A short introduction of NSAIDs useful for MBBS, BDS and BSc Nursing students

1. NSAIDS-I
Dr. Jessica Dali
Department of Pharmacology
Nobel Medical College and Teaching Hospital

2. Inflammation
• Reaction to injury of the living microcirculation and related tissues
CARDINAL SIGNS :
• Redness (Rubor),
• Swelling (Tumour),
• Heat (Calor),
• Pain (Dolor),
• Loss of function

3. NSAIDS
• Non steroidal anti-inflammatory drugs
• One of the most commonly prescribed drugs
• Mostly used for:
• Anti pyretic
• Anti inflammatory
• Analgesic action

6. COX-1 and COX-2
• Cycloxygenase-1 ( COX-1)
• Present in most of the cells
• Mediates normal physiological function
• Cycloxygenase-2 (COX-2)
• Induced during inflammation by cytokines, growth factors, etc.
• Not present in all cells at all times
• Activated by Interleukin-1 and TNF-α

7. • Majority of tissues synthesize all PGH intermediates but the
predominant PG in a tissue depends on the enzyme present and their
amount
• Example:
• Lungs and spleen- all PGs
• Platelets- Thromboxane synthase
• Blood vessels ( vascular endothelium)- Prostacyclin synthase

9. Natural Prostaglandins
1. PGE2- many receptors, many functions
• Bronchodilation
• Vasodilation
• Increase mucus secretion in stomach
• Patency of ductus arteriosus
2. PGD2 – vasodilation, inhibition of platelet aggregation
3. PGF2α – contracts smooth muscles of uterus, facilitates parturition

10. 4. PGI2 or Prostacyclin- vasodilation, inhibition of platelet
aggregation, prevents platelets adherence to healthy blood vessels
wall
5. TXA2- vasoconstriction, platelet aggregation

11. Anti- inflammatory effects of NSAIDs
A. Reduce those components of inflammatory response in which PGs
play a role:
1. Vasodilation
2. Oedema
3. Pain
B. Suppress pain, swelling and increased blood flow due to
inflammation but have little action on the actual progress of the
underlying chronic disease itself.
C. No effect on other aspects of inflammation- leucocyte migration,
lysosomal enzyme release and toxic oxygen radical production that
contribute to tissue damage in chronic inflammatory conditions

12. Fever
• Disturbance of hypothalamic thermostat leads to raised setpoint of
body temperature
• Normal temperature in humans not affected by NSAIDs
• Bacterial endotoxins cause release of IL-1, which stimulates the
generation of PGE, that elevate the temperature setpoint

13. Anti- pyretic effect

14. Analgesic effect
• Effective against mild or moderate pain from tissue damage or
inflammation
• Decrease the production of Prostaglandins that sensitize nociceptors
to inflammatory mediators such as bradykinin. Hence effective in
arthritis, muscular/vascular pain, toothache, dysmenorrhea – all
conditions associated with increased local prostaglandin synthesis
• Combined with opioids, they decrease postoperative pain
• Ability to relieve headache maybe due to stopping of vasodilator
effect of prostaglandins on the cerebral vasculature

15. Clinical Implications of PGs and NSAIDs
1. Patent Ductus Arteriosus- Ductus Arteriosus is kept open by PGE2
and PGI2 in foetal life. Aspirin and Indomethacin are given in high
doses to close ductus arteriosus if closure does not occur in usual
time.
2. Platelet aggregation- Aspirin in low doses inhibits synthesis of TXA2
and produces antiplatelet action
3. PGE2 and PGF2α are used in induction of labour as they contract
uterus, and NSAIDs used to delay the labour. NSAIDS not used for
the purpose for the fear of early closure of ductus arteriosus.

16. 4. PGF2α constricts the sphincter muscle of iris causing miosis,
increasing uveoscleral and trabecular outflow, decreasing
intraocular pressure. Latanoprost, a synthetic PGF2α has been
developed for treatment of open angle glaucoma.
5. PGE2 analogue (Misoprostol) is used in peptic ulcer to increase
gastric mucus secretion( gastro-protective effect).
6. TXA2, PGF2α both cause bronchoconstriction. In asthma, LTs are
considered to be causative. Hence, NSAIDs might direct all
production of AA to LTs increasing the severity of asthma.

