By Dr. Marcus Judge

Next Lesson - Immunosuppression and Disease-modifying Therapy

Pharmacology

Contents

  1. Introduction
  2. The Arachidonic Acid Pathway
  3. COX-1 and COX-2
  4. Mechanism of NSAID Action
  5. The Four Actions of NSAIDs
  6. The NSAID Drugs
  7. Adverse Effects
  8. Drug Interactions
  9. Paracetamol
  10. Summary
  11. Drug Summary Table
  12. Quiz

Abstract

  • Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclo-oxygenase (COX) enzymes, blocking the conversion of arachidonic acid (a fatty acid released from cell membranes) to prostaglandins, prostacyclin and thromboxane (local chemical messengers that drive pain, inflammation, fever and clotting).
  • NSAIDs have four actions: three core actions (analgesic, meaning pain-relieving, anti-inflammatory and antipyretic, meaning fever-reducing) and an antiplatelet effect (reducing platelet clumping) that is clinically meaningful only with aspirin. NSAID use is also associated with significant illness and death in the UK each year, including deaths from gastrointestinal (GI) bleeding.
  • NSAID side effects fall into four major groups: GI (peptic ulceration, meaning ulcers in the stomach or duodenum, and bleeding), renal (reduced glomerular filtration rate or GFR, which is the rate at which the kidneys filter blood; salt and water retention; and hyperkalaemia, or high blood potassium), cardiovascular (hypertension, myocardial infarction or MI, and heart failure), and respiratory (bronchospasm, or airway narrowing, in aspirin-sensitive asthma).
  • Paracetamol is not an NSAID. It has analgesic and antipyretic action but no anti-inflammatory effect. It has few GI or renal side effects at therapeutic doses. In overdose it is the leading cause of acute liver failure in the UK. The antidote is N-acetylcysteine.

Core

Introduction

NSAIDs are one of the most widely prescribed groups of medicines worldwide and are amongst the most useful and the most dangerous drugs in routine prescribing. The pharmacology is conceptually simple: NSAIDs block one family of enzymes, the cyclo-oxygenases, in one signalling pathway. The consequences of blocking that pathway in different tissues explain both the benefits and the side effects.

The closely related drug paracetamol is included in this article because it is the standard non-opioid analgesic alternative, with a strikingly different side-effect profile. Opioid analgesia is covered in Opioids.

The Arachidonic Acid Pathway

Arachidonic acid is a polyunsaturated fatty acid stored in cell membrane phospholipids. When the cell is stimulated by injury, inflammation, hypoxia (low oxygen) or hormonal triggers, the enzyme phospholipase A2 cuts arachidonic acid out of the membrane and releases it into the cytoplasm. From there it can take one of two routes:

  • Cyclo-oxygenase (COX) pathway → prostanoids (prostaglandins, prostacyclin and thromboxane: local chemical messengers that drive pain, inflammation, fever and clotting).
  • Lipoxygenase pathway → leukotrienes (inflammatory messengers, important in asthma).

The prostanoids and leukotrienes act locally as signalling molecules. They bind to receptors on the cell surface (G-protein coupled receptors). They are made on demand and have a short half-life (the time taken for their level to halve). This allows fine control of inflammation, pain, fever, gastric protection, renal blood flow and platelet aggregation.

Membrane phospholipids (cell injury triggers release) phospholipase A₂ Corticosteroids Arachidonic acid cyclo-oxygenase (COX-1 & COX-2) lipoxygenase NSAIDs Prostanoids Leukotrienes PGE₂: pain, fever, vasodilation PGI₂: vasodilation, antiplatelet TXA₂: vasoconstriction, platelet aggregation Gastric PGs: mucosal protection Renal PGs: maintain GFR LTB₄: chemotaxis LTC₄/D₄/E₄: bronchoconstriction, mucus secretion, mucosal oedema (role in asthma) Montelukast cysteinyl-LT receptor (blocked by montelukast) ▪ Drug action sites: corticosteroids block PLA₂; NSAIDs block COX (1 & 2). Coxibs are COX-2 selective; montelukast blocks the LT receptor. SimpleMed Original by Dr Marcus Judge

Diagram: The arachidonic acid pathway and the points blocked by each drug class.

