onset IM 15-30min
Epi 1hr
Effect site IV 15-30min
equilibration IM 45-90min
Duration IM 4hr 2-4hrs 30-40min
Epi 18hr
IT >24hr
Offset redistribution
Other Glucuronidation
impaired by MAOI →
prolonged action

Withdrawal:
Yawning, coryza, lacrimation, insomnia, restlessness→sweaty, abdo pain, hallucination, diarrhoea, vomiting
Spinal reflex hyperexcitability. NA pathway from locus ceruleus important.
Clonidine used to treat.
 Agent Morphine Pethidine Tramadol Naloxone
Analgesia Visceral, m/skel pain Also LA effects 30% inhibited by Binds
Not neuropathic
potency=cocaine naloxone mu>>delta/kappa
Anti-nociceptive, modulated
afferent component Complete antagonist
Euphoria Via mu >morphine
Sedation <morphine
CNS CTZ stim 40% 1st dose <morphine 30-35% first dose
desensitisation
Miosis Edinger-Westphal
nucleus stimulation
EEG Resembles sleep
Mm rigidity Inhibit interneurones
CBF ↓ unless ↑CO2
ICP ↓
Vminute ↓ dose dependent
RR ↓ more than TV
Resp TV ↑
Response CO2 ↓ central chemorec → Depression >morphine <opioids only prob in
right shift curve OD
Cough reflex ?mech (↑ with subs on Nil effect
phenol OH eg pholcodine)
Ciliary activity ↓
Raw (?↑ direct+His release)
CO (↓)
BP (↓) ↓ >morphine
CVS SVR (↓ if His release) ↓
Barorec reflex ↓orthostatic hypot >morphine
HR ↓ ↑ (atropine)
Contractility 0 ↓ (only one)
Venodilatation ↓ venous return
Arrhythmias ↓ risk VF
Mechanisms ↓Σ, vagotonic, direct
dep SA, AV nodes
GIT Motility ↓ minimal
Gastric empty ↓
Biliary spasm ½ x fent minimal minimal
3x pethidine
LES tone ↓
Mechanism Intramural plexus,
central effects
Blood flow ↓ (minor due to ↓CO)
Ureteric perist ↑
Renal Detrusor tone ↑
Sphincter tone ↑ → retention <morphine
ADH ?↑ or no effect (pain)
Obste- Uterine tone
trics Placental T/F easy
His release >5mg/min ivi
Nausea Anti-shiver (kappa) Anti-shiver ?mech Reverse analgsia
Side effects Seizures in OD / epilepsy
Other Pruritis N&v iv <2min
Sweating, xerostomia
Heaviness, warmth ↑Σ, withdrawal
Interactions Combo with N2O or benzo MAOI (↓metab) MAOI
→ ↓CO, SVR, BP Inhibit serotonin uptake
Drug Tolerance 12-24hrs
not to constipation/miosis
dependenc ↓affinity, downregulation,
e uncoupling from 2nd mess
Dependence Onset 48hr, fullblown minimal
25 days
Withdrawal Onset 15-20hr Few autonomic effects
Peak 2-3 days More rapid
Offset 10-14 days Shorter duration
 OPIOIDS
Agent Fentanyl Sufentanil Alfentanil Remifentanil
Class Phenylpiperidine Phenylpiperidine Phenylpiperidine Phenylpiperidine ester
Structure (Related to pethidine) (thienyl analogue fent)

Drug
Formulation Fent HCl 100mcg/2ml Iv Iv Crystalline powder
Transdermal
Glycine (NOT
25, 50, 75, 100mcg/hr
lollipop 5-20mcg/kg neuraxial)

