Pharmacology of analgesics The document discusses various classes of analgesic drugs including opioids, NSAIDs, and acetaminophen. It describes the mechanism of action, therapeutic uses, and adverse effects of representative drugs from each class such as morphine, tramadol, aspirin, and acetaminophen. Specifically, it details how opioids like morphine produce analgesia by binding to mu receptors in the brain and spinal cord, while NSAIDs inhibit cyclooxygenase enzymes to reduce inflammation and pain. Both classes can cause gastrointestinal adverse effects, though COX-2 selective NSAIDs have fewer GI side effects. Acetaminophen is largely devoid of anti-inflammatory effects compared to other NSAIDs.

1. Pharmacology of
analgesics
mensur.shafie@sphmmc.edu.et
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2. Introduction
• The International Association for the Study of Pain describes
pain as “unpleasant sensory and emotional experience
associated with actual or potential tissue damage, or
described in terms of such damage”
• Pain is a reaction of the body to harmful stimuli and is
therefore a protective early warning system
– But the sensation of pain in postoperative patients, cancer
patients, and other chronic pain patients has little positive
effect
– The stress response to pain can alter the healing process by
evoking massive sympathetic discharge that in turn alters
blood flow, tissue perfusion and immune function
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3. Introduction…cont
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4. Introduction…cont
• Alleviation of pain depends on its type
– In many case like pain of headache and others types of mild to
moderate arthritic pain NSAIDs are effective
– For severe or chronic malignant pain, opioids are the drugs of
choice
– Neurogenic pain responds best to anticonvulsants (for example
pregabalin), TCAs like amitriptyline, or
serotonin/norepinephrine reuptake inhibitors like duloxetine
rather than NSAIDs or opioids
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5. Opioid analgecics
• Opium, the source of morphine, is obtained from the poppy,
Papaver somniferum and P album
• Opioid: any naturally occurring, semi-synthetic or synthetic
compound that bind specifically to opioid receptors and share the
properties of one or more of the naturally occurring endogenous
opioids
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6. Collecting resin
of opium poppy
Crude opium
Opium flowers
Seeds of
opium poppy
Opioid analgecics…cont
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7. Opoid Receptor types and physiologic effects
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8. Classification of Opoids
• Opioid drugs include full agonists, partial agonists, and antagonists
– Agonists: morphine, heroin, pethidine, methadone, codeine,
oxycodeine, propoxyphene, fentanyl, remifentanil, alfentanyl,
etc
– Mixed agonist-antagonists: pentazocine, butorphanol,
nalbuphine,buprenorphine
– Antagonists: naloxone, naltrexone, nalmefene
• Morphine is prototype drug
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9. Mechanism of action of opoids
• Opioid agonists produce analgesia by binding to opoid receptors
that are located in brain and spinal cord regions involved in the
transmission and modulation of pain
– Some effects may also be mediated by opioid receptors on
peripheral sensory nerve ending
• Stimulation of opioid receptors is associated with a decrease in
activation of the enzyme adenylyl cyclase and a subsequent
decrease in cAMP levels in the cell
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10. Mechanism of action…cont
• Binding of opioids to their receptors produces a decrease in Ca
entry to cells by decreasing phosphorylation of calcium channels
and allows for increased time for the channels to remain closed
• In addition, activation of opioid receptors leads to potassium efflux,
and the resultant hyperpolarization limits the entry of Ca to the cell
– The net result of the cellular decrease in Ca is a decrease in
release of dopamine, serotonin, and nociceptive peptides, such
as substance P, resulting in blockage of nociceptive transmission
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11. Mechanism of action…cont
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12. Morphine
• Is the prototype opioid receptor agonist
• It is the standard for showing the potency of all other opioid
analgesics
• Is the major analgesic drug contained in crude opium
• It shows a high affinity for µ receptors and varying affinities for
delta and kappa receptors
• More water soluble than lipid, so it crosses the BBB fairly slowly
– Only 20% of administered morphine reaches the brain
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13. Morphine…pharmacologic actions
Analgesia:
• Morphine causes analgesia (relief of pain without loss of
consciousness)
• Opioids relieve pain both by raising the pain threshold at the
spinal cord level and by altering the brain's perception of pain
Euphoria:
• Morphine produces a powerful sense of contentment and well-
being
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14. Morphine…pharmacologic actions cont
Respiration:
• Morphine causes respiratory depression by reduction of the
sensitivity of respiratory center neurons to carbon dioxide
Depression of cough reflex:
• Morphine has antitussive properties
Miosis:
• The pinpoint pupil is characteristic of morphine use
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15. Morphine…pharmacologic actions cont
Emesis:
• Morphine directly stimulates the CRTZ in the area postrema that
causes vomiting
Sedation:
• Causes drowsiness and clouding of mentation, even disrupting
sleep
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16. Morphine…pharmacologic actions cont
Gastrointestinal tract:
• Morphine relieves diarrhea by decreasing the motility and
increasing the tone of the intestinal circular smooth muscle
Immune Function and Histamine:
• Opioids induce the release of histamine, which leads to the itching
sensation associated with use and abuse of opioids and bronchiolar
constriction
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17. Morphine…pharmacologic actions cont
Cardiovascular:
• At large doses morphine and other opoids may result hypotension
and bradycardia
Labor:
• Morphine may prolong labor by transiently decreasing the strength,
duration, and frequency of uterine contractions
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18. Morphine…pharmacologic actions cont
Hormonal actions:
• Morphine inhibits release of gonadotropin releasing hormone,
corticotropin-releasing hormone, LH, FSH, ACTH, endorphin,
testosterone, cortisol
• Increases growth hormone, prolactin, ADH
Tolerance and Physical Dependence
• All of the opioid agonists produce some degree of tolerance and
physical dependence
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19. Morphine…Therapeutic uses
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• Analgesia
• Treatment of diarrhea
• Relief of cough
• Preanesthetic medication:
• As emetics
• Anesthesia

