Lecture 15 - NSAIDs Flashcards
What are the different types of prostanoids?
Prostaglandins, prostacyclin and thromboxanes
Why type of production are prsotanoids done under?
Produced locally and on demand
What is the name of the prostanoid PGI2?
Prostacyclin
What is therapeutic benefit of prescribing NSAIDs?
They inhibit the down stream products of arachidonic acid
What types of acid is arachidonic acid mainly derived from?
Dietary linoleum acid
What are the half lives of prostanoids like?
Short half-life
What is the normal function of prostacyclin (PGI2)?
Inhibts platetl aggregation since PGI2 binds to. Platelet. Receptors increasing cAMP levels in platetls
How do Prostacylins (PGI2) and TXA2 (Thromboxane A2) typically affect the CVS?
PGI2 = cytoprotective ofCVS
TXA2 = bad for CVS
What does Thromboxane A2 do ?
Leads to platelet aggregation
Why is PGE2 and prostacyclin (PGI2) improtant to the GI tract?
PGE2 contributes to Regualtion of acid secretion in parietal cell
PGI2 contributes to maintenance of blood flow and mucosal repair
How are prostanoids signalled?
They have many receptors and differential expression in tissues and repsonse (Many GPCR)
Have fine local control
What substances often enhance the action of prostanoids?
Local autocoids like Bradykinin and HIstamine
What 2 types of prostanoids do we need to carefully balance and why?
PGI2 (prostacyclin) and Thromboxane A2
they have a posing vascular effects
Fine balance between haemodynamic and thrombogenic control
What do we increase risk of. If imbalance in TXA2 and PGI2?
Hypertension
MI
Stroke
What are the benefits of the Mediterranean diet?
More conversion of Thromboxane A3 to PGI3 which is a better prsotnatooid
What do NSAIDs inhibit?
Cyclooxygenase enzymes (COX enzymes)
Where are COX1 and COX2 located?
COX1 = across most tissues
COX2 = indibcle mostly in chronic inflammation in brain, kidney and bone
What are the main effects NSAIDs do?
Analgesia
Anti-inflammatory
What is the mechanism of action of NSAIDs?
What do they compete with?
Inhibition of COX enzymes leading to reduced prostaglandins (prostacylins and Thromboxane synthesis)
Compete with arachidonic acid for hydrophobic site of COX enzymes
What are some common NSAIDs?
Naproxen
Ibuprofen
Celecoxib
How do NSAIDs act as analgesics?
Reduces peripheral pain fibre sensitivity by BLockinng PGE2 (Prostaglandins)
What is the pathway for NSAIDs acting as analgesics?
Reduced PGE2 (prostaglandin) synthesis in dorsal horn of cord
Dec neurotransmitter release
Reduced excitability of neurons in pain relay pathway
How do NSAIDs act as antiflammtories and act against oedema?
Prostaglandins lead to vasodilation and oedema (NSAIDs reduce prostaglandins) so less vasodilation so less increased capillary permeability and less local swelling
Do NSAIIDss efffet the chronic condition?
No just symptomatic relief
How do NSAIDs act as antipyretics?
PGE2 is key in the Thermoregulation centre in the thalamus
Inhibits hypothalamic COX2 where cytokine induced prostglandin synthesis is elevated results in reduction in temperature
what are some examples of pyrogens (cytokine)?
IL-1
IL-6
Why do selective COX2 inhibitors have fewer ADRs?
They have much greater selectivity than COX1 at therapeutic doses
What are all of the NSAIDs in order from most COX2 selective to COX1 selective?
Etoricoxib
Celecoxib
Diclofenac
Naproxen
Ibuprofen
Aspirin (LOW DOSE)
What is the suffix to NSAIDs that are specific to COX2?
-Coxib
Celecoxib
Etoricoxib
What part of the body to NSAIDs most commonly cause ADRs in ?
GI system
What are the ADRs for NSAIDs on the GI tract?
Dyspepsia
Nausea
Peptic ulceration
Bleeding and perforation
INC RISK OF GI BLEED
Why do NSAIDs often cause GI problems as ADRs like Peptic ulceration, bleeding and dyspepsia?
