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Pharmacology (Semester 6) > 8.2 Paracetamol, NSAIDs and Asprin > Flashcards

8.2 Paracetamol, NSAIDs and Asprin Flashcards

1
Q

What is the 5th vital sign and what is meant by its “verbal rating scale (VRS)”?

What 2 other ‘scales’ can be used to assess this?

A

Pain

VRS: mild, moderate, severe (0-10 no pain- worst pain imaginable)

Other scales: visual analogue scale (VAS) and faces pain scale (FPS)

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2
Q

Describe the arachidonic acid cascade and what the purpose of the end products is?

A

End products = inflammatory mediators ➞ activate nociceptors on Aδ and C fibers ➞ pain and sensitization

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3
Q

Describe the cascade that occurs in response to tissue injury?

A

1) Injury trigger release of phospholipase A2 from cell membranes
2) phospholipase A2 converts phospholipids into arachadonic acid
3) COX enzymes convert arachadonic acid into PGs which have various effects

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4
Q

Where do NSAIDs / COX-2 inhibitors act in the arachidonic acid cascade + what does this result in?

A

Reduce Prostaglandins and Thromboxane ➞ results in reduced pain

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5
Q

Where are prostaglandins produced from and by what enzyme?

A

Arachidonic acid in cell membrane phospholipids by COX enzymes

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6
Q

Give 4 process prostaglandins are involved in and state which cells produce them

A

They are produced by almost all nucleated cells.

Involved in inflammation, immune response, muscle constriction and relaxation and metabolic activities

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7
Q

Describe the following about prostaglandins

  1. short or long half life?
  2. autocrine, paracrine or endocrine?
  3. hydrophilic or lipophilic?
A
  1. Short half life
  2. Autocrine and Paracrine
  3. Lipophilic
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8
Q

What are administered to soften and shorten the cervix (cervical ripening) for pre-induction of labour?

A

PGF 2α and PGE 2

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9
Q

Give the 3 general effects of NSAIDs + 2 others

A

Analgesic, Antipyretic, Anti-inflammatory

+ antiplatelet and vasoconstrictor

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10
Q

What severity of pain are NSAIDs prescribed for?

A

Mild to Moderate Pain

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11
Q

Give the MoA of NSAIDs

A

Inhibit the two isoforms of the enzyme cyclooxygenase (COX-1 and COX-2)

Results in decreased thromboxane, prostaglandins and leukotrienes ➞ reduced pain

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12
Q

NSAIDs that act on both isoforms of COX are known as _______

NSAIDs which act predominantly on COX-2 are known as _______

A

Both isoforms ➞ non-selective NSAIDs (ns-NSAIDs)

COX-2 ➞ specific COX-2 inhibitors (coxibs)

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13
Q

Compare the 2 isoforms of COX in terms of where they are found and when they are present

A

COX-1 ➞ normal constituent in body for homeostasis

  • Gastric mucosa – gastric cytoprotection
  • Kidney – Sodium and water balance / renal perfusion
  • Platelets – for aggregation

COX-2 ➞ induced in injury and inflammation and a normal constituent in the many organs

  • Kidney, brain, endothelium, ovary and uterus
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14
Q

There is also a COX-3, where is this found and what is it’s MoA

A

The brain- thought to be a varient of COX-1

Inhibits prostaglandin synthesis in the CNS ➞ produces its good antipyretic and analgesic effect

BUT shows NO Anti-inflammatory benefits (despite COX 2)

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15
Q

Give 2 examples of non-selective COX inhibitors

A

Naproxen and Ibuprofen

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16
Q

Give 2 examples of selective COX1 inhibitors

A

Indomethacin and Acetylsalicylic acid (aspirin)

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17
Q

Give 2 examples of COX-2 specific inhibitors

A

Celecoxib and Diclofenac

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18
Q

Give the NICE adverse affects of the following:

  • Selective COX-1 (general NSAIDs)
  • Non Selective COX
  • Selective COX-2
A
  1. Selective COX-1 ➞ 15% of all drug-induced AKI
  2. Non-selective NSAIDs ➞ small increased risk of thrombotic events (eg. heart attack or stroke)
  3. Coxibs ➞ ~ 3 additional thrombotic events per 1000 patients
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19
Q

What is the main complication of NSAIDs on the kidney and explain why

A

Renal prostaglandins, particularly PGE2 and PGI2 cause vasodilation of the afferent arterioles, impt to maintain GFR

NSAIDS inhibit renal prostaglandins ➞ AA CAN’T dilate ➞ harmful hypoperfusion of the kidneys + reduced GFR ➞ AKI

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20
Q

What is the normal effect of prostaglandins and thromboxane on blood vessels?

