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Clinical Pharmacology > 8.1 NSAIDs > Flashcards

8.1 NSAIDs Flashcards

1
Q

give some examples of prostanoids

A

prostaglandins ( PGE2, PGF2, PGD2)
prostacylcins
thromboxane A2

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2
Q

how are prostanoids produced?

A

phospholipids are broken down by phospholipase A2 into arachidonic acid
Arachidonic acid is broken down into prostanoids by COX-1 and COX-2 enzymes

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3
Q

what is the broad mechanism of action of all NSAIDs?

A

inhibiting down stream products of arachidonic acid, as prostanoids are inflammatory mediators. Compete with arachidonic acid for hydrophobic site of COX enzymes

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4
Q

what is arachidonic acid primarily derived from?

A

dietary linoleic acid - vegetable oils converted hepatically to arachidonic acid and incorporated into phospholipids

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5
Q

what are the general actions of prostaglandins?

A 
pain
pyrexia
inflammation 
gastrointestinal mucosal protection
bronchoconstrictor 
inhibits platelet aggregation
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6
Q

what are the actions of prostacyclin?

A

inhibits platelet aggregation by keeping surface receptors GP IIb/IIIa in an inactive state
vasodilator
- cytoprotective CVS

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7
Q

what are the actions of thromboxane A2?

A

powerful platelet aggrgator
vasocontrictor
- generally bad for the CVS

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8
Q

where are prostacyclins produced ( PGI2)?

A

produced and release by healthy endothelial cells

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9
Q

describe the molecular mechanism of action of prostcyclin?

A

PGI2 binds to platelet receptors to increase the amount of CAMP in platelets
Increasing CAMP decreases the amount of intracellular calcium and prevents platelet aggregation

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10
Q

Why is PGE2 considered as good for GI mucosa protection?

A

PGE2 contributes to regulation of acid secretion in parietal cells. When bound to a receptor on the parietal cells it inhibits adenylyl cyclase and decreases the production of cAMP.
Less cAMP means less stimulation of the proton pump

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11
Q

why is prostacyclin good for the GI system?

A

Prostacyclin (PGI2) contributes to maintenance of blood flow and mucosal repair

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12
Q

what is the function of prostacyclins?

A

Act locally at GPCRs

specific action depends on receptor subtype and location

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13
Q

what are autocoids?

A

Autocoids are biological factors which act like local hormones, have a brief duration, and act near their site of synthesis
examples are bradykinin and histamine

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14
Q

why is a fine balance between thromboxane A2 and prostacyclin crutial?

A

As TXA2 and PGI2 have apposing vascular effects. Need to have a fine balance to properly regulate haemodynamic and thrombogenic control

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15
Q

what conditions do an imbalance/disruption of prostanoids play a significant role in?

A

hypertension
MI
stroke risk

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16
Q

why is the mediterranean diet advised to lower the incidence of CVD?

A

As the diet is rich in fish oils which are proposed to lead to conversion to TXA3 and PGI3 which are better prostanoids.

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17
Q

where are cyclooxygenase enzymes found?

A 
COX-1 = constitutively active across most tissues 
COX-2 = inducible in chronic inflammation. Constitutively active in brain, kidney and bone.
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18
Q

What are the homeostatic function of COX-1?

A

GI protection (acid and mucus)
Platelet aggregation
Vascular resistance

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19
Q

what are the pathological functions of COX-1?

A

chronic inflammation
chronic pain
raised blood pressure

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20
Q

what are the homeostatic functions of COX-2?

A

renal homeostasis
tissue repair and healing
reproduction (uterine contractions)
inhibition of platelet aggregation

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21
Q

what are the pathological function of COX-2?

A

chronic inflammation
chronic pain
fever
blood vessel permeability

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22
Q

what are the main effects of NSAIDs?

A

analgesic
anti-inflammatory
anti-pyretic

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23
Q

when is aspirin an NSAID?

A

Aspirin at a high dose (300mg) can be used as an NSAID
At a low dose it functions as an irreversible COX inhibitor (remember platelets non
nuclear – new platelets needed) and has an antiplatelet aggregator function

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24
Q

how are NSAIDs used as analgesics?

A

Local peripheral action at site of pain – greater efficacy if inflamed. Inhibition of COX enzymes reduces peripheral pain fibre sensitivity by blocking PGE2 (and others)
Central component associated with decreased prostaglandin synthesis in dorsal horn -> decreased neurotransmitter release -> decreased excitability of neurones in pain relay pathway efficacious after first dose but full analgesia after several days dosing

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25
Q

how are NSAIDs used an anti-inflammatories?

A

NSAIDs reduce production of prostaglandins released at site of injury by inhibiting COX enzymes leading to decrease in vasodilation and oedema.
NSAIDs inhibit vasodilation in post capillary venules that contributes to increased permeability and local swelling
Symptomatic relief with COX inhibition – little effect on underlying chronic condition

26
Q

there is a possible link between NSAID use and reduction in some cancers. What is the proposed mechanism behind this?

