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Clinical Pharmacology, Therapeutics & Intro to Prescribing > Lecture 15– Non-steroidal anti- inflammatory drugs > Flashcards

Lecture 15– Non-steroidal anti- inflammatory drugs Flashcards

1
Q

prostanoid synthesis

A
  • 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
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2
Q

Prostanoids are

A

prostaglandins, prostacyclin and thromboxane’s

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3
Q

PGE2

A

Prostaglandin E2

maintains GI system (good stomach health)

  • regulates acid secretion in parietal cells
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4
Q

PGE3,PGF21, PGD2 responsible for

A

Pain pyrexia inflammation

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5
Q

PGI2

A

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)
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6
Q

TXA2

A

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)
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7
Q

fine balance between ……. and …… in terms of CVS health

A

PGI2 (anti-platelet aggregation) and TXA2 (pro-platelt aggregation)

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8
Q

Prostanoids signal through many GPCRs

A

Results in different reactions in different tissues

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9
Q

prostanoid summary

A
  • 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
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10
Q

action of locqal………. can enhance prostanoid action

A

autacoids- histamine and bradykinin

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11
Q

Imbalance/disruption to prostanoids plays significant role in

A

hypertension, MI and stroke risk

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12
Q

Diet rich in fish oils (Ω fatty acids) – “The Mediterranean diet” proposed to

A

lead to conversion ofTXA3 to PGI3 – better prostanoids – lower incidence of CVD?

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13
Q

Cyclooxygenases

A

Controls conversion of arachidonic acid to various prostanoids

Two functional isoforms

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14
Q

2 isoforms of COX

A

COX-1 and COX-2

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15
Q

COX-1x

A
  • COX-1- constitutively active across most tissues
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16
Q

COX-2

A

inducible (mostly)- in chronic inflammation. Constitutively in brain, kidney and bone

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17
Q

NSAIDS

A
  • Widely prescribed as analgesic and anti-inflammatories
  • Chemically dissimilar to each other resulting in varying antipyretic, analgesic and anti-inflammatory properties
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18
Q

NSAIDS single common mode of action

A
  • 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
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19
Q

COX-1 and COX-2 present in different amounts in

A

different tissues

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20
Q

NSAIDS- analgesia

A
  • 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
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21
Q

NSAIDs- antipyretic

Add

A
  • 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
22
Q

NSAID- anti-inflammatory

A
  • 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)
23
Q

other anti-inflammatory actions of NSAIDS

A
  • 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?
24
Q

NSAIDS can be differentiated by their

A
  • selectivity e.g. for COX-1 or COX-2
    • E.g. low dose aspirin favours COX-1
25
Q

what has lead to the development of selective COX-2 inhibitors

A
  • 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
26
Q

Gastrointestinal complications- most common ADR

A
  • Most common ADR
    • Dyspepsia
    • Nausea
    • Peptic ulceration
    • Bleeding
    • Perforation
    • Exacerbation of IBD
27
Q

Gastrointestinal complications- contraindications

A
  • Elderly
  • Prolonged use
  • Smoking
  • Alcohol
  • History of peptic ulceration
  • H. pylori
28
Q

GI complications - DDI

A
  • DDI
    • Aspirin
    • Glucocorticoid steroids
    • Anticoagulation (PPI should be considered)
29
Q
  • MOA of GI problems
A
  • Decrease mucus and bicarbonate secretion
  • Increase acid secretion
  • Decreased mucosal blood flow–>enhanced cytotoxicity and hypoxia
30
Q

Renal considerations- ADRs

*

A
  • 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)
31
Q

renal considerations- contraindications

A
  • CKD
  • Heart failure
    • Both due to decrease in GFR
32
Q

Renal considerations- DDIs

A
  • ACEi
  • ARBs
  • Diuretics
33
Q

renal consideration summary

A
34
Q

Selective COX-2 inhibitors

A

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
35
Q

when are selective COX-2 inhibitors used

A

Can be useful when monitored in severe osteo and rheumatoid arthritis for longer term treatment – reduced GI side effects

36
Q
  • ALL NSAIDs increase risk of
A
  • MI including in low risk people (↓PGI2 in coronary vasculature?)
    • Reduced cycloprotective of the CVS by removing PGI2 etc
37
Q

NSAIDs and protein binding

A
  • 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
  • MOA= competitive displacement
    • Likely dose adjustment needed and increase monitoring
38
Q

Indication of NSAIDS

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……???
39
Q

Contraindications of NSAID use

A
  • 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
40
Q

When prescribing NSAIDs consider…

A

LOWEST EFFECTIVE DOSE FOR THE SHORTEST TIME NECESSARY TAKING INTO ACCOUNT PATIENT SPECIFIC RISK FACTORS

41
Q

paracetamol is neither a

A

NSAID or opiate

42
Q

summary of paracetamol

A
  • 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
43
Q

MOA of paracetamol

A
  • 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
44
Q

why does paracetamol have very little anti-inflammatory action

A
  • 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

45
Q

Pharmacokinetics of paracetamol

A
  • Well absorbed from GI
  • T1/2 around 2.5 hours
  • Inactivated by conjugation in the liver
46
Q

NAPQI

A
  • 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
47
Q

paracetamol overdose caused by

A

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
48
Q

Paracetamol overdose

A

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
49
Q

Paracetamol overdose treatment

A
  • Activated charcoal- only of use if paracetamol overdose recently taken
  • Lethionine (oral drug)
  • Glutathione thiol replacement – IV N- acetylcysteine
50
Q

N-acetylcysteine in treatment of paracetamol overdose

A
  • Replaces glutathione
  • Used when [paracetamol] conc in plasma is to the right of the curve line)
51
Q
A

Clinical Pharmacology, Therapeutics & Intro to Prescribing (39 decks)

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