Pharmaco of Inflammation - Welsh 4/13/16 Flashcards Preview

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Flashcards in Pharmaco of Inflammation - Welsh 4/13/16 Deck (21):
1

inflammation signs and symptoms

SHaRP

  1. swelling
  2. heat
  3. redness
  4. pain

how?

  • vasodilation → increased blood flow to area → red/warm
  • increased vessel permeability → plasma moves into interstitial tissues, edema
  • pressure on nerves and infl chemicals → pain

2

infl response

  • purpose
  • 3 key processes

infl response serves to...

  • prevent spread of pathogens
  • minimize tissue damage
  • promote repair/healing

 

3 key processes involved:

1. vasodilation → increased blood flow

2. increased cap permeability → plasma leakage into surrounding area → edema

3. migration of neutrophils&leukocytes into area

3

infl response

 

cells that come through and what they do

1. neutrophils

  • first WBCs to come to the site
  • remove damaged tissue by phagocytosis

2. macrophages

  • come a little later than neutrophils (after 1-2h on through next few days), and are more long-lived
  • phagocytose pathogens and cellular debris
  • engulf neutrophils during resolution of inflammation

3. mast cells

  • mediate wound healing and defense against pathogens
  • release histamine (vasodil), play key role in allergies/eczema/anaphylaxis

4

kinin cascade

involved in pain reception in inflammation

together, PG and bradykinin → stimulation of pain neurons 

 

kinins cause vasodilation, increase vessel permeability, lower bp, stimulate pain receptors

  • prostaglandins produced in massive amounts in infl response potentiate bradykinin action → amplify pain signal
  • sometimes pain will continue long after infl (undesirable)

5

prostaglandins

 

nomenclature and classification

general features

originally found in prostate glands, but really found all over body

  • all derivatives of arachidonic acid
  • members of eicosanoid family (eicosa=20 → 20C molecules), which includes:
    • prostaglandins (ex. PGE2)
    • thromboxanes (ex. TXA2)
    • leukotrienes
  • *prostaglandins + thromboxanes collectively = prostanoids

 

general features

  • work like hormones BUT work locally (versus systemically)
  • same prostaglandin may behave diff in diff tissues of body

6

function of prostanoids

 

non inflammatory players

many fx unconnected with infl, such as...

  • PGE2, PGF2alpha: promote gastric mucus secretion, prevent gastric acid secretion

[below, 2 molecules with offsetting effects...]

  • PGI2 aka prostacyclin: inhibits platelet aggregation, vasodil
    • prevents clots!
  • TXA2: promotes platelet aggregation, vasoconst

[implication: need a BALANCE of these two!]

7

function of prostanoids

 

inflammatory mediates

main player: PGE2, produced by mast cells and macrophages

  • vasodilation
  • increased vasc permeability
  • pain reception
    • increased sensitivity of pain receptors to bradykinin
    • pain neuromodulation: enhances sensation of pain in dorsal horn of spinal cord
  • pyresis (fever)

8

biosynthesis of PGE2

PGE2 major inflammatory prostanoid

synthesized from arachidonic acid in mast cells and macrophages at site of injury

key step: upregulation of cyclo-oxygenase 2 [COX2]

  • induced by inflammation in mast cells/macrophages

 

compare/contrast COX2 with...COX1

  • expressed constitutively in most cells of body
  • produces PGs involved in housekeeping fx, maintaining homeostasis

9

prostaglandin synthesis: big picture

membrane PL → arachidonic acid [phospholipase] → cyclic endoperoxides [COX1 or COX2] → prostaglandins [prostaglandin synthases]

 

10

NSAIDs

 

effects

examples

Non-Steroidal Anti-Inflammatory Drugs

mechanism: inhibition of COX2

effects:

  • analgesic (pain-killing)
    • reduction in swelling/edema (counters dull pain)
    • reduction in bradykinin-induced pain
    • reduction in allodynia (hyper-tenderness)
  • antipyretic (fever-reducing)
  • in high doses, anti-inflammatory effects
    • reduce production of PGE2
    • analgesic effects occur faster than anti-infl effects
  • anti-aggregates (inhibit platelet production)

ex. aspirin, ibuprofen, indomethacin, naproxen, diclofenac

11

NSAID side effects:

  • how do they occur
  • common side effect
  • contraindications

COX1 and COX2 are isozymes: v similar structures

  • drugs targeting COX2 often bind and cross-react with COX1

 

ie. while NSAIDs can drop inflammatory PGE2 levels → anti-infl effect...

