NSAIDs – Classifications and uses

What are NSAIDs

NSAID is an acronym for Non Steroidal Anti Inflammatory Drugs. NSAIDs are the analgesics (drugs which reduce the pain and inflammation in the body) and belong to the class of Non-Opioid Analgesics.

Mechanism of action

Before understanding the classification of NSAIDs, it is important to understand the role of the COX (Cyclooxygenase) enzyme. COX is an enzyme that helps in the synthesis of prostaglandins, chemical mediators that sensitize pain nerve endings and make us feel pain. Prostaglandins are also involved in inflammation and fever.

The COX enzyme exists in two main forms:
1) COX-1
2) COX-2

COX-1 (Protective Enzyme)

COX-1 is a constitutive enzyme, meaning it is normally present in the body and performs protective physiological functions. The prostaglandins produced by COX-1 do not play a primary role in pain mediation.

Normal functions of COX-1 include:

1. Protection of the inner lining of the stomach by stimulating mucus and bicarbonate secretion
2. Promotion of blood clot formation through thromboxane A₂ (TXA₂) synthesis
3. Maintenance of renal blood flow and sodium–water balance, thereby protecting kidney function

COX-2 (Inflammatory Enzyme)

COX-2 is usually present at very low levels in the body. However, in conditions such as injury, inflammation, or infection, its level increases significantly.

Normal functions of COX-2 include:

1. Production of prostaglandins that sensitize pain nerve endings
2. Induction of fever through increased PGE₂ synthesis in the hypothalamus
3. Production of prostacyclin (PGI₂), which inhibits platelet aggregation and thus prevents excessive blood clot formation

NSAIDs exert their therapeutic effects by inhibiting COX enzymes, leading to reduced synthesis of prostaglandins. As prostaglandin levels decrease, pain sensitization is reduced and fever subsides.

In Short (Easy to Remember)
NSAIDs -> Inhibits COX -> Reduced prostaglandins → reduced pain sensitization(no sensitization of pain nerve) & No fever (No PGE₂)

Feature	COX-1	COX-2
Nature	Constitutive	Inducible
Role	Protective	Inflammatory
Stomach	Protection	No major role
Platelets	TXA₂ synthesis	No platelet action
Kidney	Blood flow support	Minor role
Pain & Fever	❌	✅
Inhibition result	GI + renal toxicity	Analgesic effect + CV risk

Classifications

NSAIDs can be classified into following categories.

Based on their chemical structure

Salicylates

Salicylates are the oldest group of NSAIDs and inhibit both COX-1 and COX-2
Aspirin, Dispirin are the drugs which belongs to this class

Propionic Acid Derivatives

This is the most commonly used group of NSAIDs and they act as non-selective COX inhibitors.
few examples are Ibuprofen, Naproxen, Ketoprofen

Acetic Acid Derivatives

This group contains highly potent NSAIDs and is commonly used for the treatment of severe inflammation and arthritis.
few examples are Diclofenac, Indomethacin, Aceclofenac

Fenamate Derivatives

Fenamates are mostly used to treat pain related to uterine contraction and abdomen pain.
Mefenamic acid is most popular drug of this class

Oxicam Derivatives

Oxicam derivatives have a long half-life and are long-acting NSAIDs, usually administered once daily.
Piroxicam, Meloxicam, Tenoxicam are some NSAIDs belonging to this class

Pyrazolone Derivatives

Drugs of this class are rarely used due to serious adverse effects and are restricted in many countries.
examples: Metamizole (Dipyrone), Phenylbutazone

Based on their Mechanism of action

Based on this mechanism NSAIDs are further classified into below categories

Non Selective COX Inhibitors

These NSAIDs inhibit both COX-1 and COX-2 enzymes, thereby reducing pain and fever.

Possible side effects (long-term use):

1. Gastric irritation, ulcer, and GI bleeding (due to COX-1 inhibition in the stomach)
2. Kidney injury (due to reduced renal prostaglandins)
3. Increased bleeding tendency (due to reduced TXA₂ synthesis)
   
   Examples: Aspirin, Ibuprofen, Diclofenac, Naproxen, Indomethacin, Aceclofenac

Preferential COX-2 Inhibitors

These NSAIDs inhibit both enzymes, but COX-2 inhibition is greater than COX-1 inhibition, resulting in fewer gastric side effects.
Examples: Nimesulide, Meloxicam, Etodolac

Selective COX-2 Inhibitors (Coxibs)

These NSAIDs selectively inhibit COX-2 while largely sparing COX-1.
Examples: Celecoxib, Etoricoxib.

Although COX-1 is spared, inhibition of COX-2 reduces prostacyclin (PGI₂) while thromboxane A₂ remains active. This imbalance favors blood clot formation, increasing the risk of cardiovascular events, especially in patients with pre-existing heart disease.

Summary

COX-1 vs COX-2

Feature	COX-1	COX-2
Nature	Constitutive (always present)	Inducible (injury/inflammation)
Main role	Protective	Inflammatory
Stomach	Mucus production (protection)	No major role
Platelets	TXA₂ → clot formation	PGI₂ → anti-platelet
Kidney	Maintains blood flow	Minor role
Pain & Fever	❌	✅
Inhibition result	GI ulcer, bleeding, renal injury	Analgesia + ↑ CV risk

NSAIDs Classification at a glance

Basis	Class	Examples	Key Point
Chemical	Salicylates	Aspirin	Oldest, irreversible COX inhibition
Chemical	Propionic acid	Ibuprofen, Naproxen	Commonly used, safer
Chemical	Acetic acid	Diclofenac, Indomethacin	Potent, more side effects
Chemical	Fenamates	Mefenamic acid	Dysmenorrhea
Chemical	Oxicams	Piroxicam, Meloxicam	Long-acting
Chemical	Pyrazolones	Metamizole	Serious side effects
MOA	Non-selective COX	Aspirin, Diclofenac	GI + renal risk
MOA	Preferential COX-2	Nimesulide, Meloxicam	Less gastric toxicity
MOA	Selective COX-2	Celecoxib, Etoricoxib	↑ CV risk