20. Morphine…Adverse drug reaction
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• Severe respiratory depression occurs and can result in death from
acute opioid poisoning
• Other effects include vomiting, dysphoria, allergy and enhanced
hypotensive effects
• The elevation of intracranial pressure, particularly in head injury,
can be serious
• Morphine enhances cerebral and spinal ischemia
• In benign prostatic hyperplasia, morphine may cause acute urinary
retention

21. Morphine…ADR cont
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• Constipation
• Morphine should be used cautiously in patients with bronchial
asthma or liver failure
• Morphine and other opioids exhibit intense sedative effects and
increased respiratory depression when combined with other
sedatives, such as alcohol or barbiturates
• Respiratory depression, miosis, hypotension, and coma are signs of
morphine overdose
• Tolerance and physical dependence

22. Morphine…ADR cont
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23. Tramadol
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• Is a centrally acting analgesic that binds to the µ-opioid receptor
– In addition, it weakly inhibits reuptake of norepinephrine and
serotonin
• It is used to manage moderate to moderately severe pain
• Its respiratory-depressant activity is less than that of morphine
• Anaphylactoid reactions have been reported

24. Opoid Antagonists and management of opoid poisoning
• Opoid antagonists are drugs that attach to opioid receptors and
displace the analgesic, rapidly reversing poisoning
• Administration of opioid antagonists produces no profound effects
in normal individuals
– However, in patients dependent on opioids, antagonists rapidly
reverse the effect of agonists, such as heroin, and precipitate the
symptoms of opiate withdrawal
• Include naloxone, naltrexone and nalmefene
• Opioid poisoning presents with coma, depressed respiration,
cyanosis, hypotension, etc
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25. Non steroidal anti-inflammatory drugs (NSAIDs)
 They can be categorized as;
– Non selective (inhibit COX1 and COX2)
• aspirin, methylsalicylate, diflunisal
• Acetaminophen
• diclofenac
• indomethacin, sulindac, etodolac
• mefenamic, meclofenamic
• ibuprofen, naproxen
• tolmetin and ketorolac
• phenylbutazone
• piroxicam
– Selective (inhibit only COX2) like valdecoxib and rofecoxib

