Drugs for Fever (Antipyretics)

Mechanism of Antipyresis

1st Line: Paracetamol (Acetaminophen)

"Acetaminophen is preferred as an antipyretic... In children, acetaminophen or oral ibuprofen must be used because aspirin increases the risk of Reye syndrome."

• Harrison's Principles of Internal Medicine, 22nd Ed. (2025), p. 180

2nd Line: NSAIDs (Ibuprofen, Naproxen, Diclofenac)

"Oral aspirin and NSAIDs effectively reduce fever but can adversely affect platelets and the gastrointestinal tract. Therefore, acetaminophen is preferred."

• Harrison's, p. 180

3rd Line / Special Situations

Aspirin (Acetylsalicylic acid)

• Effective antipyretic, anti-inflammatory, and analgesic
• Avoided in children (<12 years) due to risk of Reye syndrome with viral infections
• Used in adults for specific indications (Kawasaki disease is an exception - aspirin is specifically used)
• Irreversibly inhibits COX-1 on platelets - avoid when bleeding risk is present

Dipyrone (Metamizole)

• Effective non-opioid analgesic/antipyretic; used in parts of Europe, Latin America, and South Asia
• Not available in the UK/USA due to rare risk of agranulocytosis
• Relieves pain and fever but is not anti-inflammatory (similar profile to paracetamol)

Glucocorticoids (Dexamethasone, Hydrocortisone)

• Used for refractory fever in specific conditions (autoimmune, autoinflammatory diseases)
• Dual mechanism: (1) inhibit phospholipase A2 (block arachidonic acid release), (2) block mRNA transcription of pyrogenic cytokines (IL-1, IL-6, TNF)
• Not routine antipyretics; reserved for specific indications (e.g., Still disease, meningitis adjunct, typhoid with delirium)

Anticytokine therapy (Anakinra, Canakinumab)

• Targets IL-1 activity
• Used for autoinflammatory diseases (familial Mediterranean fever, adult Still disease, hyper-IgD syndrome)
• "Fevers associated with many of these illnesses are dramatically reduced by blocking IL-1 activity with anakinra or canakinumab" - Harrison's, p. 180

Quick Reference Summary

Physical Measures (Adjuncts)

• Cooling blankets for hyperpyrexia - but should always be combined with antipyretic medication, not used alone
• Tepid sponging is commonly used but evidence is limited

Antipyretics in CLD + CKD

The Core Problem

Drug of Choice: Paracetamol (with dose reduction)

Why paracetamol is still preferred:

• It does NOT inhibit COX peripherally, so it does not reduce renal prostaglandin synthesis or afferent arteriolar tone - no risk of functional azotemia
• No GI toxicity
• No platelet dysfunction
• Multiple clinical trials have confirmed it is safe for short-term use in liver disease at reduced doses

Mechanism of hepatotoxicity (why dose reduction matters in CLD):

• Normally, <10% of paracetamol is converted to the toxic metabolite NAPQI via CYP2E1
• NAPQI is rapidly detoxified by hepatic glutathione
• In cirrhosis: glutathione stores are depleted + hepatic enzyme function is impaired → NAPQI accumulates → hepatocyte death
• Additional risk factors: malnutrition, fasting, alcohol use (all common in CLD) - these further deplete glutathione

Dose recommendations:

"Patients with cirrhosis may also be more susceptible, thereby leading to the current recommendation not to exceed 2 g in 24 hours in this population."

• Goldman-Cecil Medicine, International Edition

"Acetaminophen has traditionally been avoided in patients with any type of liver disease, but there are several trials indicating it to be safe for short-term use, at a reduced dose of 2 grams total per day."

