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1. Opioids - an introduction
Dr. S. Parthasarathy
MD., DA., DNB, MD (Acu), Dip. Diab.
DCA, Dip. Software statistics-
PhD ( physiology), IDRA

2. History
• Opium was first mentioned in Eber’s papyrus
(1500 BC) and in the writing of Theophrastus (300
BC)
• It was used throughout the middle ages in Europe
as the preparation, named ‘laudanum’.
• Tincture !!
• Crude opium is a dark brown and resinous
material which is obtained from poppy (papaver
somniferum) capsule.
• Opos – juice of poppy

3. Originally meconium

4. In 1806, Sertürner reported the isolation of a
pure substance in opium that he named
morphine after Morpheus, the Greek god of
dreams.
It contains two types of alkaloids:
(i) alkaloid of phenanthrene derivatives–
morphine (10%), codeine (5%), thebaine (0.2%),
(ii) alkaloid of benzoisoquinoline derivatives –
papaverine (1%), noscapine (6%).

6. • 1840 – oral morphine – went on
• 1860 – 70 – hypodermic- morphine – used
• 1900 – more side effects
• 1914 – thio
• Concept of balanced analgesia
• More uses
• 1939 – pethidine
• 1960-70 – fentanyl

7. Some terms- opioid , opiate , narcotic
• Opioid
• opioid is defined as a natural, semisynthetic or
synthetic compound that acts at opioid receptors.
• May be antagonist!
• Opiate
• is a specific term to describe drugs derived from
the opium poppy (Papaver somniferum).
• Narcotic Greek word for stupor.
• At one time the term ‘narcotic’ was referred to
any drug that induced sleep and then it became
associated with opioids. But now it is often used
in legal context

8. Receptors
• Four broad classes of opioid receptors are
currently accepted.
• Mu (MOP) – morphine
• Kappa (KOP) - ketocyclazocine
• Delta (DOP) – vas deferens
• Nociceptin receptor (NOP)

9. MOP DOP KOP NOP
analgesia,
sedation,
respiratory
depression,
bradycardia,
nausea
vomiting
reduction in
gastric
motility
spinal and
supraspinal
analgesia
and reduce
gastric
motility
spinal
analgesia,
diuresis and
dysphoria.
Analgesia
Hyperalgesia
Allodynia

10. Where are mu receptors
• cerebral cortex
• basal ganglia
• presynaptic primary afferent neurones in dorsal
horn
• periaquaductal grey
• µ2 receptor has lower affinity for morphine. It
mediates spinal analgesia, respiratory depression
and constipation

11. DOP
• Found in midbrain
• nucleus raphe magnus
• part of descending inhibitory control pathway
Limited clinical use as produces side effects at doses
lower than those required for analgesia
• Side effects include diuresis, sedation, dizziness,
confusion and dysphoria

12. KOP
• Nucleus raphe magnus (midbrain),
hypothalamus, spinal cord
• Analgesia
• Dysphoria
• Sedation
• Dependence
• Miosis

13. NOP
• . Spinally, has been shown to produce analgesia and
hyperalgesia, dependent upon the administered
concentration, and allodynia.
• Supraspinally, when administered intra
cerebrovascularly it is thought to produce a pro-
nociceptive anti-analgesic effect, owing to an
inhibition of endogenous opioid tone

16. • A μ3 receptor is found in vascular tissue and in
leukocytes, and it may have roles in vascular
control and immunomodulation
• The κ1 receptor mediates spinal analgesia,
whereas activation of the κ3 receptor results
in supraspinal analgesia, sedation, and
ventilatory depression
• The majority of opioid receptors in
myocardium appear to be δ, and this receptor
may play a role in the phenomenon of
ischemic preconditioning

17. In short what ?
• Mu 1 and 2
• Delta
• Kappa
• Nociceptin

19. Mechanism of action ??
• Inhibition of calcium entry into the cell
• closes voltage sensitive calcium channels Potassium
efflux resulting in hyperpolarisation
• Inhibition of adenylyl cyclase reduces cAMP levels
• Overall result is reduced neuronal cell excitability with
a reduction in nerve impulse transmission and
inhibition of neurotransmitter release

21. Classification of opioids
• According to chemistry
– Natural
– Semisynthetic
– Synthetic
According to Pharmacodynamics
Agonists
Partial agonists
Agonists antagonists
Antagonists

22. Naturally occurring
• Morphine,
• Codeine,
• Papaverine,
• Thebaine.
Morphine and pethidine

23. Semisynthetic
• Morphine
• Diacetyl morphine
• Hydromorphone
• Hydrocodone
• Oxycodone
• Thebaine derivative – etorphine - wild life

25. Synthetic
• 1. Morphinan series: Levorphanol, butorphanol.
• 2. Diphenylpropylamine series: Methadone.
• 3. Benzomorphinan series: Pentazocine.
• 4. Phenylpiperidine series: Meperidine, fentanyl,
sufentanil, alfentanil.

