Lecture 17: NSAIDs and local anaesthetics Flashcards
What is an inflammatory response?
- the dynamic response of tissue to injury
- it is a protective response which serves to bring defense and healing mechanisms to the site of injury
What is the normal function of the inflammatory response?
- one which switches on and off.
- in diseased states this switch is broken so we require drugs to control this reaction in order to treat the symptoms
What are the causes of inflammation?
- microbial infections (bacterial, viral, fungal)
- physical agents (burns, trauma-like cuts, radiation)
- chemicals (drugs, toxins or caustic substances like battery acid.)
- immunological reactions (rheumatoid arthritis)
What are the 4 signs of inflammation?
- redness due to vasodilation
- swelling due to influx of plasma proteins, phagocytes, and other inflammatory cells into the site.
- heat due to local vasodilation and fever aimed to destroy pathogen
- pain due to local release of cytokines and increased tissue pressure
How can inflammation be controlled?
we can inhibit PG synthesis through the use of:
NSAIDs which target and block cyclooxygenase, (enzyme)
or glucocorticoids which prevents the conversion of phospholipid to arachadonic acid
What is the PG production pathway?
- phospholipids are converted into arachadonic acids.
- arachadonic acid is then converted into cyclic endoperoxidises by COX
- these will then form prostaglandins
What are the different functions of the prostaglandins?
PGA2- bronchoconstriction
PGD2- vasodilation
PGE2- increases gastric mucous and decreases gastric secretions. also involved in thermoregulation
PGI2- dilator and inhibits platelets
TXA2- activates platelets to increase pain
Why is COXII the ideal enzyme to target for NSAID drugs?
-Cox I is constructive and found in a lot of cells and involved in the formation of PGs with homeostatic roles while COXII is induced in inflammatory cells by specific stimuli and prostaglandins.
COX II has a major role in mediating inflammation, therefore it is the better anti-inflammatory target
What are NSAIDs?
- group of drugs of different chemical classes
- main functions are anti-inflammatory, analgesic and antipyretic
- normally they will target COX enzymes and bind irreversibly to the active site (aspirin is reversible)
- unwanted side effects stem from inhibition of COX I activity
What are the COXI specific drugs?
- aspirin
- indomethacin
- Sulindac
- piroxicam
Which NSAIDs bind less to COXI?
- ibuprofen
- paracetamol
- naproxen
Which NSAIDs bind equally to both COX enzymes?
- diclofenac
- keterolac
Which NSAIDs are COXII selective?
celecoxib
rofecoxib
valdecoxib
What are the desired effects of NSAIDs?
- analgesia: reduction of PG production
- antipyretic: Reduged PGE2 production in hypothalamus
- very strong anti-inflammatory effects
What are the undesired effects of NSAIDs?
- often stem from widespread, long term use
- dyspepsia, gastric ulceration, bleeding
- sometimes can cause skin reactions (rare)
- renal effects as PGs mediate afferent arteriole vasodilation
- inhibits platelets (mainly aspirin)
- exacerbation of asthma
What are the symptoms of aspirin toxicity?
- headache
- dizziness
- hearing impairment
- dimmed vision
- confusion and drowsiness
- sweating and hyperventilation
- nausea and vomiting
- disturbances in acid base balance
- fever
- dehydration
- CV or respiratory collapse
- coma, convulsions
- death
What is indomethacin?
- commonly causes adverse reactions like GI bleeds, ulceration, CNS reactions.
- can also cause depression, seizures, headaches and dizziness
- ibuprofen and naproxen are better and widely used for arthritis and will have fewer side effects
What is the cardiac risk of COX inhibitors and the example?
Vioxx was released into the market but had to be withdrawn as it was COXII selective and found there was a 4fold increased risk of heart attacks.
- due to inhibition of endothelium PGI2
- TXA2 production was not inhibited causing problems
- diclofenac is similar in the risk of CV events
- naproxen is the safest for the heart
What are the common drug interactions with NSAIDs ?
oral anticoagulatns + NSAIDs
lithium + NSAIDs
anti-hypertensive agents + NSAIDs
What is the drug interaction between oral anticoagulatns + NSAIDs?
- most cause increased risk of internal bleeding (e.g. warfarin)
- both drugs reduce platelet activity
- monitor using prothrombin time and for faecal occult test and urine test
- avoid concurrent use of aspirin
What is the interaction between lithium and all NSAIDs?
- lithium concentrations will be affected, increases risk of lithium toxicity
- need to monitor Li concentrations carefully
- these interactions are less likely to occur with aspirin than they are with naproxen or ibuprofen
What is the interaction between anti-hypertensives and NSAIDs?
- hyperkalaemia can occur with potassium sparing diuretics and ACE inhibitors
- antihypertensive effect is antagonised with NSAIDs
- need to monitor BP and cardiac function as well as K+ concentrations
- low dose aspirin (7.5mg/day) may not interact with ACE inhibitors
Why does diclofenac and warfarin cause serious internal bleeding?
- diclofenac plays a role in reducing platelet aggregation leading to poor clotting
- warfarin also induces poor clotting through reduction in vitamin K and hydroquinone in tissues.
- This also inhibits the Vitamin K dependent clotting factors (2, 7, 9, 10)
- stop the drug and change to safer drugs
What are anaesthetics?
- agents who reversibly block the conduction of APs in the nerve fibres when administered locally
- mostly esters/amides
- most modern agents are amides
