Nsaids

Question 1

What is the significance of arachidonic acid and eicosanoids

Answer 1

• The therapeutic benefit of prescribing nonsteroidal anti inflammatory drugs (NSAIDs) is heavily related to arachidonic acid and eicosanoid synthesis
• Conversely the ADRs stem from this signalling 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 and liver
• Release from phospholipids by phospholipase A2 – rate limiting step in eicosanoid generation

Question 2

How are prostanoids synthesised

Answer 2

Ss
PGE2, PGF2a, PGD2, PGI2, TXA2
Produced locally “on demand” - local autacoids
Different tissues- different enzymes - different prostanoids – short half life - fine control

Question 3

What are cox1 and 2

Answer 3

Cyclooxygenase enzymes
• Two functional isoforms: (could be others)
COX-1 constitutively active across most tissues
COX-2 inducible – mostly – typically in active/inflamed tissues
• Similar structurally, differ in physiological, pathological and pharmacological profiles
A lot of drugs act on the

Question 4

What are some of the functions of cox-1

Answer 4

Homeostatic:
GI protection (acid and mucus)
Platelet aggregation
Vascular resistance
Renal blood flow

Pathological functions
Chronic inflammation
Chronic pain
Raised blood pressure

Question 5

What are teh functions of cox -2

Answer 5

Renal homeostasis
Tissue repair and healing
COX-2
 Reproduction (uterine contractions)
Inhibition of platelet aggregation

Pathological functions
Chronic inflammations
Chronic painfever

Question 6

What are prostanoids

Answer 6

• PGE2, PGF2α, PGD2 PGI2 (prostacyclin) and TXA2 (thromboxane)
• Action locally at a number of GPCRs
specific action depends on receptor subtype and location
• Often action is enhanced by local autacoids including bradykinin and histamine

Question 7

How do txa2 and pgi2 oppose each other

Answer 7

• TXA2 and PGI2 have apposing vascular effects
fine balance between them crucial – haemodynamic and thrombogenic control
• Imbalance plays significant role in hypertension MI and stroke
• Diet rich in fish oils – northern latitudes – EPA and DHA ( fatty acids) conversion to TXA3 and PGE3 – balance shifted towards prostacyclin activity – lower incidence of CVD?

Question 8

What ae teh therapeutic targets of nsaids

Answer 8

• Pharmacologically targeting this signalling cassette affords therapeutic benefits
• MOA- inhibition of COX enzymes and subsequent reduction in
prostanoid synthesis
Dow stream affects of inhibiting or promotions prostanoids
• 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

Question 9

What are NSAIDS?

Answer 9

• Widely prescribed drug class – predominantly used for their analgesic and anti-inflammatory effects
• ~10% UK population prescribed an NSAID in any given year
• Chemically dissimilar resulting in varying antipyretic, analgesic and anti-
inflammatory properties
• Aspirin moderate dose – NSAID – the original - relegated to use as antiplatelet – low dose – irreversible COX inhibitor (remember platelets non nuclear – new platelets needed) – anti-inflammatory at high doses
Small dose - antiplatlet agent
Others are reversible

Question 10

Describe teh analgesic effects of nsaid

Answer 10

• Analgesic effects in two parts:
local peripheral action at site of pain – greater efficacy if inflamed Central component associated with ↓PGE2 synthesis in dorsal horn - ↓ neurotransmitter release → ↓excitability of neurons in pain relay efficacious after first dose but full analgesia after several days dosing

Question 11

Describe teh anti inflammatory effects of NSAIDs

Answer 11

Anti-inflammatory effects:
Reduction in production of prostaglandins released during injury esp. PGE2 and PGD2 – result of local autacoids ↑ COX activity increased vasodilatation and swelling
symptomatic relief by COX inhibition – little effect on underlying chronic condition

Question 12

Describe the antipyretic effects of NSAIDs

Answer 12

• Antipyretic effects:

inhibition of hypothalamic COX-2 where cytokine induced prostaglandin synthesis elevated

Question 13

Describe teh nsaid action on platelets

Answer 13

Platelet aggregation inhibited through COX-1 -↓ TXA2 synthesis (Lecture 12)

Question 14

What are some examples of NSAIDs

Answer 14

(Cox-1 selective) aspirin, ibuprofen, naproxen, diclofenac, celecoxib, parecoxib, etoricoxib (cox-2 selective)

Question 15

Describe cox selectivity

Answer 15

• NSAIDs differentiated by selectivity
• High prevalence of ADRs attributable to COX-1 led to selective COX-2
inhibitors (coxibs)
COX-1 activity for homeostasis
e.g. gastric mucosa, renal medulla etc. → inhibition disrupts this balance
• COX-2-selective compounds inhibit COX-2 with much greater selectivity than COX-1 at therapeutic doses
• Non-COX-2-selective comprise all other NSAIDs
• Neither have direct action on leukotrienes however indirect action
through PGE2 (consideration in asthmatics)

Question 16

Describe the pk of nsaids

Answer 16

• Most NSAIDs are weak acids
almost complete GI absorption – some in stomach - pH partition
• Typically don’t undergo first pass elimination
• t1/2 generally fall into two broad classes
short – 1-5h and long 10-60h
not necessarily indicative of therapeutic duration at site of action – synovial fluid concs. fluctuate less
• Modified release preparations of some with short t1/2
• Highly protein bound with relatively small VD
• Hepatic metabolism to inactive products
• Aspirin → salicylic acid →conjugation with glycine/glucuronic acid saturated at high doses - 1st order → zero-order (overdose)

