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Pharmacology > Anti-inflammatory Pharm > Flashcards

Anti-inflammatory Pharm Flashcards

1
Q

non pharmacological therapeutic options for inflammation

A

-rest, heat/cold, weight reduction, surgery

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2
Q

two pharmacological therapeutic options for inflammation

A

-NSAIDs
-glucocorticoids

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3
Q

three main benefits of NSAIDS

A

-anti-inflammatory effects
-anti-pyretic effects
-analgesic effects

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4
Q

what are prostaglandins required for and what are the synthesized from

A

-Prostaglandins (PGs) are required for normal homeostasis in all tissues

-They are synthesized from arachidonic acid by cyclooxygenase (COX) enzymes

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5
Q

what are the two main enzymes that prostaglandins are synthesized from

A

COX1 and COX2

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6
Q

how is COX1 normally present

A

normal housekeeping enzyme present at low levels in most tissues

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7
Q

how is COX2 normally present

A

normally present at much lower levels in most tissues but is important for homeostasis in a few tissues (renal medulla, gastric mucosa)

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8
Q

what COX is involved in healing gastric ulcers

A

COX2

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9
Q

what does thromboxane do

A

promotion of platelet aggregation

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10
Q

what does prostacyclin do

A

inhibition of platelet aggregation, vasodilation

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11
Q

what do other prostaglandins do

A

maintenance of tissue blood flow

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12
Q

what do PGE2 and PGI2 do in the stomach

A

they are involved in gastric mucosa protection (decreased acid secretion by gastric parietal cells, increased bicarb and mucus production, increased vasodilation)

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13
Q

what is the role of prostaglandins (eicosanoids) in inflammation

A

-COX2 is up-regulated in response to plasma membrane damage or inflammatory mediator release COX2 induction is a local response that occurs at the site of cell damage or mediator release = marked vasodilation occurs, promoting inflammation

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14
Q

what is phospholipase A2 stimulated by

A

cell membrane damage

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15
Q

what type of enzymes do NSAIDS inhibit

A

COX enzymes (both 1 and 2)

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16
Q

what is the effect of NSAIDS inhibiting COX enzymes (4)

A

-Reduces synthesis of PGs, including those that promote vasodilation
-Reduces blood flow to site
-Reduces sensitization of nociceptors
-Alleviates inflammation

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17
Q

what is the overall major benefit of NSAIDS

A

reduction of bloodflow to site of injury

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18
Q

what are the three main sites of adverse effects of NSAIDs

A

-gastric mucosa, platelets, kidney

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19
Q

what is the mechanism of adverse effects of the gastric mucosa

A

The normal protective effects of
PGs in the stomach are inhibited,
resulting in:
-Decreased blood flow, bicarb
secretion, & mucus secretion
-Increased acid secretion
=gastric bleeding +/- ulceration
(the most common adverse effect
associated with NSAIDs)

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20
Q

what is the most common adverse effect associated with NSAID use

A

gastric bleeding / ulceration

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21
Q

what is the mechanism of adverse effects of the platelets

A

Only COX1 is present in platelets NSAIDs inhibit the conversion of AA to thromboxane in platelets = result is a slightly increased general tendency to bleed

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22
Q

what is the mechanism of adverse effects of the kidney

A

-COX enzymes produce PGs that maintain adequate blood flow to many tissues, including the renal
medulla
-Excessive COX inhibition can lead to
renal medullary hypoxia & papillary necrosis

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23
Q

what is the outcome of NSAID use that inhibit COX2?

A

NSAIDs that preferentially inhibit COX2 (e.g., carprofen, etodolac, meloxicam, etc.) are associated with fewer episodes of gastric ulceration/bleeding, compared to non-selective blockers of COX1 & 2 (e.g., aspirin)

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24
Q

what are drugs that are selective for COX2 called

A

coxibs

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25
Q

pharmacokinetic properties of NSAIDS (4)

A

-Weak acids
-Highly protein bound
-Hepatic metabolism (Phase 2 conjugation)
-Variable elimination

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26
Q

shared adverse effects of NSAIDS (5)

A

-GI ulceration
-Inhibition of platelet aggregation = bleeding (most likely with aspirin)
-Inhibition of uterine motility
-Inhibition of PG-mediated renal perfusion
-Renal papillary necrosis in dehydrated animals (a problem with many NSAIDs)

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27
Q

clinical uses of NSAIDS

A

For the relief of musculoskeletal & inflammatory pain, including post-operative pain

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28
Q

contraindications of NSAIDS

A

As with all non-steroidal anti-inflammatory drugs (NSAIDs), administration of this drug is advised against in the following circumstances:
* Animals with gastro-intestinal ulcers, renal disease, hepatic
disorders, hypoproteinemia, dehydration, or cardiac disease;
* A known hypersensitivity to the drug;
* Concurrent use of other NSAIDs or corticosteroids.