Isomers
pKa 8.4 8.0 6.5 7.3
% unionised 8% (ion trapping) 20% 90% → fast onset 60% (no ion trapping)
@ pH 7.4
Lipid 800 x morphine → 1500 x morphine 150 x morphine
solubility ↑potency, faster onset
po absorption
P/kin Bioavailability Low (hepaticmetab, Lung uptake 60% Lung uptake 10%
lung uptake 75%)
PPB (%) 80% 93% (a1acid glyco) 92% (a1 acid glyco) 66-93%
Vdss (L/kg) 4.6 1.7 (high PPB) 0.5 – 1 (low lipid sol, 0.6
high PPB)
CL(ml/kg/min) 17 13 7 60
Metabolism Desmethylation, HHER (high lipid sol) N dealkylation, conjug Non-specific tissue and
plasma esterases (metabolite
alkylation (inactive) Inactive metab potency 1/1000)
Excretion Bile:urine 1:1 renal (metabolites)
t½α (min)
t½β (hr) 3-4hr (larger Vd) 2-3hr 1-1.5hr 15-20min
CSHT 4hr ivi 260min (saturate lung) 30min (<alfentanil up 60min 4min (independent of
to 8hrs lager Vd) infusion duration)
Potency 100 x morphine 1000 x morphine 30 x morphine 100 x morphine
10 x fentanyl (↑affinity) 1/5 – 1/10 x fentanyl 1 x fentanyl
Dose 1-2mcg/kg iv analgesia 0.1-0.4mcg/kg analgesia 15mcg/kg analgesia for 1mcg/kg over 1min or
<10mcg/kg iv non cardiac better kinetic profile for laryngoscopy, retrobulbar 0.5-1mcg/kg over 10min →
50-100mcg/kg iv cardiac infusions than alfentanil block, transient noxious stim induction
Admin 50-100mcg epi 150-300mcg/kg induction
Hepatic failure No change (?why not) No change increased 0
Renal failure ↑ 0 0
Target level
Onset Faster than morphine Rapid (90% unionised)
Effect site 6.8min 6.2min 1.4min 1.1min
equilibration
Duration <10mcg/kg iv 30-60min
50-100mcg/kg iv 6hr
Offset Redistribution to fat Rapid redistribution Rapid elimination Rapid elimination
and skel muscle (small Vd) >
redistribution
Other
Codeine:
Methylation of 3-OH gp on morhine → ↓first pass metabolism Methadone:
10% demethylated to morphine, rest to inactive norcodeine Well absorbed orally
maximum analgesia 60mg po = aspirin 650mg Long t1/2 32hrs
maximum analgesia 120mg IM = 10mg morphine 20mg iv → 24hrs pain relief post op
anti tussive. Minimal sedation, resp dep, nausea, constipation potency 4xmorphine
IV codeine → Histamine complete tolerance to miosis

Heroin Mu antagonist, delta/kappa agonist

Diacetyl morphine 50mg = 60mg po codeine
Very lipid sol→fast onset→rush→↑dependence
ceiling effect
Prodrug broken down to active morphine and monoacetyl morphine

Pentazocine:
 Agent Fentanyl Sufentanil Alfentanil Remifentanil
Analgesia Jannsen Hypothesis Selective mu
Euphoria
Sedation
CTZ stim
Miosis
EEG Seizure activity Seizure activity<<fent Seizure activity
CNS Mm rigidity With large rapid iv
CBF autoreg ↓
ICP ↑20 press autoreg ↑20 press autoreg 0
Vminute Ion trapping in stomach or
reestablish V/Q relationship
→ late resp depression
Resp RR
TV
Response CO2 Potent depressant
Cough reflex Protussive large dose
Ciliary activity
Raw
CO cardiostable
BP ↓MAP ↓
CVS SVR minimal
Barorec reflex ↓↓
HR ↓↓ ↓
Contractility
Venodilatation
Arrhythmias
Mechanisms Profound vagotonic
GIT Motility
Gastric empty
Biliary spasm 3 x morphine (3%)
LES tone
Mechanism
Blood flow
Ureteric
Renal peristalsis
Detrusor tone
Sphincter tone
ADH
Obste- Uterine tone
trics Placental T/F
His release No No
Side effects Other
Interactions Potentiate benzos
Drug Tolerance
dependenc Dependence
e Withdrawal
 OPIOIDS
Agent Morphine Pethidine Tramadol Naloxone
Class Phenanthrene Atropine-like Phenylpiperidine Thebaine derivative
Phenylpiperidine analogue of codeine
Structure