COX-1 and COX-2

There are two functional cyclo-oxygenase isoforms (slightly different versions of the same enzyme). Their distribution explains why NSAIDs cause the side-effect profile they do.

  • COX-1: constitutively expressed (made at a steady level all the time) in most tissues, including gastric mucosa (where it produces protective prostaglandins), kidneys (renal blood flow), and platelets (thromboxane A2). Its products mainly support normal everyday functions (often called housekeeping functions).
  • COX-2: mainly inducible, expressed at sites of inflammation. Constitutive expression is limited to the kidney, vascular endothelium (the lining of blood vessels) and parts of the central nervous system.

Most of the analgesic and anti-inflammatory benefit of NSAIDs comes from COX-2 inhibition; most of the gastrointestinal (GI) side effects come from COX-1 inhibition. The idea that COX-2 gives the benefit and COX-1 the harm led to the development of selective COX-2 inhibitors in the late 1990s.

Mechanism of NSAID Action

All NSAIDs compete with arachidonic acid for the active site of cyclo-oxygenase, reducing the production of prostanoids. Most are reversible competitive inhibitors. Aspirin is the exception: it covalently acetylates (permanently attaches an acetyl group to) a serine residue (a serine amino acid) in the COX active site, irreversibly inactivating the enzyme.

The consequences depend on which prostanoids are reduced:

  • Reduced prostaglandin E2 (PGE2) and prostacyclin (PGI2) at sites of injury → less pain and less inflammation. Reduced prostaglandin production by COX-2 in the hypothalamus → less fever.
  • Reduced thromboxane A2 in platelets → reduced platelet aggregation. (See Antiplatelets, Anticoagulants and Thrombolysis.)
  • Reduced protective prostaglandins in gastric mucosa → ulceration.
  • Reduced renal prostaglandins → reduced glomerular filtration rate (GFR, the rate at which the kidneys filter blood), plus salt and water retention.

The Four Actions of NSAIDs

A useful framework: NSAIDs have four actions: three core actions (analgesic, anti-inflammatory and antipyretic) and an antiplatelet effect that is clinically meaningful only with aspirin.

  • Analgesic: effective against musculoskeletal, dental and inflammatory pain. NSAIDs are also first-line treatment for renal colic (pain from a kidney stone), which is visceral (organ) pain. They are less effective against neuropathic (nerve) pain. They act both peripherally (at the site of injury) and centrally (in the dorsal horn of the spinal cord).
  • Anti-inflammatory: reduces vasodilation and oedema, providing symptomatic relief in arthritis, soft-tissue injury and dysmenorrhoea (painful periods).
  • Antipyretic: reduces fever by blocking COX-2 in the hypothalamus, where pyrogenic cytokines (fever-causing signalling proteins) normally trigger a prostaglandin-mediated rise in temperature.
  • Antiplatelet: aspirin alone has clinically useful, irreversible antiplatelet activity (covered in Antiplatelets, Anticoagulants and Thrombolysis). Other non-selective NSAIDs cause only a transient, reversible reduction in TXA2 that is not used therapeutically. COX-2 selective inhibitors lack any antiplatelet effect.

The NSAID Drugs

Non-Selective NSAIDs

The drugs commonly prescribed in the UK:

