Pharmacology - Non-opioid Analgaesics

Question 1

Discuss Paracetamol

Toxicity covered in another flashcard

IMAGE of structure

Answer 1

Class & uses
Para-aminophenol, derived from acetanilide with a phenol group

Presentation
500mg tablets ± an NSAID or weak opioid
Suppositories 125mg & 1g
Liquid 120mg/5ml
Solution for injection 1g or 500mg

Dose
1g QDS 4° standard adult dose
15mg/kg if less than 50kg, up to 60mg/kg/day
Paediatric dose 15-30mg/kg loading, then 10-15mg/kg 4°, up to 90mg/kg/day

Indications
Analgaesia and Antipyrexia

Mechanism of action
Unclear, but is a non-specific, indirect COX-3 inhibitor, although has no anti-inflammatory effect - potentially though preventing oxidation of COX-3, which is easier in the brain where peroxidase is low, compared with inflamed tissues.
Stimulates descending serotonergic pathways - which may be inhibited by 5HT-3 inhibitors such as ondansetron
May also act via cannabinoid, TNFα, and nitric oxide pathways

Pharmacokinetics
Absorption - PO bioavailability 80%
Distribution - 10% protein bound, larger Vd than NSAIDS
Metabolism - Hepatic, mainly via glucuronidation, but also sulphation and cysteine conjugates - easily saturated, leading to production of toxic N-acetyl-p-amino-enzoquinone imine (NAPQI). This is usually conjugated with glutathione, but it can be depleted quickly. N-acetyl-cysteine acts as a glutathione donor.
Excretion - Renal

Question 2

Discuss the presentation and management of paracetamol overdose

Answer 2

Most common cause of acute hepatic injury in the UK - can be either intentional, or accidental overdose.

Toxicity occurs as a result of saturating the main metabolic pathway, leading to N-acetyl-p-amino-benzoquinone imine production, and rapid depletion of hepatic glutathione stores (which are needed to metabolise NAPQI)

This leads to acute centrilobular hepatic necrosis.

Clinical features
Few initial sympoms other than vomiting
After 24 hours, RUQ pain, with possible deranged LFTs and clotting
After 72 hours, LFTs deteriatre to fulminant hepatic failure, and possible MoF.
May also present with hypoglycaemia, haemolytic anaemia, distributive shock, cholestasis

Treatment
General - ABC resuscitation, and full set of bloods (particularly clotting and LFTs)
Specific - Use nomogram to guide NAC treatment (generally very safe, some risk of hypersensitivity reaction)
Traditional regime:
150mg/kg over first hour
50mg/kg over 4 hours
100mg/kg over 16 hours

NAC indicated in staggered overdose or unknown time of ingestion, level above normogram when time of ingestion known, or evidence of liver injury.

Activated charcoal may be given if within 1 hour of a large, single dose

Liver transplant in advanced cases, discussion with liver centre if clotting not improving with NAC

NAC - N-acetyl-cysteine, a which is a glutathione donor

Question 3

What are the uses of NSAIDs?

Answer 3

Anti-inflammatory
Analgaesic
Antipyretic
Uricosuric (Promote urinary excretion of uric acid)

Question 4

Discuss Aspirin

Toxicity covered in another flashcard

IMAGE - Structure aspirin

Answer 4

Class & uses
Salicylate compound, called acetyl salicylic acid.
Anti-inflammatory at higher doses
Inhibits platelet aggregation at low doses
Anti-pyretic & analgaesic
Used in pregnancy for eclampsia and pre-eclampsia

Presentation
75 and 300mg tablets, 300mg suppository

Dose
75mg for long-term antiplatelet effect
300mg for MI/stroke
Up to 900mg for analgaesia/migraine

Indications
Inflammation, fever, pain, migraine, prevent cardiovascular events

Mechanism of action
Non-selective, irreversible inhibition of COX-1 and COX2, reducing production of pro-inflammatory prostaglandins - In particular, inhibition of PGE 1 in the brain is antipyretic.
Irreversible inhibition of Thromboxane A2 (Via COX-1), even at low doses, prevents plt aggregation, reducing risk of stroke and MI. This lasts for the length of the platelet’s lifespan, approx 7-10 days.

