5. Analgesia - Aspirin/NSAIDs Flashcards
What is the ‘proper’ name for aspirin?
acetylsalicylic acid
What are the therapeutic activities of aspirin?
- anti-pyrexic
- anti-platelet/thrombotic
- anti-inflammatory
- analgesic - mild/moderate
What is the presentation and route of aspirin?
- white tablet
- dispersible form available
- not dissolvable in the mouth
What might happen if a patient puts an aspirin directly on their mucosa in their mouth etc?
aspirin burn - sloughing/ulceration of tissues (aspirin is acidic)
In terms of mechanism of action, what do aspirin and NSAIDs affect?
COX (cyclo-oxygenase) isoenzyme
- inhibition of COX-1, COX-2, COX-3
What does COX inhibition result in?
reduction in Eicosanoid (Prostanoid) production
- reduces the production of prostaglandin (PGE2), prostacycline (PGI2), thromboxane (TXA)
- leads to irreversible inhibition, hence the permanent action of aspirin on platelet aggregation
What are some of the actions of PGE2 (prostaglandin) and TXA (thromboxane)?
- Regulate BP
- Renal Effects
- Inflammatory response
- Duration & intensity of pain
- Fever
- Gastric effects
- Inhibits platelet aggregation and thrombosis
What mechanism does aspirin use to reduce the synthesis of COX products?
irreversible acetylation of COX enzymes
What does aspirin have more of an affect on, COX-1 or COX-2?
COX-1 > COX-2 (x100 greater effect on COX-1)
What kind of functions is COX-1 involved in?
physiological/homeostatic functions - COX-1 is constitutive
What kind of functions is COX-2 involved in?
inflammation - COX-2 is inducible
What stimulates COX-1 and COX-2?
What are the indications for aspirin?
- Acute pain
- Dental Pain
- Rheumatic fever
- Rheumatoid arthritis
- Other inflammatory disease
- Fever
- Acute coronary syndrome /ischemic stroke
- Anti-thrombotic
(MI, CVA, AF, Angina, Revascularisation after CABG, IHD, peripheral artery disease…..)
How does aspirin work as an anti-pyretic (reduce fever)?
infection/inflammation results in the release of cytokines, which reuslts in prostaglandins release in the hypothalamus which leads to a raised body temperature
aspirin inhibits prostaglandins —> reduces fever
How is aspirin absorbed?
by the GI, mainly small intensive (and stomach) and then quickly hydrolysed to salicylate
What is the half life of aspirin?
20-30mins
What is a normal dose of aspirin?
300-600mg - dose related efficacy, generally has a plateau effect up to about 1000mg
What is the half life of salicylate at anti-inflammatory doses?
~12 hrs
What is the % plasma binding of salicylate to albumin?
80-90%
How is aspirin’s distribution in the body?
widely distributed, crosses placenta, evident in breast milk
Where does aspirin undergo biotransformation?
in the liver via conjugation
How is aspirin excreted from the body?
by glomerular filtration and active proximal tubular secretion in the kidney, 10% is excreted unchanged
Why should aspirin be avoided in the 3rd trimester of pregnancy?
may cause premature closure of the ductus artereosis which could lead to pulmonary vascular abnormalities in the baby
What are the contraindications and side effects of aspirin?
- Gastrointestinal effects
- Respiratory –AERD
- Renal ( 3x increase Renal failure)
- CVS K+, HBP, Oedema
- Haematological
- Gout (increases uric acid)
- Tinnitus at higher doses.
- Skin reactions
- Glycaemic control
- Pregnancy (avoid in 3rd trimester)
What GI side effects can aspirin have?
- epigastric pain, dyspepsia and nausea
- occult stomach ulceration and bleeding (in potentially 70% of long-term users)
What respiratory side effects can aspirin have?
- bronchospasm (particularly asthma or those with hypersensitivity reactions to NSAIDs)
- urticaria
- angioedema
- rhinitis
- AERD - aspirin exacerbated respiratory disease
Why is aspirin contraindicated in congestive heart failure/what is the potential renal side effect?
if pt has congestive heart failure they may have reduced flow to the kidneys which may precipitate acute renal failure
In those with renal impairment how is the risk of renal failure impacted by NSAID used?
