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Pharmacology Term 6 > 8.2- NSAIDs > Flashcards

8.2- NSAIDs Flashcards

1
Q

What are the main therapeutic effects of NSAIDs?

Physiologically name 2 actions of NSAIDs

A
  • analgesia
  • anti-inflammation
  • antipyresis in fever
  • antiplatelet
  • vasoconstrictor
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2
Q

How is arachidonic acid produced?

A
  • Phospholipase A2 is needed to produce arachidonic acid from phospholipid in the cell membrane
  • acid is the biggest pro-inflammatory mediator in the body
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3
Q

What is the action of Cyclo-oxygenase?

A
  • Cyclo-oxygenase is produced from Arachidonic acid
  • produces PGH2 which produces prostaglandins and thromboxane
  • Thromboxane causes platelet proliferation
  • Prostaglandins act on endothelium
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4
Q

What is another general group of arachidonic acid metabolites?

A

LIPOXYGENASE

5- HPETE

produces leukotrienes

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5
Q

How do inflammatory mediators cause pain?

A

activate the nociceptors on Adelta and C fibres resulting in pain and sensitisation

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6
Q

Where are PGE2 released? ( prostaglandins)

A
  • brain
  • kidney
  • smooth muscle
  • Platelets
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7
Q

Where are prostglandins PGD2 used?

A
  • mast cells
  • airways
  • inflammation
  • pain
  • allergic reactions
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8
Q

How do NSAIDs act on COX2?

A

COX-2 inhibitors

therefore no prostaglandin production in endothelium

no thromboxane production—> no platelets

reduced pain

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9
Q

What are prostaglandins?

A
  • Arachidonic acid metabolits
  • produced by almost all nucleated cells
  • inflammation, immune response, muscle constriction and relaxation
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10
Q

Describe the molecular structure and pharma of prostaglandins

A
  • short half life
  • autocrine and paracrine
  • lipophilic
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11
Q

Where are PGF2alpha and PGE2 used?

A

in obstetrics to soften and shorten the cervix for pre-induction cervical ripening

- PGF2 acts on uterus, eye and smooth muscle

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12
Q

Describe the types of NSAIDs

A

NSAIDs act through inhibition of the two isoforms of cyclooxygenase ( COX) ; COX1 and COX2

  1. Non-selective NSAIDs; act on both COX1 and COX2
  2. Specific COX-2-inhibitors; act on COX-2 enzymes only
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13
Q

Describe COX 1

A
  • normal constituent in the body for homeostasis
  • continuously produced in
  1. Gastric mucosa- gastric cytoprotection
  2. Kindey-sodium and water balance/renal perfusion
  3. Platelets for aggregation
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14
Q

Describe COX2

A
  • INDUCED in presence of injury and inflammation, in inflammatory cells, producing the inflammatory mediators

also a normal constituent in kidney,brain, endothelium, ovary and uterus

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15
Q

Name one for each:

a) Non-selective NSAID
b) Semi-selective NSAID
c) COX-2 inhibitor

A

a) Aspirin, ibuprofen
b) Diclofenac
c) Celecoxib

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16
Q

What are the potential complications of the use of NSAIDs?

A
  • Prostaglandins normally MAINTAIN renal blood flow by
  • INDUCING VASODILATION in afferent arterioles

BUT

  • NSAIDs inhibit prostaglandin production–> harmful hypoperfusion of kidneys and reduced GFR
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17
Q

How is PGE2 affected by COX inhibitors?

A
  • PGE2 is involved in the protection of gastric mucosa; inhibits acid secretion and stimulates mucosal production
  • PGE2 INHIBITION by COX inhibitors will
  • increase mucosal permeability
  • decrease mucosal blood flow and protection

can damage stomach, ulceration, haemorrhage, perforation ( in high doses)

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18
Q

Give an example of :

a) Selective COX1 Inhibitor
b) Non-selective COX inhibitor
c) Selective COX 2 inhibitor

A

a) Aspirin
b) Ibuprofen, Naproxen
c) Diclofenac

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19
Q

What are some risk factors for GI adverse effects of NSAIDs? (5)

A
  • age>65
  • history of GI bleed or ulcer
  • concurrent use of drugs that increase risk of GI adverse events; steroids
  • Heavy smoking/ alcohol use
  • prolonged NSAID use
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20
Q

What are some highly protein bound drugs that can interfere with NSAIDs?

