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Here are your exam-oriented quick notes on NSAIDs, Gout, and Rheumatoid Arthritis drugs from Shanbhag Pharmacology:

📚 NSAIDs - QUICK EXAM NOTES

1. CLASSIFICATION (Must Know!)

Class	Drugs
Non-selective COX inhibitors - Salicylates	Aspirin, Diflunisal
Non-selective - Propionic acid	Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen
Non-selective - Fenamates	Mefenamic acid, Flufenamic acid
Non-selective - Acetic acid	Ketorolac, Indomethacin
Non-selective - Enolic acid	Piroxicam, Tenoxicam, Lornoxicam
Preferential COX-2 inhibitors	Diclofenac, Aceclofenac, Nimesulide, Meloxicam
Highly selective COX-2 inhibitors	Etoricoxib, Parecoxib
Weak anti-inflammatory (analgesic/antipyretic)	Paracetamol, Nefopam

Exam tip: "DNAM" = Diclofenac, Nimesulide, Aceclofenac, Meloxicam (preferential COX-2)

2. MECHANISM OF ACTION

COX-1 = constitutive (in stomach, kidney, blood vessels) - physiological functions
COX-2 = induced by inflammation (cytokines, endotoxins) - produces prostanoid mediators
NSAIDs inhibit both COX-1 and COX-2 → ↓ PGs and Thromboxane
Aspirin = IRREVERSIBLE inhibition of COX (unique!)
All other NSAIDs = reversible inhibition

3. PHARMACOLOGICAL ACTIONS (4 + 1 Key Actions)

A. Analgesic Effect

Dose: 2-3 g/day (aspirin)
Acts peripherally (↓ PG synthesis) + central (↑ pain threshold at subcortical site)
No sedation, respiratory depression, tolerance, or dependence

B. Antipyretic Effect

Dose: 2-3 g/day (aspirin)
Acts on hypothalamic thermostat
Does NOT lower normal body temperature
Causes heat loss by cutaneous vasodilation + sweating

C. Anti-inflammatory Effect

Dose: 4-6 g/day (aspirin) - HIGH dose needed
Symptomatic relief only - does NOT alter disease progression

D. Antiplatelet Effect (ASPIRIN UNIQUE - exam favourite!)

Low dose: 50-325 mg/day
Irreversibly inhibits platelet TXA₂ → antiplatelet effect lasts 8-10 days (platelet lifespan)
Low dose aspirin: inhibits only TXA₂ (vasoconstrictor, pro-aggregatory)
High dose (2-3 g/day): inhibits BOTH PGI₂ AND TXA₂ → antiplatelet effect LOST
Withdraw aspirin 1 week before elective surgery

E. Acid-Base Effects

Therapeutic dose: respiratory alkalosis (compensated by ↑ HCO₃ excretion)
Toxic dose: respiratory acidosis → uncompensated metabolic acidosis

4. ASPIRIN DOSAGE (Must Memorize!)

Use	Dose
Analgesic	2-3 g/day divided doses
Anti-inflammatory	4-6 g/day divided doses
Antiplatelet	50-325 mg/day (low dose)

5. ADVERSE EFFECTS OF ASPIRIN/NSAIDs

S.No	Effect	Key Point
1	GIT (nausea, ulcer, bleeding)	Major drawback - prevented by buffered aspirin, PPIs, selective COX-2
2	Hypersensitivity	Bronchospasm (aspirin-induced asthma via ↑ leukotrienes) - avoid in asthma, nasal polyps
3	Haemolytic anaemia	In G6PD deficiency
4	Bleeding tendency	Interferes with Vitamin K → ↓ clotting factors (hypoprothrombinemia) - treat with Vit K
5	Reye's syndrome	Salicylates in children with viral infection → hepatic damage + encephalopathy - CONTRAINDICATED
6	Pregnancy	Delay labour, premature closure of ductus arteriosus
7	Analgesic nephropathy	Chronic high dose → slowly progressive renal failure

6. SALICYLISM vs ACUTE SALICYLATE POISONING

Salicylism (mild toxicity):

Headache, tinnitus, vertigo, confusion, nausea, vomiting, diarrhea, hyperpnea
Reversible on stopping therapy

Acute Poisoning (common in children):

Vomiting, dehydration, acid-base disturbances, hyperpnea, confusion, coma, convulsions, pulmonary edema, death

Treatment of Acute Poisoning:

Hospitalize
Gastric lavage + activated charcoal (physical antagonism)
Fluid and electrolyte balance
IV sodium bicarbonate (treats metabolic acidosis + alkalinizes urine → ↑ excretion)
External cooling
Haemodialysis (severe)
Vitamin K + blood transfusion if bleeding

No specific antidote for salicylate poisoning!

