NSAIDs Flashcards
Briefly describe the process of eicasanoid synthesis
Phospholipids–>Arachidonic acid–>Prostanoids
What are some of the enzymes involved in the eicosanoid synthesis?
COX enzymes
Cell specific syntheses/isomerase
Give examples of prostanoids
PGE2 PGF2 PGD2 PGI2- prostacyclin TXA2- thromboxane
What are some features of prostanoids?
Produced locally on demand
What are some features of the enzymes involved in prostanoid synthesis?
Short half life and fine control
What do the therapeutic benefits of prescribing NSADIs come from?
From inhibition of down stream products of arachidonic acid
Why do adverse effects form?
Also from the inhibition of the downstream pathway
Where is arachidonic acid derived from?
Primarily from linoleum acid- vegetable oils
How is linoleum acid converted to arachidonic acid?
Hepatically converted to arachidonic acid and then incorporated into phospholipids
Where is arachidonic acid found in the body?
Everywhere, in particular muscle, brain and liver
What are the functions of proastacyclin?
Inhibits platelet aggregation Vasodilator Endothelium Kidney Brain
What is the overall effect go prostacyclin on CVS?
Cytoprotective
What are the functions of thromboxane?
Platelet aggregation
Vasoconstictor
Macrophages
Kidney
What is the importance of interactions between prostacyclin and thromboxane?
Have a fine balance for vascular tone and platelet aggregation
Fine balance between haemodynamic and thrombogenic control
What are the two functional forms of cyclooxygenase enzymes?
COX-1
COX-2
What is the predominant COX enzyme?
COX-1, constitutively active across most tissues
Where is COX-2 inducible?
Mostly in chronic inflammation, constitutively in brain, kidney and bone
Give some examples of the homeostatic functions of COX-1
GI protection
Platelet aggregation
Vascular resistance
Give some examples of the homeostatic functions of COX-2
Renal homeostasis
Tissue repair and healing
Reproduction
Inhibition of platelet aggregation
Give some examples of the pathological functions of COX-1
Chronic inflammation
Chronic pain
Raised blood pressure
Give some examples of the pathological functions of COX-2
Chronic inflammation Chronic pain Fever Blood vessel permeability Tumour cell growth
How can drugs be targeted to just one type of COX enzyme?
COX 2 has a larger more flexible substrate channel than COX 1 and a larger space at the site of inhibitor binding which can be used as a target
What do prostanoids signal through?
Locally via GPCRs which are expressed in different amounts in different parts of the body
What does the specific action on the prostanoids depend on?
Depends on the receptor subtype and location
What can enhance the action of prostanoids?
Local autocoids
What are some examples of local autocoids?
Bradykinin
Histamine
Seratonin
What is the imbalance between thromboxane and prostacyclin?
Imbalance has a role in hypertension, MI and stroke
What are some examples of better prostanoids?
TXA3 and PGI3
Diet rich in fish oils
What foods can TXA3 and PGI3 be found in?
Mediterranean foods
What are the predominant uses of NSAIDs?
Analgesic and anti-inflammatory effects
What is the single common mode of action of NSAIDs
`inhibition of COX–> decrease in prostanoid synthesis
How do COX inhibitors work?
Compete with arachidonic acid for hydrophobic site for COX
How do NSAIDs have an analgesic effect peripherally?
Inhibition reduces peripheral pain fibre sensitivity by blocking PGE2 in the dorsal horn
How do NSAIDs have an analgesic effect centrally?
The central component is associated with PGE2 synthesis in dorsal horn–>Decreased NT release–>Decreased excitability of neurones in pain relay pathway to higher centres
Which dose is most efficacious?
First dose has efficacy but full analgesia after several dosing
How do NSAIDs have an anti-inflammatory effect?
NSAIDs inhibit vasodilation in post capillary venues to increase permeability and local swelling
Also reduce production go prostaglandins released during injury
What is important to consider with NSAIDs and their anti-inflammatory effects?
Just symptomatic relief but COX inhibition
Describe the mechanism of pyrexia
Pyrogen–>Prostaglandins–? thermoregulatory centres–> Increases the set point f temoerature–> Patient is febrile
Where is the location of the thermoregulatory centre?
