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MBBS II MSS > L24 - Non-opioid Analgesics > Flashcards

L24 - Non-opioid Analgesics Flashcards

1
Q

List the 2 classes and subclasses of Non-opioid analgesics?

A

1) Paracetamol/ Acetaminophen

2) NSAIDs
a) traditional non-selective NSAIDs
b) selective cyclooxygenase -2 inhibitors

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2
Q

Advantages of paracetamol?

A
  • Cheap
  • Analgesic effect (= preferred drug against mild to moderate pain)
  • Therapeutically safe (skin rash, minor allergic reactions)
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3
Q

Toxic effects of paracetamol/ acetaminophen?

A

Liver and/ or kidney damage at toxic dosage

Kidney excretion = kidney damage

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4
Q

Explain why patients with low GSH must be cautious taking paracetamol?

A

Normal:

Paracetamol converted to reactive toxic intermediate NAPQI, which is converted by GSH to meracapturic acid conjugate

Low GSH = massive increase in plasma NAPQI concentration = liver cell death triggered

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5
Q

Explain how paracetamol can trigger asthma?

A

Mercapturic acid conjugate from paracetamol metabolism can use up Glutathione (an antioxidant) in GSH conjugation of NAPQI

Depletion of glutathione in lungs trigger asthma

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6
Q

Risk of hepatotoxicity from paracetamol is increased in which patients?

A
  • Glutathione (GSH) depletion (low level, e.g. fasting / malnutrition, smoking (uses up antioxidants))
  • Cytochrome enzyme induction (e.g. heavy / chronic alcohol consumption)
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7
Q

Risk of hepatotoxicity by paracetamol is reduced by what?

A

Risk reduced by treatment with N-acetylcysteine&raquo_space; increase antioxidant reserve before irreversible toxic damage

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8
Q

List the 3 effects of NSAIDs?

A
  • Anti-inflammatory effect
  • Analgesic effect
  • Anti-pyretic effect
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9
Q

Describe the physiological responses in inflammation.

A

Pathogen antigen binds to receptors on surface of dendritic cells and macrophages

> > Trigger release of Pro-inflammatory Cytokines: Tumour necrosis factor-a (TNF-a); Interleukin-1 (IL-1)

> > Cause vasodilation and increased vascular permeability

> > Cause expression of adhesion molecules for WBC migration

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10
Q

Describe the pathway to make prostanoids in inflammation?

A

Stimuli stimulates phospholipase A2 to convert membrane phospholipids into Arachidonic acid

COX converts arachidonic acids into:

1) Prostaglandins:
 PGE2 in macrophages
 PGI2 in endothelial cells
 PGD2 in mast cells

2) Thromboxane: TXA2 in platelets

Lipoxygenase converts arachidonic acid into Leukotrienes

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11
Q

What cytokine cascades are triggered in acute inflammatory response

A

1) Plasma fibrinogen cascade
2) Complement cascade (release histamine for lysis of bacteria by WBC)
3) Factor XIIa triggering Coagulation cascade, Fibrinolytic cascade and Kinin cascade (Bradykinin released)

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12
Q

Function of bradykinin?

A
  • Increase vascular permeability
  • Spasmogen

Generates eicosanoids and NO for vasodilation (like histamine)

  • Causes pain
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13
Q

What are the cardinal signs of acute inflammation?

A

Redness, Swelling, Fever, Pain

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14
Q

Explain the physiological reactions that cause swelling in acute inflammation?

A

Action of prostanoids:

Increase postcapillary venule permeability by histamine and bradykinin

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15
Q

Explain the physiological reactions that cause redness in acute inflammation?

A

Dilate precapillary arterioles to increase blood flow and cause redness

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16
Q

Explain the physiological reactions that cause pain in acute inflammation?

A

Potentiate pain by bradykinin

Sensitization of pain nerve endings

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17
Q

Explain the physiological reactions that cause fever in acute inflammation?