26. MOA
 Anti-inflammatory
 Inhibits COX enzyme and hence prostaglandin synthesis
 All NSAIDs, with the exception of Aspirin, are competitive
inhibitors of COX and aspirin irreversibly acetylates the enzyme
 Analgesic
 Prostaglandins (PGs), bradykinin & cytokines (such as TNF-,
IL-1, and IL-8) are important in eliciting the pain of
inflammation
 Antipyretic
• Increases in PGE2 increases cAMP & triggers the
hypothalamus to elevate body temperature by promoting an
increase in heat generation and a decrease in heat loss

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28. Pharmacologic effects
• In addition to many different effects, these drugs may
produce the following with varying degrees
 As antipyretics
 Reduce body temperature in febrile states
 As analgesics
 Relieve mild to moderate pain such as dental pain,
dysmenorrhea, and headache
 Unlike the opioid analgesics, they do not cause
neurological depression or dependence
 As anti-inflammatory agents
 Used to treat different types of inflammatory
conditions

29. Therapeutic uses
 All NSAIDs are antiinflammatory, antipyretic and analgesic,
with the exception of acetaminophen, which is largely devoid of
antiinflammatory activity
 Analgesic
 Effective only in pain of low-to-moderate intensity
 Antipyretic
 Reduce fever in most situations
 Anti-inflammatory
 In the treatment of musculoskeletal disorders, such as
rheumatoid arthritis, osteoarthritis and also used for treatment
of ankylosing spondylitis and gout

30. Adverse Effects
 Gastrointestinal
 Anorexia, nausea, dyspepsia, abdominal pain, and diarrhea
which is related to induction of gastric or intestinal
ulcers
– Inhibition of COX-1 in gastric epithelial cells depresses
synthesis of PGI2 and PGE2 and direct local irritation of
gastric mucosa
 Cardiovascular
 Causes bleeding
 Aspirin is associated with cardioprotection

31.  Renal & renovascular adverse events
– COX-2 inhibition in kidney attributed for ed
generation of vasodilator PGs (PGE2 and PGI2)
• Loss of PG-induced inhibition of reabsorption of
Cl- and the action of ADH result retention of salt
and water
• May result renal damage
Adverse Effects…cont

32. Para-Aminophenol Derivatives: Acetaminophen
 AKA paracetamol; N-acetyl-p-aminophenol
 It is an effective alternative to aspirin as an analgesic-
antipyretic agent; however, its antiinflammatory effects are
much weaker
ADRs and toxicity
 Is well tolerated and has a low incidence of GI side effects
 Rash and other allergic reactions occur occasionally
 Neutropenia, thrombocytopenia
 Over dosage causes a potentially fatal hepatic necrosis and

33. COX-2 Selective NSAIDs
Non-selective COX inhibitors
 Cause frequent GI side effects due to significant inhibition
of cytoprotective PGs synthesized by the COX-1 enzyme
Selective COX-2 inhibitors
 Do not affect the house keeping activity of COX-1
 Inhibits COX-2 which is believed to be dominant in
inflammatory sites
 Hence, drugs cause inhibition of PG synthesis in
inflammatory sites while the gastric cytoprotective

34. COX-2 Selective NSAIDs…cont
 Drugs include rofecoxib, valdecoxib, celexoxib, etoricoxib,
lumiracoxib
 The relative degree of selectivity for COX-2 inhibition is
lumiracoxib = etoricoxib > valdecoxib = rofecoxib >> celecoxib
 Adverse Effects
 Hypertension and edema due to inhibition of PG production in
the kidney
 Degree of COX-2 inhibition and the selectivity with which it is
attained suggest the likelihood of hypertension due to NSAIDs
 Coxibs avoided in patients prone to CV or cerebrovascular

35. Thank You
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