A

Reduction in other anti-inflammatory mediators independent of COX may be associated with some effects of decreased reactive oxygen species by oxygen scavenging properties?
- link to possible reduction in some cancers?

27
Q

how are NSAIDs used as antipyretics?

A

PGE2 is a critical component in the preoptic area of the hypothalamus (thermoregulatory centre)
Prostaglandins can be stimulated by pyrogens e.g. cytokines to increase body temperature
Inhibition of hypothalamic COX-2 where cytokine induced prostaglandin synthesis is elevated results in a reduction in temperature

28
Q

how are NSAIDs differentiated?

A

based on their selectivity of COX-1 and COX-2 enzymes

29
Q

when do COX-2 inhibitors (coxibs) lose their selectivity?

A

only selective for COX-s over COX-1 at therapeutic doses

At supratherapeutic doses the selectivity is lost and COX-1 would also be targetted

30
Q

what NSAIDs are the most selective for COX-2?

A 
from most to least:
etoricoxib
celecoxib
diclofenac
naproxen
ibuprofen
31
Q

what are the pharmacokinetics of NSAIDs?

A

absorption = most are weak acids that have almost complete GI absorption
metabolism = typically don’t undergo first pass metabolism, hepatic metabolism to inactive products
half life= either short (1-5 hours) or long (10 to 60hours)
can use modified release preparations in those with short half life.

32
Q

describe the metabolism of aspirin

A

aspirin -> salicylic acid -> conjugated with glycine/glucuronic acid
1st order at therapeutic doses. zero order kinetics in supratherapeutic doses

33
Q

what are the renal considerations that must be made when prescribing NSAIDs?

A

NSAIDs produce reversible decreased GFR and decreased renal blood flow issues. This may be an issue in patients with underlying CKD and heart failure where there is greater reliance on prostaglandins for vasodilation and renal perfusion

34
Q

what is the role of prostaglandins at the kidney?

A

prostaglandins cause vasodilation at the afferent arteriole which is vital when there is systemic vasoconstriction such as in heart failure resulting in hypotension, and when the afferent arteriole needs to dilate such as in AKI and CKD.
also prostaglandins inhibit sodium absorption in the collecting duct causing natriuresis . NSAIDs inhibit this and therefore increase BP

35
Q

what gastrointestinal considerations must be made when prescribing NSAIDs?

A

can cause a lot of GI ADRs = dyspepsia, nausea, peptic ulceration, bleeding and perforation.
NSAIDs decrease mucus and bicarbonate secretion, and increase acid secretion by inhibiting prostaglandin secretion (PGE2)
decreased mucosal blood flow due to inhibition of prostacyclin (PGI2) - enhanced cytotoxicity and hypoxia
Exacerbation of inflammatory bowel disease

36
Q

when are NSAIDs contraindicated?

A

elderly, prolonged use, smoking, alcohol, history of peptic ulceration, helicobacter pylori
patients with pro-thrombotic risk, coronary or cerebrovascular disease should not be prescribed NSAIDs
Third trimester of pregnancy – not sustained use – delayed labour and early closure of ductus arteriosus

37
Q

what are the important drug interactions of NSAIDs?

A
  • aspirin, corticosteroids, anticoagulants (PPI should be considered) - drugs that may worsen GI ADRs
    ACEi,ARBs, diuretics - drugs that may worsen renal ADRs
  • sulfonylurea (gliclazide) - concentrations are increased as NSAIDs displace from protein complexes. Can cause hypoglycaemia
  • methotrexate - accumulation and hepatotoxicity
  • warfarin - increased risk of bleeding
38
Q

give some examples of selective COX-2 inhibitors?

A

celecoxib

etoricoxib

39
Q

what are the benefits of COX-2 selective NSAIDs over non-selective NSAIDs?

A

Less GI ADRs, but renal ADRs are similar

40
Q

why are selected COX-2 inhibitors considered as more harmful for the CVS than non-selective NSAIDs?

A

As COX-2 is the enzyme used in the production of prostacyclin, which has a vasodilation and anti aggregatory effect. by inhibiting this pathway, this means that the thromboxane A2 actions (vasoconstriction and platelet aggregation) are unopposed as this pathway is mediated by COX-1 enzyme which is not being inhibited. This imbalance is bad for the CVS. However all NSAIDs increase the risk of MI

41
Q

what are the indication of selective COX-2 inhibitors?

A

can be useful when monitored in severe osteo and rheumatoid arthritis for longer term treatment

42
Q

what are the cardiovascular ADRs associated with NSAIDs?