  • Ibuprofen: the over-the-counter standard. Lowest GI risk among non-selective NSAIDs at standard doses. Short half-life (~2 hours).
  • Naproxen: a longer-acting agent (half-life ~14 hours). Has a comparatively favourable thrombotic risk profile, as does low-dose ibuprofen (1,200 mg/day or less). Neither is risk-free; use the lowest effective dose for the shortest necessary duration. See advice from the Medicines and Healthcare products Regulatory Agency (MHRA).
  • Diclofenac: effective analgesic and anti-inflammatory but the cardiovascular risk profile is similar to that of selective COX-2 inhibitors. The MHRA has contraindicated it in established ischaemic heart disease (heart disease caused by a reduced blood supply), peripheral arterial disease (narrowed arteries, usually in the legs), cerebrovascular disease (for example, previous stroke) and congestive heart failure (New York Heart Association class II to IV). In people with significant cardiovascular risk factors, diclofenac should only be started after careful consideration.
  • Indometacin: a powerful NSAID used in rheumatic disease (for example ankylosing spondylitis, an inflammatory arthritis of the spine) and in acute gout (crystal arthritis). In premature neonates (babies born early), indometacin or ibuprofen can be used to close a patent ductus arteriosus (a fetal blood vessel that has failed to close after birth).
  • Mefenamic acid: used in dysmenorrhoea and menorrhagia (heavy periods). It has only minor anti-inflammatory properties and can cause convulsions in overdose.
  • Ketorolac: a potent NSAID given by injection. It is licensed only for short-term treatment (a maximum of 2 days) of moderate to severe pain after surgery.

Selective COX-2 Inhibitors (Coxibs)

Celecoxib and etoricoxib are the COX-2 selective drugs (coxibs) taken by mouth in the UK. Parecoxib is a coxib given by injection and is licensed for short-term management of pain after surgery. Compared with non-selective NSAIDs, coxibs cause:

  • Fewer GI side effects: less peptic ulceration and bleeding (the original rationale for the drug class).
  • Similar renal side effects.
  • Increased cardiovascular risk: selective inhibition of vascular COX-2 reduces prostacyclin (PGI2, vasodilatory and antiplatelet) without affecting platelet TXA2, tipping the balance toward thrombosis. Rofecoxib was withdrawn worldwide in 2004 because of excess MI events.

NICE Clinical Knowledge Summaries (CKS) advise a coxib together with a proton pump inhibitor (PPI, a drug that lowers stomach acid) for people at high risk of GI complications who need an NSAID. Coxibs are contraindicated in ischaemic heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.

Aspirin

Aspirin deserves separate mention because it bridges the analgesic, anti-inflammatory and antiplatelet uses:

  • At analgesic doses (300-900 mg) it is a non-selective NSAID with the typical action profile.
  • At antiplatelet doses (75 mg daily) it predominantly inhibits platelet COX-1 with relatively spared endothelial COX-2, producing the cardiovascular benefit covered in Antiplatelets, Anticoagulants and Thrombolysis.
  • At high doses aspirin metabolism becomes saturated and follows zero-order kinetics (a fixed amount is cleared per hour, however high the level). Blood levels then rise steeply, which is the basis of salicylate (aspirin) overdose toxicity.
  • Avoid aspirin in children under 16. The British National Formulary (BNF) lists this as a contraindication because of the risk of Reye's syndrome (acute encephalopathy, which is brain dysfunction, together with hepatic failure, which is liver failure). The exception is when aspirin is specifically indicated, for example in Kawasaki disease (inflammation of the blood vessels in childhood).

Adverse Effects

Gastrointestinal

By far the most important. The mechanism is reduced prostaglandin-mediated mucosal protection. There is less mucus and bicarbonate, less mucosal blood flow, and lower mucosal surface hydrophobicity (a water-repelling surface layer; losing it may let acid pass into the lining more easily). The lining is then more easily damaged by the acid in the stomach. NSAIDs increase the risk of peptic ulceration (ulcers in the stomach or duodenum) and of serious upper GI complications such as bleeding. The size of the risk depends on the drug and the dose. In one large meta-analysis (a study that pools the results of many studies), compared with not taking an NSAID, the relative risk (how many times more likely) of upper GI complications was about 1.5 with celecoxib, 2 with ibuprofen, 3 with diclofenac and 4 with naproxen or indometacin. The relative risk with high daily doses was 2 to 3 times that with low daily doses. NSAID use is also associated with deaths from upper GI bleeding each year in the UK. One 1997 study, extrapolating from two English hospitals, estimated that about 2,230 deaths a year among emergency admissions for upper GI disease were attributable to NSAID use, plus a further 330 deaths in the community. These figures are old and extrapolated, so they show the scale of the problem rather than a current count.

