The document discusses various opioids including morphine, fentanyl, sufentanyl, meperidine, remifentanil, tramadol and pentazocine, outlining their history, classification, mechanisms of action, pharmacokinetics, clinical uses, and adverse effects. It provides details on the endogenous opioid peptides and opioid receptors in the body, as well as the therapeutic uses and pharmacology of morphine as the prototype opioid analgesic.

1. OPIOIDS
PRESENTOR :-AKHILENDRA
CHOPRA
MODERATOR:-DR VIRENDRA
KUMAR

2. INTRODUCTION
 The term “opioid” is used to denote all exogenous substances natural
and synthetic, that bind to opioid receptors and produce at least some
agonist effects.
 Opioids have remain mainstay of modern perioprative pain
management.
 The word opium is derived from the Greek word opion (“poppy juice”).
 Opium is a dark brown, resinous material obtained from the capsule of
the poppy plant (Papaver somniferum).
 There are 20 natural alkaloids derived from the juice of poppy plant.
 Opiate is the term used for drugs derived from opium

3. HISTORY
 Opioids are world's oldest known drugs.
 1805- German chemist Friedrich Serturner isolated the pure active
ingredient in opium. He named this chemical “morphine”.
 1874: German chemists invented heroin by adding two acetyl
groups to morphine .
 1939: Meperidine the first opiate with a structure altogether different
from morphine.
 1942: Weijlard and Erikson produced nalorphine, the first opiate
antagonist.

4. HISTORY CONT…
 1959:Fentanyl was first synthesized by Paul Janssen.
 1973: Candace Pert and Solomon Snyder discovered that opioids
act by attaching to specific receptors within the brain. These
receptors were called the opioid receptors.
 1975: Scottish neuroscientists John Hughes and Hans Kosterlitz
discovered neurotransmitter that activate the opiate receptors.-
“endorphins”.
 1974 to 1976: Other fentanyl congeners like alfentanyl, sufentanyl
were synthesized.

5. CLASSIFICATION
ON THE BASIS OF SOURCE
A) Naturally occuring
 Phenanthrene :Morphine, Codeine ,Thebaine
 Benzylisoquinoline: Papaverine, Noscapine, Narcine
B)Semisynthetic
 Heroin
 Dihydromorphone
 Thebaine derivatives: Etorphine, Buprenorphine.
C)Synthetic
 Phenylpiperidines: Meperidine, Fentanyl, Sufentanil, Alfentanil,
Remifentanil.
 Phenyl-heptylmine: methadone.
 Benzomorphans: Pentazocine.

6. CLASSIFICATION CONT…
THE BASIS OF ACTION
A)OPIOID AGONISTS
 Morphine
 Meperidine
 Fentanyl
 Sufentanyl
 Remifentanyl
 Alfentanyl
 Codeine
 Methadone
 Tramadol
 Heroin
B)OPIOD AGONIST-
ANTAGONIST
 Pentazocine
 Butorphanol
 Buprenorphine
 Nalorphene
C)OPIOD ANTAGONIST
 Naloxone
 Naltrexone
 Nalmefene

7. ENDOGENOUS OPIOID PEPTIDES
ENDORPHINS:
Derived from Pro-
opiomelanocortin
• ß-endorphins: 2 Types –
• ß-endorphin1 and ß-
endorphin-2
• Primarily μ agonist and also
has δ action
ENKEPHALINS:
• Derive from Proenkephalin
• Met-ENK and leu-ENK
• Met-ENK - Primarily μ and δ
agonist and leu-ENK – δ
DYNORPHINS:
• Derive from Prodynorphin:
DYN-A and DYN-B
• Potent κ agonist and also
have μ and δ action
ENDOMORPHINS:
• Binds to the µ-receptor with
high affinity and high selectivity.