Question 17

What are the gi adrs of nsaids

Answer 17

• Probably the most common
Dyspepsia, nausea, peptic ulceration, bleeding and perforation
• Overall NSAID use 4X incidence of severe GI haemorrhage up to 2000 deaths annually in UK
• ↓ mucus and bicarbonate secretion, ↑ acid secretion
• ↓ mucosal blood flow → enhanced cytotoxicity and hypoxia
• ↓ hydrophobicity of mucus layer due to acidic nature of NSAIDs locally
• Exacerbation of inflammatory bowel disease
• Local irritation and bleeding from rectal admin.
• Risk:
Age, prolonged use, glucocorticoid steroids, anticoagulants, smoking, alcohol, history of peptic ulceration, helicobacter pylori

Question 18

What are the renal adrs of NSAIDs

Answer 18

• NSAIDs produce reversible ↓GFR ↑creatinine ↓ renal medullary blood flow
• more likely in underlying CKD and blood flow compromoise- congestive heart failure, cirrhosis with ascites - greater reliance on
prostaglandins for vasodilatation and renal perfusion
• ↑ salt and water retention in otherwise functioning kidney → hypertension and oedema (increase expression of Na/K/2Cl co-transporter)
• ↓ renin secretion → hyperkalaemia
• Very young and elderly at greatest risk

Question 19

Describe selective cox 2 inhibitors

Answer 19

Celecoxib, etoricoxib, parecoxib
• Reduction in ADRs associated with targeting physiological prostanoid action via COX-1 – this was the intention
• Less inhibitory action on COX-1 but selectivity for COX-2 varies among drugs metabolism and polymorphisms in COX
• Less GI ADRs, renal ADRs similar to non-selective
patients have often taken non-selective previously and COX-2 needed for recovery so not ideal fix
• Do not share antiplatelet action but impair PGI2 potentially leading to unopposed aggregatory effects
• Some evidence of less analgesic effect
• Can be useful when monitored in severe osteo and rheumatoid arthritis

Question 20

What are the cvs adrs of nsaids

Answer 20

• ↑ salt and water retention → exacerbate HF and ↑ BP ~3-5 mmHg
• vasoconstriction through reduced antagonism of vasopressin
(ADH) by prostaglandins
• Efficacy of antihypertensives is reduced with NSAIDs
• Traditional and COX-2 selective NSAIDs ↑ risk AMI
timing of risk, treatment duration, dose and comparative risk of NSAIDs poorly understood
• Meta analysis suggests that all at high dose for 8-30 days associated with greatest risk
• Rofecoxib (Vioxx) withdrawal from USA assumed COX-2 class effect
• NICE guidelines recommend that patients with pro-thrombotic risk, coronary or cerebrovascular disease should not be prescribed NSAIDs (inc. coxibs, excl. low dose aspirin) – many are though!

Question 21

What are the ddis of nsaids

Answer 21

• Combination NSAIDs increase risk of ADRs due to protein binding PK and PD affected
• NSAIDs and low dose aspirin – competition for COX-1 ↓ CV protection
• Particularly high protein bound drugs
sulfonylurea – hypoglycaemia (diabetes lecture)
methotrexate - accumulation and hepatotoxicity, leukopenia rheumatoid arthritis (immunosuppressants Lecture 20)
warfarin – increased risk of bleeding
• Competitive displacement – likely dose adjustment needed
• Aspirin - Reye’s syndrome rapid progressive encephalopathy – febrile
viral infections – not for children <12
• Delay labour increase blood loss and premature closure of ductus arteriosus – paracetamol preferred choice

Question 22

What are factors to consider when prescribing an sad

Answer 22

• Cardiovascular disease – risk
• Renal function - age
• GI disease - previous use of NSAIDs
• DDIs – ACEi and ARBs, diuretics, sulfonylureas, methotrexate, warfarin (not exhaustive)
• Level of pain, pyrexia, level of inflammation

Question 23

What are indications for NSAIDs due

Answer 23

• 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
• Close ductus arteriosus
• Cancer reduction – by up to 30 - 50% - nuclear transcription factors, reduced cell proliferation…

Question 24

What is paracetamol

Answer 24

• A unique case – non-NSAID, non-opiate analgesic with antipyretic action
• For mild to moderate analgesia AND fever
• At therapeutic doses generally well tolerated with fewer common ADRs
does not inhibit homeostatic prostaglandin action
• Well absorbed from GI tract – t1/2 2h – predominantly inactivated by conjugation in the liver

Question 25

What is the moa of paracetamol

Answer 25

• MOA still not completely elucidated – 150 years and counting! COX-2 selective inhibition in CNS (spinal chord) - ↓ pain signals to higher centres peroxidases in peripheral inflammation limit action – little anti- inflammatory action

Question 26

What is napping

Answer 26

• Minor oxidation product of paracetamol – highly reactive (phase 1)
- some analgesic effect suggested
• At normal therapeutic doses - conjugation with glutathione renders it harmless
• Hepatic glutathione is limited – balance of conjugation determines build up of NAPQI
• Highly nucleophilic - oxidising thiol groups on key metabolic enzymes inc. mitochondrial function
ultimately cell death – necrosis and apoptosis
• 150mg/kg sufficient to cause severe irreversible hepatocellular and renal tubular damage
10-20 tablets in one dose

Question 27

Gove an overview of paracetamol pk

Answer 27

Ss

Question 28

Describe paracetamol overdose

Answer 28

• Can be asymptomatic for many hours
• Nausea, vomiting, abdominal pain – first 24h
• Liver damage and upper quadrant pain - 24-48h
• Maximal liver damage ~ 3-4 days
• Prothrombin time - sensitive indicator of damage
• Activated charcoal – we rarely
know precisely when overdose was taken
• Bloods > 4h – extent of overdose
• Glutathione thiol replacement
– i.v. acetylcysteine
• Why not give glutathione?

Question 29

Descirbe the action of acetylysteine

Answer 29

Donate thiol groups