14) NSAIDs Flashcards by Oliver Blake

What are the primary therapeutics effects of NSAIDs?

Analgesia, anti-inflammatory, antipyretic

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Give some examples of autocoids:

Bradykinins, histamine, cytokines and leuckotrienes

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What are the features of eicosanoids?

Localised release

Short half life

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What are eicosanoids derived from?

Arachidonic acid

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Give some examples of eicosanoids:

Prostaglandins
Prostacyclins
Thromboxanes

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How are prostaglandins synthesised?

Cyclo-oxygenase enzymes

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What prostaglandin is most important in mediating the inflammatory response and what is its effect?

PGe

Vasodilation, hyperalgesia, fever, immunomodulation

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Describe the features of COX1 (including production):

Constitutively expressed in a wide range of tissues

Short half life

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Where is COX1 commonly found?

Gastric mucosa, myocardium, renal parenchyma

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Describe the features of COX 2 (including production):

Induced by inflammatory mediators

Constitutively expressed in brain and kidney

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How do the structures of COX1 and 2 allow for selective inhibition?

COX1 has a ‘tight’ tunnel for arachidonic acid, whereas COX2 is ‘baggy’

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Describe the binding of prostaglandins and their effects at the receptor:

Bind with GPCRs - synthesis of autocoids, potent vasodilators and peripheral nociception

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Where does PGE2 bind in the periphery?

C fibres by EP1 receptor

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What is the effect of PGE2 binding in C fibres?

Increased C fibre activity by increased sensitivity to bradykinin

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What is allodynia?

Triggering of pain from stimuli that don’t usually provoke pain

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What is hyperalgesia?

Increased pain from a stimulus that usually provokes pain

Where does PGE2 bind centrally, and what’s its effect?

EP2 receptors - increase sensitivity and discharge rate of secondary interneurones

How do prostaglandins cause pyrexia?

IL-1 release by macrophages causing production of PGE2 in hypothalamus that acts on EP3 to cause increased heat production

Describe the pharmacokinetics of NSAIDs:

First order elimination
Half lives can vary
Heavily plasma protein bound

When are NSAIDs indicated?

MSK disorders for mild-moderate pain

When are renal adverse effects from NSAIDs common?

Heart failure
Renal disease
Hepatic cirrhosis
Hypovolemia

What are some common GI adverse effects of NSAIDs?

Stomach pain, nausea, heartburn, gastric bleeding, ulceration

Why do NSAIDs cause GI side effects?

Gastric prostglandins stimulate mucus production

What are some common renal adverse effects of NSAIDs?

Sodium, potassium, chloride and water retention - hypertension

Why do NSAIDs cause renal side effects?

Decrease renal perfusion, usually maintained by prostaglandins

What are some other adverse effects of NSAIDs (not renal/GI)?

Increased bleeding time Skin rashes - Stevens Johnson syndorme Bronchial asthma Reye's syndrome

What drugs can NSAIDs displace?

Sulphonylureas Warfarin Methotrexate

What is the mechanism of action of aspirin?

Irreversibly inhibits COX enzymes by acetylation

Describe the pharmacokinetics of aspirin:

Half life is short | High doses - zero order elimination

What are some added beneficial effects of aspirin?

Reduces platelet aggregation | May reduce risk of GI and breast cancers

What are the effects of paracetamol?

Mild/moderate analgesia and antipyrexial

What are the potential mechanisms of action of paracetamol?

Weak COX1+2 inhibitor | Metabolite can bind with arachidonic acid

When is paracetamol contraindicated?

Compromised hepatic function | Chronic alcoholics

How is paracetamol usually metabolised?

Phase II conjugation by glucoronide and sulphate | Some phase I oxidation into NAPQI

Describe the metabolism of paracetamol in overdose:

Phase II saturated so build up of NAPQI which can't be removed due to glutathione depletion

What are the effects of paracetamol overdose?

Necrotic hepatocyte death | Renal failure

What is the treatment plan for someone with paracetamol overdose?

If within 4 hrs: activated charcoal orally 0-36 hrs - N-acteylcysteine IV Methionine oral if NAC can't be given promptly