A
  • sulphonylurea ( increased can cause HYPOGLYCAEMIA)
  • warfarin (displaced by aspirin for plasma protein binding–> therefore increased active free conc of Warfarin; INCREASED BLEEDING
  • Methotrexate
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21
Q

What 3 drugs make up the Triple Whammy?

A

concurrent used of :

  1. ACE inhibitor
  2. NSAID
  3. Diuretic
22
Q

Explain the dangers of each drug in the Triple Whammy

A
  • ACEi: decrease glomerular filtration by causing vasodilation of efferent renal arteriole
  • NSAIDs; block COX-2–> prevent prostacyclin synthesis; causing afferent arteriolar constriction
  • Diuretics; contribute to AKI by causing hypovolaemia
23
Q

What do you do if the triple whammy of meds cannot be avoided ie it is necessary?

A
  • baseline testing of serum creatinine and electrolytes
  • patients should be advised to maintain adequate fluid intake

If triply whammy side effects, develop, main goals are

  • Restoration of fluid balance
  • withdrawal of nephrotoxic medicines
24
Q

Give a side effect of ns-NSAID in asthma patients

A
  • non-specific NSAIDs can cause bronchoconstriction in sensitive asthmatic patients
    *
25
Q

Can NSAIDs treat gout?

A
  • yes
  • they inhibit the phagocytosis of urate crystals
26
Q

Name 5 contraindications for the use of NSAIDs

A
  • Pregnancy 3rd trimester
  • Hypertensive
  • Renal and liver disease
  • Asthma
  • Stomach ulcer
27
Q

How do NSAIDs cause side effects?

A
  • NSAIDs competitively block COX1 and COX2 therefore inhibiting prostaglandin synthesis
  • directly irritate GI tract—> increase bleeding time ( inhibit thromboxane A2)
  • cause a renal glomerular vasoconstriction ( prostaglandin inhibition)
28
Q

Give an example of:

a) A protein pump inhibitor
b) Histamine antagonist

A

a) Omeprazole
b) Ranitidine

29
Q

Give some side effects of Mefenamic acid

A
  • acute pain including dysmenorrhoea
  • menorrhagia
30
Q

Describe the pharmacology of paracetamol

A
  • inhibits COX1 and COX2 through metabolism by peroxidase function of these isoenzymes
  • inhibits COX3 predominantly in the brain—> this inhibition of prostaglandin synthesis in the CNS—> produces its antipyretic and analgesic effect

gets metabolised in liver–> to glucoronide and sulpjaye conjugates that are then excreted renally.

31
Q

Describe the absorption of paracetamol

A
  • time taken to reach maximum plasma concentration (Tmax) is 15-30 minutes
  • well tolerated when taken orally
  • On oral administraton, it is absrobed from the intestine (70%), stomach and colon ( 30%)
  • rate of absorption is rapid and depends on the dose
32
Q

Describe the elimination of paracetamol

A

paracetamol is metabolised in the liver and only 2-5% is excreted unchanged

33
Q

What are the indications for paracetamol use?

A
  • analgesic drug for mild to moderate pain
  • First line treatment for chronic pain conditions e.g. osteoarthritis, back pain
34
Q

Name 2 combos/ routes for paracetamol

A
  • Paracetamol + Codeine co-codamol
  • Paracetamol + dihydrocodeine co-dydramo
35
Q

What are the hepatic and renal cautions for use of paracetamol?

A
  • if Liver impairment, use w caution or omit as it is metabolised in the liver
  • in patients w renal impairment, reduce dose of paracetamol
36
Q

What are the cautions of paracetamol?

A
  • alcohol dependency/ liver disease
  • malnutrition
  • chronic dehydration
  • body weight < 50 kg
  • Use of liver enyme (CYP450) inducing drugs e.g. Rifampicin, carbamazepine, phenytoin
  • increasing age/ frailty
37
Q

Why is paracetamol use cautioned in older people?