These risk factors add to the GI risk of an NSAID. They help to decide who needs stomach protection (gastroprotection):

  • Older age (especially over 65).
  • Prolonged use.
  • Concurrent corticosteroids (steroid anti-inflammatory drugs), anticoagulants (drugs that reduce clotting) or another antiplatelet drug.
  • Smoking, heavy alcohol.
  • Past peptic ulcer disease.
  • Helicobacter pylori infection (a bacterial stomach infection that can cause ulcers).

For patients in whom an NSAID is unavoidable but GI risk is high, a co-prescribed PPI is the standard mitigation. If the patient has no cardiovascular disease, CKS advises that a COX-2 selective drug can be used together with the PPI.

Renal

NSAIDs cause:

  • Reversible reduction in GFR, particularly in patients dependent on prostaglandin-mediated afferent arteriolar dilation (widening of the small vessel that carries blood into the glomerulus, the kidney's filter). This includes chronic kidney disease (CKD), heart failure, cirrhosis with ascites (fluid in the abdomen) and hypovolaemia (low blood volume).
  • Salt and water retention → worsening hypertension, oedema and heart failure.
  • Hyperkalaemia (high blood potassium): via reduced secretion of renin, the kidney enzyme that starts the renin-angiotensin-aldosterone system (the hormone system that raises blood pressure and keeps salt and water in the body).
  • Acute interstitial nephritis (inflammation of the tissue between the kidney tubules): rare but well-described.
  • Chronic high-dose use (especially historically with phenacetin, an old painkiller): analgesic nephropathy (long-term kidney damage from regular painkiller use).

The combination of NSAID + angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) + diuretic in a hypovolaemic patient ("the triple whammy") increases the risk of acute kidney injury (AKI). In one meta-analysis the odds of AKI were about twice as high with the combination as without it, although the certainty of the evidence was low. The NSAID narrows the vessel carrying blood into the glomerulus. The ACE inhibitor or ARB widens the vessel carrying blood out. The diuretic lowers blood volume. Together they can cut the filtration pressure.

Cardiovascular

All NSAIDs (with the partial exception of low-dose aspirin) increase the risk of myocardial infarction (MI, or heart attack), stroke, hypertension and heart failure to varying degrees. The risk is dose- and duration-dependent and highest with diclofenac and the coxibs. Naproxen has a comparatively favourable thrombotic risk profile, as does low-dose ibuprofen (1,200 mg/day or less); this does not guarantee safety in a person with cardiovascular disease.

NSAIDs also reduce the antihypertensive effect of most blood-pressure-lowering drugs.

Asthma, Allergy and Other

  • NSAID-exacerbated respiratory disease ("aspirin-sensitive asthma"): bronchospasm (airway narrowing) in around 10% of adults with asthma. When COX is blocked, more arachidonic acid is diverted into the leukotriene pathway, and this causes the reaction. Caution with all NSAIDs in this group.
  • True hypersensitivity reactions: urticaria (hives), angio-oedema (swelling of the deeper layers of the skin) and anaphylaxis (a severe, life-threatening allergic reaction). Cross-reactivity between NSAIDs is common.
  • Pregnancy: per MHRA guidance, systemic NSAIDs (those that act throughout the body) are contraindicated from 28 weeks (third trimester). They should be avoided from 20 weeks unless clinically necessary. The risks are premature closure of the ductus arteriosus, oligohydramnios (too little amniotic fluid) and fetal renal impairment.
  • Hepatotoxicity (liver damage; rare).
  • Headache and dizziness with indometacin.