7. DRUG INTERACTIONS (NSAIDs)

Interaction	Effect
NSAIDs + Glucocorticoids	↑ GI complications
NSAIDs + Anticoagulants/Sulfonylureas/Methotrexate	↑ plasma levels (displace from protein binding)
NSAIDs + Thiazides/Furosemide	↓ diuretic efficacy (NSAIDs promote Na⁺/H₂O retention)
NSAIDs + Antihypertensives	↓ antihypertensive efficacy
NSAIDs + Lithium (e.g. Piroxicam)	↑ Lithium toxicity

8. CLINICAL USES OF NSAIDs

Condition	Drug of Choice
Antipyretic in children	Paracetamol (not aspirin - Reye's syndrome risk)
Acute rheumatic fever	Aspirin
Osteoarthritis (mild)	Paracetamol; severe - other NSAIDs
Ankylosing spondylitis, acute gout, psoriatic arthritis	Indomethacin (very effective)
Thromboembolic disorders (TIA, MI)	Low-dose Aspirin (50-325 mg)
Medical closure of PDA	Indomethacin
Renal colic, post-op pain	Ketorolac (analgesic = morphine)
Dysmenorrhoea	Mefenamic acid, Nimesulide

9. SELECTIVE COX-2 INHIBITORS

Examples: Etoricoxib, Parecoxib (prodrug of valdecoxib - parenteral), Celecoxib
Gastric friendly (less GI side effects)
Renal toxic (↑ Na⁺/H₂O retention → oedema)
Cardiovascular risk ↑ (inhibit PGI₂ mainly; TXA₂ unaffected → thrombotic events)
No antiplatelet effect

10. PARACETAMOL (Acetaminophen) - KEY DIFFERENCES

Feature	Aspirin	Paracetamol
Class	Salicylate	Para-aminophenol
Anti-inflammatory	Potent	Poor/absent
GI irritation	Yes	No
Antiplatelet	Yes	No
Acid-base imbalance	Yes	No
Antidote	None	N-acetylcysteine
Safe in peptic ulcer, asthma, children	No	Yes
Reye's syndrome risk	Yes	No

Paracetamol Acute Poisoning:

Main toxicity: Hepatotoxicity (also nephrotoxicity)
Toxic metabolite: NAPQI (N-acetyl-p-benzoquinoneimine)
NAPQI depletes glutathione → binds liver/kidney proteins → necrosis
At risk: Alcoholics, malnourished (low glutathione)
Antidote: N-acetylcysteine (IV) or Oral Methionine (replenish glutathione)
Also: Activated charcoal (↓ absorption), Haemodialysis if renal failure

💊 DRUGS USED IN GOUT

Classification

1. Acute Gout:

NSAIDs: Indomethacin, Naproxen, Diclofenac, Etoricoxib
Colchicine
Glucocorticoids: Prednisolone, Methylprednisolone, Triamcinolone (intra-articular)

2. Chronic Gout / Long-term Control:

Uricosuric agents: Probenecid, Sulphinpyrazone
Uric acid synthesis inhibitors: Allopurinol, Febuxostat

Colchicine (Exam Favourite!)

Alkaloid - NOT an analgesic, NOT uricosuric
MOA: Prevents release of chemotactic factors → inhibits migration of neutrophils to affected area
Rapid acting, poorly tolerated
Adverse effects: Nausea, vomiting, diarrhea, abdominal pain
Chronic use: Myopathy, alopecia, aplastic anaemia, agranulocytosis

Uricosuric Agents (Probenecid, Sulphinpyrazone)

Inhibit active tubular reabsorption of uric acid → ↑ excretion
NOT started within 3 weeks of acute attack (mobilize uric acid from deposits → fluctuating levels → precipitate attack)
High fluid intake advised (prevent urate crystals in urine)
Contraindicated in renal failure
Probenecid × β-Lactam antibiotics: Blocks tubular secretion of penicillins/cephalosporins → ↑ their plasma levels (useful!)

