This document provides an overview of opioid agonists and antagonists. It discusses the classification, chemistry, receptors, endogenous peptides, central nervous system effects, pharmacokinetics, tolerance, therapeutic uses, drug interactions, and antagonism of opioids like morphine, codeine, heroin, hydromorphone, fentanyl, meperidine, methadone, and diphenoxylate. It also covers opioid receptor antagonists naloxone and naltrexone, which are used to reverse the effects of opioid agonists and treat opioid overdose and addiction.

2. BY; SHUAIB AHMAD
MPHIL SCHOLAR-PHARMACOLOGY
22-DEC-16
OPIOID AGONISTS AND
ANTAGONISTS

3. CONTENTS
INTRODUCTION
CLASSIFICATION OF OPIOD
CHEMISTRY
OPIOD RECEPTOR
RECEPTOR STIMULATION
CNS EFFECTS OF OPIOD
PHARMACOKINETICS
TOLERANCE
THERAPEUTIC USES
DRUG INTERACTION
ANTAGONIST OF OPIOD

4. INTRODUCTION
Narcotics Those drugs which possess both an
analgesic (pain relieving) and sedative
properties.
Opioid refer to drugs in a generic sense, natural
or synthetic, with morphine- like actions

5. Classification of OPIOIDS
Natural
 phenanthrene
 morphine 10%
 codeine 0.5%
 thebaine 0.2%
semisynthetic
 heroin
 oxymorphone
 Hydromorphone
synthetic
 meperidine
 methadone
 morphinians
 benzamorphans

6. Chemistry
Morphine
pentacyclic alkaloid (five ring structure)
oxygen bridge at 4,5 position
three major rings (a, b, c)
phenolic groups (s/a hydroxyl, alcoholic, OH) at position 3
and 6
modifications at those positions changes pharmacokinetics
and potency of drug
nitrogen at 16 position (n16)
changing it by adding an alkyl group converts it to naloxone
(i.e. go from a agonist to an antagonist)

7. OPIOID receptors
CNS distribution is not uniform
they are at areas concerned with pain
receptor locations beginning with highest
concentration areas
1. cerebral cortex
2. amygdala
3. septum
4. thalamus
5. hypothalamus
6. midbrain
7. spinal cord

8. Endogenous Opioid Peptides
Three distinct families of peptides have been
identified: the enkephalins, the endorphins, and the
dynorphins. Each family is derived from a distinct
precursor polypeptide
These precursors are now designated as
proenkephalin (also proenkephalin A),
proopiomelanocortin (POMC), and prodynorphin
(also proenkephalin B)

9. ENDORPHIN
POMC is processed into melanocyte-stimulating hormone
(g-MSH), adrenocorticotropin (ACTH), and b-lipotropin
(b-LPH); within the 91-amino-acid sequence of b-LPH are
found b- endorphin and b-MSH
30 amino acid peptide
last 5 amino acids are the same sequence as enkephalins
endorphins are neurohormones
conservation between species
little difference in humans

10. ENKEPHALINS
they are 5 amino acids long
also have met enkephalin (methionine at 5' position) and
leu enkephalin (leucine at 5' position)
enkephalins are neuromodulators
since they are small peptides, it was found that they came
from larger peptides (pro enkephalins) proenkephalin gene
codes for peptide 276 amino acid in length
cleavage of proenkephalin gives 4 to 5 pieces of activated
enkephalins

11. PRODYNORPHIN
Prodynorphin yields more than seven peptides
that contain leu-enkephalin, including dynorphin
A(1-17), which can be cleaved further to dynorphin
A(1-8), dynorphin B(1-13), and a- and b-
neoendorphin, which differ from each other by only
one amino acid.

12. Receptor Stimulation
mu
 P hysical dependence
 E uphoria
 A nalgesia (supraspinal)
 R espiratory depression
kappa
 S edation
 A nalgesia (spinal)
 M iosis

13. Receptor Stimulation
delta
 analgesia (spinal & supraspinal)
 release of growth hormone
sigma
 dysphoria (opposite of euphoria)
 hallucination (both visual & auditory)
 respiratory and vasomotor stimulation
 mydriasis