17. 7. PGE2 and PGI2 are vasodilators, increase renal blood flow due to
direct action on renal tubules, causing natriuresis, diuresis and
kaliuresis. NSAIDs, hence, cause retention of sodium and water and
may block the effect of diuretics.

19. Common adverse effects of NSAIDs
1. Effect on gastric mucosa: PGs like PGE2 and PGI2 protect gastric
mucosa by inhibiting gastric acid secretion, increasing mucus, and
increasing the gastric blood flow. Loss of these actions damages
gastric mucosa causing ulcers.

20. 2. Renal toxicity: In hypovolemia or decreased renal perfusion, PGs
synthesized in the kidneys maintain perfusion by vasodilation,
antagonizing action of ADH and other mechanisms. NSAIDs block
this mechanism and give rise to analgesic nephropathy – a slow
developing renal failure. Avoid by
• short course or after gap of few weeks
• Only one NSAID at a time

21. 3. Cardiovascular adverse effects:
a) Inhibition of PG production in the kidney may retain sodium and
water. NSAIDs are therefore associated with risk of hypervolemia-
hence worsening heart failure, especially if controlled by diuretics
b) Risk of increase in BP.
c) Increased stroke and Myocardial infarction due to inhibition of
prostacyclins

22. Classification
1. Non- selective COX inhibitors
• Salicylic acids: Aspirin
• Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen
• Fenamate: Mephenamic acid
• Enolic acid derivatives: Piroxicam
• Acetic acid derivatives: Ketorolac, Indomethacin
• Pyrazolone derivatives: Phenylbutazone

23. 2. Preferential COX-2 inhibitors:
Nimesulide, Diclofenac, Meloxicam
3. Selective COX-2 inhibitors:
Celecoxib, Etoricoxib

24. Aspirin (Acetyl Salicylic Acid)
• Derived from Willow bark, which used for centuries
• Prototype drug with a range of actions
• Used for
1. Pain- sp. Tension headache
2. Fever
3. Acute Rheumatic Fever
4. Post myocardial infarction and
post stroke patients

25. Actions
1. Pain, fever, inflammation
• Inflammatory, connective tissue related pain
• Peripheral pain receptors desensitized, PG- mediated sensitization of
nerve endings prevented. Also, pain threshold increases.
• Resets hypothalamic thermostat, rapidly reduces fever by promoting
sweating, cutaneous vasodilation
• Inhibits PG synthesis, suppress signs and symptoms of inflammation
but do NOT affect the progression of the disease

26. 2. Antiplatelet effect:
• In lower doses( 50-325 mg) Irreversibly inhibits platelet TXA2
synthesis producing antiplatelet effect, which lasts for 8-10 days, i.e.
the lifetime of platelets.
• In high doses (2-3 g/day) inhibits both PGI2 and TXA2 synthesis,
hence beneficial effect of PGI2 is lost.
• Aspirin should be withdrawn 1 week prior to elective surgery because
of this risk of bleeding.
3. At high doses, increased respiration/ hyperventilation is stimulated
by Aspirin. Even higher doses can cause respiratory failure.

27. 3. Acid- base and electrolyte balance:
• At high doses, hyperventilation drives out CO2 causing respiratory
alkalosis, which is compensated by increased renal excretion of HCO3
-.
• Still higher doses- depressed respiration- more CO2 produced in the
body- respiratory acidosis.
• Metabolic acids produced in excess + metabolites of salicylic acid
present, decreased HCO3
- in the body- uncompensated metabolic
acidosis

28. 4. GIT: Ion trapping prominent
• Aspirin is easily absorbed into the gastric mucosal cells as it remains
unionized in the acidic medium of the stomach. But once inside the
gastric cells, most part of it gets ionized and cannot cross the cell
membrane to reach the bloodstream
• Irritates gastric mucosa, causing nausea, v
vomiting and epigastric distress.
• Also stimulates CTZ

29. 5. Urate excretion:
<2 g/day- urate retention, antagonize other uricosuric drugs
2-5g/day- variable effects
>5 g/day- increased urate excretion
6. Metabolic effects: At high doses,
• Uncoupling of oxidative phospholylation
→ increased heat production
• Increased utilization of glucose →
hyperglycemia

30. Pharmacokinetics
• Rapidly absorbed from upper GIT
• Metabolized in liver
• Low dose- 1st order kinetics of elimination
• High doses- 0 order kinetics of elimination, as the metabolizing
enzymes are saturated