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29
Q

what is the only NSAID that blocks COX enzymes irreversibly?

A

aspirin

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30
Q

in vitro vs in vivo effects of aspirin inhibition

A

In vitro it is a non-selective inhibitor of COX 1 & 2, but in vivo it acts mainly to inhibit COX 1

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30
Q

what species is aspirin approved in

A

cattle and horses

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31
Q

is the therapeutic margin wide or narrow for aspirin

A

narrow

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32
Q

adverse effects of aspirin (4)

A
  • Bleeding; inhibits platelet function
    (in humans, 3-8 mL blood lost per day with ordinary doses) bovine platelets not affected
  • Dose-dependent gastric ulceration
    (subclinical at low doses)
  • Renal damage in dehydrated animals
  • Avoid in cats (deficient in glucuronide conjugation)
33
Q

contraindications of aspirin

A
  • Cats (though it has been used)
  • Animals with bleeding disorders
  • Animals prone to GI ulcers
    (e.g., those receiving glucocorticoids)
34
Q

what is the most popular NSAID for horses

A

phenylbutazone

35
Q

inhibition features of phenylbutazone

A

Non-selective inhibitor of COX 1 & 2

36
Q

duration of action of phenylbutazone in horses

A

24h

37
Q

adverse effects of phenylbutazone

A
  • GI ulceration common; more likely
    with high dosages or prolonged use
  • Renal papillary necrosis in
    dehydrated animals
  • IM injection causes tissue necrosis
38
Q

contraindications of phenylbutazone

A
  • Animals with bleeding disorders
  • Animals prone to GI ulcers
    (e.g., those receiving glucocorticoids)
39
Q

what species is carprofen approved in

A

dogs

40
Q

selective nature of carprofen

A

Somewhat selective for COX 2, therefore fewer GI adverse effects compared to other NSAIDs (incl. meloxicam)

41
Q

what is a rare but serious ADR for carprofen and how to avoid it

A

Rare but serious Type B ADR: idiosyncratic acute hepatotoxicity in <1 in 2,000 dogs; can be fatal -> monitor hepatic function before & during therapy

42
Q

therapeutic margin for carprofen

A

narrow

43
Q

when to use/avoid carprofen and side effects

A

-Used mainly to manage musculoskeletal pain associated with arthritis, trauma, & surgery
-GI ulcers & perforation are uncommon
-Vomiting, anorexia, and diarrhea are the most common adverse effects
-Avoid in cats

44
Q

what species is ketoprofen approved in

A

most of them

45
Q

selective nature of ketoprofen

A

Inhibits COX enzymes non-selectively, and to some extent LOX enzymes = inhibits leukotriene & bradykinin production in addition to inhibiting PG synthesis

46
Q

half life vs duration of action for ketoprofen

A

Short serum half life (~ 2 h) but long duration of action (~24 h) because it distributes to inflamed tissue well

47
Q

what species if flunixin approved for

A

horses and cattle

47
Q

most common adverse effect of ketoprofen

A

vomiting

48
Q

selective nature of flunixin

A

Inhibits COX enzymes non-selectively,
also inhibits some leukocyte functions

49
Q

what is the result of high doses/long duration of flunixin

A

High dosages or prolonged use cause
GI ulceration

50
Q

does flunixin have a long or short duration of action

A

long

51
Q

meloxicam inhibition

A

Inhibits both COX1 & COX2 (COX2 more so)

52
Q

what species is meloxicam used in to alleviate musculoskeletal pain and inflammation

A

dogs, cats, pigs, & cattle

53
Q

adverse effects of meloxicam

A

-Dogs: occasional GI distress, vomiting, diarrhea, loss of appetite, hematuria
-Renal papillary necrosis in dehydrated animals
-Cats: renal problems (elevated creatinine / BUN; acute renal failure)

54
Q

contraindications of meloxicam

A

-Animals with bleeding disorders
-Animals prone to GI ulcers (e.g., those receiving glucocorticoids)

55
Q

what are the adverse effects of meloxicam most commonly associated with and how can you prevent them

A

Most often these problems are associated with overdose or coadministration of another NSAID or a corticosteroid
=Monitor GI and renal parameters during tx

56
Q

most common adverse effect with non selective NSAIDS

A

GI ulceration & bleeding, which is greatly reduced with coxibs if the patient has no pre-existing gastric lesions (COX2 PGs are involved in healing of GI lesions)

57
Q

what is an example of a coxib (3)

A

deracoxib, firocoxib, rovenacoxib (onsior)

58
Q

what species and use is deracoxib approved for

A

-Approved for dogs only
-Approved for osteoarthritis, post-op pain
-Little effect on platelets/bleeding because platelet COX1 not inhibited
significantly

