L29-30 NSAIDS and Inflammatory Steroids →

Question 1

Mechanism of Actions of NSAIDS

Answer 1

Inhibit the Activity of Cyclooxygenase
→ ↓production of prostanoids
→→ ↓vasodilatation and vascular permeability
→→→ ↓oedema, swelling and redness

→→ ↓sensitization of pain nerve endings
→→→ ↓low to moderate pain arisen from integumental structures [i.e. analgesic effect]

→→ ↓set-point of the hypothalamic thermoregulatory center
→→→ ↓ relieve fever [i.e. antipyretic effect]

Question 2

Adverse Effects of NSAIDS

Answer 2

Gastrointestinal Disturbances
→dyspepsia, diarrhoea (or constipation), nausea and vomiting
→ in chronic users
→→gastric damage [i.e. haemorrhage and ulceration]

due to inhibition of prostaglandins production in the gastrointestinal tract
→ ↓ gastric mucus secretion
→ ↑ gastric acid secretion

→ contraindicated in patients with gastric ulcer

Prolonged Bleeding (Especially for Aspirin)
→due to inhibition of thromboxane A2 production in the platelets (irreversible inhibition of cyclooxygenase
→→Platelets - incapable of synthesizing new cyclooxygenase)

Skin Reactions
→rashes, urticaria and photosensitivity reactions

Renal Insufficiency
→ reversible in susceptible patients at therapeutic doses
→→ due to inhibition of prostanoids production in the kidneys
→→→ impair regulation of renal blood flow
→ irreversible “analgesic-associated nephropathy in chronic users

→ Liver Disorders - less common

→Bronchospasm - less common
→→due to leukotrienes production in the airways

Question 3

Precautions with NSAIDS

Answer 3

Pre-Existing Conditions e.g. gastric ulcer, renal disease, cirrhosis, asthma

Drug Interactions
→blood thinners (e.g. heparin or warfarin) [→ ↑ risk of bleeding]
→ angiotensin converting enzyme inhibitors [→ hyperkalemia]
→ protein-bound drugs (e.g. sulfonylurea hypoglycemic agents, warfarin)
→ anti-inflammatory glucocorticoids [→ ↑ risk of gastric bleeding]

Question 4

Classification of NSAIDS

Answer 4

Traditional NSAIDs (tNSAIDs)
→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

Selective Cyclooxygenase Inhibitors →celecoxib

→ Paracetamol (Acetaminophen)

Question 5

Names of preacustion of Salicylates

Answer 5

Representative Drugs
aspirin
→long history of safety
→most commonly used for reducing pain
→considered as an antiplatelet drug

diflunisal
→ lack of antipyretic effect
→ more potent than aspirin
→ no salicylate intoxication

cautions of drug interaction

→salicylates reduce the effects of uricosuric agents (e.g. probenecid or sulfinpyrazone)
→salicylates prolong the effects of penicillin

cautions in patients with the following conditions:
→ compromised cardiac function [→ congestive cardiac failure and pulmonary oedema]
→hypoprothrombinemia or vitamin K deficiency
[due to antiplatelet effect of aspirin → ↑ risk of bleeding]
→ gout [because salicylates compete with urate for organic acid secretory system in proximal
tubule → hyperuricemia]

Question 6

Comparison of Different Traditional NSAIDs

Answer 6

Therapeutic Disadvantages
Salicylates 
→ Aspirin
→→  Upper GI disturbances (COX-1 selective)
→ Diflunisal  
→→No antipyretic effect

Acetic acids
→Indomethacin
→→ Upper GI disturbances
→→Greater toxicity
→Sulindac

Advantage

Salicylates 
→ Aspirin
→→Low cost; 
→→Long history of safety
→Diflunisal
→→Less GI irritation

Propionic acids (Lower toxicity due to COX-2 selectivity)
Ibuprofen
Naproxen

Acetic acids
→Sulindac
→→Longer half-life

Oxicams
→Piroxicam
→→Longer half-life

Question 7

Name Adverse effect of Selective Cyclooxygenase-2 Inhibitors

Answer 7

celecoxib, etoricoxib

anti-inflammatory, analgesic and antipyretic effects

Therapeutic Advantages Compared with Traditional NSAIDs
→ ↓gastrointestinal adverse effects
→ lack of effects on platelets [ no bleeding risk]

