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OPIOID ANALGESICS
& ANTAGONISTS
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Opioids: natural or synthetic compounds
morphine-like effects
Opiates: a term reserved for those drugs,
such as morphine or codeine, obtained from
the juice of opium poppy Papaver
somniferum
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Opium Poppy
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Commercial poppy
cultivation in France
Capsule of Papaver
somniferum showing latex
(opium) exuding from incision
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Endogenous opioids: endorphins,
enkephalins, dynorphins & even morphine
itself
Morphine mimics endogenous endorphins
responsible for analgesia (pain reduction or
relief) sleepiness & feelings of pleasure
They are released in response to pain,
strenuous exercise, orgasm or excitement.
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Opioid receptors:
mu (), kappa (k) &
delta (o), through G-
proteins (G
i
),
1) Facilitate opening of K
+

channels hyperpolarization
2) --- Adenylate cyclase +
cAMP
3) --- Ca
2+
channels opening
+ transmitter release
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-Receptors analgesia, sedation, miosis,
euphoria, respiratory depression, GI motility
depression & dependence
k-Receptors analgesia, sedation, miosis &
dysphoria
o-Receptors, more important in the
periphery, may contribute to analgesia
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ANALGESIA
Sedation
Miosis
EUPHORIA
Respiratory depression
GI motility depression
Dependence
k
-
R
e
c
e
p
t
o
r
s

-
R
e
c
e
p
t
o
r
s

-Receptors
DYSPHORIA
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Opioid Agonists & Antagonists
I. Pure Agonists
II. Mixed Agonist-
Antagonists
III.Antagonists
A.STRONG AGONISTS B.MODERATE AGONISTS
1. Morphine
2. Diamorphine
(Heroin)
3. Meperidine
4. Methadone
5. Fentanyl
6. Sufentanil
7. Etorphine
1. Propoxyphene
2. Codeine
1. Pentazocine
2. Cyclazocine
3. Nalorphine
4. Nalbuphine
5. Buprenorphine
1. Naloxone
2. Naltrexone
3. Nalmefene
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I.STRONG AGONISTS
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1. Morphine
The gold standard of analgesics used to
relieve severe or agonizing pain & suffering
Acts directly on the CNS
A high potential for addiction; tolerance and
both physical and psychological dependence
develop rapidly
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Mechanism of action
Interaction with opioid receptors in the CNS &
GIT
1) hyperpolarization of nerve cells -- nerve firing
2) presynaptic inhibition of transmitter release
At -receptors + release of substance P
which modulates pain perception
-- release of many excitatory transmitters
from nerve terminals carrying painful stimuli
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Pharmacological Effects
1. CNS:
a) Analgesia & sedation
b) Euphoria
c) Respiratory depression
d) Depression of cough reflex (antitussive)
e) Nausea & vomiting
f) Miosis
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Pharmacological Actions (Contn.)
2. Smooth muscles (GIT, urinary T., bronchi
& uterus)
3. Cardiovascular & cerebral b.v.
4. Histamine release
5. Hormonal actions
6. Straub tail reaction
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Tolerance & Dependence
Repeated administration tolerance to the
analgesic, sedative, euphoric & respiratory
depressant effects.
Tolerance DOES NOT develop to the pupillary
constriction & constipation.
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Physical & psychological dependence readily
occur with morphine.
Withdrawal abstinence symptoms; a series
of autonomic, motor and psychological
responses that incapacitate the individual
serious, almost unbearable symptoms
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Pharmacokinetics
GI absorption is slow & erratic.
Significant hepatic 1
st
pass metabolism to
glucuronides
Other routes of administration should be
followed; i.m., s.c., i.v., inhalation!!!
The duration of action of morphine is 4-6
hours in naive individuals.
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Morphine rapidly enters all body tissues,
including the fetus of pregnant women.
Infants born of addicted mothers show
physical dependence on opiates and exhibit
withdrawal symptoms if opioids are not
administered.
Morphine is the least lipophilic opioid only
a small % crosses the BBB
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Side effects
1. Severe respiratory depression??
2. Other effects: vomiting, dysphoria &
allergy-enhanced hypotensive effects
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Precautions & Contraindications
1. Infants & elderly (more sensitive to resp. dep.)
2. Resp. insufficiency (e.g. emphysema, fibrosis)
3. Bronchial asthma
4. Head injury !!!
5. Hypotensive states & hypovolemia
6. Undiagnosed abdominal pain !!!
7. Prostatic hypertrophy retention
8. Adrenal insufficiency or myxedema extended &
enhanced effects (patients are more sensitive to morphine)
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Uses
1. Analgesia ?
2. Diarrhea & dysentry ?
3. Antitussive ?
4. Acute pulmonary edema (i.v.) secondary
to left ventricular failure (cardiac
asthma) ?
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2. Diamorphine (heroin; diacetylmorphine)
morphine in the body
More potent than morphine (2-4)
A greater lipid solubility
1) Crosses BBB more readily than morphine
2) Smaller doses can be given orally
A shorter duration of action than morphine
Similar to morphine, diamorphine resp.
depression & physical dependence
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3. Meperidine (pethidine)
1
st
synthetic opioid (1939) with additional
antimuscarinic properties !!!!
Similar to morphine in pharmacological effects
except that it tends to cause RESTLESSNESS !!
rather than SEDATION.
A faster onset & a shorter duration of action
A similar euphoric effect & equally liable to
cause dependence
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Used in moderate to severe pain:
Pethidine is superior to morphine in R
x
pain
associated with biliary spasm or renal colic due
to its antispasmodic effects. G.R.
It is preferred for analgesia during labor (due
to its shorter duration of action (120-150 min)
less resp. depression than morphine) G.R.
Concurrent administration of pethidine with
MAOIs severe reactions; excitement,
hyperthermia & convulsions death
(serotonin syndrome)
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t

