Paracetamol (Acetaminophen) Pharmacology and Toxicology

These flashcards cover the pharmacological mechanics, metabolic pathways, toxic effects, and clinical management of paracetamol and paracetamol overdose.

Paracetamol (acetaminophen)

A synthetic non-opioid analgesic and antipyretic that acts primarily in the central nervous system as an inhibitor of cyclo-oxygenase ($COX-2$ and $COX-3$).

COX-2 and COX-3

Enzymes involved in prostaglandin synthesis located in the brain and spinal cord, where they facilitate nerve transmission for pain and fever.

Glucuronidation

The most common Phase II conjugation reaction for paracetamol, accounting for $45-55\%$ of its metabolism and resulting in the non-toxic metabolite acetaminophen glucuronide.

Sulphate Conjugation

A Phase II reaction accounting for $30-35\%$ of paracetamol metabolism, catalyzed by sulphotransferases in the liver, kidney, and intestine.

NAPQI (N-acetyl-p-benzoquinoneimine)

A highly reactive and toxic alkylating metabolite formed through the N-hydroxylation of paracetamol by the Cytochrome P450 system (specifically $CYP2E1$ and $CYP3A4$).

Glutathione

A tripeptide comprising glutamic acid, glycine, and cysteine that conjugates with NAPQI to form inactive, non-toxic cysteine and mercapturate derivatives.

Hepatotoxicity

Liver damage caused by the buildup of toxic NAPQI when glutathione stores are depleted and the conjugation pathways (Glucuronidation and Sulfation) are saturated.

Encephalopathy

A malfunction of the brain due to the buildup of toxins, occurring as a symptom of acute liver failure following paracetamol overdose.

Rumack-Matthew Nomogram

A clinical tool used to assess the risk of severe liver damage by plotting plasma paracetamol concentration against the time since ingestion; the treatment threshold is $200\,mg/L$ at $4\,\text{hours}$.

N-acetylcysteine (NAC)

An intravenous treatment used to replenish cellular glutathione stores for NAPQI conjugation and to repair oxidative damage caused by paracetamol overdose.

Kings College Criteria

A set of clinical markers used to determine immediate referral for liver transplant, including arterial $pH < 7.3$, $INR > 6.5$, and Grade III or IV hepatic encephalopathy.

Activated charcoal

A management option used to prevent drug absorption if administered within $1\,\text{hour}$ of paracetamol ingestion.

Methionine

A glutathione donor that can be used as an antidote, though its combination with paracetamol is limited by side effects like raised plasma homocysteine and endothelial dysfunction.

CYP2E1

A hepatic cytochrome P450 isoenzyme that is induced by alcohol, increasing the conversion of paracetamol into the toxic metabolite NAPQI.

Oliguria

A condition characterized by low urine output, which may develop as part of renal failure approximately $72\,\text{hours}$ post-ingestion of a paracetamol overdose.

Glutathione S-transferase

The enzyme that catalyzes the irreversible conjugation of NAPQI with the sulphhydryl groups of the cofactor glutathione.