A

Inflammation factors Increase set-point of hypothalamic thermoregulatory center

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18
Q

MoA of NSAIDs?

A

Inhibit the activity of cyclooxygenase = decrease production of prostanoids:

1) Decrease vasodilation and vascular permeability = lower edema, swelling and redness
2) Lower sensitization of pain nerve endings = decrease low to moderate pain/ analgesic effect
3) Decrease set-point of the hypothalamic thermoregulatory center = relieve fever/ antipyretic

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19
Q

NSAIDs can be used to treat pain in internal viscera. True or False?

A

False

NSAIDs have no effect on viscera except uterus (during menstruation)

Only lower pain from integumental structures

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20
Q

Adverse effects of NSAIDs?

A
  • GI disturbances: dyspepsia, diarrhoea (or constipation), nausea and vomiting
  • Prolonged bleeding
  • Skin reactions: e.g. rashes, urticaria and photosensitivity reactions
  • Renal insufficiency
  • Liver disorders
  • Bronchospasm
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21
Q

Explain why NSAIDs cause GI disturbances?

A

Inhibit prostaglandins production in gastrointestinal tract (defensive factor):

Decrease gastric mucus secretion and increase gastric acid secretion

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22
Q

Explain how NSAIDs can cause prolonged bleeding?

A

due to inhibition of thromboxane A2 production in the platelets
» Decrease platelet aggregation means poor coagulation

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23
Q

Explain the drug interaction between aspirin and NSAIDs?

A

Aspirin = Irreversible inhibition of cyclooxygenase

Platelets have no ability to code for proteins and make new COX&raquo_space; Inhibition of platelet activation for the life time of the platelet

NSAIDs = COX inhibitor = worsen decrease in platelet aggregation = poor coagulation

24
Q

Explain why NSAIDs can cause renal insufficiency?

A

inhibition of prostanoids (RENAL ANGIOTENSIN) production in the kidneys
= impair regulation of renal blood flow

irreversible “analgesic-associated nephropathy” in chronic users

(Kidneys rely on renal angiotensin for blood flow regulation in ppl with heart problems and renal dysfunction)

25
Q

Explain how NSAIDs can cause bronchospasm?

A

Arachidonic acid is converted to Lipoxygenase to Leukotriene

COX inhibition creates excess of arachidonic acid&raquo_space; excess Leukotrienes made&raquo_space; NSAIDs-induced
bronchoconstriction

26
Q

What drugs can be used to overcome NSAIDs-induced

bronchoconstriction ?

A
  1. 5-LO inhibitors (e.g. Zileuton): inhibit 5-lipoxygenase&raquo_space; cannot convert arachidonic acid to cysteinyl-leukotrienes
  2. LT antagonists (e.g. Montelukast)&raquo_space; Block leukotrienes from acting on CysLT1 receptors&raquo_space; block trigger of bronchoconstriction
27
Q

NSAIDs precautions and contraindications? (not including drug interactions)

A
  • Elderly
  • Pregnancy [impaired fetal circulation and ↑ risk of postpartum haemorrhage]
  • Gastric ulcer patients
  • Renal disease patients
  • Liver cirrhosis patients
  • Asthma patients
28
Q

List all 5 drug interactions of NSAIDs?

A
  • blood thinners (e.g. heparin or warfarin) [NSAID block coagulation cascade]
  • angiotensin-converting enzyme inhibitors (NSAID contribute to hyperkalemia and arythmia)
  • protein-bound drugs (e.g. sulfonylurea hypoglycemic agents, warfarin)
  • anti-inflammatory glucocorticoids [↑ risk of gastric bleeding]
  • Other OTC NSAIDs [increase risk of adverse effects]
29
Q

5 classes of traditional NSAIDs? (SAPOF)

A
  • Salicylates e.g. aspirin, diflunisal
  • Propionic Acids e.g. ibuprofen, naproxen
  • Acetic Acids e.g. indomethacin, sulindac
  • Oxicams e.g. piroxicam
  • Fenamates e.g. meclofenamic acid
30
Q

What plasma concentration of salicylate is the threshold for intoxication?