A
  • with increasing age and frailty, there is a reduction in clearance
  • elderly people hvae comorbidities and polypharmacy–> can increase risk of inadvertent paracetamol toxicity and overdose
38
Q

Describe the overdose of paracetamol

A
  • saturation of Phase II paracetamol pathway ( normal/ zero order) bc enzymes are saturated
  • drug is INSTEAD metabolised via phase I CYP450
  • NAPQI intermediate is conjugated with glutathione but if glutathione reserves are depleted due to excess dose of paracetamol
  • Therefore the reactive intermediate (NAPQI) will exert its toxic effect
39
Q

Give signs of paracetamol overdose

A
  • nausea and vomiting ( but normally none)

LATER FEATURES:

12-36 hrs; abdominal pain

24+ hrs; loin pain, haematuria and proteinuria=signs of renal failure

2-3 days; right subcostal pain, vomiting and jaundice after 2-3 days are features of Hepatic Necrosis

40
Q

What is defined as a paracetamol overdose?

How would you resolve it?

A
  • Single doses> 10g ( ie 20 tablets) potentially fatal to thsoe with compromised hepatic function or alcoholics
  • ANTIDOTE: N-acetylcysteine (NAC) for paracetamol poisoning—> most effective when administered within 8-10 hrs after ingestion
41
Q

Describe the pharmacokinetics of aspirin

A
  • irreversibly inhibits COX enzymes and blocks the production of thromboxane
  • half life is less than 30 mins; rapidly hydrolysed in plasma to salicylate
  • absorbed from stomach
  • converted to salicylate acid, gut liver and plasma
  • 80-85% is bound to plasma proteins and crosses placenta and CSF
42
Q

How exactly does aspirin work?

A
  • TXA2 is synthesized in platelets
  • PGI2 is synthesixed in vascular endothelium

When aspirin inhibits COX, the platelets cannot regenerate TXA2. The vascular endothelium, however, can synthesise PGI2.This creates a relative excess of PGI2 so inhibiting platelet aggregation.

43
Q

How long does aspirin effect on platelets last if only given in a single dose?

A

7-10 days then a new cohort of platelets is produced

44
Q

What are the respiratory effects of aspirin?

A

Direct Stimulation of respiratory centre—> Hyperventilation (occurs due to uncoupling

If phosphorylation ↑ CO2 in Overdose this is the cause of death

– Resp. Alkalosis – Renal Compensation – ↓BP, Resp Acidosis + Metabolic Acidosis

45
Q

What are the metabolic effects of aspirin?

A
  • Increased Cellular Metabolism
  • Increased Utilization of glucose reducing Blood sugar
46
Q

What are the most common signs of aspirin overdose?

A
  • Hyperventilation
  • Respiratory alkalosis
  • Metabolic acidosis after resp alkalosis–> increased anion gap bc of
  1. accumulation of intracellular lactate
  2. excretion of bicarbonate by kidney to compensate for resp alkalosis
47
Q

Name some mild signs of aspirin overdose

A
  • Nausea and vomiting • Tinnitus
  • Deafness
  • lethargy or dizziness.
48
Q

Name 4 moderate to severe signs of aspirin overdose

A
  • dehydration
  • sweating
  • restlessness
  • warm extremities
49
Q

What is Reye syndrome?

A

caused by using aspirin to treat a viral condition in children/ teenagers w an underlying fatty acid oxidation disorder

Children 4-12yrs
• Presents with Encephalopathy & Liver disease
• Diagnosis based on History and presentation
• Medical Emergency - NO ASPIRIN FOR CHILDREN

50
Q

Compare and contrast aspirin with Paracetamol

A

ASPIRIN:

  • Irreversible inhibitor of COX1 and COX2
  • 70% absorbed from upper GI
  • metabolised by esterases in gut wall and liver
  • renal excretion

PARACETAMOL:

  • selective inhibitor of COX3 in CNS
  • upper GI 70-90% absorption
  • metabolised in liver
  • renal excretion
51
Q

Give 3 toxic effects of aspirin and 3 of paracetamol

A

Aspirin:

  1. Reyes syndrome in children
  2. Hepatic/renal impairment
  3. GI upset

PARACETAMOL:

  1. Thrombocytopenia
  2. Liver necrosis
  3. GI upset

Pharmacology Term 6 (10 decks)

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