8. OPIOID RECEPTORS

9. LOCATION OF OPIOID RECEPTORS
1.Brainstem: respiration, cough, nausea & vomiting, BP, pupill and GI
secretion.
• 2. Thalamus: poorly localized deep pain
• 3. Spinal cord: substantia gelatinosa ,involved painful afferent
stimuli
• 4. Hypothalamus: mediating neuroendocrine secretion.
• 5. Limbic system: major role in emotional behavior & little
analgesic effect.
• 6. Peripheral nerve fibers

10. MORPHINE-PROTOTYPE OPIOID
PHARMACOLOGICAL ACTIONS
• A)Analgesia
 Produces strong analgesia without loss of consciousness.
 Other sensory modalities are not affected.
 Increases the threshold of pain.
 Nociceptive pain is better relieved than neuritic pain.
 Visceral pain is relieved better than somatic pain.
• B) Sedation:
 Drowsiness.
 Colorful day dream.
 Larger doses produce sleep.

11. MORPHINE-PROTOTYPE OPIOID
CONT…
C)Mood effects:
 Opioids produce euphoria.
D) Depression
 Pontine and medullary ventilatory centre – for both rate
and depth of respiration is diminished.
 Medullary cough centre .
 Temperature regulating centre.
 Vasomotor centre – High doses cause fall in BP.

12. MORPHINE-PROTOTYPE OPIOID
CONT…
E)Stimulation
 CTZ – sensitize CTZ.
 Edinger Westphal Nucleus – miosis .
 Vagal centre – Bradycardia .
 Hippocampal cells – convulsions (inhibition of GABA release).
 Increases ADH release – oliguria..
F)CVS:
 No direct action on the myocardium.
 Histamine release.
 Depression of vasomotor centre
 Vasodilatation leading to hypotension.

13. PHARMACOKINETICS OF MORPHINE
ABSORPTION AND DISTRIBUTION:
 Variable absorption orally.
 Well absorbed after IM administration with onset of action in 15 -
30min.
 Duration of action is about 4 hrs.
 Widely distributed,IV administration,However CNS penetration is
poor.
 Crosses placental barrier – hypoxia and apnoea fetus.

14. PHARMACOKINETICS OF MORPHINE
F) Metabolism:
 Conjugation with glucuronic acid in hepatic and extra hepatic sites.
 Produce water soluble metabolites.
 Morphine-3-glucuronide (70-80%): Pharmacologically inactive.
 Morphine-6-glucuronide (5-10%): Agonist action at μ–receptors
G)Excretion:
 Via Urine, Plasma t1/2 = 2-3 hrs
 Completely eliminated in 24 hrs.
 Elimination of morphine glucuronides may be impaired in renal
failure.

15. ADVERSE EFFECT-VENTILATORY DEPRESION
All μ-receptor agonists- dose dependent depression of respiration:
 Decrease brainstem sensitivity to CO2
 Increase Apnoeic threshold
 Decrease Hypoxic drive to respiration
 Pontine & medullary centres involved in rhythmic respiration
 Periodic breathing resembling Cheyne- Stokes breathing.
Effect increased :
 CNS depressants like
 Inhalational anesthetics ,
 BZDs and most of the sedative
 Standard therapy is Naloxone
 Dose 0.5 mcg-1mcg I every 2-3 minute.

16. ADVERSE EFFECT CONT….
 CVS:
 Orthostatic hypotension.
 Bradycardia may be due to direct or idirect.
 CNS:
 Sedation.
 Mental clouding – sometimes dysphoria.
 Skeletal muscle rigidity.
 Raised ICT.
 Smooth Muscle contraction:
 Biliary colic.
 Urinary retention.
 Bronchospasm.

17. ADVERSE EFFECT CONT….
Tolerance and dependence:
 Most common problem.
 Exhibited in most actions except constipation and miosis.
 Psychological and physical dependence.
MORPHINE WITHDRAWAL SYNDROME:
 Anxiety, fear, restlesness, diarrhoea, abdominal colic, delirium and
convulsion.
 Treatment is methadone

18. ADVERSE EFFECT CONT….
Acute Morphine Poisoning:
 Occurs if >50 mg (Lethal dose – 250 mg) is administered.
 Depression of ventilation may progress to apnoea.
Triad:
 Miosis,
 Hypoventilation and
 Coma
Treatment:
 Gastric lavage with KMnO4.
 Specific antidote: Naloxone: 0.4 to 0.8mg IV repeatedly in 2-3
minutes till respiration picks up.

