Analgesics Tutorial
Dr. S. Alwis
Analgesics - Questions
• 1.Compare and contrast the mechanism of
action and the side effects of opioids and
NSAIDS.
• 2. Compare and contrast the
pharmacology of morphine and fentanyl.
• 3. Write short notes on
a) remifentanil
b) tramadol
c) naloxone
Q. No. 1
Opioids and NSAIDS are analgesics, opioids being
comparatively stronger.
Mechanism of opioids action
Opioids act on opioid receptors which are G protein
coupled.
1. Opioid receptor activation Alfa subunit interaction
with K & Ca channel and adenyl cyclase.
Closing of voltage sensitive Ca channels
K efflux hyperpolarisation
2. Inhibition of adenyl cyclase CAMP
Inhibition of neurotransmitter release
neuronal cell activity ( Diagram)
NSAIDS
• Phospholipids
• Phospholipase
Arachidonic Acid
COX1 Lipoxygenase
COX2
PGH2 Leucotrine A-E
PGE PGP syn TXA2 syn
Syn.
PGE2 PGI2 TXA2
(PROSTA) .
Adverse Effects
• Opioids NSAIDS
CVS No major effects. COX2 inhibitors
mild bradycardia cause platelet
vasodilatation aggregation &
Histamine BP vasoconstrict.
MCI & CVA
RS Res. Depression No central effect.
Cough suppress. Bradykinin broncho.
Histamine bronch. Spasm.
Adverse Effects ctd.
• Opioids NSAIDS
CNS Sedation/ euphoria Drugs cross the
dysphoria BBBhead ache
dependence Aseptic meningitis
tolerance Reye’s synd.
GIT Nausea & vomit. Less N&V.
Gastric mucosal
damage
END. Prolac& ACTH
ADH ADH
A.E. ctd.
• Opioids NSAIDS
Ocular miosis none.
Obs. Foetal depression prolong labour
premature PDA
closure & inc.
risk of abortion
HIST. + +
A.E. ctd.
• Drug interaction
Opioids NSAIDS
Other CNS depress. Impaired renal func.
inc. drug effects
Warfarin & heparin
Morphine & Fentanyl
• Morphine Fentanyl
Phenanthrene Phenylpiperidine
Natural Synthetic
Phys. Colourless liquid Colourless
15mg vials 50mcg/ml
Oral 5mg tab. Oral not available
Pharmacokinetics
Morphine Fentanyl
Oral bioavailability Oral not used
15 – 49%
Liver 1st pass met . 1st pass pulm. uptake
Cross BBB<fentanyl Readily crosses.
Protein binding 35% 80%
Lipid solubility 1 600
Pharmacokinetics ctd.
• Morphine Fentanyl
PKa 8 8.4
Ionis. 23% 10%
Vd 3-4l/kg 3-5l/kg
CL. 15-20ml/min/kg 10-20
El.t1/2 120-140 min. 180-200
Pharmacokinetics ctd.
Morphine Fentanyl
Met. Demethylation & Dealkylation
conjugation Hydroxylation
Hydrolysis
Mor.6 glucouronide Norfentanyl
( 3% - active ) inactive
Mor.3 glucouronide
( 75-85% - inactive)
Nor- morphine (inac.)
Exc. Renal & biliary Renal & biliary
M-6 G accumulate
in renal dysfunction
10% unchanged 8% unchanged
Pharmacokinetics
Morphine Fentanyl
CVS Histamine release Less hypoten.
causes hypotension Bradycardia is
more common.
CNS More or less same.
RS Chest wall rigidity + More chest wall
rigidity.
Late onset resp. No late onset resp.
depression after depression.
epidural injection
Pharmaco. Ctd.
Morphine Fentanyl
Potency 1 80-100
Routes Oral/ IM/ IV/ SC IV/ transdermal/
intrathecal intrathecal/
transmucosal
Dose Bolus- 0.1-0.2mg/kg 2-5mcg/kg
infus.-0.02-0.04mg/ 2-10mcg/kg/h
kg/h
Spinal-0.2-1.0mg 10-25mcg
Epidu- 2-4mg 25-100mcg
Oral - 5-20mg 4hrly
Question 3
• Tramadol
Physico-chemical
Cyclohexanol drivative.
Racemic mixture.
Tablets / capsules
sachets -100mg/2ml
IM /IV Inj.- 50- 400mg vials .
Tramadol ctd.
• Pharmacodynamics
Acts on all opioid receptors, esp. mu.
Inhibits the reuptake of nor. & 5HT.
Stimulates presynaptic 5HT release.
CNS – Less res. depression < morphine
Less constipation < morphine
Analgesia is reversed by naloxone -30%
GIT - Nausea & vomiting
Pharmacokinetics
• Oral bioavailability – 70%
• Metabolism in the liver –demethylation &
conjugation
O- desmethyltramadol analgesic.
Vd – 4l/kg
EL t ½ - 5-6 hrs.
Drug inter.- drugs inhibiting 5-HT & Nor.
Eg. TCAD / selective serotonine
reuptake inhibitors fits
C.I in epilepsy.
Remifentanil
• Synthetic phenylpiperidine derivative of fentanyl.
• Selective mu agonist.
Physico. – Crystalline white powder.
1,2,5mg vials. Contains glycine.
Not licensed for spinal / epidural
Structurally not similar to fentanyl.
( ester bond)
Once dissolved, stable for 24 hrs.
Pharmacokinetics
• Small Vd – 30l
• Protein binding – 60-90%
• El T1/2 – 6min.
*Rapid effect-site equlibration time-1.1min.
*Short duration of action – few min.( peak-1min.)
*Precise titrated effect
*Rapid recovery
*No cumulative effects ( CSTH 4min. Independent
of duration of infusion)
Metabolism
• Nonspecific plasma and tissue
cholinestereses.
• Inactive metabolites.
• Renal excretion.
Uses- bolus -1mcg/kg
infusion – 0.05-2.0mcg/kg min.
Induction of anaes.- 1mcg/kg
Adverse Effects
• Needs a long acting drug once infusion is
stopped.
• Large doses – chest wall rigidity.
• Nausea & vomiting.
• Resp. depression
• Mild hypotension (no histamine release)
Naloxone
• Pure MOP receptor antagonist.
• N- alkyl derivative of oxymorphone.
• Displaces the opioid agonist from the mu
receptor.
• Colorless liquid. 400mcg vials.
• Oral bioavailability is good. 1st pass met +.
• Conjugation in the liver.
• Duration – 30-45 min.
• DOSE – 1-4mcg/kg Infusion – 5mcg /kg/hr.
Adverse Effects
• GIT – Nausea & vomiting
Awakening at the same time.(no
aspiration)
• CVS – Symp. stim. tachy. / hypertnsion
pul. Oedema/ arrhy.
• Crosses the placenta.