• Tintinalli's Emergency Medicine

Why NSAIDs Must Be Avoided (Both Conditions)

In CKD:

• NSAIDs inhibit COX → reduce renal prostaglandin (PGE2, PGI2) synthesis
• These prostaglandins normally dilate the afferent arteriole to maintain GFR in states of low perfusion
• NSAID use in CKD → afferent arteriolar constriction → fall in GFR → functional azotemia to frank AKI
• Risk is dose-dependent, often manifests within the first few weeks
• Can progress from reversible azotemia to acute tubular necrosis (weeks to resolve, sometimes permanent)
• Other effects: hyperkalemia, peripheral edema, fluid retention

In CLD (Cirrhosis):

• Cirrhosis causes effective intravascular volume depletion (splanchnic vasodilation, portal hypertension)
• Kidney in cirrhosis is already dependent on prostaglandin-mediated vasodilation to maintain perfusion
• NSAIDs in this setting = hepatorenal syndrome precipitant
• Rheumatology textbook explicitly lists cirrhosis as a setting where NSAIDs are relatively contraindicated alongside nephrotic syndrome and heart failure

"NSAIDs are relatively contraindicated in settings of preexisting renal hypoperfusion... such as nephrotic syndrome, congestive heart failure, cirrhosis, and protein-wasting enteropathies."

• Rheumatology (Firestein), 2022

Why Aspirin is Avoided

• Platelet dysfunction + risk of variceal bleeding in cirrhosis (portal hypertension patients have high bleeding risk)
• GI ulceration
• Causes fluid retention and further reduces GFR in CKD

Practical Algorithm for CLD + CKD Patient with Fever

Fever in CLD + CKD patient
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AVOID: NSAIDs, Aspirin
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Use PARACETAMOL
  - Max 2 g/day
  - Dose every 8 hours (500 mg q8h)
  - Short-term use preferred
  - Avoid if: active alcohol use, severe malnutrition, decompensated cirrhosis (Child C)
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If decompensated cirrhosis (Child C) or GFR <10:
  - Use LOWEST effective dose (500 mg q8h or q12h)
  - Monitor LFTs, renal function
  - Consider physical cooling methods as adjunct
        │
        ▼
Refractory/high fever in specific disease (e.g., autoinflammatory):
  - Short-course GLUCOCORTICOIDS (only if specific indication)
  - Avoid opioids; if unavoidable - FENTANYL at reduced dose
    (no active toxic metabolites, unlike morphine/codeine)

Key Points to Remember

1. Paracetamol ≤ 2 g/day is the drug of choice - not contraindicated, just dose-reduced
2. NSAIDs are contraindicated in both CLD and CKD - they precipitate AKI and hepatorenal syndrome
3. Aspirin avoided due to bleeding risk in cirrhosis
4. Opioids avoided in CLD (encephalopathy risk); if unavoidable, fentanyl is safest (no active toxic metabolites)
5. Treat the underlying cause of fever (antibiotics for SBP, antivirals, etc.) - antipyretics are adjunctive

GRBS 89 mg/dL + Sweetened Tea: Time to Rise

First - Is GRBS 89 Truly Hypoglycemia?

Time for Sweetened Tea to Raise Blood Sugar

Physiology of glucose absorption after oral intake:

The "15-15 Rule" (Standard Clinical Protocol):

"If adults are conscious and able to swallow, the best approach is 15 to 20 g of rapid-acting carbohydrate... If the capillary glucose remains less than 72 mg/dL, oral treatment can be repeated up to three times, 15 minutes apart."

• Goldman-Cecil Medicine, International Edition

• Give 15-20 g of fast-acting carbohydrate
• Recheck GRBS after 15 minutes
• Repeat if still low

How Much Sugar Does Tea Contain?

Why Fat Slows the Response

"Foods with a high fat content (e.g., chocolate) should be avoided because they delay gastric emptying, thereby slowing the absorption of carbohydrate."

• Goldman-Cecil Medicine

• No fat to delay gastric emptying
• Sugar dissolved in hot water absorbs faster than solid foods
• Effect begins in ~15 minutes

Practical Summary