1. N A R C O T I C
A N A LG E S I C S
BY
Gurubarath M
M.Pharm !st Sem
Dept. of Pharmacology
PSGCOLLEGEOFPHARMACY
2. Narcotics
Narcotics are group of drugs that act on Central Nervous
System to produce Morphine-like effects such as pain relief
and euphoria
May also be called as Opioids
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3. Pain
• Pain begins at the nociceptors, which are the branching ends of
sensory neurons found within the peripheral nervous system
• These high threshold primary sensory neurons respond to damage to
the body by transmitting the painful stimulus to second order neurons
in the dorsal horn of spinal cord
• From there the signal is carried through the spinothalamic tract to the
thalamus and then to the somatosensory cortex where the pain is
perceived
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5. Pain
• On a microscopic level, the pain signals takes the form
of a series of action potential that fire repeatedly
depending on the intensity of pain
• To enhance the movement across the synaptic cleft,
transmitter chemicals are released from the
presynaptic cleft neurons, including Glutamate,
Substance P, and calcitonin gene related peptide
(CGRP)
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6. Glutamate
• Glutamate is one of the most important neurotransmitters for pain
and activate both NMDA and AMPA receptors, which permit influx of
positively charged calcium and sodium ions respectively
• The flow of positively charged ions into the neurons, makes the
neuron more likely to fire
• In this way, glutamate excites the secondary neurons in the dorsal
horn, which leads to propagation of a sharp, localized pain signal
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7. Substance P
• Substance P binds to the Neurokinin 1 (NK-1) receptors, which leads
to intracellular signaling that involves activation of arachidonic acid
pathways, nitric oxide synthesis and activation of NMDA receptors
• NMDA receptors are activated when substance P attached to NK-1
receptors and then incorporated into the cell, activating Protein
kinase C
• This action removes the Magnesium that under normal conditions is
blocking the NMDA receptors
• This in turn allows Glutamate to attach to NMDA receptor and thus
permit the inflow of Calcium ions ultimately causing the pain signal to
increase and fire more rapidly
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8. Calcitonin Gene Related Peptides
• The released CGRP binds to its receptor on second order neurons
leading to changes in the receptor expression and function and
thereby altered neuronal activity
• This in turn contributes to the central sensitization that is
characterized by lowered threshold for evoking action potentials
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9. Endogenous Opioids
• Our bodies can cope up with certain amount of pain by releasing
endogenous opioids
• There are three major families of endogenous opioids,
The Enkephalins
Dynorphins
Endorphins
• Endogenous opioids exert their effect by binding to opioid receptors
which are abundantly present in the central and peripheral nervous
system
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10. Opioid receptors
• There are 3 major types of opioid receptors i.e.,
μ (mu), δ (delta) and κ (kappa)
• In general, all three receptors present in their cellular distribution,
their relative affinity for various opioid ligands and their contribution
to specific opioid effects
• All opioid receptors are 7- transmembrane spanning proteins that
couple to inhibitory G-protein and they are present in high
concentration in the dorsal horn of the spinal cord
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11. Opioid receptors
• Activation of these receptors by an agonist such as endorphin causes
closing of the voltage-gated calcium channels on the presynaptic
nerve terminals which in turn decrease the release of
neurotransmitters such as glutamate, substance P and CGRP
• In addition to that activation of opioid receptors leads to opening of
potassium channels allowing efflux of potassium ions which in turn
results in hyperpolarization rendering neurons less sensitive to
excitatory inputs
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12. Synthetic opioid agonists
• Mimic the effects of endogenous opioid peptides binding to the μ
receptors
• Eg of synthetic opioid agonists are
Fentanyl, Hydrocodone, Hydromorphone, Methadone, Meperidine,
Oxycodone and Oxymorphone.
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13. Methadone
• Methadone is not only a potent μ receptor agonist but also a
potent antagonist of the NMDA receptor as well as
norepinephrine and serotonin reuptake inhibitor
• These properties make Methadone useful for treatment of both
nociceptive and neuropathic pain
• In addition to producing analgesia, activation of the opioid
receptors in other parts of the body can bring about many side
effects
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14. Side effects
All opioids produce some degree of Nausea which is due to direct stimulation
of the chemoreceptor trigger zone in medulla
All opioid receptor agonist also produce a dose dependent Respiratory
depression. Opioids produce respiratory depression by reducing brain stem
respiratory center responsiveness to CO2.
Produce an anti-tussive effect by depressing the cough center in the medulla
Opioids are associated with the suppression of immune system as
opioid receptors are involved with regulation of immunity
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15. Side effects
Morphine as well as Meperidine may provoke release of Histamine, which
plays a major role in producing Hypertension
When given by injection Morphine and Meperidine can cause
dilation of cutaneous blood vessels, which results in the flushing of
skin of face, neck and upper thorax
Meperidine in particular produce Tachycardia due to its structural
similarity to atropine
Other opioids generally produce a dose dependent Bradycardia by
increasing the centrally mediated vagal stimulation
All opioids can cause Itching via central action on pruriticeptive
neural circuits
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16. Side effects
Opioids also decrease Gastric motility and prolong gastric emptying time,
which may cause constipation
Likewise, opioids depress renal function and produce Antidiuretic effects
They also increase sphincter tone and thus may cause Urinary retention
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17. Addiction
• The biggest problem with opioids is that they have the potential to cause addiction by
causing both Physical and Psychological dependence
• The euphoric effect appears to involve GABA inhibitory interneurons of the ventral
tegmental area of the brain
• Normally GABA reduces the amount of Dopamine released in the nucleus accumbens,
which is a brain structure that is part of our pleasure and reward system
• However, when opioids attach to and activate the μ receptors in that area the release of
GABA becomes suppressed – This in turn increases the amount of pleasure felt
• Now on the other hand, Prolonged regular use of opioids leads to desensitization of
receptor signals and down regulation of receptor and thus a decrease in sensitivity to
effect of opioids
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18. Addiction - withdrawal symptoms
• As a result when regular use is reduced or suddenly stopped the lack of receptor
activity is manifested as withdrawal symptoms
• These symptoms are generally opposite to the pharmacological effects of the
opioid drugs
• So rather than causing constipation and slowing respiration, the brain stem
triggers Diarrhea and elevates blood pressure
• Instead of triggering happiness the nucleus accumbens and amygdala reinforce
feelings of dysphoria and anxiety
• All of the negativity feeds into the Prefrontal cortex, further pushing a desire for
opioids
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19. Addiction - withdrawal symptoms
Prolonged regular use of opioids leads to desensitization
of receptor signals
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20. Buprenorphine
• A partial μ receptor agonist
• A partial agonist binds to the receptor and activates it
with a small shape change which leads to only a partial
receptor response
• The effects of partial agonists increase only until they
reach a plateau
• Like all opioids Buprenorphine can cause respiratory
depression and euphoria, but its effects are much smaller
than those of full agonists
• The benefits of this are lower risk of abuse, addiction and
side effects
• It is also an antagonist in the δ and κ receptors and
because of that it is referred to as Mixed agonist-
antagonist
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21. Naloxone
• It is an opioid antagonist that can be used to block or
reverse the effects of opioid drugs
• Naloxone works by knocking off the opioids attached to
the receptors in the brain, thereby temporarily stopping
the opioid effect
• This is possible because Naloxone has a stronger affinity
for opioid receptor and thus is able to kick the opioids
out and block them from attaching again
• So during an emergency situation when a person’s
breathing has slowed down or stopped due to an
opioid overdose Naloxone can quickly restore normal
breathing and save the life
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