14. CNS EFFECT
analgesia
sedation
euphoria
mood change
mental cloudiness

15. Morphine analgesia
**Changes our reaction and our perception of pain
severe cancer pain is tolerated more when person is given
morphine
relieves all types of pain, but most effective against
continuous dull aching pain
sharp, stabbing, shooting pain also relieved by morphine
Morphine given to a pain free individual
first experience is dysphoric
not experienced in person in pain

17. SEDATION AND EUPHORIA
Morphine sedation - morphine causes sedation
effect, but no loss of consciousness
Morphine euphoria
sense of well being
reason why morphine is abused

18. Effects of morphine on respiration
There is a primary and continuous depression of
respiration related to dose
decrease rate
decrease volume
decrease tidal exchange
mu receptor activation produces respiratory depression;
with increase in dose can cause further respiratory
depression
CNS becomes less responsive to pCO2 thereby causing a
build up of CO2
 rhythm and responsiveness causes irregular breathing patterns; one
will see periods of apnea

19. NAUSEA AND VOMITING
nausea and vomiting – Stimuation of CTZ, in
area postrema of medulla
stimulation by stretch receptors causes nausea and
vomiting
has afferents from gut and ear
involved in motion sickness

20. Cardiovascular effects
Cardiovascular effects of morphine lead to
vasodilation, thus a decrease in blood
pressure
morphine causes the release of histamine and
suppression of central adrenergic tone and
suppression of reflex vasoconstriction

21. Morphine effects on the
gastrointestinal system
increase in tone and decrease in mobility leads to
constipation
decreased concentration of HCl secretion
increased tone in stomach, small intestine, and large
intestine
delay of passage of food (gastric contents) so more
reabsorption of water
**tolerance does not develop (i.e. same amount of effect
each time) to this constipation effect

22. Morphine effects on various smooth muscles
 biliary tract
 marked increase in the pressure in the biliary tract
 10 fold increase over normal (normal is 20 mm H20 pressure)
 increase due to contraction of Sphincter of Oddi
 urinary bladder
 tone of detrusor muscle increased
 feel urinary urgency
 have urinary retention due to increased muscle tone where sphincter closed
off
 bronchial muscle
 bronchoconstriction can result
 **contraindicated in asthmatics, particularly before surgery
 uterus
 contraction of uterus can prolong labor

23. Neuroendocrine Effects
inhibit the release of gonadotropin-releasing
hormone (GnRH) and corticotropin-releasing
factor (CRF), thus decreasing circulating
concentrations of luteinizing hormone (LH),
follicle-stimulating hormone (FSH), ACTH, and b-
endorphin; the last two peptides are usually
released simultaneously from corticotrophs in the
pituitary. As a result of the decreased
concentrations of pituitary trophic hormones, the
concentrations of testosterone and cortisol in
plasma decline. Secretion of thyrotropin is
relatively unaffected.

25. Tolerance to morphine
nausea
analgesia
sedation
respiratory depression
cardiovascular
euphoric

26. Toxicity of morphine
acute overdose
respiratory depression
pinpoint pupils (miosis)
coma
Treatment
1. establish adequate ventilation
2. give OPIOID antagonist (naloxone)

27. Pharmacokinetics
Metabolism/Excretion
metabolic transformation in liver
conjugation with glucuronic acid
excreted by kidney
half life is 2.5 to 3 hours (does not persist in body
tissue)
morphine 3 glucuronide in main excretion product
lose 90% in first day
duration of 10 mg dose is 3 to 5 hours

28. Pharmacokinetics
Absorption
readily absorbed from GI tract, nasal mucosa, lung
subcutaneous, intramuscular, and intravenous
route
distribution
bound free morphine accumulates in kidney, lung,
liver, and spleen
CNS is primary site of action (analgesia/sedation)

29. Morphine administration

oral morphine not given due to erratic oral
availability
significant variable first pass effect from person to
person and have intraspecies effect (same dose will
vary in person day to day)
IV morphine acts promptly and its main effect is at
the CNS

30. Therapeutic uses of morphine
relief of pain
terminal illness
preoperative medications
postoperative medications
acute pulmonary edema
constipating effect
cough
obstetrical analgesia

31. Drug interactions with Opioids
**in general, the coadministration of CNS
depressants with OPIOID often produces
at least an additive depression
(potentiation)