Drug Interactions

Most clinically important NSAID interactions come from one of three mechanisms. NSAIDs add to the risk of bleeding or GI damage. They blunt the prostaglandin-dependent effects of blood-pressure-lowering drugs. They reduce the kidneys' clearance of some drugs, such as lithium and methotrexate:

  • Anticoagulants and antiplatelets: additive bleeding risk.
  • Corticosteroids: markedly increased GI bleeding.
  • Sulphonylureas (tablets that lower blood glucose in diabetes): potentiation, increasing risk of hypoglycaemia.
  • Methotrexate (an immunosuppressant and chemotherapy drug): reduced renal clearance, accumulation, marrow suppression. Particular caution at high methotrexate doses.
  • Lithium: reduced renal clearance, elevated lithium levels.
  • Antihypertensives: reduced efficacy of ACE inhibitors, diuretics, beta-blockers.
  • Aspirin: ibuprofen competes with low-dose aspirin at the platelet COX-1 enzyme and can reduce its antiplatelet effect. The MHRA says that regular long-term use of ibuprofen might reduce the cardioprotective (heart-protecting) effect of low-dose aspirin, but that occasional use is unlikely to matter. Both drugs also increase the risk of bleeding.

Paracetamol

Mechanism

Paracetamol (acetaminophen) is an analgesic and antipyretic with negligible anti-inflammatory action. The mechanism is incompletely understood. The analgesic effect is thought to be mainly central (in the brain and spinal cord). It involves activation of descending serotonergic pathways (nerve pathways that use serotonin to dampen pain signals), and the cannabinoid system (the body's own cannabis-like signalling) may also play a part. Paracetamol also inhibits COX-1 and COX-2 weakly, mainly when the levels of arachidonic acid and peroxides (reactive oxygen compounds) are low. The older idea of a separate "COX-3" enzyme is unlikely to be clinically relevant.

What matters at pre-clinical level is the practical profile:

  • Effective analgesic for mild-moderate pain and fever.
  • No anti-inflammatory action at usual doses.
  • Few GI, renal or platelet effects at therapeutic doses (it is well tolerated by the gut and has little effect on platelets): a major safety advantage over NSAIDs.
  • Safe in pregnancy and breastfeeding when used at the lowest effective dose for the shortest time (the analgesic of choice).
  • The adult dose by mouth is 0.5 to 1 g every 4 to 6 hours, to a maximum of 4 g in 24 hours. The dose may need to be reduced in patients under 50 kg or with risk factors for liver damage, such as chronic alcohol use, dehydration or malnutrition.

Paracetamol Overdose

Paracetamol overdose is the leading cause of acute liver failure in the UK. Around 10-15 g (20-30 standard tablets) can be fatal in an adult of average size; less in patients with depleted glutathione (chronic alcohol use, malnutrition, liver disease).

The toxicity stems from a minor metabolic by-product:

  1. At therapeutic doses, paracetamol is conjugated (attached) to glucuronic acid or sulphate (Phase II metabolism), which makes it water-soluble, and is then excreted.
  2. A small fraction is oxidised by CYP2E1 (a liver enzyme) to NAPQI (N-acetyl-p-benzoquinone imine): a highly reactive intermediate.
  3. NAPQI is normally inactivated by conjugation with hepatic glutathione (the liver's main protective antioxidant).
  4. In overdose, glutathione is used up and NAPQI accumulates. It oxidises critical thiol groups (sulphur-containing groups on essential proteins) and causes hepatocyte necrosis (liver cell death) in the centrilobular zone (around the central vein of each liver lobule).

Clinical course of overdose:

  • 0-24 hours: often asymptomatic, occasionally nausea, vomiting and abdominal discomfort.
  • 24-72 hours: right upper quadrant pain and tenderness (usually starting on day 2 or 3) and rising liver enzymes (aspartate aminotransferase, AST, and alanine aminotransferase, ALT) as liver injury develops. The prothrombin time (a clotting test) also rises. An INR (international normalised ratio, a standardised clotting measure) above 1.3 suggests acute liver injury.
  • 3-4 days: peak hepatic damage; jaundice, coagulopathy (impaired clotting) and encephalopathy (brain dysfunction) in severe cases.
  • 4-14 days: recovery or progression to acute liver failure.