8-12 h
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The severe side effects unique to pethidine -
serotonin syndrome, seizures, delirium, dysphoria
& tremor- are due to norpethidine.
Norpethidine is toxic and has convulsant and
hallucinogenic effects.
These toxic effects CANT be countered with
naloxone because they are due to its
anticholinergic activity & monoamine (NE,
dopamine & 5-HT) reuptake inhibition.
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1/8
th
the potency of morphine
Well absorbed orally
Biotransformed to a toxic metabolite (norpethidine)
that can cause seizures
A faster onset & a shorter duration !!!
Fewer smooth muscle spasms than morphine !!!
Less histamine release safer in asthmatic
No miosis
Tachycardia
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4. Methadone
1) A synthetic, orally effective opioid that is ~ equal
analgesia in potency to morphine
2) Less euphoria & sedative actions blockade of
euphoric effects of heroin, morphine & similar drugs
3) A long duration of action due to long plasma t
1/2
(>
24 h) & duration of action | with repeated use
1, 2 & 3 use in controlled withdrawal of addicts
from heroin & morphine (anti-addictive)
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5. Fentanyl & sufentanil & alfentanyl
Highly potent phenylpiperidine derivatives, with
actions similar to morphine, but short-lasting,
particularly sufentanil
Fentanyl is 80-100 more potent than morphine
Sufentanil is a highly potent analgesic (5-10 more
potent than fentanyl) used in heart surgery.
Alfentanil is an ultra-short acting (5-10 minutes)
opioid.
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Fentanyl is extensively used for anesthesia &
analgesia, most often in the operating room
and intensive care unit.
Fentanyl is sometimes given intrathecally as
part of spinal anesthesia or epidurally for
epidural anesthesia & analgesia.
Fentanyl is available as a patch & as an oral
slow-release device
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6. Etorphine:
A semi-synthetic morphine analogue with an
analgesic potency ~1000-3000 that of
morphine (but otherwise very similar in its
actions)
Used to immobilize wild large animals, like
elephants, for trapping & research purposes.
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Tramadol
Opioid receptor agonist
A low affinity for receptors and a very low affinity
for k & o !!!!
NE & 5-HT reuptake blocker (antidepressant) &
2

adrenoceptor agonist
These 2 actions are synergistic for analgesia
Analgesic action is partially reversed by naloxone
Used in mild-to-moderate short-lasting pain &
chronic pain
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II.MODERATE
AGONISTS
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1. Codeine
More oral absorption than morphine (due to
its higher lipid solubility)
A marked antitussive activity used in
cough mixtures
s 20% of the analgesic potency of morphine
used as oral analgesic for mild types of
pain (headache, backache, etc.)
Little or no euphoria & rarely addictive
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2. Dextropropoxyphene
Well absorbed orally (peak plasma levels
occurring in 1 hour)
Similar to CODEINE but has a longer duration
of action & free from dependence liability
Often used in combination with aspirin or
acetaminophen for a greater ANALGESIA than
that obtained with either drug alone
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III.MIXED AGONIST-
ANTAGONISTS
(Pentazocine, Nalorphine & cyclazocine,
Butorphanol & Nalbuphine)
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1. Pentazocine ( partial agonist and k & o agonist)
At low doses, its potency & effects are very similar
to morphine.
| Dose a corresponding | in produced effects &
at high doses, pentazocine slight resp. dep. ()
marked dysphoria, with nightmares &
hallucinations (k), rather than euphoria
Used in moderate to severe pain
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Its antagonist activity is apparent when given
concurrently with morphine as pentazocine +
the analgesic & other actions of morphine
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2. Nalorphine
In low doses, it competitively antagonizes
(blocks) most actions of morphine.
In high doses, it is analgesic, and mimic the
effects of morphine.
These effects reflect an antagonist action on
-receptors, coupled with a partial agonist
action on o- and k-receptors, the latter
causing dysphoria.
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IV.ANTAGONISTS
(Naloxone, Naltrexone & Nalmefene)
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Signs of Overdose
o stuporous or in coma
o low body temp.
o pinpoint pupils
o extremely low resp. rate (resp. dep.)
o flaccid skeletal muscles, relaxed jaw
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1. Naloxone
Naloxone is used to reverse the resp.
depression & coma of opioid overdose.
It rapidly displaces all receptor-bound
opioids reversal of heroin overdose effect
Within 30 seconds of its i.v. injection, the
resp. depression & coma; characteristics of
high doses of heroin, are reversed the
patient is revived and alert
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A short t
1/2
of 60-100 min.
Not effective orally
In normal individuals, naloxone no
pharmacologic effects, but it precipitates
withdrawal symptoms in morphine or heroin
abusers
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2. Naltrexone
Actions similar naloxone
A long t
1/2
a longer duration of action than
naloxone; a single oral dose blocks the effect
of injected heroin for up to 48 hours
Available in oral form only
It is used in opiate-dependence maintenance
programs and chronic alcoholism.
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3. Nalmefene
Intermediate duration (4-6 hr)
orally active
no hepatotoxicity
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THANK YOU
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