NSAIdS

Question 1

What are prostanoids?

Answer 1

Prostanoids are a subclass of eicosanoids consisting of the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes (mediators of vasoconstriction), and the prostacyclins (active in the resolution phase of inflammation.)

Produced locally on demand depending on different enzymes, short t1/2, fine control

Signal through many GPCRs with differential expression in tissues and response

Question 2

How are eicosanoids e.g. prostanoids + leucotrienes synthesised? How do NSAIDS stop this?

Answer 2

Phospholipids (phospholipase A2) -> arachidonic acid 
Lipoxogenase pathways (make leucotrienes) OR 
-> cyclooxygenase pathways (COX-1/2) -> prostanoids 

NSAIDS inhibit COX1 or COx2

Question 3

List the 5 main prostanoids and state their functions

Answer 3

PGE2 - GI mucosa, protection, uterine contraction, brain (good for stomach)

PGF2a - bronchocontrictor, uterine contraction

PGD2 - bronchoconstrictor, inhibits platelet aggregation

Above 2 both cause pain/ pure is/ inflammation

PGI2 (prostacyclin) - inhibits platelet aggregation, vasodilation, endothelium, kidney, brain = cytoprotecive CVS

TXA2 (thromboxane) - platelet aggregation, vasoconstrictor, macrophages, Kidneys = generally bad for the CVS

Fine balance between 2 above

Question 4

Compare the two functional isoform cyclooxygenase enzymes COX-1 and COX-2

Answer 4

COX-1 (main one) - constitutive,y active across most tissues, GI protection, platelet aggregation, vascular resistance, chronic inflammation, chronic pain, raised BP

COX-2 - inducible, mostly in chronic inflammation, brain/ kidney/ bone, renal homeostasis, tissue repair and healing, reproduction uterine contractions, inhibition platelet aggregation, chronic inflammation, chronic pain, fever, Bv permeability, tumour cell growth
Slightly bigger substrate channel

Question 5

How can prostanoids actions be enhanced?

Answer 5

By local autacoids including bradykinin and histamine

Question 6

How can a diet rich in fish oils help prevent CVD?

Answer 6

Fatty acids can then by converted to thromboxane and PGI3 - better prostanoids

Question 7

How do NSAIDS generally work?

Answer 7

Varying antipyrexial, analgesic, anti- inflammatory properties

Inhibition of COX reduces prostaglandin, prostacyclin, thromboxane

Competes with arachidonic acid for site of COX (competitive inhibitor)

Question 8

How do NSAIDS have an analgesic action?

Answer 8

Local peripheral action at site of pain - greater efficacy if inflamed

Decreased PGE2 synthesis in dorsal horn - less neurotransmitter release - less excitation of neurones in pain relay pathway

Full analgesia after several days dosing

Question 9

How do NSAIDS produce an anti-inflammatory action?

Answer 9

NSAIDS inhibit: prostaglandin production, vasodilation, oedema, decrease ROS by oxygen scavenging properties

Question 10

How do NSAIDs perform antipyretic action?

Answer 10

PGE2 critical component in preoptic area of hypothalamus - thermoregulatory centre

Can be stimulated by pyrogens e.g. cytokines

Inhibition of hypothalamic COX-2 so prostaglandins don’t increase the set point in the thermoregulatory centre

Question 11

List some examples of NSAIDS from increasing CoX- 1 selectivity to increasing CoX-2 selectivity

Answer 11

Aspirin - only COX1*
Inbuprofen
Naproxen
Diclofenac

*Only COX-2:
CeleCOXIB
etoriCOXIB

*as increase dose becomes less selective

Question 12

What’s the most common adverse NSAIDs reaction? How is it caused? Cautions

Answer 12

GI - dyspepsia, nausea, Peptic ulceration, bleeding, perforation

Decreased mucus/ bicarbonate, increased acid secretion, decreased mucosal blood flow enhanced cytotoxicity and hypoxia

Exacerbations of IBD, local irritation and bleeding from rectal administration

Cautions: elderly, glucocorticoid steroids, anticoagulants, smoking, alcohol. History peptic ulceration, helicobacter pylori

Question 13

How do NSAIDs cause renal ADRs?

Answer 13

Reversible decrease GFR/ renal blood flow

More likely in underlying CKD/ heart failure

V young/ elderly at risk

Question 14

How can NSAIDs increase BP?

Answer 14

Prostaglandins inhibit Na absorption in collecting duct - natriuresis (NSAIDs inhibit so increase Na/ H20)

Question 15

Benefits and cons of COX-2 inhibitors

Answer 15

Avoid inhibition of homeostatic actions mediated by COX-1, less GI/ renal ADRs
Useful in severe osteo/ rheumatoid arthritis

❌impair PGI2 potentially unopposed aggregators effects, less analgesic

Question 16

How can NSAIDs increase free drug concentrations?

Answer 16

NSAIDs are highly protein bound so can displace other protein bound drugs

E.g. sulfonylurea used for hypoglycaemia, methotrexate (hepatotoxicity, leukopenia RA)

Warfarin - risk of bleeding increased

Competitive displacement so dose adjustment needed

Question 17

Indications for NSAIDs

Answer 17

Inflammatory conditions - joint and soft tissues
Osteoarthritis 
Postoperative pain 
Cornea
Menorrhagia
Platelet aggregation inhibition 
Opioid sparing 
Cancer reduction

Question 18

What does paracetamol do? How does it work do we believe?

Answer 18

Non- NSAID, non-opiate analgesic with antipyreixal action

COX-2 selective inhibition in CNS - decreased pain signals to higher centres

t1/2 2hrs, predominantly inactive by conjunction in liver

In many OTC drugs

Question 19

What is NaPQI? How do we get rid of it?

Answer 19

Highly reactive paracetamol metabolite - binds covalently to thiol groups and inactivates cellular proteins
-> necrosis and apoptosis

150mg/kg sufficient cause irreversible damage (12 tablets small person)

Hepatic glutathione breaks it down to eventually become acetylcysteine conjugate excreted I’m urine but glutathione limited

Question 20

Symptoms of paracetamol overdose and treatment

Answer 20

Can be asymptomatic hours - nausea, vomiting, abdo pain (first 24hrs), maximal liver damage 3-4days

✅glutathione thiol replacement - IV N-acetylcysteine (glutathione doesn’t get absorbed into hepatocytes)

✅activated charcoal only if v recent if not can impede other drugs

Bloods >4hrs show extend of overdose