32. Drug interactions with Opioids
OPIOID and phenothiazines
produces an additive CNS depression as well as
enhancement of the actions of OPIOID (respiratory
depression)
this combination may also produce a greater incidence of
orthostatic hypotension
OPIOID and tricyclics antidepressants
can produce increased hypotension
meperidine and MOA inhibitors
results in severe and immediate reactions that include
excitation, rigidity, hypertension, and severe respiratory
depression

33. Drug interactions with Opioids
OPIOID and barbiturates
increased clearance
morphine and amphetamine
enhanced analgesic effect

34. Codeine
 change in the methyl group on 3 position (substituted for the hydroxyl
group)
 one tenth the potency (analgesic properties) of morphine
 absorbed readily from GI tract
 the absorption is more regular than morphine and more predictable
 given orally
 metabolized like morphine through glucuronic acid
 physical dependence is necessity of drug so you don't go through
withdrawal
 tolerance and physical dependence is protracted from morphine since
potency of codeine is low
 withdrawal from codeine is mild in relation to morphine
 antitussive drug for cough

35. Heroin
Heroin (diacetylmorphine)
at 3 and 6 hydroxy positions, there are acetyl
groups instead of hydroxyl groups
it is anywhere from 3 to 4 times the analgesic
potency of morphine
heroin is the most lipophilic of all the OPIOID
morphine is the least lipophilic of all the OPIOID
OPIOID withdrawal is NOT fatal

36. Heroin
When heroin is ingested, it crosses the blood brain barrier
rapidly (morphine crosses slow) where it is hydrolyzed to
monoacetyl morphine (acetyl group got cleaved off) and
then it is hydrolyzed to morphine making more of the drug
in the brain making it 3 to 4 times more potent
withdrawal symptoms of heroin similar to morphine, but
more intense (rebound effect)
 mydriasis
 diarrhea
 vasoconstriction
 dysphoria
 etc.

37. Hydromorphone
(trade name is dilaudid)
have ketone at 6 hydroxyl position of morphine
also strong agonist
9 times more potent than morphine
more sedation than morphine so less euphoric feeling so
not abused much
less constipation
does not produce miosis
tolerance and physical dependence is more intense than
morphine because of its high potency
respiratory depression same as morphine

38. Fentanyl (Sublimaze)
synthetic drug
different structure than morphine
80 to 100 times more potent than morphine
rapidly acting drug
used as preoperative medication
short acting (30-45 min)
onset of action is 5 minutes
very high potency
highly abused ,known as china white as street name

39. Meperidine
produced in 1940's
 wanted drug with less addictive liability than morphine, but it
has same addictive liability as morphine
same CNS actions as morphine
sedation, analgesia, respiratory depression
potency same as morphine

40. Meperidine
 unlike morphine:
 more respiratory depression
 more bronchoconstriction activity
 less constipation
 no antitussive activity
 **it causes mydriasis (not miosis)
 toxic effects similar to atropine
 dry as a bone, blind as a bat, red as a beet, mad as a hatter
 have dry mouth
 drug absorbed orally
 drug most abused by health care professionlas due to its availability
 withdrawal similar to morphine

41. Methadone
pharmacological activity similar to morphine,
same potency as morphine
long duration of activity
absorbed well orally
16 to 20 hour duration of action
powerful pain reliever
used in maintenance program for narcotic
treatment

42. Diphenoxylate
can be OTC drug now
**therapeutic use is antidiarrhea drug (treats diarrhea)
meperidine type drug
has very little analgesic properties at therapeutic dose
no antitussive effect
at high doses it has analgesic problems
causes respiratory depression and euphoria at high doses

43. Antagonism of Morphine
two drugs: naloxone and naltrexone (pure
antagonist)

44. Naloxone
no analgesic activity at all
competitive antagonist at mu, kappa, and sigma receptor
displaces morphine and other OPIOID from receptor site
reverses all actions of the OPIOID and does it rather quickly
it will precipitate withdrawal
person on heroin, then naloxone will precipitate withdrawal, but
naloxone effects are seen in the first five minutes and it only lasts
for 30 minutes:
increased blood pressure
metabolized same as morphine through glucuronic acid and
excreted through kidney

45. Naltrexone
same effect of naloxone except it is used orally so can't use
it if for person with acute toxicity
long duration of activity
single dose block action of heroin effects for 24 hours
used for emergency treatment
once stabilized, give patient naltrexone
patient get no euphoric effect from heroin so person gets off
heroin (negative reinforcement)
approved for use by the FDA
also used for treatment of alcoholism