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
– fentanyl

7. Some terms- opioid , opiate , narcotic
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. Morphine and pethidine
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