Non-steroidal anti-inflammatory drugs
(NSAIDs)
Dr Azza Abouelella
Lecturer of Pharmacology
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Major therapeutic uses of NSAIDs
Major adverse effects of NSAIDs
Compare between non selective and
selective cyclooxygenase inhibitor drugs
NSAIDS
.
Classifications
Non selective COX inhibitors Selective COX2 inhibitors
Salicylates High selective:
Paraminophenols - Etoricoxib
Acetic acid derivatives - Celecoxib
Enolic acid derivatives Slight selective:
Propionic acid derivatives - meloxicam
Fenamic acid derivatives
Classifications
Non selective COX inhibitors
Category Examples
.
Salicylates Acetyl salicylic acid (aspirin) - Sodium
salicylate-Diflunisal - Salicylic acid & methyl
salicylic
Paraminophenols Paracetamol (acetaminophen)
Acetic acid derivatives Indomethacin - Sulindac -Diclofenac -
Tolmetin Ketorolac
Enolic acid derivatives Piroxicam
Propionic acid Ibuprofen – Ketoprofen – Fenoprofen -
derivatives Naproxen
Fenamic acid Mefenamic acid
derivatives
Mechanism of action
.
NSAIDs
Acts by inhibition of COX which responsible for synthesis of:
PG (Physiological function on GIT, kidney & platelet (aggregation
by thromboxane A2)
PG (inflammation, pain and fever)
NOTE: All NSAIDs induce reversible inhibition of COX except aspirin
which causes irreversible acetylation of COX.
Salicylates
Pharmacological actions
.
1) Antipyretic action:
Inhibiting PGE2 (which can cross BBB and ↑ heat loss by vasodilation of
superficial blood vessels with ↑sweating). Toxic dose of salicylates
produce hyperpyrexia because of uncoupling of oxidation from
phosphorylation
2) Analgesia:
a) Peripheral action: inhibit PG in the inflamed tissues → prevent
sensitization of pain receptors to mechanical and chemical stimuli.
b) Central action: due to depression of pain stimuli at a subcortical site
Pharmacological action
3) Anti-inflammatory:
Prostacyclin
(PGI2) and PGE2
.
Mediate inflammation by increasing local blood flow, permeability and
leukocyte infiltration through activation of their receptors.
PGD2
Contributes to inflammation in allergic responses, particularly in lung
by increasing perfusion and vascular permeability
4)Acid-base balance & electrolytes:
Therapeutic dose leads to
Respiratory
alkalosis
.
Direct stimulate respiratory center
Uncoupling oxidation from phosphorylation →↑O2 consumption & CO2
Production. So Stimulate respiration →↑Co2 wash out
Compensatory
renal acidosis
Respiratory alkalosis is compensated by ↑renal excretion of bicarbonate,
PH return to normal.
Pharmacological action
Toxic dose leads to
Respiratory
acidosis Metabolic
. acidosis
Depression of respiratory center
→↑CO2 in blood.
- Accumulation of salicylic acid radical.
- Disturbance in carbohydrate metabolism →
accumulation of pyruvic, lactic and acetoacetic
acid.
Pharmacological action
5) CVS
Low .dose (˂ 100 mg/day) is cardioprotective & ↓ MI.
Large dose (˃ 3g/day) → salt & water retention
In high dose for long period in elderly → non cardiogenic pulmonary
edema.
Pharmacological action
6) GIT
1.Epigastric distress (nausea, vomiting): stimulation of CTZ and
peripheral gastric irritation.
.
2.Gastric ulceration, bleeding (hematemesis,
melena): due to inhibition of synthesis of
gastric prostaglandins (PGI2, PGE2).
can be prevented by misoprostol
(synthetic analog of PGE1). Use it after meal
Or use enteric coated form.
7) Liver
Reversible ↑ of hepatic transaminases,
so it is contraindicated in chronic liver diseases.
Pharmacological action
8) Urate excretion:
Small doses: 1-2 g / day Hyperuricema
.
Large doses: over 5 gm / day Has a uricosuric effect
Intermediate doses: 2-4 gm / day Has no effect on serum level
of urate.
Alkalinization of urine
Enhance uricosuric effects of salicylates & ↑solubility of uric acid →
prevent precipitation of uric acid crystals in the urinary tract.
Pharmacological action
9) Blood
Small doses (75-150mg/day) Have antiplatelet effect by irreversible
inhibition of platelet COX, so prevent the formation of TXA2 (platelets
.
aggregation) which lasts for up to 8 days till synthesis of new platelets as
platelets have no the ability for synthesis of enzymes
Large doses Produce hypoprothrombinemia by interfere with
synthesis of prothrombin as salicylates interfere with the role of vit. K.
