Paracetamol

Question 1

What class of agent is paracetamol and why

Answer 1

It has been classified as a Non-steroidal anti-inflammatory drug due to its analgaesic and anti-pyretic properties despite having no effect on cyclo-oxygenase.

Proposed mechanism is CNS prostaglandin synthesis by inhibition of CNS COX-3, a COX 1 variant

Question 2

What are the proposed mechanisms of action of paracetamol

Answer 2

1. CNS COX 3 INHIBITION
   Inhibition of COX 3 in the central nervous system. COX-3 is described as a variant of the COX 1 enzyme. Therefore the proposed mechanism of action is inhibition of prostaglandin synthesis in the central nervous system.
2. INHIBITION of CNS PROSTAGLANDIN F
3. ACTIVITY AT CANNABINOID RECEPTORS IN SPINAL CORD
4. SERITONERGIC SYSTEM MODULATION

Question 3

Describe presentation paracetamol

Answer 3

1. 500 mg tablets
2. Combination with weak opioids (various)
3. Paed: 120 mg/5 ml syrup
4. IV: 1g or 500 mg in 100 ml clear colourless over 15 mins
   - -> 10mg/ml paracetamol
   - -> Preservative: Cysteine hydrochloride monohydrate
   - -> Excipients: Mannitol + others

Question 4

Describe the dosing of paracetamol and adjustments for renal/hepatic disease

Answer 4

Adult: 1 g 6 hourly (max 4g/day)
Children: 15 mg/kg/dose 6 hourly (max 60 mg/kg/day)
Neonate: 7.5 mg/kg/dose 6 hourly (max 30 mg/kg/day)

Question 5

Describe the pharmacokinetics of paracetamol

Answer 5

ADME

Absorption

• Bioavailability 80%
• Peak [serum]: 1 hour tablets, 30 minutes syrup

Distribution

• Protein bound 20%
• Vd = 0.9 L/kg

Metabolism

• 95 % glucoronidation and sulfation
• 5 % CYP 2E1 –> NAPQI generated rapidly detoxified by glutathione (unless glutathione depleted)

Excretion
- Glucoronide, sulfate, cysteine conjugates excreted in urine

Question 6

How is the oral bioavailability of paracetamol calculated.

Define bioavailability

List the factors that influence bioavailability

Answer 6

Draw plasma concentration - time curve

Bioavailability = AUC (oral) /AUC (IV)

Bioavailability is defined as the fraction of a drug dose reaching the systemic circulation, compared with the same dose given intravenously.

Factors influencing:

1. Pharmaceutical properties (Particle size/binding agents)
2. Physicochemical interactions (Ca+ - tetracyclines)
3. Patient factors (Stasis/malabsorption/trauma)
4. Pharmacokinetic interactions and 1st pass metabolism (Gut wall and liver)

FB = FA x FG x FH

FB - bioavailable fraction
FA - Fraction absorbed
FG - Fraction remaining after GIT metabolism
FH - Fraction remaining after HEPATIC metabolism

Question 7

What does NAPQI stand for

Answer 7

N - acetyl - p - amino - benzoquinone

Question 8

Describe the metabolic pathway of paracetamol toxicity

Answer 8

Paracetamol overdose –> glucoronidation and sulfation pathways saturated, metabolism proceeds via CYP 2E1 and CYP3A4 –> rapid glutathione depletion leading to accumulation of NAPQI:

1. Inactivation of ± 20 important enzymes/proteins –> toxicity
2. Inhibits mitochondrial cytochrome enzymes –> uncoupling of oxidative phosphorylation –> Failure ATP synthesis and release of sequestered calcium –> toxicity

–> HEPATOCELLULAR APOPTOSIS AND NECROSIS

Question 9

Describe the mechanism of action of N-acetylcysteine (NAC)

Answer 9

N-acetylcysteine is converted to cysteine. This is combined to glutamate to form Glutamylcysteine. Glutamylcysteine is combined with Glycine to form more glutathione.

1. Supplies more glutathione to bind to NAPQI
2. Antioxidant
3. Supplies sulfate from cysteine for more sulfation and less pracetamol down CYP 2E1 pathway

Question 10

What is the recommended dosing schedule for NAC

How long is NAC given for

Answer 10

First hour: 150 mg/kg
Next 4 hours: 50 mg/kg
Next 16 hours: 100 mg/kg

Duration: at least 20 hours
STOP if:
1. Paracetamol levels < 10 mg/L
2. ALT < 50
3. INR < 2
4. Patient clinically well

Question 11

When does NAC no longer convey benefit in paracetamol overdose

Answer 11

After the onset of established liver failure (72 hours).

Question 12

What can be used to assist decision making with regard to treating a paracetamol overdose

Answer 12

Prescott nomogram

Question 13

Can the prescott nomogram be used if the sustained release paracetamol has been given?

Answer 13

NO

Question 14

What dose and when should activated charcoal be given in paracetamol overdose

Answer 14

50 g within 4 hours of ingestion

50 g within 24 hours ingestion if sustained release taken

Question 15

Which patients have depleted glutathione stores

Answer 15

1. Eating disorders
2. Prolonged starvation
3. HIV
4. Cystic Fibrosis
5. G6PD deficiency

Question 16

Which patients have hyperactive liver enzymes predisposing to paracetamol toxicity

Answer 16

P450 enzyme inducers
B CRAPP SSS HE

Barbiturates
Carbamazepine
Rifampicin
Alcohol (chronic)
Phenytoin
Phenobarbtione

Steroids
Sulfonylureas
Smoking cigarettes

Halothane
Enflurane