A

Above 50 mg/dL

31
Q

What are the effects of Salicylate i.e. aspirin at therapeutic dosage?

A 
Analgesic 
Antipyretic 
Antiplatelet 
Uricosuric 
Anti-inflammatory
32
Q

What are the adverse effects of Salicylate i.e. aspirin at therapeutic dosage?

A

Gastric intolerance
Bleeding
Hypersensitivity reactions

33
Q

Adverse effects of salicylate at mild intoxication dose?

A

Tinnitus

Central Hyperventilation

34
Q

Adverse effects of salicylate at moderate intoxication dose?

A

Fever
Dehydration
Metabolic Acidosis

35
Q

Adverse effects of salicylate at severe intoxication dose?

A

Vascular Collapse
Coma
Hypoprothrombinemia

36
Q

Adverse effects of salicylate at lethal intoxication dose?

A

Renal and Respiratory Failure

37
Q

Precautions of Salicylates?

A
  • Children with fever due to viral illness (Reye’s syndrome: liver, brain damage)
  • Gout (gouty flare)
  • hypoprothrombinemia or vitamin K deficiency
  • compromised cardiac function
38
Q

Contraindicated drugs against use of salicylate?

A
  • uricosuric agents (e.g. probenecid or benzbromarone)

- penicillin [block its active transport in the proximal tubule of the kidneys]

39
Q

Advantages and Disadvantages of Diflunisal?

A
  • Advantage: as potent as aspirin + no salicylate intoxication (cannot cross BBB)
  • Disadvantage: No antipyretic effect
40
Q

Why is COX 2 inhibition better than COX 1?

A

COX-1 = constitutive in body, important for normal physiological function

COX-2 = Induced only at inflammatory sites

COX-2 inhibition = more targeted and less broad adverse effects:

  • Less GI adverse effects
  • Less effects on platelets
41
Q

Which NSAIDs have long half life?

A

Sulindac

Piroxicam

42
Q

Which NSAIDs have low toxicity?

A

Ibuprofen

Naproxen

43
Q

Which NSAID have low cost and long history of safety?

A

Aspirin

44
Q

Which NSAID has low GI irritation but no antipyretic effect?

A

Diflunisal

45
Q

Which NSAIDs causes Upper GI disturbances?

A

Aspirin

Indomethacin

46
Q

Which NSAID has great toxicity?

A

Indomethacin

Very potent; Other COX-independent actions

47
Q

List 2 NSAIDs -highly COX 1 selective?

A

Aspirin

Tolmetin

48
Q

List 2 NSAIDs - highly COX 2 selective?

A

Celecoxib

Rofecoxib

49
Q

Which NSAIDs are neither selective towards COX-1 or COX-2?

A

Diclofenac

Naproxen

50
Q

COX -2 inhibitors are better at causing less renal damage than COX -1 inhibitors. True or False?

A

False

cyclooxygenase-2 is constitutively active in kidney

51
Q

Explain how selective COX -2 inhibitors can cause cardiovascular thrombotic events?

A

Inhibit cyclooxygenase-2 in endothelial cells

> > less PGI2 made

> > loss of inhibition on platelet adhesion, activation, aggregation

52
Q

Which NSAIDs have blackbox warning for thrombotic events?

A

Celecoxib
Rofecoxib

Highly COX-2 selective

53
Q

What are 5 considerations when choosing NSAIDs?

A
  • Efficacy
  • Safety (more COX-2 selective but not totally COX-2 only)
  • Cost-effectiveness
  • Patient individual differences (age, allergy…etc)
  • Avoid combo of NSAIDs
54
Q

Which NSAIDs are more effective than aspirin?

A

ibuprofen, naproxen and diflunisal are more effective than aspirin

55
Q

What patient group should avoid NSAIDs totally?

A

High GI risk + High CV risk

MBBS II MSS (31 decks)

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