Lecture 15– Non-steroidal anti- inflammatory drugs Flashcards
prostanoid synthesis
- The therapeutic benefit of prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) is a result of inhibiting down stream products of arachidonic acid
- Most of the adverse effects of NSAIDs stem form the inhibition of this pathway too
- Arachidonic acid derived primarily from dietary linoleic acid – vegetable oils converted hepatically to arachidonic acid and incorporated into phospholipids
- Found throughout the body – particularly in muscle, brain, liver and kidney
- Prostanoids are prostaglandins, prostacyclin and thromboxane’s
- Prostanoids are produced locally on demand – different enzymes, different prostanoids, short half lives so fine local control
Prostanoids are
prostaglandins, prostacyclin and thromboxane’s
PGE2
Prostaglandin E2
maintains GI system (good stomach health)
- regulates acid secretion in parietal cells
PGE3,PGF21, PGD2 responsible for
Pain pyrexia inflammation
PGI2
prostacyclin released by healthy endothelium to prevent platelet aggregation- increases cAMP, decreases calcium
- Cytoprotective CVS
- Also contributes to maintenance of blood flow and mucosal repair (good for GI)
TXA2
thromboxane A2 - most potent endogenous platelet aggregatory factors (secreted in granules from platelets leading to activation of other platelets via TXA2 receptors
- Generally bad for the CVS (e.g. platelet aggregation)
fine balance between ……. and …… in terms of CVS health
PGI2 (anti-platelet aggregation) and TXA2 (pro-platelt aggregation)
Prostanoids signal through many GPCRs
Results in different reactions in different tissues
prostanoid summary
- Types: PGE2, PGF2α, PGD2, PGI2 (prostacyclin) and TXA2 (thromboxane)
- TXA2 and PGI2 have apposing vascular effects
- Fine balance between them crucial – haemodynamic and thrombogenic control
- Act locally at GPCRs specific action depends on receptor subtype and location
action of locqal………. can enhance prostanoid action
autacoids- histamine and bradykinin
Imbalance/disruption to prostanoids plays significant role in
hypertension, MI and stroke risk
Diet rich in fish oils (Ω fatty acids) – “The Mediterranean diet” proposed to
lead to conversion ofTXA3 to PGI3 – better prostanoids – lower incidence of CVD?
Cyclooxygenases
Controls conversion of arachidonic acid to various prostanoids
Two functional isoforms
2 isoforms of COX
COX-1 and COX-2
COX-1x
- COX-1- constitutively active across most tissues
COX-2
inducible (mostly)- in chronic inflammation. Constitutively in brain, kidney and bone
NSAIDS
- Widely prescribed as analgesic and anti-inflammatories
- Chemically dissimilar to each other resulting in varying antipyretic, analgesic and anti-inflammatory properties
NSAIDS single common mode of action
- inhibition of COX ↓prostaglandin, prostacyclin and thromboxane synthesis (which is good and bad)
- Compete with arachidonic acid for hydrophobic site of COX enzymes – COX enzyme inhibitors
COX-1 and COX-2 present in different amounts in
different tissues
NSAIDS- analgesia
- Local peripheral action at side of pain- greater efficacy if tissue inflamed
- Inhibition reduces peripheral pain fibre sensitivity by blocking PGE2 (causes pain)
- Most effective after several days dosing
NSAIDs- antipyretic
Add
- PGE2 is a critical component in the preoptic area of the hypothalamus - thermoregulatory centre
- Can be stimulated by pyrogens e.g. cytokines
- Inhibition of hypothalamic COX-2 where cytokine induced prostaglandin synthesis is elevated results in a reduction in temperature
NSAID- anti-inflammatory
- During inflammation ↑COX activity → prostaglandin mediated increase in vasodilatation and oedema
- NSAIDs reduce production of prostaglandins released at site of injury
- Vasodilation in post capillary venules contributes to increased permeability and local swelling- NSAIDs inhibit this
- Symptomatic relief with COX inhibition – little effect on underlying chronic condition (wont cure just helps with inflammation)
other anti-inflammatory actions of NSAIDS
- Other MOAs - Reduction in other anti-inflammatory mediators independent of COX may be associated with some effects ↓reactive oxygen species by oxygen scavenging properties?
- link to possible reduction in some cancers?