Preoptic area of the hypothalamus
What are some examples of pyrogens?
Cytokines
Interleukins e.g. IL-1 and IL-6
How do NSAIDs have anti-pyrexic effects?
Inhibits hypothalamic COX-2 where cytokine induces prostaglandin synthesis election results in reduction of temperature
What do neither COX inhibitors have?
Neither have direct action on leukotrienes but do have indirect action through PGE2
State a list of COX inhibitors
Aspirin Ibuprofen Naproxen DIclofenac Celecoxib Etoricoxib
What are some example pf the most COX-1 selective drugs?
Aspirin
Ibuprofen
Naproxen
What are some example pf the most COX-2 selective drugs?
Etoricoxib
Celecoxib
What are the most common ADR’s of NSAID’s?
GI including
Dyspepsia, nausea, peptic ulceration, bleeding and perforation
What is the mechanism of action that NSAIDs have on GI
Decreased mucus and bicarbonate secretion–> Increased acid secretion
Decreased mucus blood flow–> enhances cytotoxicity and hypoxia
What should you be cautious of in terms of GI ADRS
Elderly Prolonged use Glucocorticoid steroids Anticoagulants Smoking Alcohol History of peptic ulceration H. Pylori
Which of the 2 COX inhibitors has lower GI risks?
COX-2
What effect does NSAIDs have on the kidney
Decreased GFR, decreased renal blood flow
Who is most affected by NSAID renal ADRs?
People with underlying CKD or HF where there is a greater reliance on prostaglandins for vasodilation and renal perfusion
Very young and elderly
How do NSAID’s affect the arterioles?
NSAIDs prevent afferent vasodilation by inhibiting PGE2 and PGI2 therefore doesn’t attain the back pressure needed for renal function
How do prostaglandins affect absorption?
Prostaglandins inhibit Na absorption in the collecting duc- natriuresis- NSAIDs inhibit this acton- Increase Na, H20 and thus increase BP
Give examples of COX2 inhibitors?
Celecoxib
Etoricoxib
What was the initial intention of COX 2 inhibitors?
To avoid inhibition of homeostatic actions mediated by COX-1 with greater selectivity
What is the ADR profile of COX 2 inhibitors?
Less GI ADR
Similar renal ADR
Potential unopposed aggregator effects
Why are there COX 2 inhibitor potential unopposed aggregatory effects?
Do not share anti=plataelt action but impair PGI2 potentially
What effect does NSAIDs have on other drugs?
Displace other bound drugs, increasing free drug concentration that can have effects
What are the particular DDI’s to be aware of and its effects?
SUlfomylurea- hypoglycaemia
Methotrexate- accumulation and hepatotoxicity, leukopenia and rheumatoid arthritis
Warfarin- Increased risk of bleeding
What is the displacement of bound drugs by NSAIDs known as?
Competitive displacement
What are the pharmacological implications of competitive displacement?
Like dose adjustment needed
Extra considerations and indications for NSAID use
Inflammatory conditions Osteoarthritis Postoperative Post-opertaive pain Topical use on cornea Menorrhagia Low dose aspirin for platelet aggregation inhibition Opioid sparing when used in contraindications
What are the uses of Paracetamol?
For mild to moderate analgesia and fever
What are the pharmacodynamics of paracetamol including the absorption and excretion?
Well absorbed from GI- t1/2 2 hrs
Predominantly inactivated by conjugation in the liver
What is NAPQI?
Highly reactive metabolites
How is NAPQI rendered harmless physiologically?
Glutathione conjugation
What is the problem with hepatic glutathione?
Hepatic glutathione is limited
What are the negative effects of NAPQI?
Highly nucleophilic- oxidising key metabolic enzymes which lead to cell death- necrosis and apoptosis
What dose of Paracetamol is enough to cause irreversible damage?
150mg/kg
What is the antidote for NAPQI accumulation?
N-acetylcysteine
Activated charcoal
What are the side effects of paracetamol overdose?
First 24 hrs?
3-4 days later?
24 hrs- nausea, vomiting and abdominal pain
3-4 days- maximal liver damage
What is the mechanism of action of N-acetylcysteine?
Replaces glutathione