Allopurinol

Inhibits xanthine oxidase → ↓ uric acid synthesis
Active metabolite: Alloxanthine (non-competitive inhibitor of xanthine oxidase)
Use: Chronic gout, asymptomatic hyperuricaemia, cancer chemotherapy (↓ uric acid)
NOT started within 3 weeks of acute attack
Adverse effects: Hypersensitivity (Stevens-Johnson syndrome), GI (nausea, diarrhea), hepatotoxicity
Contraindicated: Children, pregnancy, lactation, liver/kidney disease
Allopurinol × 6-Mercaptopurine: Inhibits xanthine oxidase → ↓ metabolism of 6-MP → ↑ toxicity → reduce 6-MP dose

Febuxostat

Xanthine oxidase inhibitor (like allopurinol but newer)
Used in patients intolerant to allopurinol
Once daily oral; adverse effects: diarrhea, headache, hepatotoxicity

Rasburicase & Pegloticase

Urate oxidase - converts uric acid → allantoin (soluble, excreted in urine)
Rasburicase: IV; used in children with leukaemia on anticancer drugs
Pegloticase: IV infusion; refractory cases

🦴 DRUGS IN RHEUMATOID ARTHRITIS (RA)

Classification of Drugs in RA

1. DMARDs (Disease-Modifying Antirheumatic Drugs)

Mnemonic: MEDICALS R Gold (E, I, A and R = Biologics)

Letter	Drug
M	Methotrexate
E	Etanercept (biologic)
D	D-Penicillamine
I	Infliximab (biologic)
C	Chloroquine / Hydroxychloroquine
A	Anakinra (biologic)
L	Leflunomide
S	Sulphasalazine
R	Rituximab (biologic)
Gold	Gold compounds

2. NSAIDs - Symptomatic relief only, do NOT alter disease progression

3. Glucocorticoids - Adjuvant, rapid effect

Methotrexate (Preferred DMARD)

Folate antagonist (dose in RA << cancer dose)
MOA: ↓ neutrophil chemotaxis, ↓ proinflammatory cytokines by activated T-cells
Dose: 7.5-15 mg once weekly, ↑ by 2.5 mg weekly if no improvement
Also used in: Psoriasis, polymyositis, giant cell arteritis, dermatomyositis
Adverse effects: Nausea, mucosal ulcers, dose-dependent hepatotoxicity (monitor LFTs)
Minimized by: Folic acid / Folinic acid
Contraindicated: Pregnancy, liver disease, peptic ulcer

Chloroquine / Hydroxychloroquine

Antimalarial drugs - also used in RA (mild disease)
MOA in RA: unclear - stabilize lysosomal membrane, scavenge free radicals
Well tolerated; deposited in melanin-containing tissues (especially eye)
Ophthalmologic exam once yearly (risk of corneal opacity, retinal damage)
Relatively safe in pregnancy

Sulphasalazine

Split in gut → Sulphapyridine + 5-Aminosalicylic acid
Sulphapyridine: inhibits superoxide + inflammatory cytokines (ILs, TNF-α)
5-ASA: local anti-inflammatory in gut (used in ulcerative colitis)
Also used in: chronic inflammatory bowel disease
Side effects: Nausea, vomiting, diarrhea, headache, skin rashes, leukopaenia

Leflunomide

Inhibits dihydroorotate dehydrogenase → ↓ pyrimidine synthesis → inhibits T-cell proliferation
Long plasma half-life 2-3 weeks → loading dose given
Note 'L's: Loose stools (diarrhoea), Liver toxicity (hepatotoxicity), Leukopaenia, rashes
Contraindicated: Children, pregnancy, lactating mothers

Biologics (Table Summary)

Drug	Route	MOA	Adverse Effects	Uses
Etanercept, Infliximab, Adalimumab, Golimumab	S.C.	TNF-α antagonists	Opportunistic infections incl. TB	RA, psoriasis, Crohn's, ankylosing spondylitis
Anakinra	S.C.	IL-1 antagonist	Opportunistic infections	RA
Abatacept	IV infusion	Inhibits T-cell activation	Opportunistic infections	RA
Rituximab	IV infusion	Depletes peripheral B lymphocytes	Skin rashes	RA (with methotrexate, resistant cases)

Key: All biologics risk opportunistic infections (TB, Pneumocystis jiroveci)

Quick Comparison Table (Exam Must-Know)

Feature	Non-selective COX inhibitors	Selective COX-2 inhibitors
Analgesic	+	+
Antipyretic	+	+
Anti-inflammatory	+	+
Antiplatelet	+	None
GI side effects	Marked ++	Less (less ulcerogenic)
Renal toxicity	+	+
CVS risk	Less	More (↑ thrombotic events)

High-yield exam mnemonics:

Aspirin unique features: Irreversible COX inhibition, antiplatelet 8-10 days, Reye's syndrome risk, no specific antidote

Paracetamol antidote: N-acetylcysteine (NAPQI toxicity)

Allopurinol × 6-MP: Reduce 6-MP dose

MEDICALS R Gold = DMARDs in RA (E, I, A, R = Biologics)

Indomethacin special uses: Ankylosing spondylitis, acute gout, psoriatic arthritis, close PDA

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