1. Pain, Inflammation, NSAIDs and Analgesics
BY DR KAUKAB AZIM

2. Learning Outcomes
By the end of the lecture the student should be able to
Define and discuss the pathobiology of pain pathways
Explain the molecular mechanism of action common to all nonsteroidal antiinflammatory drugs (NSAIDs)
Describe the pharmacological effects of each drug in each class.
Describe the pharmacokinetics of salicylates.
Describe the main adverse effects of the drugs of each class.
Describe the clinically important drug interactions of the drugs of each class.
Describe the principal contraindications of the drugs of each class.
Describe the main therapeutic uses of NSAIDs and acetaminophen.

3. What is inflammation?
Inflammation: is a reaction to tissue injury caused by the release of chemical mediators that cause both vascular response and the migration of fluids and cells to the injured site.
It is a protective mechanism in which the body attempts to neutralize and destroy harmful agents at the site of tissue injury and establish condition for tissue repair.

4. What is Pain
Pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage
Hyperaesthesia (hypersensitivity): Increased sensitivity to stimulation, excluding the special senses.
Hyperalgesia: Increased pain in response to a noxious stimulus
Allodynia: Pain due to a stimulus that does not normally produce pain
From the International Association for the Study of Pain (IASP) definitions (Merskey, and Bogduk 1994)

5. Pain is the most feared complication of illness
Physicians Have a Moral Obligation to Provide Comfort and Pain Management Especially for those near the end of life!
Pain is the most feared complication of illness
Pain is the second leading complaint in physicians’ offices
Often under-diagnosed and under-treated
Effects on mood, functional status, and quality of life
Associated with increased health service use

6. Common Causes of Pain In Elderly Persons
Osteoarthritis of back, knee, hip
Night-time leg cramps
Claudication
Neuropathies can be idiopathic, traumatic, diabetic or herpetic
Cancer

7. Pain Receptors

8. Pain Pathway

9. Mechanisms associated with peripheral sensitization to pain
Agents that Activate or Sensitize Nociceptors:
Cell injury  arachidonic acid  prostaglandins   vasc. permeability
(cyclo-oxygenase)  sensitizes nociceptor
Cell injury  arachidonic acid  leukotrienes   vasc. permeability
(lipoxygenase)  sensitizes nociceptor
Cell injury   tissue acidity   kallikrein   bradykinin   vasc. permeability
 activates nociceptors
  synthesis & release of prostaglandins
Substance P (released by free nerve endings)  sensitize nociceptors
  vasc. perm., plasma extravasation
(neurogenic inflammation)
 releases histamine (from mast cells)
Calcitonin gene related peptide (free nerve endings)  dilation of peripheral capillaries
Serotonin (released from platelets & damaged endothelial cells)  activates nociceptors
Cell injury  potassium  activates nociceptors

10. Nonsteroidal antiinflammatory drugs (NSAIDs)
Salicylic acid derivatives
Propionic acid derivatives
Acetic acid derivatives
Oxicams
Indole derivatives
Selective COX-2 inhibitors
-Acetylsalicylic acid
-Sodium
salicylate
-Diflunisal
-Mesalamine
Ibuprofen
Ketoprofen
Naproxen
Diclofenac
Ketorolac
Piroxicam
Meloxicam
Indomethacin
Celecoxib
Analgesic-antipyretic drug:
Acetaminophen

11. Prostaglandins as mediators√

12. ▼ ► Non-selective (t NSAIDS) inhibit both isozymes.
Side effects occur due to inhibition of COX-1(house keeping” enzyme) ►
With selective COX-2 inhibitors (Coxibs), chances of GIT toxicity are less.
CVS side effects can occur

13. NSAIDS: Mechanism of action
Main mechanism: Inhibition of COX
Reversible (competitive) inhibitors
Irreversible inactivation (by Aspirin) OR
Nonselective COX inhibitors (traditional NSAIDS)
Selective COX-2 inhibitors (Celecoxib)

14. NSAIDS: Effects Anti-inflammatory effect
Reverses vasodilation, edema, tenderness
Analgesic effect
By preventing PG mediated sensitization of nerve endings
Antipyretic effect
Resets the hypothalamic thermostat by decreasing PG synthesis
Vasodilation and heat loss
DO NOT cause hypothermia

15. Antiplatelet aggregation effect
Platelets have COX-1.
Aspirin acetylates COX-1 to inhibit its activity in an “irreversible manner”.
All other tNSAIDS- reversible inhibitors.
Selective COX-2 inhibitors DO NOT disturb platelet aggregation at therapeutic doses.
Acetaminophen DO NOT inhibit platelet aggregation.

16. Common side effects of NSAIDS
Gastrointestinal:
Nonselective NSAIDS COX-1 inhibition ↓ gastroprotective PGs
Effects
Gastric irritation, erosions, ulcers, gastric bleeding
Misoprostol (PGE1) can be used to prevent gastric ulcers caused by tNSAIDS.
Selective COX-2 inhibitors are safer.

17. Renal:
Sodium water retention, Papillary necrosis
CVS:
↑ Na and water retention
Platelet inhibition : bleeding
Selective COX-2 inhibitors and acetaminophen do not disturb platelet function.
CNS:
Headache, confusion, seizures
Hypersensitivity:
“Pseudoallergic reaction” (due to increased leukotrienes)

18. Salicylates Acetylated salicylate: Aspirin (Acetylsalicylic acid)
Non-acetylated salicylates: sodium salicylate, diflunisal, mesalamine (5-ASA)
Mechanism of action:
Aspirin: non-selective COX inhibitor; Irreversible inhibition” by acetylation.
Other salicylates: weak COX inhibitors; other mechanisms are involved.