A
  • inhibition of prostaglandins increase the reabsorption of sodium and water -> exacerbate HF and increase BP
  • efficacy of antihypertensives is reduced with NSAIDs as they oppose vasodilation and increase circulating volume
  • Both traditional and COX-2 selective NSAIDs increase the risk of MI
  • patients with pro-thrombotic risk, coronary or cerebrovascular disease should not be prescribed NSAIDs
43
Q

NSAIDs are highly protein bound. Why is this an important consideration?

A

NSAIDs have more affinity and therefore displace other bound drugs, increasing free drug concentration
Particularly high protein bound drugs e.g. sulfonylurea – hypoglycaemia
methotrexate - accumulation and hepatotoxicity
warfarin – increased risk of bleeding
likely dose adjustment and increased monitoring necessary

44
Q

what are the indications of NSAID use?

A
  • 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……???
45
Q

how should NSAIDs be prescribed?

A

Lowest effective dose for the shortest time necessary taking into account patient specific risk factors

46
Q

what are the indications of paracetamol?

A

mild to moderate analgesia

fever (antipyretic)

47
Q

what is the mechanism of action of paracetamol?

A

mechanism still not completely elucidated
COX-2 selective inhibition in CNS (spinal chord) - decreases pain signals to higher centres
Peroxidases in peripheral inflammation so very little anti-inflammatory action

48
Q

describe the pharmacokinetics of paraceptamol?

A

well absorbed from GI
half life of 2.5 hours
inactivated by conjugation in the liver

49
Q

what is NAPQI?

A

a highly reactive metabolite of paracetamol that has some analgesic effect

50
Q

what is the mechanism of action of paracetamol overdose?

A

paracetamol is broken down to NAPQI, a highly reactive metabolite.
at normal doses NAPQI conjugates with glutathione and is rendered harmless.
Hepatic glutathione is limited and a paracetamol dose of 150mg/kg means the glutathione protective mechanism are overcome and irreversible damage can occur.
NAPQI is highly nucleophilic and oxidises key metabolic enzymes to ultimately cause cell death and necrosis and apoptosis

51
Q

how does paracetamol overdose present?

A

Can be asymptomatic for many hours
Nausea, vomiting, abdominal pain in hepatic quadrant – first 24h
Maximal liver damage occurs at ~ 3-4 days

52
Q

how is paracetamol overdose treated?

A
  • Activated charcoal? – we rarely know precisely when overdose taken but possibly if very recently
  • Bloods >4h – indication of extent of overdose before this limited information
  • Glutathione thiol replacement – i .v. acetylcysteine
53
Q

what is the mechanism of action of N-acetylcysteine?

A

N-Acetylcysteine replaces glutathione, reducing it and replenishing thiol groups

54
Q

why is glutathione itself not given in the treatment of paracetamol overdose?

A

Glutathione struggles to enter hepatocytes, where as N-acetylcysteine which is a thiol donor to glutathione, can enter cells typically following a I.V administration

55
Q

Why can NSAIDs exacerbate CKD and why do ACEi/ARB compound this?

A

NSAIDs exacerbate CKD as they reduce the vasodilatory protective effects of the afferent arteriole to maintain good perfusion of the kidney. Inhibition of prostacyclin (PGI2) which causes vasodilation is associated with CVD risk.
ACEi/ARBs act at the efferent arteriole to cause vasodilation due to decreased effects of angiotensin II.
ACEi/ARB compound the effects of NSAIDs as they both reduce intraglomerular pressure and renal perfusion. This can predispose to prerenal AKI due to hypoperfusion

56
Q

Explain the difference in action of COX-1 inhibition vs COX-2 inhibition in relation to platelet aggregation

A

COX-1 inhibition causes inhibition of thromboxane A2 production from arachidonic acid. This has a CVS protective action as thromboxane A2 cause platelet aggregation and vasoconstriction. Aspirin therefore is used as secondary prevention following CVD and stroke.
COX-2 inhibition inhibits the production of prostacyclin from arachidonic acid. Prostacyclin has a protective mechanism causing vasodilation and preventing platelet aggragation

57
Q

How does N-Acetylcysteine help in paracetamol overdose?

A

it replenishes the thiol group of glutathiones. The reduced glutathione is then available to conjugate NAPQI and render it harmless

58
Q

Which of the NSAIDs discussed is most selective for COX-2?

A

etoricoxib

59
Q

How does inhibition of prostaglandins broadly cause GI ADRs related to NSAID use?

A

inhibition of prostaglandins especially PGE2 - increased acid secretion and decreased mucus and bicarbonate secretion
inhibition of prostacyclins (PGI2) - decreased mucosal blood flow, less regeneration and repair. Enhanced cytotoxicity and hypoxia.

60
Q

Describe how NSAIDs may increase free plasma concentrations of other drugs

A

NSAIDs are highly protein bound and cause competitive displacement of other drugs. They increase their plasma concentrations by increasing the amount of free drug as less is bound to proteins.

Clinical Pharmacology (26 decks)

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