Effects of, and Uses for Paracetamol

Paracetamol, also known as acetaminophen, is a widely used medicinal drug available over the counter

The chemical name for Paracetamol is N-acetyl-p-aminophenol.

Over-the-counter (OTC)

Analgesic and antipyretic action with weak anti-inflammatory action

Synergic effect with other analgesics, especially codeine and NSAIDs, resulting in better overall pain control

Major ingredient in cold & flu remedies

Used in combination with opioid analgesics

Oral Paracetamol has an oral bioavilabity of 63-89%. A drug given orally goes through first pass metabolism.

Intravenous Intravenous administration of paracetamol has a bioavilabity of 100%

Rectal Paracetamol has a rectal bioavilabity of 24-98%.

Bioavailability is the amount of dose absorbed from the site of administration

Oral administration has a little first pass metabolism in the liver and is well absorbed from the gastrointestinal tract

First pass metabolism involves the drug being absorbed into the portal vein system via the intestine wall after which it is carried to the liver. Before the drug reaches its target site it may therefore to some extent be metabolised in the liver.

A plasma concentration of 10-20mcg.ml^-1 for paracetamol results in an antipyretic effect however the concentration needed to lead to an analgesia effect is not properly known. All three routes of administration have a significant difference in the time needed to reach peak plasma concentrations. Of all three routes intravenous administration reaches peak plasma concentration in the shortest amount of time and suppository takes the longest,

Oral : For adults 325-650mg tablets can be taken every 4 to 6 hours 1 gram can be taken every 4 hours with a maximum of 4 doses in 24 hours.

Rectal: suppositories are available in 250 and 500mg. Two 500mg suppositories can be taken by adults and children over 12

IV: The maximum dose that can be given is 3g in 24 hours

For children there new dosage guidelines that put children into 7 precise age groups

Since IV administration has 100% bioavilabity there is a high chance of toxicity in patients that have renal and/or hepatic problems

Absorbed through the wall of the intestine and into the blood.

Speed and efficiency of the absorption is determined by several factors which include the pKa, log P and molecular mass of the drug

Low molecular mass and is almost completely unionised in the small intestine which allows it to be absorbed more easily

Oral Bioavailability – 70%-90%

Rectal Bioavailability – 30%-70%

Distributed throughout the body fluids in a homogeneous way

Analgesic activity is attributable to the small fraction that penetrates into the brain

Binds to plasma proteins at less than 20%

A high degree of protein binding makes the drug long acting

The glucuronidation and sulfation pathway for paracetamol metabolism lead to the production of unharmful and on toxic products. The middle N-Hydroxylation and rearrangement pathway mediated by the isoenzyme of cytochrome p450 (CYP2E1 and CYP3A4) pathway leads to the production of toxic metabolite NAPQ1 which covalently binds to cell macromolecules in overdose. In normal cases NAPQ1 binds with glutathione resulting in an unrhamful and nontoxic product.

Part A of the figure shows the metabolism of paracetamol in a healthy individual. Around 95% of the drug is conjugated with glucuronide and excreted in the urine. The leftover is conjugated with glutathione

Part B shows the metabolism of paracetamol in an individual that is starved. The conjugation of glutathione does not take place adequately and its depletion results in the build of hepatotoxic NAPQ1

Excreted in urine

Predominantly in the form of inactive glucuronide and sulphate conjugates

A small amount of the drug is converted to a very reactive alkylating metabolite that is inactivated with reduced glutathione and is excreted in the urine as cysteine and mercapturic acid conjugates

Paracetamol is absorbed from the GI tract and a peak plasma concentration occurs within 10-60 minutes after being taken orally. It has a half-life of approximately 2 hours

It is distributed into the majority of body tissues

Has an elimination half life ranging from 1-3 hours

The volume of distribution for paracetamol is around 1L/Kg of body weight with an insignificant amount of the drug binding to plasma protein.

Inhibition of cyclooxygenase (COX) – specifically COX-2

Reduces the oxidised form of the COX enzyme, preventing it from forming pro-inflammatory chemicals

Peripheral anti-inflammatory activity is usually limited by high level of peroxides present in inflammatory lesions (including several other factors)

Metabolites of paracetamol act upon the spinal cord via TRPA1-receptors

modulates the endogenous cannabinoid system

Paracetamol works inhibiting the synthesis of prostaglandins

Because of its selectivity for COX-2 it does not significantly inhibit the production of the pro-clotting thromboxanes.

Metabolies: suppressing the signal transduction from the superficial layers of the dorsal horn to alleviate pain.

The nuclear receptor constitutive androstane receptor (CAR) can be activated by paracetamol.

This induces the expression of three cytochrome P450 enzymes that lead to the transformation of paracetamol into N-acetyl-p-benzoquinone imine

(NAPQI) is a reactive and toxic metabolite.

It can be detoxified by conjugation with glutathione

Paracetamol is a safe drug and doesn’t cause toxicity unless taken in the wrong dosage or in extreme circumstances such as starvation. Also when taken with alcol for long periods of times it enhances toxicity as the coentration of toxic metabolites such as NAPQ1 increases.

NAPQ1 firstly goes through detoxification in the liver via glutathione conjugation catalysed by the enzyme GST and then goes through acetylation in the kidneys. This step is catalysed b M-acetyl transferase. It then gets excreted in the urine.

The cytochrome p450 enzyme (isoenzyme CYP2E1) procures hepatoxic metabolites in small quantities.

The phase 1 metabolism of paracetamol mediated by p450 gives rise to NAPQ1, that is detoxified by phase 2 conjugation with glutathione. During overdose depletion of glutathione occurs and NAPQ1 accumulates

Phase 1 metabolism is where the drug molecule foes though basic structural alteration through reduction, hydrolysis, or oxidation (which is catalysed cytochrome p450 enzymes) Phase 2 metabolism involves conjugation (an ionised group attaches to the drug) making it metabolite water soluble.

In the case of paracetamol overdose NAPQ1 can accumulate and can possibly lead to liver damage if left untreated

It can also damage other organs that contains P450 enzymes such as the kidneys where the toxicity could result in renal dysfunction and pancreas.

Liver toxicity can be prevented by blocking the activation of CAR with an antagonist or

Paracetamol overdose occurs at around 7-8 g in an adult and more than 150 mg/kg in children.

Liver damage : The centrilobular zone is the first zone in the liver that gets affected by the toxicity. In extreme cases zones 1 and 2 present in the parenchyma get damaged.

Kidney damage: renal dysfunction leads to the need of dialysis as a tubular necrosis table place because of the localised formation of NAPQ1.