A

Under normal conditions there is an important balance between:

1) PGI2, synthesized by COX2 in the vascular endothelium ➞ responsible for vasodilation and inhibition of platelet aggregation
2) TXA2, synthesized in platelets by COX1 ➞ responsible for vasoconstriction and promotion of platelet aggregation

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21
Q

What is the main complication of NSAIDs on the CVS and explain why

Incl which COX isoform this is associated with

A

Agents with COX 2 selectivity cause more inhibition of PGI2 thus resulting in a relative excess of TXA.

This make vasoconstriction and platelet aggregation more likley to occur ➞ leads to increased risk of CVS events (MI and stroke)

Note: asprin which is COX 1 has the opposite effect and can therefore be used for mangement in CVS conditions

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22
Q

Give 2 complications of NSAIDs on the GI tract and explain why each occurs

Incl which COX isoform this is asspciated with

A

1) GI bleeding ➞ Inhibition of TXA causes increased anti-platelet effect
2) Peptic ulcers ➞ COX 1 mediated inhibition of PGE2 and PGI2 result in decreased synthesis of gastric mucus (defence)

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23
Q

Are gastric or duodenal ulcers more common with NSAID use?

A

Gastric ulcers

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24
Q

Give 4 risk factors for GI bleeding on NSAIDs

A
  1. over 65
  2. history of GI bleeds or ulcers
  3. concurrent use of drugs which increase risk (ie steroids)
  4. heavy smoking or alcohol use
  5. prolonged NSAID use (particular high dose)
  6. serious co-morbidity
  7. PMH/FH
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25
Q

Give 3 examples of highly protein bound drugs which are affected by NSAIDs + the effect on each

Explain why this is the case and what must always be done if prescribing togther

A
  1. ↑Sulphonylurea - Hypoglycaemia
  2. ↑Warfarin – Increased Bleeding
  3. ↑Methotrexate – Wide ranging serious ADRs

Due to competitive displacement of these drugs by NSAIDs

Dose adjustment required to avoid changes in PK and PD

26
Q

Why are we concerned about prescribing NSAIDs along with highly protein bound drugs?

How do we overcome this?

A

Competitive displacement of these drugs may require dose adjustment to avoid changes in PK and PD

↑Sulphonylurea - Hypoglycaemia

↑Warfarin – Increased Bleeding

↑Methotrexate – Wide ranging serious ADRs

27
Q

What is the “Triple Whammy”?

Explain the negative effects of each drug and why they should NEVER be prescribed togther

A

ACE inhibitor + diuretic + NSAID ➞ Acute kidney injury!!

ACE inhibitors can decrease GFR by causing vasodilation of efferent arteriole

Diuretics can cause hypovolaemia which contribute to AKI

NSAIDs block COX-2 enzyme preventing prostacyclin synthesis preventing afferent arteriole dilation

28
Q

What must we do if the “triple whammy” combination of medicines is necessary?

A

Always do baseline testing of serum creatinine and electrolytes + advise patients to maintain adequate fluid intake

29
Q

What are the immediate goals of care if patients do develop triple whammy adverse effects?

A

Restoration of fluid balance and withdrawal of nephrotoxic medicines

30
Q

What is Stevens-Johnson Syndrome?

A

Serious but rare condition which occurs as a result of ADR.

Affects the mucus membrane, skin, genitals and eyes. Patient initially develops flu like symptoms and a red/purple rash ➞ progresses to blistering.

Refer to ITU and burns clinic

31
Q

What is the effect of NSAID’s in asthmatics?

A

Some ns-NSAIDs can cause bronchoconstriction in sensitive asthmatic patients

32
Q

How may NSAID’s be useful in the treatment of gout?

A

Inhibit phagocytosis of urate crystals

33
Q

Give 4 contraindications for use of NSAIDs

A
  1. liver and renal disease
  2. asthma
  3. stomach ulcer
  4. pregnancy 3rd trimester
  5. hypertensive
34
Q

?????

A
35
Q

Give 2 similarities between paracetamol and NSAIDs

A

1) Both analgesics and antipyretics
2) Both used for mild-moderate pain

36
Q

Give 3 differences between paracetamol and NSAIDs

A

1) NSAIDs are anti-inflammatory, Paracetamol is NOT (except in teeth/gum’s)
2) Paracetamol has no contraindications, NSAIDs do
3) Paracetamol has less ADRs than NSAIDs (at therapeutic dose)

37
Q

What is the most common drug cause of hepatic failure in UK

A

Paracetamol

38
Q

Give the MoA of Paracetamol

A

Inhibits COX-1 and COX-2 through metabolism by the peroxidase function of these isoenzymes

39
Q

Paracetamol is primarily metabolised in the ______ where it forms conjugates with ______ and ______ that are then excreted ______

A

liver, glucuronide, sulphate, renally

40
Q

Define Tmax and state what the value of this is for paracetamol?

A

Tmax = time taken to reach maximum plasma concentration

Tmax of paracetamol is 15-30 minutes (depends on preparation)

41
Q

How is paracetamol most commonly taken and why?