Adverse Effects
→ renal insufficiency [due to cyclooxygenase-2 being constitutively active in kidneys]
→ risk of developing cardiovascular thrombotic events

Question 8

Paracetamol (Acetaminophen)

Answer 8

analgesic and antipyretic effects

• lack of anti-inflammatory effect
• therapeutically safe
• only mild adverse effects
  (e. g. skin rash and minor allergic reactions)

BUT: risk of liver and/or kidney damage
[only at toxic dosage]

Avoid Combinations of NSAIDs [risk of additive adverse effects]

Question 9

Anti-inflammatory and Immunosuppressive Effects of Glucocorticoids

Answer 9

→Inhibit Interactions of White Cell Adhesion Molecules with Those on
Endothelial Cells

→ Inhibit the Function of Macrophages and Other Antigen-Presenting Cells
(→ limited phagocytosis, reduced production of cytokines, reduced T cell activation)

→Cause Vasoconstriction and Reduce Capillary Permeability

→Inhibit Production of Prostanoids, Leukotrienes and Platelet-Activating
Factor
(→ ↓ vasodilatation, ↓ vascular permeability, ↓ pain sensitization, ↓ platelet activation)

Question 10

Other Biological Actions of Glucocorticoids

Answer 10

↑ Blood Glucose Level
→ ↑ generation of glucose (gluconeogenesis)
→ ↓ tissue uptake and utilization of glucose

↓ Protein Synthesis and ↑ Protein Breakdown
(→ amino acid for gluconeogenesis in liver)

↑ Lipolytic Responses to Various Hormones
(→ glycerol for gluconeogenesis in liver)

↓ Calcium Absorption from Gastrointestinal Tract and ↑ Calcium
Excretion by the Kidney

Enhance Vascular Reactivity to Other Vasoactive Substances

Affect Neuronal Survival and Activity

Question 11

Mechanism of Action of Glucocorticoids

Answer 11

Bind to glucocorticoid receptors
→ activation / inhibition of gene transcription in the nucleus
→ ↑ / ↓ expression of proteins

Question 12

Different Glucocorticoids

Answer 12

Endogenous Glucocorticoids
→ cortisol (short-acting)

Synthetic Glucocorticoids
→ hydrocortisone and prednisolone
→→ short- to intermediate-acting

-→cortisone and prednisone
→→pro-drug; need to be converted by 11β-hydroxysteroid dehydrogenase type 1
(11β-HSD1) in the liver to biologically active forms (hydrocortisone and
prednisolone, respectively) [ avoided in patients with impaired 11β-HSD1 activity (e.g.
patients with severe hepatic failure)]

→betamethasone and dexamethasone
→→ long-acting
-→→ess commonly used for oral therapy [to avoid adverse effects]

Question 13

Adverse Effects of Glucocorticoids (I)

Answer 13

•  risk with  dose and  duration of treatment

Infections and Peptic Ulcer
→due to suppression of responses to infection

Impaired Wound Healing
→ due to suppression of responses to injury

Insomnia, Euphoria and Depression
→ due to the effects on the nervous system

Osteoporosis
→ due to the effects on calcium metabolism
→due to inhibition of vitamin D activity in osteoblasts

Hyperglycemia → Diabetes Mellitus
→ due to the effects of glucocorticoids on
carbohydrate metabolism

Muscle Wasting and Weakness
→ due to the effects of glucocorticoids on protein metabolism

Redistribution of Fat
→ due to the effects of glucocorticoids on lipase activity and insulin secretion

→ Iatrogenic Cushing’s Syndrome
→→Muscle Weakness and Fatigue
→→ Weight Loss and Loss of Appetite
→→ Hypotension
→→Hyperpigmentation (Patchy or Dark Skin)

Question 14

Withdrawal of Glucocorticoids

Answer 14

→ Adrenal Insufficiency
→→disturbances in fluid and electrolyte balance
→→ hypoglycaemia
→→→Hypoglycaemia during fasting
→→→ Impaired capacity to resist stressful circumstances
e.g. noxious, traumatic or infectious stimuli

→→→→ circulatory shock and even death