19. THERAPEUTIC USES OF MORPHINE
 Analgesic: Dose- 0.1-0.15mg/kg iv bolus F/B 0.01mg/kg/hr
maintenance.
 Surgical and post operative analgesia
 Long bone fracture,
 Burns.
 Myocardial infarction.
 Palliative therapy in cancer.
 Visceral pains – pleurisy, acute pericarditis.
 Other Uses
 Pre-anaesthetic medication
 Acute left ventricular failure – Cardiac asthma
 Congeners eg. loperamide and diphenoxylate :severe intractable
diarrhoea.

20. MEPERIDINE (PETHIDINE)
 Phenylepiperidine derivative having structural similarities with
atropine.
 Pharmacokinetics:
 Better oral absorption.
 1/10th as potent as morphine, but efficacy is similar.
 Rapid but short acting (2-3 Hrs).
 It produces as much sedation, euphoria and respiratory depression
as morphine.
 Producess Less spasmodic action.
 Less miosis,constipation and urinary retention.
 Less histamine release – safer in asthmatics.

21. MEPERIDINE (PETHIDINE) CONT…
 Clinical Uses:
 Labour and post operative analgesia.
 Post operative shivering.
 Adverse Effects:
 Similar to morphine.
 Dry mouth, blurred vision,tachycardia (not use in borderline
cardiac function)
 Overdose :
 Tremors, mydriasis, delirium and convulsion due to norpethidine
accumulation

22. FENTANYL
 Phenylpiperidine derivative ,structurally related to meperidine
 Pharmacokinetics:
 75 to 125 times as potent as morphine.
 Rapid onset and shorter duration.
 Rapidly redistributed to fat and skeletal muscles.
 75% of the initial dose undergoes first-pass pulmonary uptake.

23. CLINICAL USE OF FENTANYL
 Analgesia: Low IV dose 1-2 μg/kg.
 Adjuvant to anaesthetics (2-20 μg/kg) to blunt circulatory response
for Intubation and to decrease requirement of inhalational agents.
 TIVA – Dose 50-150 μg/kg.
 Intrathecal: labour analgesia and anaesthesia ,DOSE-5-25μg.
 Oral transmucosal :fentanyl 5- 20 μg/kg for decrease pre-operative
anxiety and smooth induction.
 Transdermal fentanyl patch: delivering 75 - 100 μg/hr for treatment of
chronic pain in cancer and also for post op pain.

24. ADVERSE EFFECT OF
FENTANYL
 Similar to morphine.
 Persistent/ recurrent respiratory depression.
 Carotid sinus baroreceptor reflex control is markedly depressed-
caution in neonates.
 Bradycardia is more prominent.
 Myoclonus: may produce clinical picture of seizure activity in the
absence of EEG changes.
 Modest increases in ICP in head injury patients inspite of an
unchanged PaCO2.

25. FENTANYL AS A SOLE ANAESHETIC AGENT
 Advantages:
 Lack of direct myocardial depressant effects.
 Absence of histamine release.
 Suppression of stress respone to surgery.
 Disadvantages:
 Failure to prevent sympathetic response to surgical stimulation.
 Possible patient awareness.
 Postoperative ventilatory depression.

26. SUFENTANIL
 Thienyl analogue of fentanyl.
 Pharmacokinetics:
 Potency is 5 to 10 times that of fentanyl.
 Lipophilic nature permits rapid penetration into the BBB and onset of
CNS effects.
 Approx. 60% of the drug undergoes first pass pulmonary uptake.
 Extensive protein binding - mainly glycoprotein.
 Enhanced effect in neonates probably due to α1 acid glycoprotein.

27. SUFENTANIL
 Metabolism :
 N-dealkylation→ inactive metabolite
 O-demethylation→ desmethyl sufentanyl has10% activity of
sufentanyl.
 Extensively metabolised by hepatic microsomal enzymes.
 Hepatic clearance sensitive to hepatic blood flow.
Sufentanyl Vs Fentanyl:
 Faster analgesia and less ventilatory depression.
 More rapid induction.
 Earlier emergence and earlier tracheal extubation

28. ALFENTANIL
 Fentanyl analogue with lesser potency and shorter duration ofaction.
 Despite its lower lipid solubilty it has a more rapid onset of action
due to the higher degree of non-ionisation.
 It is used to provide analgesia when the noxious stimulation is acute
but transient as in laryngoscopy, tracheal intubation and performance
of a retrobulbar block.
 Associated with a lower incidence of PONV.