Drug

Formulation

Isomers
pKa
% unionised
@ pH 7.4
Lipid
solubility
po absorption
P/kin Bioavailability
PPB (%)
Vdss (L/kg)
CL(ml/kg/min)
Metabolism
Excretion
t½α (min)
t½β (hr)
CSHT 4hr ivi
Potency
Dose
Hepatic failure
Renal failure
Admin Target level
Onset
Effect site
equilibration
Duration
Offset
Other

Withdrawal:
Yawning, coryza, lacrimation, insomnia, restlessness→sweaty, abdo pain, hallucination, diarrhoea, vomiting
Spinal reflex hyperexcitability. NA pathway from locus ceruleus important.
Clonidine used to treat.
 Agent Morphine Pethidine Tramadol Naloxone
Analgesia
Euphoria
Sedation
CTZ stim
Miosis
CNS EEG
Mm rigidity
CBF
ICP
Vminute
RR
Resp TV
Response CO2
Cough reflex
Ciliary activity
Raw
CO
BP
CVS SVR
Barorec reflex
HR
Contractility
Venodilatation
Arrhythmias
Mechanisms
GIT Motility
Gastric empty
Biliary spasm
LES tone
Mechanism
Blood flow
Ureteric perist
Renal Detrusor tone
Sphincter tone
ADH
Obste- Uterine tone
trics Placental T/F
His release

Side effects Other

Interactions
Drug Tolerance
dependenc Dependence
e Withdrawal
 OPIOIDS
Agent Fentanyl Sufentanil Alfentanil Remifentanil
Class Phenylpiperidine Phenylpiperidine Phenylpiperidine Phenylpiperidine ester
Structure (Related to pethidine) (thienyl analogue fent)

Drug
Formulation

Isomers
pKa
% unionised
@ pH 7.4
Lipid
solubility
po absorption
P/kin Bioavailability
PPB (%)
Vdss (L/kg)
CL(ml/kg/min)
Metabolism
Excretion
t½α (min)
t½β (hr)
CSHT 4hr ivi
Potency
Dose
Hepatic failure
Renal failure
Admin Target level
Onset
Effect site
equilibration
Duration
Offset
Other
Codeine:
Methylation of 3-OH gp on morhine → ↓first pass metabolism Methadone:
10% demethylated to morphine, rest to inactive norcodeine Well absorbed orally
maximum analgesia 60mg po = aspirin 650mg Long t1/2 32hrs
maximum analgesia 120mg IM = 10mg morphine 20mg iv → 24hrs pain relief post op
anti tussive. Minimal sedation, resp dep, nausea, constipation potency 4xmorphine
IV codeine → Histamine complete tolerance to miosis

Heroin Pentazocine:
Diacetyl morphine Mu antagonist, delta/kappa agonist
Very lipid sol→fast onset→rush→↑dependence 50mg = 60mg po codeine
Prodrug broken down to active morphine and monoacetyl morphine
ceiling effect
 Agent Fentanyl Sufentanil Alfentanil Remifentanil
Analgesia
Euphoria
Sedation
CTZ stim
Miosis
EEG
CNS Mm rigidity
CBF
ICP
Vminute
RR
Resp TV
Response CO2
Cough reflex
Ciliary activity
Raw
CO
BP
CVS SVR
Barorec reflex
HR
Contractility
Venodilatation
Arrhythmias
Mechanisms
GIT Motility
Gastric empty
Biliary spasm
LES tone
Mechanism
Blood flow
Ureteric
Renal peristalsis
Detrusor tone
Sphincter tone
ADH
Obste- Uterine tone
trics Placental T/F
His release
Side effects Other
Interactions
Drug Tolerance
dependenc Dependence
e Withdrawal