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Semester 4 - Clinical Pharmacology And Therapeutics > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

What is Arachadonic acid derived from?

A

Linoleic acid - vegetable oils.

It is the converted hepatic ally to arachidonic acid and incorporated into phospholipids.

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2
Q

Where is arachidonic found?

A

Found throughout the body - particularly in the muscle, brain and liver.

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3
Q

What is the rate limiting step in eicosanoid generation?

A

Release from phospholipids by phospholipase A2.

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4
Q

Describe Eicosanoid synthesis

A

Phospholipids are converted into arachidonic acid by phospholipase A2.

Arachidonic acid then gets converted into Prostaglandin H2 via the cyclooxygenase pathways (where COX1 and COX2 work).
Prostaglandin H2 then gets converted into various prostanoids which act in different ways depends on where in the body they are.

The prostanoids all have a short half life so are under fine control.

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5
Q

What are prostanoids used for?

A

They have various different functions depending on where in the body they are produce and the type.

PGE2 - stomach for GI mucosal protection, uterine contraction and brain.

PGE2, PGF2a, PGD2 - pain, pyrexia and inflammation

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6
Q

What is the difference between COX1- and COX2?

A

They are the two functional isoforms of cycooxygenase enzymes.

COX1 - constitutively active across most tissues
COX2 - Inducible (mostly) typically in active / inflamed tissues.

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7
Q

Homeostatic functions of COX-1

A

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

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8
Q

Homeostatic functions of COX-2

A

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

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9
Q

Pathological functions of COX-1

A

Chronic inflammation
Chronic pain
Raised blood pressure

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10
Q

Pathological function of COX-2

A 
Chronic inflammation
Chronic pain
Fever
Blood vessel permeability
Tumour cell growth
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11
Q

How can prostanoid action be enhanced?

A

Local autacoids including bradykinin and histamine

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12
Q

TXA2 and PGI2 have apposing vascular effects. Why is this significant?

A

Because it is important to maintain a fine balance between them for haemodynamic and thrombogenic control.

Imbalance plays a significant role in hypertension, MI and stroke.

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13
Q

Why might a diet rich in fish oils be protective?

A

EPA and DHA concession of TXA3 and PGE2 - balance shifted towards prostacyclin activity which could lead to a lower incidence of CVD.

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14
Q

What is the single MOA of NSAIDs?

A

Inhibition of COX enzymes causing a decrease in prostanoid (prostaglandins, prostacyclin and thromboxane) synthesis.

This is good or bad depending on what actions (homeostatic or pathogenic) actions are being targeted.

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15
Q

How does aspirin work at a high die?

A

Original NSAID

Aspirin irreversibly inhibits COX - why issue with platelet aggregation.

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16
Q

How do NSAIDs have an analgesic effect?

A

Local peripheral action at site of pain - greater efficacy if inflamed.

Central component associated with decrease PGE2 synthesis in the dorsal horn causing decrease neurotransmitter release resulting in decreased excitability of neurones in pain relay.

Efficacious after first dose but full analgesia after several days of dosing.

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17
Q

How do NSAIDs have an anti-inflammatory effect?

A

Reduction in production of prostaglandins released during injury esp. PGE2 and PGD2.

This is a result of of local autacoids, increasing COX activity and increased vasodilation and swelling.

There is symptomatic relief by COX inhibition but little effect on the underlying chronic condition.

18
Q

How do NSAIDs have an antipyretic effect?

A

Inhibition of hypothalamic COX2 where cytokine induced prostaglandin synthesis is elevated.

Platelet aggregation is also inhibited through COX1 by decreased TXA2 synthesis

19
Q

How does COX selectivity differ depending on the drugs?

A 
Most COX1 selective
Aspirin
Ibuprofen
Naproxen
Diclophenac
Celecoxib
Parecoxib
Etoricoxib
Most COX2 selective
20
Q

Why are COX2 selected?

A

Because of ADRs

COX2-selective compounds inhibit COX2 with much greater selectivity than COX1.

But, they’re not the wonder drug we thought they were going to be.

21
Q

Why not for asmatics?

A

Because, although none of the NSAIDs have a direct action in leukotrienes, they have an indirect action through PGE2

22
Q

Describe the pharmacokinetics of NSAIDs

A

Most NSAIDs are weak acids. Almost complete GI absorption - some in stomach -pH partition.

Typically don’t undergo 1st pass metabolism.

t1/2 fall into two classes:
Short - 1-5hrs
Long 10-60hrs
Not necessary indicative of therapeutic duration at site of action - synovial fluid concentrations fluctuate less.

