10 Anti-Inflammation Drugs

Question 1

biosynthesis of eicosanoids/organization

Answer 1

• membrane lipids + PLA C/PLA A2 –> free arachidonic acid
• free AA + COX –> PG, TX
• or free AA + LOX –> LT

Question 2

what do glucocorticoids inhibit?

Answer 2

PLA C, PLA A2

Question 3

what do NSAIDs inhibit?

Answer 3

COX

Question 4

what do LOX inhibitors inhibit?

Answer 4

LOX

Question 5

• what are 2 types of prostanoids?
• generated from? by what enzyme?
• MOA
• targets

Answer 5

• PG and TXA2
• from AA by COX
• regulate physiological processes by binding to GPCRs
• smooth muscle, platelets, CNS, ANS, sensory nerves, endocrine organs, adipose tissue

Question 6

physiological effects of prostanoids on smooth muscle

Answer 6

• vascular
• • vasodilation, vasoconstriction
• GI
• • smooth muscle contraction
• • decreased gastric acid secretion
• lungs
• • vasodilation & constriction
• bronchodilation & constriction

Question 7

physiological effects of prostanoids on platelets

Answer 7

• increase or decrease platelet aggregation

Question 8

physiological effects of prostanoids on reproductive organs

Answer 8

• uterine contractions

- menstrual pain

Question 9

physiological effects of prostanoids on kidneys

Answer 9

• compensatory vasodilation

- increased glomerular filtration rate

Question 10

physiological effects of prostanoids on pro-inflammatory effects

Answer 10

• fever
• pain
• vasodilation & increased vascular permeability

Question 11

• 3 types of adrenocorticosteroids and 4 functions

Answer 11

• glucocorticoids
• mineralocorticoids
• sex hormones
• maintain homeostasis
• mediate stress response
• regulate body fluids
• regulate cell metabolism

Question 12

glucocorticoid regulation and what happens under chronic high glucocorticoid therapy

Answer 12

• hypothalamus releases CRH which stimulates (ant) pituitary
• ACTH from pituitary gland
• ACTH presence causes adrenocortical cells to increase cortisol
• negative feedback of hypothalamic pituitary adrenal axis
• under therapy, ACTH release decreases, adrenal suppression so rapid stopping of therapy –> adrenal insufficiency

Question 13

cortisol MOA

Answer 13

• cortisol enters cell
• complexes
• activates receptor
• inside nucleus, binds to glucocorticoid RE
• gene activation
• mRNA –> protein synthesis to inhibit PLA

Question 14

metabolic effects of glucocorticoids

Answer 14

• carbohydrate metabolism
• protein metabolism
• fat metabolism

= maintenance of glucose to brain

Question 15

anti-inflammatory/immunosuppressive effects of glucocorticoids

Answer 15

• decrease inflammation due to effects on
• • WBC movements
• – neutrophilia
• – decrease all other WBCs
• • effects on WBC and other cell function
• – decrease chemotaxis, enzymes, free radicals
• – decrease PLA A2
• – decrease arachidonic acid –> PG & LT
• – decrease fibroblasts & collagen –> decrease healing
• – decrease macrophage responsiveness
• • vascular effects
• – decrease kinins & histamine release –> decrease capillary permeability/vasoconstriction
• • anti-immune effects
• – decrease macrophage and T cell function
• – decrease T-helper cell function

Question 16

• most important therapeutic effect of glucocorticoids

- problem with this?

Answer 16

• decrease neutrophils & monocytes at site of inflammation
• decrease phagocytic, bactericidal, Ag processing activfity
• decrease eicosanoid production
• immune system is compromised - px susceptible to opportunistic infections

Question 17

• common glucocorticoids - short, intermediate and long acting
• level of anti-inflammatory activity and mineralo-corticoid activity?

Answer 17

• short - eg. prednisone
• intermediate - eg. triamciniolone
• long - eg. dexamethasone
• all high (dexamethosone is VERY high) as anti-inflammatories and low as mineralo-corticoids

Question 18

toxicities (high doses, long periods)

Answer 18

• Cushing’s syndrome (like adrenal tumor - increase in glucocorticoids)
• suppression of immune system
• osteoperosis
• impaired wound healing
• suppression of hypo-pit-axis
• development of diabetes and peptic ulcers
• behavioral problems (psychoses)
• growth problems

Question 19

• NSAID goals
• MOA
• clinical effects

Answer 19

• decrease inflammation, pain, fever
• decrease COX –> decrease PG, TX
• anti-inflammatory
• analgesia
• antipyretic
• platelet effects
• minimal effect on underlying tissue damage or immunologic reactions

Question 20

• 2 eg. salicylates
• MOA
• effects

Answer 20

• eg. aspirin, celecoxib
• decrease COX1 & COX2 –> decrease PG, TXA2
• decrease pain
• decrease temperature/fever,
• decrease inflammation
• increasing bleeding

Question 21

difference between COX 1 & 2?

Answer 21

• COX 1 - constitutive (always present)

- COX 2 - inducible (produced with inflamed)

Question 22

• 3 advantages of aspirin vs opioids

Answer 22

• no tolerance to analgesia
• no dependency
• no CNS depression

Question 23

disadvantage of aspirin

Answer 23

• not for fever in children –> Reye’s (use acetaminophen)

Question 24

NSAID toxicity, general

Answer 24

• blocking both COX 1 & 2 –> decreases PG –> GI disturbances & bleeding
• aspirin irreversibly decreases COX
• newer NSAIDs are reversible

Question 25

NSAID toxicity for - GI - CNS - kidney - bleeding - allergic rx to NSAID - Reye's

Answer 25

- GI - gastric upset, ulceration - CNS - salicylism (tinnitus, nausea, vomiting) - kidney - decreased renal blood flow (necrosis) - bleeding disorder (not for hemophiliacs) - allergic rx --> bronchoconstriction/shock - Reye's - fatty liver and encephalopathy in children with viral disease

Question 26

- rational of selective COX-2 inhibitors - 1 eg. and its MOA - advantages

Answer 26

- allows analgesia and decreases inflammation without side effects - eg. celecoxib - - highly selective only for COX2 - - adverse CV events - - binds to a pocket on active sit of COX2, not found in COX1

Question 27

- advantages of COX2 inhibitor | - toxicity

Answer 27

- effective analgesia - decrease GI toxicity - no effect on TX ad platelets --> no increased bleeding time & decrease platelet aggregation - no renal toxicity - tox - increased risk of heart attack and stroke

Question 28

COX 2 inhibitor indications and other uses

Answer 28

- if acetaminophen doesn't give enough analgesia - if NSAID doesn't provide enough analgesia/can't tolerate GI toxicity - need analgesia for chronic conditions - decrease tumor growth

Question 29

acetaminophen (Tylenol)

Answer 29

- non-opioid - little COX inhibition (non-anti-inflammatory) - may decrease PG synthesis (analgesic, antipyretic) - no antiplatelet effects - overdose --> depletes flutathion --> hepatotoxicity - - treat overdose with N-acetyl cysteine to regenerate glutathion