Opioid Analgesics and Antagonists.pdf file

Opioid Analgesics and Antagonists.pdf file

1. Opioid Analgesics and
Antagonists

2. Drugs for Pain Management
•Pain can be defined as a somatic sensation of acute
discomfort, a symptom of some physical hurt or disorder,
or even emotional distress
•Analgesics: are medications that relieve pain without
causing loss of consciousness
•Pain can be classified into two:
–Acute pain: Sudden in onset and usually subsides
once treated
–Chronic pain: Persistent or recurring and often
difficult to treat

3. Cont…
•What causes pain?
•Pain is caused by the stimulation of pain receptors
(Nociceptors) which are free nerve endings
•Tissue injury causes the release of Bradykinin,
Histamine, Potassium, Prostaglandins, Serotonin
–These substances stimulate nerve endings, starting
the pain process.

4. Cont…
A.Opioid analgesics (Narcotic analgesics)
•Are substances obtained from the crude extract of
Papaver somniferum (poppy plant)
•Morphine is the prototype opioid and acts by agonistic
activity on µ, k and δ receptors

5. Cont…
•Actions mediated by opioid receptors

6. Cont…
•Certain endogenous peptides (endorphins, dynorphins
and enkephalins) act on these opioid receptors to
produce analgesic effects.
•Recently a new endogenous peptide, nociceptin is
isolated that acts on nociceptin/orphanin FQ (N/OFQ) or
orphanin like receptors (ORL
1)

7. Cont…
Pharmacokinetics
•Sufentanil is the most potent whereas Meperidine
(pethidine) and Propoxyphene are the least potent
opioids.
•Morphine is metabolized mainly to morphine-3-
glucuronide (M3G) that has neuroexcitatory properties.
–Approximately 10% of morphine is metabolized to active
product M6G.
–Renal failure can lead to accumulation of these
metabolites and can result in seizures (due to M3G) or
prolonged opioid action (due to M6G)

8. Cont…
•Pethidine is metabolized mainly to meperidinic acid by
MAO and very little is demethylated to norpethidine.
–Norpethidine has seizure inducing and cumulative
properties.
–Pethidine can result in seizures if used for prolonged
periods, in patients with renal failure or those taking
MAO inhibitors (due to accumulation of norpethidine)

9. Cont…

10. Cont…
•Actions of pure opioids: Morphine, Methadone,
Pethidine, Levorphanol, Codeine, Hydrocodone,
Oxycodone & Propoxyphene.
•CNS actions
–Morphine produces spinal and supraspinal analgesia
by acting on µ, κ and δ receptors.
–µ receptor opioids have dependence producing
actions due to euphoric action.
–κ receptors mediate psychomimetic effects
(dysphoria).

11. Cont…
–Tolerance develops to all actions of opioids except
3Cs (Constipation, convulsions and constriction of
pupil)
–Opioids produce marked sedation but chances of
sedation are less with pethidine and fentanyl.
–Opioids can produce respiratory depression and
cough suppression.
–Miosis can occur with morphine use and pin point
pupil is a valuable sign in diagnosis of opioid
poisoning.

12. Cont…
–Highly lipid soluble drugs like fentanyl, alfentanyl
and sufentanil can result in truncal rigidity on rapid
i.v. infusion.
–By stimulating CTZ, opioids can result in nausea and
vomiting.
•Peripheral effects
–Opioids have no direct effect on heart except
pethidine and pentazocine (that increase heart
rate).

13. Cont…
-Blood pressure may decrease due to depression of
vasomotor system and release of histamine.
–Constipation can result due to decreased motility and
increased tone of GIT.
–Opioids increase intrabiliary pressure by constricting
biliary smooth muscle. (C/I in biliary colic).
–These may aggravate bronchoconstriction in asthmatics
by releasing histamine. (C/I in asthmatics).
–Spinal or epidural administration of opioids may result in
intense pruritus over lips and torso (due to histamine
release).

14. Cont…
Actions of mixed agonists-antagonists
•Buprenorphine is partial agonist at mu receptor with k and δ
antagonistic property.
–Useful as an analgesic and as an alternative to
methadone for the management of opioid withdrawal
•Nalbuphine, Pentazocine and Dezocine are k agonists and
µ receptor antagonists.
–Can produce psychomimetic effects with hallucinations,
nightmares and anxiety.
•Butorphanol is a predominant k agonist that produces
equivalent analgesia but more sedation than morphine

15. Cont…
Clinical uses of Opioids
•Used as analgesic agents. Visceral, dull and constant
pain is relieved more effectively than inflammatory pain.
•Opioids are however contraindicated in biliary colic.
•Morphine (IV) is useful in myocardial infarction as well
as in acute pulmonary edema
•Codeine, pholcodeine, dextromethorphan and
noscapine are effective cough suppressants.
–Dextromethorphan is devoid of constipating action
unlike other drugs in this group

16. Cont…
•Loperamide and diphenoxylate can be used for the
treatment of noninfective diarrhea.
•Highly lipid soluble drugs (like fentanyl, alfentanil,
sufentanil etc) are used as adjuncts to anaesthetic
agents whereas morphine is useful as a pre-anaesthetic
medication
•Pethidine is used to reduce shivering after anaesthesia
[by its action on α
2 receptor]

17. Cont…
Routes of administration
•Morphine can be administered by oral, rectal, i.v., i.m.,
intrathecal or epidural routes.
•Fentanyl can be applied as transdermal patch or can
be administered by buccal transmucosal route.
•Butorphanol is the only opioid available in nasal
formulation

18. Cont…
Adverse effects and toxicity
•Respiratory depression, nausea, vomiting, constipation,
urinary retention, itching and dysphoria
•Tolerance develops to most of the actions of opioids except
miosis, constipation and convulsions.

19. Cont…
•Opioids are highly addictive substances and can lead
to development of psychological as well as physical
dependence.
•Sudden discontinuation of these drugs in a dependent
subject may lead to withdrawal syndrome
characterized by rhinorrhoea, lacrimation, yawning,
chills, mydriasis, vomiting, diarrhea and anxiety.
•Most of these symptoms are opposite to the normal
actions of opioids

20. Cont…
Contraindications and Precautions
•Morphine is absolutely contraindicated in head injury
because it increases intracranial tension by causing
retention of CO
2 (due to respiratory depression).
–It also interferes with the assessment of neurological
function by masking the important pupillary signs
(causes miosis).
•Opioids should be used cautiously in patients with
pulmonary, hepatic or renal dysfunction

21. Cont…
•Use of opioids in infants and elderly also require caution.
•Patients of hypothyroidism may show exaggerated
response to opioids.
•Prolonged use of opioids in pregnancy may lead to in-
utero physical dependence of fetus and severe
withdrawal symptoms may be precipitated after birth

22. Cont…
B.Opioid antagonists
•are used to treat opioid overdose
•Have strong binding affinity for the mu receptors
•They work by competitive inhibition
•Naloxone: is a competitive antagonist at µ, K and δ receptors,
with higher affinity for µ than for δ receptors.
–Used to reverse the coma and respiratory depression of
opioid overdose.
•Naltrexone: is more potent than Naloxone and is used in the
treatment of alcohol addiction but its mechanism in this
treatment is unknown