Highly protein bound with small Vd

Hepatic metabolism to inactive products

23
Q

What ADRs are most troublesome with regards to NSAIDs?

A

GI ADRs - Also most common

Dyspepsia, nausea, peptic ulceration, bleeding and perforation.

Overall NSAID use 4x incidence of severe GI haemorrhage up to 2000 deaths in UK anually.

24
Q

Why do you get GI ADRs with NSAIDs?

A

Decrease mucus and bicarbonate secretion results in increased acid secretion.

Decreased mucosal blood flow results in enhanced cytotoxicity and hypoxia

Decrease hydrophobicity of mucus layer due to acidic nature of NSAIDs locally.

25
Q

What does NSAIDs make worse?

A

IBS

26
Q

What are risks for GI ADRs when taking NSAIDs?

A 
Age 
Prolonged use 
Glucocorticoid steroids
Anticoagulants
Smoking
Alcohol
History of peptic ulceration
H. Pylori
27
Q

Renal ADRs from NSAIDs

A

NSAIDs produce reversible:
Decrease in GFR
Increase in creatinine
Decrease in renal medullary blood flow

More likely if underlying CKD and blood flow compromise (CHF, cirrhosis with ascites) as there is greater reliance on prostaglandins for vasodilation and renal perfusion.

Increased salt and water retention in otherwise functioning kidney = hypertension and oedema

Decrease renin secretion= hyperkalaemia

The very young and elderly are at greatest risk.

28
Q

Give examples of selective COX-2 inhibitors

A

Celecoxib
Etoricoxib
Parecoxib

29
Q

How are COX2 inhibitors different to COX1?

A

Reduction in ADRs associated with targeting physiological prostanoid action via COX-1.

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 anti platelet action but impair PGI2 potentially leading to unopposed aggregators effects.

Some evidence of less analgesic effect.

Can be useful when monitored in severe osteo and rheumatoid arthritis.

30
Q

What are the cardiovascular ADRs from NSAIDs?

A

Increase salt and water retention - exacerbate HF and increase BP by 3-5mmHg.

Vasoconstriction through reduced antagonism of ADH by prostaglandins.

Efficacy of antihypertensives is reduced with NSAIDs.

Increase risk of MI

31
Q

Who should not have NSAIDs?

A

Patients with a pro-thrombotic risk, coronary or cerebrovascular disease.

32
Q

Describe the DDIs of NSAIDs

A

NSAIDs and low dose aspirin - competition for COX1 so decreased CV protection

Sulfonylurea - hypoglycaemia

Methotrexate - accumulation and hepatotoxicity, leukopenia

RA

Warfarin - increased risk of bleeding

Aspirn can cause Reye’s syndrome in young children (under 12)

Pregnancy = delay labour, increase blood loss and premature closure of ductus arteriosus - prefer paracetamol.

33
Q

When do you use NSAIDs?

A 
Inflammatory conditions 
Osteoarthritis
Postoperative pain
Topical use on cornea 
Menorrhagia 
Platelet aggregation
Opioid sparing (in combination)
Close ductus arteriosus
34
Q

How is paracetamol used for?

A

Moderate analgesia and fever

35
Q

Describe the MOA of paracetamol

A

Still not completely understood.

COX-2 selective inhibition in CNS.

Decrease pain signals to higher centres peroxidases in peripheral inflammation limit action - little anti-inflammatory action.

Well absorbed in GI tract. 2hrs half life. Predominantly inactivated by conjugation in the liver.

36
Q

What is NAPQI?

A

Minor oxidation product of paracetamol - highly reactive.

At normal therapeutic doses - conjugation with glutathione renders it harmless.

37
Q

Why can NAPQI be dangerous?

A

If not enough glutathione (so paracetamol overdose) will not metabolise paracetamol properly and result in a build up of NAPQI.

This is highly nucleophilic so it oxidises thiol groups in key metabolic enzymes. Therefore, it ultimately leads to cell death.

38
Q

What do you take in paracetamol overdose?

A

Acetylcysteine

39
Q

What happens in paracetamol overdose?

A

Can be asymptomatic for many hours.

Nausea, vomiting, abdominal pain - first 24hours

Liver damage and upper quadrant pain - 24-48hours

Maximal liver damage - 3-4 days

Prothrombin time - sensitive indicator of damage.

40
Q

Why dont you use glutathione for paracetamol overdose?

A

As glutathione would not get into hepatocytes

Semester 4 - Clinical Pharmacology And Therapeutics (26 decks)

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