This effect can be reversed by administration of vit. K.
Therapeutic uses of aspirin
1-Antipyretic: Treatment for fever, not affect the cause.
2-Analgesic:
Used to control mild to moderate pain as headache, arthritis, myalgia,
neuralgia, & dysmenorrhea.
3-Anti-inflammatory:
a)Acute rheumatic fever b) Rheumatoid arthritis
4-Antiplatelet:
Used in prophylaxis of cerebral and coronary artery thrombosis and
prophylactic in DVT.
5-↓ risk of cancer colon & cancer rectum: by sustained &
Regular use of aspirin
6-Niacin Tolerability: Aspirin inhibit facial flushing induced by
niacin due to inhibition of PGD2 release
Side effects of aspirin
1-GIT manifestations:
a) Gastritis, ulceration, bleeding.
.
b) Nausea, vomiting due to stimulation of CTZ.
2-Hypersensitivity reaction:
Occur in 0.2% of patients, more in middle aged females.
Manifestations: skin rashes, angioneurotic edema, bronchial asthma,
purpura, anaphylactic shock in severe cases.
Aspirin must be used with great care in asthmatic persons.
3-Reye’s syndrome:
Hepatitis, encephalitis occur in children with febrile viral illness
(chicken pox, viral influenza).
In such conditions use of paracetamol is safe.
Side effects of aspirin
4-Ototoxic Effects: Hearing impairment and tinnitus:
• Common in high-dose of salicylate
• Disappear within 2 or 3 days after withdrawal of drug.
.
• Occurs due to: - Effect on hair cells of cochlea
- Secondary to vasoconstriction in auditory vasculature
.
5-Analgesic nephropathy:
• Slowly progressive renal failure.
• Risk factors: chronic use of high doses of combinations of NSAIDs
• Discontinuation of NSAIDs permits recovery of renal function.
Side effects of aspirin
6-Acute salicylate poisoning:
.
Disturbance in electrolyte balance, acid-base balance →respiratory,
metabolic acidosis.
Hyperpyrexia: as toxic dose of salicylates
Dehydration: due to hyperpyrexia, sweating, vomiting and loss of
water vapor during ventilation.
GIT: nausea, vomiting, bleeding.
CNS: delirium, convulsions, coma then followed by CNS depression.
Side effects of aspirin
Treatment of acute salicylate poisoning: (in hospital):
Supportive
. treatment for respiration.
Symptomatic treatment for hyperpyrexia, dehydration & acid-base
imbalance, electrolyte disturbance.
Alkalinization of urine by IV Na bicarbonate to help its excretion.
Prevention of further absorption (induction of vomiting, gastric
lavage, NaHCO3 orally).
Hemodialysis in severe cases as salicylates have low Vd.
Side effects of aspirin
7-Chronic salicylate poisoning (Salicylism):
Produced by repeated administration of large doses of salicylates as in
rheumatic
. fever.
Symptoms:
• Neurological: headache, dizziness, tinnitus, hearing loss, confusion.
• GIT: nausea, vomiting, diarrhea.
8-If used during pregnancy:
• During pregnancy: ↑ risk of post-partum hemorrhage & premature
closure of the ductus arteriosus.
• During delivery: Prolongation of gestation due to inhibition of PG
which play a role in onset of delivery.
Aspirin
Contraindications:
1. Hypersensitivity
.
to aspirin.
2. GIT ulceration or bleeding.
3. Hepatic, renal dysfunction as they may cause hepatitis, ↓ GFR.
4. Pregnancy & lactation.
5. Children with febrile viral infection.
6. Hemophilia as ↑ bleeding.
7. Gout as low dose ↑ serum urate.
b)Diflunisal
Diflunisal used mainly in RA, OA, cancer pain with bone
metastases and analgesic in dental surgery.
. intense GIT, ototoxic and antiplatelet effects than does aspirin.
Less
2- Paracetamol
Differ from aspirin in:
No anti-inflammatory
Not. produce disturbance in acid-base balance or electrolyte balance,
Not cause GIT irritation,
No uricosuric effect.
No antiplatelet effect.
Side effects:
Allergic reactions.
Dose-dependent hepatic toxicity, hypoglycemic coma, renal tubular
necrosis (acute toxicity).
Chronic use → nephrotoxicity.