Antidote: N-acetylcysteine (NAC, Parvolex). NAC is a thiol donor (it supplies sulphur-containing thiol groups) that replenishes glutathione and detoxifies NAPQI. Most effective if started within 8 hours of ingestion, but is given even late if liver injury has developed. After a single overdose, treatment is guided by a paracetamol level taken at least 4 hours after ingestion (earlier levels cannot be interpreted) and plotted on the treatment nomogram (a chart of drug level against time). Current UK practice (since 2012) is to use a single treatment line, which starts at 100 mg/L at 4 hours. The nomogram is not used for a staggered overdose (taken over more than an hour) or when the time of ingestion is unknown. Those patients are managed as staggered overdoses, and the MHRA advises treating them with NAC without delay.

Mnemonic for time course:

Paracetamol overdose: rule of 24s
Day 1 (0-24 h): asymptomatic / mild GI
Days 2-3 (24-72 h): rising liver function tests (LFTs), right upper quadrant pain
Days 3-4: peak hepatic damage
Beyond day 4: recovery or acute liver failure

Summary

  • NSAIDs inhibit cyclo-oxygenase (COX-1 and COX-2), reducing prostanoid synthesis from arachidonic acid.
  • NSAIDs have four actions: analgesic, anti-inflammatory, antipyretic and, with aspirin only, antiplatelet.
  • COX-1 is constitutive (gastric, renal, platelet); COX-2 is mainly inducible (inflammation). COX-2 selective drugs (celecoxib) reduce GI side effects but increase cardiovascular (CV) risk.
  • Major NSAID side effects: GI ulceration and bleeding; reduced GFR; salt and water retention with worsening hypertension and heart failure; bronchospasm in aspirin-sensitive asthma.
  • The triple whammy of NSAID + ACE inhibitor or ARB + diuretic in a hypovolaemic patient (low blood volume) raises the risk of AKI.
  • Aspirin is irreversible (acetylates COX-1); avoid in children under 16 (Reye's syndrome).
  • Naproxen has a comparatively favourable thrombotic profile, as does low-dose ibuprofen (1,200 mg/day or less).
  • Paracetamol is not an NSAID. Effective analgesic and antipyretic; no anti-inflammatory action; safe in pregnancy. Overdose causes hepatic necrosis through accumulation of NAPQI; antidote is N-acetylcysteine.

Drug Summary Table

Drug Class Notable feature Key uses
Ibuprofen Non-selective NSAID Lowest GI risk among non-selective NSAIDs at standard dose; available over the counter Mild-moderate pain, fever
Naproxen Non-selective NSAID Comparatively favourable thrombotic profile (also low-dose ibuprofen); longer half-life Inflammatory pain, dysmenorrhoea, gout
Diclofenac Non-selective NSAID CV profile similar to coxibs (MHRA cautions) Acute pain
Indometacin Non-selective NSAID Powerful; used to close patent ductus arteriosus in premature neonates Acute gout, ankylosing spondylitis
Mefenamic acid Non-selective NSAID Minor anti-inflammatory properties; convulsions in overdose Dysmenorrhoea, menorrhagia
Aspirin Non-selective NSAID; irreversible COX-1 inhibitor Antiplatelet at low dose (75 mg); avoid <16 (Reye's) Secondary prevention of cardiovascular disease (CVD); analgesia at higher dose
Celecoxib, etoricoxib COX-2 selective ↓ GI risk; ↑ CV risk; no antiplatelet effect High-GI-risk patients with low CV risk needing NSAID
Paracetamol Not an NSAID (analgesic / antipyretic) No anti-inflammatory action; safe in pregnancy; overdose → NAPQI hepatotoxicity (antidote NAC) First-line for acute mild to moderate pain and fever; NICE does not routinely recommend it for osteoarthritis

Reviewed by: Dr. Marcus Judge

Quiz

Preview the NSAIDs quiz

274