NSAIDs can also affect COX1-mediated non-infl housekeeping effects of prostaglandins

  • ex. reduction in PGE2/PGF2alpha that promote gastric mucus secretion to protect stomach → GI upset

 

contraindicated in: pt with peptic ulcer, hypersensitivity to aspirin, coag defects, severe heart failure, etc

12

aspirin-induced asthma

 

mechanism

aspirin is an NSAID : blocks COX2 mediated rxn by which arachidonic acid → PGE2

  • now you have a backlog of arachidonic acid, which is shunted into alt pathway: 5-lipoxygenase pathway

arachidonic acid → 5HPETE → leukotrienes [5-lipoxygenase]

  • LTC4, LTD4, LTE4 are major players in pathways associated with inflammatory and immune response (allergic rxn, anaphylactic shock)

13

aspirin as NSAID

 

  • modern use and why 
  • unique mech

among oldest, but now less popular due to GI symptoms and Reye's syndrome

today: more popular as anti-platelet drug for CAD patients at risk for thrombosis

  • inhibits TXA2 production in platelets → reduces ability to coagulate with fibrin
  • lower doses can be used to avoid GI upset

 

unique mechanism (among NSAIDS): irreversible covalent binding to active site of platelet COX1 and COX2 → long lasting effect!

  • since platelets are anuclear (no nucleus, no transc/transl to make new proteins...), only way around it is to make NEW proteins!

14

COX2-selective inhibitors

 

why?

why not?

if you could selectively inhibit COX2, you could...

  • downreg inflamatory PGE2 → get analgesic, anti-infl effects

AND

  • NOT affect COX1-derived housekeeping PGE2, PGF2alpha in gut → not get GI side effects

 

didn't work out too well...

  • Vioxx and other COX2-selective drugs led to increased risk of CV events → too great a shift in PGI2/TXA2 balance towards vasoconst/aggregation 

15

low dose aspirin and CHD

beneficial for preventing CHD

  • inhibits both COX1 and COX2 → blocks synthesis of TXA2, but not really of PGI2
  • net result: reduced platelet aggregation

16

major effects of NSAIDs

 

  • 3 sites and effects at each
  •  

@ site of infl: inhibition of COX2 → decreased PGE2 → decreased infl

@ GI tract/stomach: inhibition of COX1 → decreased PGE2, PGF2alpha → GI upset

@ CV system: effect on homeostasis via offsetting effects of TXA2, PGI2

  • COX1-derived TXA2 in platelets → vasoconstriction & aggregation
  • COX2-derived PGI2 (prostacyclin) in endothelium → vasodilation & anti-aggregation

17

summary of major effects of:

non-selective NSAIDs

COX2-selective NSAIDs

baby aspirin

 

  • inflammation, GI tract, CV effect

A image thumb
18

why does a COX2-selective inhibitor have a negative CV effect while baby aspirin has a positive CV effect?

inhibition of COX2 leads to an imbalance in TXA2 (pro-clotting, COX1-derived) and PGI2 (anti-clotting, COX2-derived) → negative CV effect

  • seen in COX2-selective NSAIDs

baby aspirin hits a sweet spot where it can inhibit COX1 in platelets → forcing shift in TXA2/PGI2 towards PGI2

  • TXA2 is made in platelets (anuclear) → aspirins effects are long lasting bc platelets cant just make more enzyme

19

acetaminophen

  • effect
  • mechanism
  • adverse effects
    • antidote

not an NSAID : analgesic and anti-pyretic, but NOT ANTI-INFL

mechanism: not sure exactly how, but somehow reduces prostaglandin synthesis

  • reduction of PG in CNS/hypothalamus → anti-pyretic effect

adverse effects: hepatotox can occur at only 2-3x therapeutic dose → production of NAPQI [P450, 2E1], which depletes glutathione reserves → liver necrosis

  • NAPQI producing pathway (via 2E1) is favored in alcoholics

antidote: N-acetylCys (NAC) via IV → increases stores of antiox glutathione → promotes drug metabolism/excretion

20

steroidal anti-inflammatory drugs

  • anti-infl mechanism
  • key side effect

 

examples

  • other side effects

cortisol (endogenous) and hydrocortisone, prednisolone, methylprednisolone, dexamethasone (synthetic)

  • direct anti-infl effects: downregulate COX2 → downreg production of infl prostaglandins
  • immunosuppressive effects: reduces activity of mast cells, macrophages → reduces production of histamine, infl activity
    • therefore, prefer moderate-acting steroids at min dosage

indicated in many disorders with inflammatory components: allergic rxns, asthma, IBS, arthritis, bursitis, etc.

 

side effects

  • suppression of injury response, wound healing, response to infection
  • suppression of endogenous corticosteroids
  • muscle wasting
  • osteoporosis
  • fluid retention
  • Cushingoid face ("moon face")

21

metabolic complications of corticosteroid therapy

carbohydrates

  • stimulate gluconeogenesis, glycogen synthesis
  • inhibit uptake of glucose by muscle cells
  • hyperglycemia, weight gain, diabetes, insulin resistance

lipids

  • stimulate hormone-sensitive lipase (HSL) → lipolysis
  • dyslipidemia, altered fat distribution (moon face)

proteins

  • protein catabolism
  • muscle wasting, osteoporosis