Paracetamol
Metabolism:
Mainly by conjugation with glucuronic and sulfuric acid in liver
Minor part undergoes hydroxylation to form N-acetyl-P-benzoquinone-
imine
. (NAPQI):- Highly reactive chemically
- Reacts with SH-groups of glutathione & becomes harmless.
But if: • Glutathione supply by liver is limited
• Or metabolite formed is greater than the glutathione available
Metabolite will react with SH-groups in hepatic proteins
Hepatic necrosis (may be fatal), can be treated by N-acetyl cysteine
(provide glutathione to liver).
Paracetamol
Therapeutic uses: Analgesic and antipyretic.
Conditions
. in which paracetamol is better than aspirin i.e.
Contraindications to aspirin:
1. Hypersensitivity to aspirin.
2. GIT bleeding.
3. Children with febrile viral infection.
4. Bleeding tendency.
5. Pregnancy.
3- Acetic acid derivatives
a) Indomethacin
Has anti-inflammatory, analgesic, antipyretic action similar to salicylates.
Therapeutic uses:
Antipyretic in control of fever due to Hodgkin’s disease.
Bartter’s syndrome: (children with juxtaglomerular hyperplasia,↑renin,
↑aldosterone, hypokalemia due to excess production of renal PG).
Patent ductus arteriosus in neonates.
Toxic manifestation: more with chronic use, so not used for long time
CNS: headache, dizziness, vertigo, confusion, psychotic disturbance.
GIT: nausea, vomiting, diarrhea, peptic ulceration.
Blood: thrombocytopenia, aplastic anemia.
Hypersensitivity: rash, itching, asthma.
Hyperkalemia
b) Sulindac
½ of the potency of indomethacin.
less GIT toxicity as GIT is exposed to low concentration of active drug.
Prodrug and change to active sulfide in the body.
Used in articular inflammatory conditions, ↓risk of colorectal tumours.
c) Tolmetin
Analgesic, anti-inflammatory, antipyretic action as salicylates.
Side effects: CNS, GIT as indomethacin.
d) Diclofenac (voltaren, olfen)
Has analgesic, anti-inflammatory, antipyretic effects as salicylates.
Articular and extra-articular inflammations.
Post-operative, post-traumatic pain & dysmenorrhea
Side effects: GIT - CNS – Allergic - Hepatic dysfunction
e) Ketorolac
Has potent analgesic, moderate anti-inflammatory effects.
Side effects:
- Sedation, headache, dizziness, nausea
- If used ˃ 5 days→↑risk of peptic ulcer & renal impairment.
Uses:
Postoperative pain alternative to opioids & given orally, I.M or I.V.
4- Enolic acid derivatives
Have analgesic, anti-inflamatory, antipyretic effect as salicylates
a) Piroxicam (feldene):
Uses:-
• Articular & extra articular inflammatory conditions.
• Post-operative, post-traumatic pain and primary dysmenorrhea
Side effects: GIT –CNS -Allergic reactions
b) Meloxicam:
Slight selective COX-II inhibitor, so less GIT irritation & renal side effects.
Used once/day for treatment of OA& RA
5- Propionic acid derivatives
Include: Ibuprofen - Fenoprofen- Ketoprofen –
Naproxen
Uses: as piroxicam
Side effects: hepatic & renal dysfunction.
6-Fenamic acid derivatives
Include: Mefenamic acid:
Drug of choice in treatment of dysmenorrhea.
Side effects as other NSAIDs, but diarrhea,
hemolytic anemia are more, so not used more
than one week and if diarrhea occur stop it.
Selective COX-2 inhibitors
Members: Celecoxib& Etoricoxib
Therapeutic uses
1-Antiinflammatory (osteoarthritis and rheumatoid arthritis)
2- antipyretic
3-analgesic (dysmenorrhea).
4-Celecoxib is better than nonselective COX inhibitors in protecting
against colon carcinogenesis (↑ expression of COX-2 in some cancer cells &
angiogenesis essential to tumor growth requires COX-2 activity.
Advantages
2-Little or no effect on GIT, kidney or platelet
(not inhibit platelet aggregation).
Selective COX-2 inhibitors
Adverse effects
.
They inhibit COX-2-mediated prostacyclin synthesis in the vascular
endothelium. So, COX-2 inhibitors do not offer cardioprotective effects
& ↑ risk of CVS side effects as MI& stroke.
Referrences
Elsevier integrated review: pharmacology E book(2).
Chapter 10 page 164-168.
Lippincott illustrated review: Integrated system (Richard
Harv), page 112.
.