Where does majority absorption occur and what does rate of absorption depend on?

A

Oral, because it is well tolerated when taken orally

Oral administration ➞ absorption in intestine (70%) and stomach and colon (30%)

Rate of absorption is rapid and depends on the dose

42
Q

When is paracetamol recommended as first line treatment?

A

For chronic conditions, such as osteoarthritis and back pain

43
Q

Give 2 examples of paracetamol-combinations

A

Co-codamol ➞ Paracetamol + Codeine

Co-dydramo ➞ Paracetamol + dihydrocodeine

44
Q

What is the main caution that must be taken with paracetamol?

A

Since it is metabolized in the liver it must be used with caution/ or not given in patients with liver impairment

In patients with renal impairment, the dose given should be reduced

45
Q

Give 4 other instances where paracetamol should be precribed/used with caution

A
  1. alcohol dependency / liver disease
  2. malnutrition
  3. chronic dehydration.
  4. body weight less than 50 kg
  5. Increasing age and/or frailty
  6. alongside liver enzyme-inducing drugs (rifampicin, carbamazepine, and phenytoin)
  7. children
46
Q

Why must we be cautious when prescribing paracetamol to elderly and/or frail individuals?

A

Associated with reduced clearance of paracetamol

In addition, elderly people have co-morbidities and polypharmacy, which can further increase risk of paracetamol toxicity and overdose

47
Q

Explain the toxic mechanism of paracetamol overdose

A

Involves saturation (zero order kinetics) of the Phase II enzymes that normally metabolise paracetamol

This causes drug to be metabolised instead by Phase I CYP450s producing a highly reactive intermediate metabolite NAPQI

NAPQI conjugates with glutathione ➞ depletes glutathione reserves ➞ NAPQI then exerts its toxic effect.

48
Q

Give the common overdose signs of paracetamol + how this progress in severe cases

A

Usually none but nausea and vomiting have been self reported

Later features in severe cases:

  • 12-36 hrs: abdominal pain
  • 24+hrs: loin pain, haematuria, proteinuria ➞ signs of renal failure
  • 2-3 days: right subcostal pain, vomiting, jaundice
  • 3+ days: features of hepatic necrosis
49
Q

In rare cases where plama conc of paracetamol is extremley high what may occur?

A

Coma and severe metabolic acidosis

50
Q

How is paracetamol overdose treated?

What is the difficulty of this?

A

N-acetylcysteine (NAC)

Difficulty is it is most effective when administered within 8-10 hours after OD…. narrow window

51
Q

Asprin has a unique PK profile as its t1/2 is less than ______ minutes.

It is absorbed in the ______ and rapidly hydrolysed to ______ in the gut, ______ and ______.

80-85% is bound to plasma and can freely cross the ______ and ______

A

30, stomach, salicylate acid, liver, plasma, placenta, CSF

52
Q

Give the MoA of Asprin and explain how this acts as an anti-coagulant

A

Irreversibly inhibits COX 1 which blocks production of thromboxane (TXA2).

Inhibition of COX 1 means platelets cannot regenerate TXA2.

However, vascular endothelium can still synthesise PGI2 (controlled by COX 2) which creates a relative excess of PGI2 ➞ inhibits platelet aggregation

53
Q

How long does it take once asprin has been stopped to regenerate a new cohort of platelets?

A

7-10 days

54
Q

Give 2 metabolic effects of Asprin

A

1) Increased cellular metabolism
2) Increased utilization of glucose ➞ reduces blood sugar

55
Q

What is the respiratory effect of Asprin?

What acid/base changes does this progress too?

A

Can cause direct stimulation of respiratory centre ➞ uncouples phosphorylation which leads to ↑CO2 ➞ hyperventilation

(In overdose this is the cause of death)

Hyperventilation ➞ Respiratory alkalosis ➞ Metabolic acidosis follows

56
Q

What happens to the anion gap in asprin overdose and why?

A

Increased anion gap due to accumulation of intracellular lactate as well as excretion of HCO3 by the kidney to compensate for respiratory alkalosis

57
Q

What is the haematological effect of Asprin?

A

Inhibition of Thromboxane A2

58
Q

Give 4 mild signs of an Asprin overdose

A
  1. nausea and vomiting
  2. tinnitus
  3. deafness
  4. lethargy or dizziness.
59
Q

Give 4 moderate to severe signs of a Asprin overdose

A
  1. dehydration
  2. restlessness
  3. sweating
  4. warm extremities
60
Q

What is Reye Syndrome?

Who does it most often affect and how does it present?

A

A rare but serious condition that causes swelling in the liver and brain.

Most often affects children aged 4-12yrs

Presents with Encephalopathy and Liver disease

Medical Emergency - NO ASPIRIN FOR CHILDREN

61
Q

Give 4 comparisons between asprin and paracetamol

A

Pharmacology (Semester 6) (17 decks)

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