29. REMIFENTANIL
 Selective μ agonist with potency similar to fentanyl.
 Predictable onset and termination of effect because of
Rapid clearance
No significant redistribution to inactive storage sites
 Unique ester-linkage ,metabolised by non-specific plasma and
tissue esterases, Safe in hepatic and renal failure.
 Blood-brain equilibration time similar to alfentanil.

30. REMIFENTANIL CONT….
 Clinical Uses
 Short intense analgesia.
 Suppressing transient sympathetic response to laryngoscopy of at
risk patients.
 Intermittent administration as PCA during labour and delivery.
 Sedation and analgesia.
 To attenuate haemodynamic response to electroconvulsive therapy.
 Side effects:.
 Termination of analgesic effect on accidental stoppage of infusion.
 Induce seizure like activity
 Decrease in B.P and H.R.

31. TRAMADOL
 Centrally acting opioid.
 Moderate affinity for μ receptors and weak κ and δ activity.
 Dual mechanism of action
 Opioid agonist effect.
 5-HT and NA uptake inhibition enhancing function of spinal inhibitory
pathways.
 Effective both orally and IV (100mg = 10 mg Morphine).
 Dose-50-100 mg IV, repeat 6 hr ,and maximum dose upto 400 mg/day

32. TRAMADOL CONT…
 Uses
 Effective for the treatment of chronic pain.
 Can be used where NSAIDS are contraindicated.
 Post-operative shivering.
DOSE-2 mg/kg
 Disadvantages
 Seizures have been demonstrated.
 High incidence of nausea and vomiting.

33. OPIOID AGONIST-ANTAGONIST
 PENTAZOCINE:
 Benzomorphan derivative.
 Weak μ-receptor antagonist and agonist of κ and δ receptor.
 Given orally( dose -50-100 mg)
 Parenterl (dose-30-60 mg)
 both analgesia and respiratory depression occur after 30 to 70 mg
of pentazocine.
 Low abuse liability. However can precipitate withdrawal symptoms

34. OPIOID AGONIST-ANTAGONIST
PENTAZOCINE CONT..
USES:
Moderately severe pain in injury, burns, trauma and orthopaedic
manuevers
DISADVANTAGES
 Depresses myocardial contractility.
 Inhibits gastric emptying and GIT transit.
 High incidence of PONV.
 Limited analgesia.
 Partially antagonizes other opioids.

35. BUTORPHANOL
 Agonist- antagonist opioid that resembles Pentazocine.
 Compared to Pentazocine, its agonist action is 20 times greater and
antagonist activity is 15- 30 times greater.
 Rapidly and almost completely absorbed after I.M administration.
 Respiratory depression is similar to morphine
 Less abuse and has less addictive potential than morphine or
fentanyl.
 Transnasal butorphanol is effective in relieving migraine and
postoperative pain.

36. BUPRENORPHINE
 Buprenorphine is a thebaine derivative.
 Approximately 33 times more potent than morphine Has 50 times
higher affinity for μ- receptor than morphine.
 Given Sublingually or parenterally but not orally – high 1st pass
metabolism
 The onset of action of is slow, peak effect takes 3 hours, and its
duration of effect is prolonged (>10 hours).

37. BUPRENORPHINE
USES
 Analgesic component in balanced anesthesia.
 Excellent analgesic for relieving pain in the post operative period,
cancer, renal colic.
 Adjuvant for spinal and epidural analgesia. High lipid solubility limits
ADVERSE EFFECTS:
 Hypotension,drowsiness, nausea, vomiting and Pulmonary oedema
has been observed in some patients
 Respiratory depression (fatal in neonates) and cannot be reversed
by Naloxone

38. OPIOID ANTAGONIST
 Naloxone , naltrexone, nalmefene
 Higher affinity for μ-receptors results in displacement of the opioid agonists
from thereceptor sites.
 NALOXONE
Non-selective antagonist of all types of opioid receptors
Uses
 Treat opioid induced depression of ventilation in postoperative peiod and in
neonates due to maternal opioid administration.
 Opioid overdose.
 In hypovolaemic and septic shock, naloxone is useful to promote myocardial
contractility and inproves patient outcome.