They decrease mucus and bicarbonate secretion leading to increased acid secretion
Decreased mucosal blood flow leads to enhanced cytotoxicity and hypoxia
What are contradinnidcataions of NSAIDs?
Elderly (Bleeds)
Prolonged use
Smoking
Alcohol
Hx of peptic ulceration
Helicobacter pylori infection (inc acid production)
What are the contraindications to NSAIDs?
Aspirin
Glucocorticoid steroids
Anticoagulants
What drug should also be prescribed with NSAIDs?
Proton Pump INhibtors (Omeprazole)
What are the renal adverse affects of NSAIDs?
Reversible reduced GFR and renal blood flow
What are the contraindications to NSAIDs when considering the kidneys?
CKD
Heart failure
So anytime theres greater reliance on prostaglandins for vasodilation and renal perfusion
Why are NSAIDs bad for the kidneys?
Prostaglandins vasodilates the afferent Arterioles so inhibiting prostaglandins means reduced GFR leading to increased H20 Na+ and therefore BP in the body
Prostaglandins inhibit sodium absorption
What are the drug tot drug interactions from NSAIDs whine considering the kidneys?
ACEi
ARBs
Diuretics
Why are ACEi and ARBs with NSAIDs bad?
NSAIDs = less prostaglandins so afferent arterial constricted
ACEi and ARBs means efferent areteriole dilates
What is the danger of using selective COX2 inhibtors??
Inhibit PGI2 so doesn’t have antiplatelt action
So the balance between levels of TXA2 and PGI2 lost, More TXA2 made by COX1 so more platelet aggregation
ALL NSAIDS INCREASE risk of MI
What are the 2 selective COX2 inhibtors?
Celecoxib
Etoricoxib
Why do NSAIDs often affect the concentrations of other drugs in the body?
Have a very high affinity for transport proteins so displace most other drugs leading to the free concentration of that dis[placed drug increasing
What drugs do NSAIDs increase the plasma concentration of?
Sulfonylurea
Methotrexate
Warfarin
What is the side effect of NSAIDs displacing sulfonylureas leading to their increased plasma concentration?
Hypoglycaemia
What is the side effect of NSAIDs displacing methotrexate leading to their increased plasma concentration?
Accumulation and hepatotoxicity
What is the side effect of NSAIDs displacing warfarin leading to their increased plasma concentration?
Increased risk of bleeding
What are some situations you should be careful of giving NSAIDs for?
Cardiovascular disease risk
Renal function
GI disease
ACEi, ARBs, Diureitcs, methotrexate and warfarin
Third trimester of. Pregnancy (early closure of ductus arteriosus and delayed labour)
What are the indications for using NSAIDs?
Inflammatory conditions
Osteoarthritis
Postoperative pain
Topical use of cornea
Menorrhagia
Low o dose aspirin for platelet aggregation inhibition
Opioid sparing when used in combination
What is paracetamol used for?
Moderate analgesia
Fever (Antipyretic)
Why does paracetamol have few affects on platelets and limited effect on GI?
Its selective to COX-2 in the CNS
What inactivates Paracetamol?
Conjugation in the liver
What is the toxic highly reactive metabolite of paracetamol?
NAPQI
What is the pathway of a paracetamol overdose?
GSH needed to convert NAPQI into its safe metabolite in Phase 2 liver metabolism
Eventually GSH depleted and NAPQI builds up leading to cell necrosis (NAPQI nucleophilic)
What are the symptoms of a paracetamol overdose?
Nausea, vomiting and abdominal pain in the first 24h
Mex liver damage at 3-4 days
What is the cure for a paracetamol overdose?
IV Acetylcysteine
How does IV Acetylcysteine work to cure a paracetamol overdose?
Replenishes Glutahione thione (GSH) so NAPQI can be Phase 2 metabolised to a safe product
Why cant you just give glutathione in a paracetamol overdose?
GSH cant get into hepatocytes but Acetylcysteine can