NSAIDS can be differentiated by their
- selectivity e.g. for COX-1 or COX-2
- E.g. low dose aspirin favours COX-1
what has lead to the development of selective COX-2 inhibitors
- High prevalence of ADRs attributable to COX-1 led to selective COX-2 inhibitors (coxibs)
- COX-2 selective compounds inhibit COX-2 with much greater selectivity than COX-1 at therapeutic doses (if higher than this would also work on COX-1) e.g. celecoxib and etoricoxib
- Non-COX-2 selective compromise all other NSAIDS
- COX-2 selective compounds inhibit COX-2 with much greater selectivity than COX-1 at therapeutic doses (if higher than this would also work on COX-1) e.g. celecoxib and etoricoxib
Gastrointestinal complications- most common ADR
- Most common ADR
- Dyspepsia
- Nausea
- Peptic ulceration
- Bleeding
- Perforation
- Exacerbation of IBD
Gastrointestinal complications- contraindications
- Elderly
- Prolonged use
- Smoking
- Alcohol
- History of peptic ulceration
- H. pylori
GI complications - DDI
- DDI
- Aspirin
- Glucocorticoid steroids
- Anticoagulation (PPI should be considered)
- MOA of GI problems
- Decrease mucus and bicarbonate secretion
- Increase acid secretion
- Decreased mucosal blood flow–>enhanced cytotoxicity and hypoxia
Renal considerations- ADRs
*
- NSAIDs produce reversible decrease in GFR and decreased renal blood flow due to reduced amounts of PGE2/PGI2 which causes vasodilation
- Therapeutic dose in healthy person- less issue
- Concern with chronic use and people with CKD
- Prostaglandins inhibit sodium absorption in the collecting duct- natriuresis- NSAIDS inhibit this action therefore increase in
- Sodium
- Water
- BP (5mmHg)
renal considerations- contraindications
- CKD
- Heart failure
- Both due to decrease in GFR
Renal considerations- DDIs
- ACEi
- ARBs
- Diuretics
renal consideration summary
Selective COX-2 inhibitors
e.g. Celecoxib and etoricoxib
The intention of COX-2 inhibitors was to avoid inhibition of homeostatic actions mediated by COX-1 – reducing GI ADRs
- Less inhibitory action on COX-1 but selectivity for COX-2 varies among drugs
- Less GI ADRs, renal ADRs similar to non-selective
- Do not share antiplatelet action
- But inhibit PGI2 - potentially leading to unopposed aggregatory effects – CVS risk problem
- Some evidence of less analgesic effect
when are selective COX-2 inhibitors used
Can be useful when monitored in severe osteo and rheumatoid arthritis for longer term treatment – reduced GI side effects
- ALL NSAIDs increase risk of
- MI including in low risk people (↓PGI2 in coronary vasculature?)
- Reduced cycloprotective of the CVS by removing PGI2 etc
NSAIDs and protein binding
- NSAIDs displace other protein bound drugs- increasing free drug conc of other drugs
- Particularly high protein bound drugs e.g.
- sulfonylureas- hypoglycaemia
- methotrexate – accumulation and hepatotoxicity
- warfarin- increased risk of bleeding
- Particularly high protein bound drugs e.g.
- MOA= competitive displacement
- Likely dose adjustment needed and increase monitoring
Indication of NSAIDS
- Inflammatory conditions – joint and soft tissue
- Osteoarthritis – topical NSAID and paracetamol should be tried first
- Postoperative pain
- Topical use on cornea
- Menorrhagia (moderate reduction in blood loss)
- Low dose aspirin for platelet aggregation inhibition
- Opioid sparing when used in combination
- Cancer reduction – by up to 30 - 50% - nuclear transcription factors, reduced cell proliferation, inflammation……???
Contraindications of NSAID use
- Cardiovascular disease – risk
- Renal function - age
- GI disease - previous use of NSAIDs
- DDIs – ACEi and ARBs, steroids, diuretics, methotrexate, warfarin (not exhaustive list)
- Level of pain, pyrexia, level of inflammation
- Third trimester of pregnancy – not sustained use – delayed labour and early closure of ductus arteriosus
When prescribing NSAIDs consider…
LOWEST EFFECTIVE DOSE FOR THE SHORTEST TIME NECESSARY TAKING INTO ACCOUNT PATIENT SPECIFIC RISK FACTORS
paracetamol is neither a
NSAID or opiate
summary of paracetamol
- Analgesic and antipyretic action
- For mild to moderate analgesia and very useful in fever
- Generally well tolerated with fewer ADRs
- No effect on platelets and limited effect on GI
MOA of paracetamol
- Still not understood
- Activity may be mediated by COX-2 selective inhibition in CNS (spinal cord)- decreasing pain signals to higher centres
- Very little anti-inflammatory action
why does paracetamol have very little anti-inflammatory action
- Related to peroxidases
- Peroxide is important for the activity of paracetamol
In peripheral inflammation there is high levels of peroxidases which break down peroxide- therefore cant help with inflammation in peripheral tissue
Pharmacokinetics of paracetamol
- Well absorbed from GI
- T1/2 around 2.5 hours
- Inactivated by conjugation in the liver
NAPQI
- Reactive metabolite of paracetamol (phase 1 reaction)- some analgesic effect
- At normal therapeutic doses- conjugation with glutathione renders NAPQI harmless (Phase 2 reaction)
- HOWEVER hepatic glutathione is limited so if too much paracetamol is taken there is not enough glutathione to power the phase 2 reaction - toxic
paracetamol overdose caused by
limited amount of glutathione
- Therefore another reaction takes place
- NAPQI highly nucleophilic- oxidising key metabolic enzymes ultimately causing cell death- necrosis and apoptosis (particularly to the liver)
- 150mg/kg sufficient to cause irreversible damage
Paracetamol overdose
Paracetamol overdose
- Can be asymptomatic for many hours
- Nausea, vomiting and abdominal pain – first 24 hours
- Maximal liver damage occurs at 3-4 days
- Due to accumulation of NAPQI (not enough glutathione to power phase 2 reaction)
- Therefore NAPQI starts causing necrosis of cells esp in the liver
Paracetamol overdose treatment
- Activated charcoal- only of use if paracetamol overdose recently taken
- Lethionine (oral drug)
- Glutathione thiol replacement – IV N- acetylcysteine
N-acetylcysteine in treatment of paracetamol overdose
- Replaces glutathione
- Used when [paracetamol] conc in plasma is to the right of the curve line)