39. NALOXONE CONT…
 Adverse Effects
 Antagonizes analgesic actions of opioids.
 Nausea/ vomiting .
 Increased sympathetic nervous system activity- tachycardia,
hypertension, pulmonary oedema and cardiac dysrhythmias.
 Administration of naloxone to an opioid dependent parturient may
produce acute withdrawal in the neonate.
 Antagonizes the depressant effect of inhaled anaesthetics.

40. OPIOID ANTAGONIST CONT…
NALTREXONE
Highly effective orally and duration of action is as long as 24 hrs.
Nalmefene
 6-methylene analogue of naltrexone.
 Equipotent to naloxone.
 Primary advantage is its longer duration of action as compared to
naloxone – as long as 24hrs.
 Prophylactic administration decreases the need for anti-emetics and
anti-pruritic medications in patients receiving opioid analgesics.

41. ANAESTHETIC USE OF OPIOIDS
 1.ANALGESIA
 2.SEDATION
 3.BALANCED ANAESTHESIA
 Reduce post-operative pain and anxiety.
 Decrease the somatic and autonomic responses to airway
stimulation.
 Improve haemodynamic stability.
 Reduce the dose of sedative agents.
 Reduce the requirement of inhalational agents.

42. ANAESTHETIC USE OF OPIOIDS
4.NEUROLEPTANALGESIA- ANAESTHESIA
 Neuroleptanalgesia is characterized by
 analgesia,
 absence of motor activity.
 suppression of autonomic reflexes.
 maintenance of cardiovascular stability.
 amnesia in most patients.
 Neuroleptanalgesia is achieved by:
 Potent opioid analgesic (fentanyl)
 The addition of an inhaled agent, usually N2O, improves amnesia
and has been called Neuroleptanaesthesia.

43. ANAESTHETIC USE OF OPIOIDS
5.Total Intravenous Anaesthesia (TIVA)
 Useful when delivery of inhalational agents are compromised or
contraindicated.
 Most commonly an opioid is combined with another drug which
provide hypnosis and amnesia.
 Combination of alfentanil and propofol produces excellent TIVA.
 Alfentanil: analgesia, haemodynamic stability and blunting of
responses to noxious stimuli.
 Propofol: hypnosis and amnesia and is anti-emetic.

44. ANAESTHETIC USE OF OPIOIDS
6.HIGH-DOSE OPIOID ANESTHESIA FOR CARDIACSURGERY
 stress-free anesthetic method for cardiac surgery.
performed with morphine later fentanyl and sufentanilwere
recommended
 Advantage of providing stable haemodynamics due to.
 Lack of myocardial depressant effect.
 Absence of histamine release (fentanyl congeners).
 Supression of stress response to surgery.
 Postoperative depression of ventilation and Possible awareness
have diminished the popularity

45. ANAESTHETIC USE OF OPIOIDS
 7)INTRATHECAL INFUSION
 Direct access to the substantia gelatinosa of dorsal horn of
the spinal cord.
 Lowered dose required than oral or parenteral administration.
 Intrathecal opioids combined with local anesthetics permits
the use of lower concentrations of both agents.
dose-dependent side effects
 Itching, nausea,vomiting,
 Respiratory depression,
 Urinary retention.
Use of lipophilic opioids reduces delayed respiratory
depression .

46. TAKE HOME MASSAGE
 Opioids are widely used in the practice of anaesthesia for pre-
anaesthetic medication, systemic and spinal analgesia and
supplementation of general anaesthetic agents.
 A proper understanding of the pharmacokinetic and
pharmacodynamic properties of opioids, is essential for their
judicious use.
 New opioid delivery systems are continually being developed.
Such systems allow more flexibility in providing analgesia, both
inside and outside the operating room.

47.  THANK YOU