31. Adverse effects
1. GIT: Nausea, vomiting, epigastric pain, gastric ulcer and bleeding.
2. Hypersensitivity: Patients with asthma, nasal polyps, recurrent
rhinitis or urticarial
3. Reye’s syndrome: Children with viral infection- Avoid NSAIDs as
they can cause liver damage with fatty infiltration and
encephalopathy
4. Pregnancy: Delay natural contractions of labour, increase chances of
postpartum hemorrhage. Also in the newborn, inhibition of PG
synthesis results in premature closure of ductus arteriosus.
5. Analgesic nephropathy: Renal failure

32. Aspirin poisoning
• Symptoms:
• CNS: headache, tinnitus, vertigo, convulsions, coma
• GIT: nausea, vomiting, diarrhoea
• Sweating and hyperventilation
• Hypo/hyperglycemia
• Hyperpyrexia
• Death by respiratory failure/ Cardiovascular collapse

33. Treatment:
NO ANTIDOTE, Symptomatic treatment
1. Gastric lavage + activated charcoal
2. Fluid and electrolytes, acid-base balance
3. IV sodium bicarbonate to treat metabolic acidosis, also alkalinizes
urine and increases excretion of salicylates
4. External cooling
5. Hemodialysis in severe cases
6. Vitamin K1 and blood transfusion if there is bleeding

34. Dose of Aspirin
• Antiplatelet effect- 50-325 mg/day
• Analgesic effect- 2-3 g/day
• Anti-inflammatory effect- 4-6 g/day
• Anti- gout effect (uricosuric effect)- >4-5g/day

35. Paracetamol
• COX-3 is a variant of COX-1, sensitive to Paracetamol
• Weak inhibitor of PG synthesis of COX-1 and COX-2
Adverse effects
1. Rare, occasionally causes skin rashes and nausea
2. Hepatotoxicity
3. Nephrotoxicity Chronic use

36. Paracetamol
1. NO ANTI INFLAMMATORY ACTION: Increases pain threshold;
produces analgesic and antipyretic action due to action in CNS.
Weak inhibitor of cyclooxygenase in presence of high concentration
of cyclic endoperoxides at peripheral inflammatory sites
2. No effect on cardiovascular/ respiratory function
3. No acid base imbalance
4. No gastric irritation/ bleeding
5. No effect on platelets, bleeding time
and uric acid

37. Acute Paracetamol Poisoning

39. • Alcohol is an inducer of CYP2E1, increases conversion of paracetamol
to NAPQI, increasing paracetamol toxicity
• Fatal dose reduced to 5-6 g in chronic alcoholics
• Overdose occurs when high dose (>8 g/day) is consumed
• Symptoms: Nausea, vomiting, abdominal pain, liver tenderness,
jaundice, unconsciousness
• ANTIDOTE: N-acetylcysteine (NAC)- repletes the glutathione
• Alternatively, methionine can be used- avoid with charcoal as it will
get bound in charcoal particles hence useless
• Supportive measures: Activated charcoal, gastric lavage

40. Diclofenac
• Used for
• Rheumatoid arthritis,
• Osteoarthritis
• Ankylosing spondylitis
• Toothache,
• Renal colic,
• Postoperative
inflammatory pain

41. Ketorolac
• Good for postoperative pain ( analgesic action
equal to morphine)
• Reduces the dose of opioids in severe pain
• Renal toxicity more than other NSAIDs
• Continuous use >5 days orally and >2 days
i.m/i.v. not recommended due to high
incidence of GIT bleeding and bleeding at
surgical site

42. Indomethacin
• Drug of choice for Acute Gout
• Rheumatoid arthritis
• Ankylosing spondylitis
• Antipyretic in Hodgkin’s disease- fever refractory to other antipyretics
• Medical treatment of Patent Ductus Arteriosus

43. Ibuprofen
• Safest among the traditional NSAIDs
• Effective and safe antipyretic as paracetamol
• Well tolerated in patients who
cannot tolerate other NSAIDs

44. Nimesulide
• Partially selective COX-2 inhibitor, less gastric effects
• Serious life threatening toxic effect- hepatic damage and
agranulocytosis
• BANNED IN MANY COUNTRIES