NSAIdS Flashcards
What are prostanoids?
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
How are eicosanoids e.g. prostanoids + leucotrienes synthesised? How do NSAIDS stop this?
Phospholipids (phospholipase A2) -> arachidonic acid Lipoxogenase pathways (make leucotrienes) OR -> cyclooxygenase pathways (COX-1/2) -> prostanoids
NSAIDS inhibit COX1 or COx2
List the 5 main prostanoids and state their functions
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
Compare the two functional isoform cyclooxygenase enzymes COX-1 and COX-2
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
How can prostanoids actions be enhanced?
By local autacoids including bradykinin and histamine
How can a diet rich in fish oils help prevent CVD?
Fatty acids can then by converted to thromboxane and PGI3 - better prostanoids
How do NSAIDS generally work?
Varying antipyrexial, analgesic, anti- inflammatory properties
Inhibition of COX reduces prostaglandin, prostacyclin, thromboxane
Competes with arachidonic acid for site of COX (competitive inhibitor)
How do NSAIDS have an analgesic action?
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
How do NSAIDS produce an anti-inflammatory action?
NSAIDS inhibit: prostaglandin production, vasodilation, oedema, decrease ROS by oxygen scavenging properties
How do NSAIDs perform antipyretic action?
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
List some examples of NSAIDS from increasing CoX- 1 selectivity to increasing CoX-2 selectivity
Aspirin - only COX1*
Inbuprofen
Naproxen
Diclofenac
*Only COX-2:
CeleCOXIB
etoriCOXIB
*as increase dose becomes less selective
What’s the most common adverse NSAIDs reaction? How is it caused? Cautions
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
How do NSAIDs cause renal ADRs?
Reversible decrease GFR/ renal blood flow
More likely in underlying CKD/ heart failure
V young/ elderly at risk
How can NSAIDs increase BP?
Prostaglandins inhibit Na absorption in collecting duct - natriuresis (NSAIDs inhibit so increase Na/ H20)
Benefits and cons of COX-2 inhibitors
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
How can NSAIDs increase free drug concentrations?
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
Indications for NSAIDs
Inflammatory conditions - joint and soft tissues Osteoarthritis Postoperative pain Cornea Menorrhagia Platelet aggregation inhibition Opioid sparing Cancer reduction
What does paracetamol do? How does it work do we believe?
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
What is NaPQI? How do we get rid of it?
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
Symptoms of paracetamol overdose and treatment
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