26. • Agonists : morphine, pethidine fentanyl etc..
• Partial agonists – buprenorphine
• agonist- antagonists – pentazocine,
butorphanol , nalbuphine
• Pure antagonists – naloxone , naltrexone ,
nalmefene

29. Pharmacodynamics

30. Analgesia
• Relief of almost any pain
• Acute burning severe pain – more effective
• Neuropathic pain less
• First pain ? √ Second pain !!
• Blunt reflexes
• Perception of pain- it acts
• Descending pathways and spinal cord
• Don’t put to sleep always and don’t numb
• Euphoria - yes

31. Does it affect touch
??
No

32. CNS effects – euphoria
• Dysphoria and agitation rare with analgesic
doses
• Hypnosis and sedation will occur with high
doses
• No amnesia
• Elevate ICP with PaCO2 only
• Seizures with norpethidine

33. Ventilation
• Opioids produce a dose-related depression of
the ventilatory response to CO2 by a direct
effect on ventilatory centers in the medulla.
• Morphine also blunts the response to hypoxia
• Sleep will increase blunting
• Difficult to reverse without reversing analgesia
• Extremes of age , other potent depressants-
danger

34. Respiratory system

35. Skeletal muscle rigidity
• Generalized hypertonus of skeletal muscle can be
produced by large IV doses of most opioid agonists.
• Common with fentanyl, alfentanil, sufentanil, severe
form, “lead pipe” muscle rigidity
• very little loss of compliance when opioids are given
to patients with tracheotomies, suggesting that the
primary etiology is supraglottic obstruction from
constriction of laryngeal and pharyngeal muscles.

36. Antitussive
• Suppression of cough centres in medulla
• Codeine
• Dextromethorphan ( dextro isomers - better
antitussive )
• Heroin
• Antitussive activity – in fibreoptic intubation -
• Less analgesia with codeine – different
mechanism

37. Miosis
• Opioids stimulate the Edinger-Westphal
nucleus of the oculomotor nerve to produce
miosis
• Hypoxia – mydriasis – beware
• Small doses – maximal effect
• Qualitative but not quantitative

38. CVS effects
• Bradycardia and peripheral vasodilatation are
seen at higher doses and when opioids are
combined with other anesthetic drugs.
• No myocardial depression, no autonomic activity
–
• Ideal for cardiac anesthesia
• Fentanyl – brady , pethidine and pentazocine –
tachycardia and hypertension
• Reduces the size of infarct

39. Histamine release
• Some opioids, particularly morphine and meperidine,
produce a nonimmunologic release of histamine from
circulating basophils and tissue mast cells.
• most often seen as local itching, redness, or urticaria near
the site of intravenous injection,
• often mistake for true allergy.
• Anti H1 and anti H2 drugs as prevention
• Perioral itch by fentanyl – no histamine – naloxone ok but
antihistaminics ?

40. Naloxone may increase vomiting

41. GI and smooth muscle
• Opioids decrease the passage of fluids and solids at
every level of the GI tract—so-called opioid bowel
dysfunction (OBD). They delay gastric emptying and
increase antral tone.
• Opioids cause contraction of smooth muscle in the
gall bladder and spasm of the sphincter of Oddi.
biliary colic -? Intra op cholangiogram - ?

42. • Opioid receptors are found throughout the enteric
plexus of the bowel;
• their activation or stimulation causes tonic
contraction of gastrointestinal smooth muscle,
thereby decreasing coordinated, peristaltic
contractions.

43. Smooth Muscle Effects
• increase the contractions of the ureter although they
relieve the pain caused by ureteral stones.
• They also decrease detrusor contraction in response
to bladder distension (the voiding reflex) and
increase the tone of the urinary sphincter by both
central and peripheral mechanisms.

44. Pregnancy and fetus
• Opioids have no specific teratogenic effects,
but chronic opioid use by the mother can lead
to physical dependence by the fetus.
• Neonatal withdrawal may occur shortly after
delivery and in some instances may be life-
threatening.

45. • When tolerance to an opioid occurs, there is
simultaneous development of cross-tolerance
to all other opioid agonists.
• In general, tolerance develops to depressant
effects (analgesia, ventilatory depression,
euphoria),
• less tolerance to some of the stimulant effects,
like constipation or pupillary constriction.

46. • Hormonal effects = ? Use in the perioperative
scenario
• OPIOIDS MODULATE ANGIOGENESIS
• OPIOIDS ARE IMMUNOSUPPRESSIVE
• Cardiac protective
• Neuro protective
• Meperidine and shivering why ??

47. Pictures from the net / journals for closed academic purpose only

48. May be next time individual drugs
• History
• Receptors
• Classification – two types
• CNS
• CVS
• RS
• GUT
• Smooth muscles
Thank you
all