59
Q

what is long term coxib use associated with in humans

A

increased MI risk

60
Q

what is the mechanism behind long term coxib use and intravascular coagulation

A

Coxibs block only COX2, and therefore inhibit PGI2 synthesis while leaving TXA2 synthesis intact

This tips the balance in favour of aggregation = overall increased risk of intravascular coagulation and
therefore stroke & myocardial infarction

61
Q

why isnt acetaminophen considered an NSAID anymore

A

-Inhibits PG synthesis centrally (in CNS) = antipyretic, analgesic
-Little peripheral activity so poor anti-inflammatory effect and no effect on blood clotting

62
Q

where are steroid hormones produced

A

adrenal cortex

63
Q

what are mineralocorticoids required for

A

Na+ & water conservation

64
Q

what are glucocorticoids required for

A

-increase blood glucose levels
-inhibit inflammation
-inhibit leukocyte function

65
Q

two types of corticosteroids

A

glucocorticoids and mineralocorticoids

66
Q

what are corticosteroids synthesized from

A

cholesterol

67
Q

what indirectly inhibits phospholipase A2 and what is the outcome of that

A

glucocorticoids = This inhibits the synthesis of AA, and therefore the synthesis of not only PGs, but also
leukotrienes= inhibits inflammation & essentially all WBC functions

68
Q

what do glucocorticoids do to acheive elevated blood glucose levels (4)

A

-Stimulate hepatic glucose synthesis from amino acids and lipids
-Inhibit glucose uptake by muscle & adipose
-Stimulate fat breakdown in adipose
-Mobilize amino acids from non-hepatic tissues

69
Q

what is the effect of glucocorticoids on leukocytes and the outcome of that

A

they inhibit virtually all leukocyte functions which leads to higher susceptibility to infection

70
Q

what do high levels of glucocorticoids lead to? and what are the catabolic effects of that

A

hyperadrenocorticism

Catabolic effects:
* Decreased muscle mass
* Thinning of skin
* Osteoporosis

Also cause “centripetal” redistribution of fat, antagonize effect of vitamin D on calcium absorption, etc.

71
Q

what is a common adverse effect of CHRONIC glucocorticoid administration

A

osteoporosis

72
Q

absorption, distribution, metabolism and elimination of glucocorticoids

A

absorption = Oral; IM / SQ; intra-articular; topical

distribution = Carried in blood by albumin & transcortin

metabolism = Hepatic ADRs possible

excretion = Urine / feces

73
Q

when do you tend to see adverse effects with glucocorticoid use

A

Serious adverse effects are usually only seen after ~2 weeks of continuous therapy (dose-dependent)

74
Q

what are some adverse effects of glucocorticoid use

A
  • Increased appetite, thirst, & urination
  • Impaired wound healing/thinning of skin
  • Hypertension (mineralocorticoid activity, RAS activation, etc.)
  • Edema
  • Negative calcium balance (osteoporosis)
  • Gastric ulcers
  • Psychoses / euphoria
  • Infection
  • ‘Centripetal’ fat distribution & hair loss
75
Q

therapeutic principles for glucocorticoid use (8)

A

1) Except for replacement therapy, use is largely empirical = alleviation of a patient’s symptoms until initial insult has been resolved (if possible)

2) Consider risks / benefits in that patient (Goal is toleration of condition, not complete relief)

3) Dose very dependent on disease/patient = trial and error (Use smallest possible dose)

4) Re-evaluate periodically (Gradually reduce dose to minimum acceptable)

5) Generally, even large single doses are harmless (Crisis situation)

6) < 1 week unlikely to be harmful

7) Time & dose related to toxicity (> 1 week)

8) With chronic use, abrupt cessation = adrenal insufficiency (e.g., hypoglycemia +/- hyperkalemia, hyponatremia, hypotension) = MUST wean patient off drug GRADUALLY

76
Q

what must you do when stopping glucocorticoid use

A

MUST wean patient off drug GRADUALLY

77
Q

what is secondary to abrupt glucocorticoid cessation

A

HYPOadrenocorticism

78
Q

why does HYPOadrenocorticism happen after glucocorticoid use

A

-Drugs such as cortisone, prednisone, and prednisolone, which have some
mineralocorticoid activity, will suppress the patient’s aldosterone levels during therapy
-Aldosterone levels may be inadequate following abrupt cessation of the glucocorticoid, resulting in:
=Na+ and water loss  low BP
=K+ retention  arrhythmias

–> These effects may be fatal!

79
Q

clinical use of glucocorticoids for arthritis

A

-Provide early to minimize damage from inflammation - patient should exercise affected joints moderately to slow disease progress
-Caution re: “masking” of pain = patient may overuse & injure inflamed joints (e.g., athletes)

Pharmacology (16 decks)

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