Effects
Respiratory - Direct stimulation of respiratory centre, hyperventilation in overdose
CVS - Inhibits vessel vasodilation at high doses
Haematological - Bleeding
GI - Mucosal ulceration, inhibits gastric mucus production
Renal - Reduces renal perfusion, inhibits renal excretion of urate at low doses, inhibits reabsorption at higher doses (uricosuric)
Metabolic - Uncouples oxidative phosphorylation (increasing O₂ consumption & CO₂ production)
Can trigger Reye syndrome in children

Pharmacokinetics
Absorption - well absorbed from stomach (weak acid with pKa 3, so unionised in stomach, and passes passively through stomach lining and proximal duodenum, with peak plasma levels 1.5-2hours post-ingestion) 80-100% bioavailability
Distribution - not signficantly protein bound, but main metabolite (salicylate) is 50-90% protein bound, largely to albumin. Aspirin can acetylate molecules, such as DNA, haemoglobin, and proteins.
Metabolism - Hydrolysis in the plasma to salicylic acid, which then undergoes hepatic metabolism (CYP2C19 & CYP3A4).
Half-life of 2-3 hours at low dose, and 15-30 hours at high dose.
Excretion - Salicylate & salicyluric acid renally excreted. Salicylate has a half life of around 4 hours.

Question 5

Discuss features of aspirin toxicity

Answer 5

Affects multiple organ systems, may be acute (2% mortality) or chronic (25% mortality) - worse as a result of higher tissue levels of the drug.

CNS
Tinnitus, blurred vision, hallucinations & confusion, seizures & coma if severe

CVS
Tachycardia & hypotension (driven by dehydration as a result of uncoupled phosphorylation & pyrexia)

GI
N&V (stimulates chemoreceptor trigger zone), GI bleeding & ulceration

Respiratory
Stimulation of respiratory centre by CSF acidosis causes initial respiratory alkalosis. Pulmonary oedema & ARDS if severe

Renal
Respiratory alkalosis leads to bicarbonate excretion, followed by water & potassium loss
At low doses, inhibits urate secretion, worsens gout symptoms. At high doses promotes excretion
Oliguria & Hypokalaemia

Haematological
Bleeding, due to plt inhibition & irritation of gastric mucosa

Metabolic
Uncoupling of oxidative phosphorylation - high anion-gap metabolic acidosis (ketones & lactic acid)
May lead to hypo/hyper glycaemia

The metabolic acidosis worsens the toxicity further, promoting unionisation and therefore further distribution into the CNS, as well as renal re-absorption.

Lethal dose of aspirin may be as low as 150mg/kg

Question 6

Discuss management of Aspirin toxicity

Answer 6

Recognition
History - Differentials (pneumonia, meningitis & sepsis)
Treatment
ABC approach, and use a guideline (such as ToxBase)

Airway & breathing - if intubation required, hyperventilate to counteract acidosis - aim for blood pH 7.5

Circulation - Likely severe dehydration - give cool IV fluids to correct hypovolaemia & pyrexia.
If pH < 7.5, consider isotonic bicarbonate.
Use plasmalyte & hartmann’s if pH > 7.5
0.9% NaCl will worsen acidosis

Disability - measure and correct glucose, and monitor GCS if not intubated. Consider IV dextrose if symptomatic, even if normal BM.

Specific considerations
Measure salicylate level, and correlate with time of ingestion if possible.
Correct acidosis as soon as possible, reducing the effective dose of aspirin.
Consider activated charcoal if >150mg/kg ingested within past hour
Urinary alkalinisation with sodium bicarbonate to increase renal excretion - give 50ml 8.4% bicarbonate over 10 minutes, repeated as necessary, aiming for urinary pH >7.5, and replace potassium as needed

Haemodialysis indications
Neurological symptoms/pulmonary oedema
pH < 7.2
High salicylate level (>7mmol/L)