What are the effects of prostanoid PGI2? (prostacyclin)

Inhibits platelet aggregation Vasodilation Affects endothelium of kidney and brain

NSAIDs Flashcards by Katie Wilkinson

What are the 2 different pathways arachidonic acid can follow?

Lipoxygenase pathways

Prostanoids

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What are the effects of prostanoid thromboxane A2?

Platelet aggregation
Vasoconstriction
Affects macrophages

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What are the effects of prostanoid PGI₂? (prostacyclin)

Inhibits platelet aggregation
Vasodilation
Affects endothelium of kidney and brain

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When are prostanoids produced?

Prostanoids are produced on demand by different enzymes

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Where is arachadonic acid derived from?

Linoleic acid (vegetable oils)

Converted hepatically to arachidonic acids and incorporated into phospholipids

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Where is arachadonic acid mainly found within the body?

Found throughout but main sites; brain, muscle and liver

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Which prostanoid is generally good for the stomach?

PGE₂

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Which prostanoid causes pain, inflammation and pyrexia?

PGF 2-alpha

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Which prostanoids are cytoprotective for the CVS and which are generally bad for the CVS?

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What are the 2 isoforms of cycloxygenase and when is each active?

COX-1 is constitutively active across most tissues

COX-2 is inducible in chronic inflammation. constitutively active in brain, kidney & brain

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How do COX -1 and COX -2 differ structurally?

COX 2 has a larger, more flexible substrate channel where inhibitors can bind

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What are the homeostatic functions of COX 1 and COX 2?

COX 1:

GI protection (PGE₂)
Platelet aggregation
Vascular resistance

COX 2:

Renal homeostasis
Tissue repair and healing
Reproduction (uterine contractions)
Inhibition of platelet aggregation

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What are the pathological functions of COX 1 and COX 2?

COX 1:

Chronic inflammation
Chronic pain
Raised blood pressure

COX 2:

Chronic inflammation
Chronic pain
Fever
Blood vessel permeability
Tumour cell growth

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What type of receptors do prostanoids acts on?

GPCR mediated receptors

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How does a diet rich in fish oils (omega fatty acids) cause lower incidence of cardiovascular disease?

Omega acids convert TXA₃ → PGI₃

A form of prostanoid that’s better for the CVS

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What is the single common mode of action of NSAIDs?

Inhibition of COX enzyme (either 1,2 or both)

Decreases prostaglandin, prostacylin and thromboxane synthesis

How do NSAIDs provide analgesia?

Block PGE₂ synthesis in the dorsal horn which reduces peripheral pain fibre sensitivity
reduced neurotransmitter release
reduced excitability of neurones in pain relay pathway

When do the analgesic effects of NSAIDs have the greatest effect?

Greatest efficacy if inflammed
Efficacious after first dose but full effect comes after several days dosing

How do NSAIDs exert their anti-inflammatory effects?

Without NSAIDS, COX activity causes prostaglanding release → vasodilation and oedema

Vasodilation in post capillary venules causes local swelling

With NSAIDs this is inhibited → relief is symptomatic won’t affect chronic underlying condition

How do NSAIDS exert their antipyretic effects?

PGE₂ affects the thermoregulatory centre in they hypothalamus
Inhibition of hypothalamic COX-2 reduces temperature

Which form of COX inhibition has more adverse drug reactions?

COX 1 inhibition leads to greater ADR

Which NSAIDs are more selective for COX 1 vs COX 2?

What is the most common ADR for taking NSAIDs?

GI disturbance:

Dyspepsia
Nausea
Peptic ulceration
Bleeding
Perforation

How do NSAIDs cause GI disturbances?

Cause decreased mucus and bicarbonate secretion
Increase acid secretion
Decrease mucosal blood flow
Causes enhanced cytotoxicity and hypoxia

In which patients would you use NSAIDs with caution due to their GI risk?

* Elderly * Prolonged Use * Glucocorticoid steroids (need to give PPI alongside) * Anticoagulants * Smokers * Alcoholics * History of peptic ulceration * Patients with *Helicobacter Pylori*

How do NSAIDs cause ADRs with the kidney?

* NSAIDs produce **reversible** decrease in **GFR** and **Renal Blood Flow** * In a healthy person at therapeutic doses - less issues * ADR more likely in underlying CKD, heart failure ( have a greater reliance on prostaglandins for vasodilation and renal perfusion)

Why can NSAIDs counterbalance the effects of anti-hypertensives when given together?

Prostaglandins **inhibit Na⁺ absorption** at the collecting duct → naturesis When giving NSAIDs action is inhibited→ Na⁺ **is absorbed**, increases Na, H₂O and BP

Name 2 NSAIDs that are selective for COX-2

Celecoxib Etoricoxib

What are the effects of using a selective COX-2 inhibitor?

* Less GI ADR * Do not share antiplatelet action but **inhibit PGI₂** leading to potentially **unapposed** aggregatory effects of **TXA₂** * Some evidence that they are less analgesic

How do NSAIDs affect protein binding?

NSAIDs can **displace other bound drugs** → increases free drug concentration of other drugs * sulfonylurea → hypoglycaemia * methotrexate → accumulation and hepatotoxicity, leucopenia * warfarin → increased risk of bleeding Likely **dose adjustment needed**

When would you consider using NSAIDs?

* Inflammatory conditions (joint and soft tissue) * Osteoarthritis * Post op pain * Menorrhagia * Topical use on cornea * Low dose aspiring to inhibit platelet aggregation * Cancer reduction (reduced cell proliferation by reducing nuclear transcription factors)

When would paracetamol use be indicated?

For mild to moderate analgesia and fever

How does paracetamol cause toxicity in overdose?

* At normal therapeutic doses toxic metabolite **NAPQI** is conjugated with **glutathione** * But... hepatic glutathione is **limited** * In overdose, supply is used up and NAPQI is increased * NAPQI is highly nucelophilic and oxidises key metabolic enymes → ultimate cell death

Why can't you give glutathione to help with paracetamol overdose?

Glutathione **does not get absorbed** into hepatocytes

What symptoms occur in paracetamol overdose?

* Can be asymptomatic for many hours * Nausea, vomiting and abdominal pain first 24 hours * Maximal liver damage 3-4 days

What drug can you give for paracetamol overdose?

N-Acetylcysteine given i.v. Replaces glutathione levels driving phase 2 reactions