19. Dose dependent effects of Aspirin
Toxic levels
High Levels

20. Effects of aspirin Antiplatelet effect:
Irreversible inactivation of COX-1 in platelets causes decreased production of TXA2 (aggregation promoter). Platelets (enucleated) cannot regenerate COX; effect lasts for 7-8 days.
Irreversible inactivation of COX in endothelial cells causes decreased production of PGI2 (aggregation inhibitor). Endothelial cells can regenerate cyclooxygenase in a matter of hrs.
Net effect is decreased platelet aggregation and increase in bleeding time.
Low doses (80-160mg) are enough to inhibit aggregation without anti-inflammatory effects.

21. Aggregation inhibitor
ANTIPLATELET EFFECT OF ASPIRIN
Aggregation promotor
Aggregation inhibitor
Irreversible inhibition by Aspirin.
Nucleated endothelial cells can regenerate COX.
COX
PG I2
COX-1
Irreversible inhibition by Aspirin.
Enucleated platelets cannot regenerate COX.

22. Other effects of aspirin
↑ Plasma uric acid levels (at low dose)
↓ Plasma uric acid levels (at high dose)
Hyperventilation and compensated alkalosis (At high levels)
Stimulates respiratory center, ↓ pCO2, Increased bicarbonate in urine
Metabolic acidosis: (At toxic levels)
Accumulation of salicylic acid due to zero order kinetics at high levels.
Respiratory center depression; ↑ pCO2

23. Salicylates: Adverse effects
Hypersensitivity reactions
Pts with asthma, nasal polyps, chronic urticaria are more susceptible.
Pseudoallergic reaction.
Cross reactivity with other NSAIDS.
Reye’s syndrome: Encephalopathy, hepatotoxicity.
Do not use aspirin in children with viral fever.
Salicylism:
Tinnitus, dimness of vision, mental confusion, sweating, hyperventilation, nausea and vomiting, diarrhea

24. Salicylate intoxication
Tinnitus, Nausea and vomiting, abdominal cramps, gastric bleeding.
Respiratory depression, Acidosis, generalized convulsions.
Marked hyperthermia, dehydration.
Skin eruptions, petechial hemorrhages
Coma and death (due to respiratory failure)
Treatment: Symptomatic and supportive.
External cooling and I.V. fluids with Na, K, and glucose.
Gastric lavage to remove unabsorbed drug
Forced alkaline diuresis to remove absorbed drug

25. Salicylates: Therapeutic uses
Keratolytic: salicylic acid
Counterirritant: Methylsalicylate
Antiinflammatory, analgesic, antipyretic
Diflunisal: does not enter CNS; no antipyretic effect
Mesalamine (5-ASA):
inflammatory bowel diseases
Aspirin (Low doses):
MI, Angina
Atrial flutter/fibrillation
Transient ischemic attacks

26. Other tNSAIDS Ibuprofen, Naproxen:
Widely used NSAID for pain and inflammation
GIT and CNS side effects are less
Diclofenec:
Inhibits COX and lipooxygenase (to minor extent)
Decreases free radical production
Accumulates in synovial fluid
Ketorolac:
Can be administered IV, IM
Used in postoperative pain

27. Indomethacin
One of the most potent COX inhibitor
Inhibits COX
Inhibits Phospholipase A2
Reduces neutrophil migration
Reduces T and B cell proliferation
Severe side effects (in 1/3rd pts)
Abdominal pain, diarrhea, GI bleeding
Frontal headache
Dizziness, confusion, depression, hallucinations
Therapeutic Uses:
Arthritis (osteoarthritis, rheumatoid arthritis, Ankylosing spondylitis, Gout)
Closure of ductus arteriosus

28. Selective Cox-2 inhibitors “Coxibs”
Celecoxib: first selective COX-2 inhibitor
Potent antiinflammatory, analgesic and antipyretic activity
Incidence of GI bleeding and peptic ulcers is lower than tNSAIDS
Does not inhibit platelet aggregation
Increased risk of cardiovascular side effects: Hypertension, Thrombotic events

29. Acetaminophen Analgesic and antipyretic agent Inhibits COX-3 in CNS… ?
Lacks significant anti-inflammatory and antiplatelet activity: very weak COX 1& 2 inhibitor
Metabolized in the liver
Toxic doses deplete glutathione
A metabolite, N-acetyl-p-benzoquinoneimine accumulates and causes hepatic necrosis.
Acetylcysteine administered as antidote.

30. Acetaminophen: Metabolism
MAJOR
PATHWAY
(Sulphate Conjugation)
MAJOR
PATHWAY
(Glucuronide conjugation)
MINOR
PATHWAY
P450 Enzyme
CYP2E1 and CYP1A2
RENAL EXCRETION
TOXIC METABOLITE
NAPQI
N-acetyl-p-benzo-quinone imine)
Therapeutic Doses
Toxic Doses (4gm+)
Glutathione
Available
Glutathione
Depleted
RENAL EXCRETION
Hepatic Necrosis

31. Antiinflammatory agents: Steroids

32. Glucocorticoids: Mechanism of action

33. Steroids: Antiinflammatory effect

34. Therapeutic uses Adrenal Uses Non-adrenal uses: Inflammatory disorders
Asthma
Allergies: Allergic rhinitis, Acute allergic reactions
Autoimmune disorders: RA, SLE, glomerulonephritis
Carcinomas
For immunosuppression
This part will be given in details in the Endocrine pharmacology…..

35. OPIOID ANALGESICS

36. History of Opioids Opium is extracted from poppy seeds
Used for thousands of years to produce:
Euphoria
Analgesia
Sedation
Relief from diarrhea
Cough suppression
This part will be given in details in the CNS pharmacology…..

37. Opioid Agonists Opioid antagonist Naloxone Morphine Naltrexone Heroin
Hydromorphone
Fentanyl
Codeine

38. Good luck