3x increased risk of renal failure compared to those not using NSAIDs
What CVS side effects can aspirin have?
- hyperkalaemia
- peripheral oedema
- elevated blood pressure
- decompensation of heart failure
What haematological contraindications does aspirin have?
effects platelets so avoided in congenital or acquired bleeding disorders e.g.
- haemophilia
- anticoagulant therapy
- liver disease
Why is aspirin generally avoided in gout?
as it increases uric acid concentrations in the blood, worsening gout
What doses of aspirin may cause hypoglycaemia?
higher doses, particularly over 5g/day
Why should NSAIDs be avoided in some renal issues?
inhibits the prostaglandins which are modulating blood flow in the kidneys, which can therefore reduce kidney perfusion and cause acute renal failure
some renal issues to avoid NSAIDs in:
- congestive heart failure
- nephrotic syndrome
- liver cirrhosis
- salt depletion
Why are GI issues common as a side effect of aspirin?
ulcerogenic properties related to the reduced prostaglandin production in the gastric mucosa
Why can prostaglandin inhibition cause GI issues?
the effects of prostaglandin are protective, and are essential for mucous secretion
prostaglandin inhibition:
- decreases mucous production
- increases acid production
- mediates bicarbonate
- influence cell permeability H+
- mucous layer less hydrophobic
Why should aspirin be avoided in children (under 16 in UK)?
Reye’s syndrome:
- generally presents with acute enphelophatic illness and fatty degeneration of the viscera especially the liver
- often occurs after infectious illness
- aetiology unknown
- mechanism likely due to damage to cellular mitochondria especially in the liver
What doses on aspirin can cause overdose, and why can it be fatal?
10-30g
Complex acid-base disturbances:
- CO2 in skeletal muscle presents as hyperventilation, hyperthermia and dehydration, tinnitus, deafness, vasodilations, and sweating
How are complex acid-base disturbances caused by aspirin overdose treated?
require hospitalisation to monitor pH, electrolytes and plasma salicylate, fluid replacement and bicarbonate tot balance, may require haemodialysis
What are the principle interactions with aspirin?
4 ANTS like aspirin - AAAANTS
- Anticoagulants
- Antihypertensives
- Antidepressants
- Anti-epileptics
- NSAIDs
- Thrombocytes (drugs that affect)
- Steroids (corticosteroids)
What can aspirin and anticoagulant interaction cause?
it may displace anticoagulants from their plasma bound state, increasing their effect
e.g. warfarin only has around 3% non-plasma bound exerting its action, increasing this can cause fatal bleeding
What can aspirin and antihypertensive interaction cause?
may lead to risk of renal impairment and a blunting of the antihypertensive effect
What can aspirin and antidepressant interaction cause?
can lead to increased risk of bleeding with the likes of SSRIs
What can aspirin and anti-epileptic interaction cause?
enhances the effects of anti-epileptics
What can aspirin and thrombocyte affecting drug interaction cause?
can get enhanced bleeding through a combination with any other drug that effets platelets and thrombocytes e.g. clopidogrel
What can aspirin and corticosteroid interaction cause?
enhanced GI effects
What is the difference between aspirin and ibuprofen’s effect on platelet COX?
most NSAIDs are reversible inhibitors of COX whereas aspirin is a permanent inhibitor
What is the absorption and binding of most other NSAIDs (not aspirin)?
rapid absorption via oral administration - peak plasma conc. 1.5hrs, extensive binding 99%
What percentage of people discontinue their use of NSAIDs due to the side effects?
15%
What should NSAIDs be avoided in?
- pregnancy, asthmatics, anti-coagulated, methotrexate, allergy
- caution in elderly, renal or hepatic insufficiency, IHD, GI complications
What is the standard adult dose of aspirin?
300-900mg 4-6 hourly, maximum of 4g daily (preferably with food)
What is the standard adult dose of ibuprofen?
oral 400mg approx. 3 times per day (~8 hourly), maximum 1.8g-2.4g/day
What is the standard adult dose of diclofenac?
oral 50mg 3 times/day, maximum 150mg/day
What should be given to patients alongside NSAIDs if they are at risk of gastric upset?
proton pump inhibitor (PPI) omeprazole/lansoprazole
Summary of aspirin
