Anti-inflammatory Pharm Flashcards
non pharmacological therapeutic options for inflammation
-rest, heat/cold, weight reduction, surgery
two pharmacological therapeutic options for inflammation
-NSAIDs
-glucocorticoids
three main benefits of NSAIDS
-anti-inflammatory effects
-anti-pyretic effects
-analgesic effects
what are prostaglandins required for and what are the synthesized from
-Prostaglandins (PGs) are required for normal homeostasis in all tissues
-They are synthesized from arachidonic acid by cyclooxygenase (COX) enzymes
what are the two main enzymes that prostaglandins are synthesized from
COX1 and COX2
how is COX1 normally present
normal housekeeping enzyme present at low levels in most tissues
how is COX2 normally present
normally present at much lower levels in most tissues but is important for homeostasis in a few tissues (renal medulla, gastric mucosa)
what COX is involved in healing gastric ulcers
COX2
what does thromboxane do
promotion of platelet aggregation
what does prostacyclin do
inhibition of platelet aggregation, vasodilation
what do other prostaglandins do
maintenance of tissue blood flow
what do PGE2 and PGI2 do in the stomach
they are involved in gastric mucosa protection (decreased acid secretion by gastric parietal cells, increased bicarb and mucus production, increased vasodilation)
what is the role of prostaglandins (eicosanoids) in inflammation
-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
what is phospholipase A2 stimulated by
cell membrane damage
what type of enzymes do NSAIDS inhibit
COX enzymes (both 1 and 2)
what is the effect of NSAIDS inhibiting COX enzymes (4)
-Reduces synthesis of PGs, including those that promote vasodilation
-Reduces blood flow to site
-Reduces sensitization of nociceptors
-Alleviates inflammation
what is the overall major benefit of NSAIDS
reduction of bloodflow to site of injury
what are the three main sites of adverse effects of NSAIDs
-gastric mucosa, platelets, kidney
what is the mechanism of adverse effects of the gastric mucosa
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)
what is the most common adverse effect associated with NSAID use
gastric bleeding / ulceration
what is the mechanism of adverse effects of the platelets
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
what is the mechanism of adverse effects of the kidney
-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
what is the outcome of NSAID use that inhibit COX2?
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)
what are drugs that are selective for COX2 called
coxibs
pharmacokinetic properties of NSAIDS (4)
-Weak acids
-Highly protein bound
-Hepatic metabolism (Phase 2 conjugation)
-Variable elimination
shared adverse effects of NSAIDS (5)
-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)
clinical uses of NSAIDS
For the relief of musculoskeletal & inflammatory pain, including post-operative pain
contraindications of NSAIDS
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.
what is the only NSAID that blocks COX enzymes irreversibly?
aspirin
in vitro vs in vivo effects of aspirin inhibition
In vitro it is a non-selective inhibitor of COX 1 & 2, but in vivo it acts mainly to inhibit COX 1
what species is aspirin approved in
cattle and horses
is the therapeutic margin wide or narrow for aspirin
narrow
adverse effects of aspirin (4)
- 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)
contraindications of aspirin
- Cats (though it has been used)
- Animals with bleeding disorders
- Animals prone to GI ulcers
(e.g., those receiving glucocorticoids)
what is the most popular NSAID for horses
phenylbutazone
inhibition features of phenylbutazone
Non-selective inhibitor of COX 1 & 2
duration of action of phenylbutazone in horses
24h
adverse effects of phenylbutazone
- GI ulceration common; more likely
with high dosages or prolonged use - Renal papillary necrosis in
dehydrated animals - IM injection causes tissue necrosis
contraindications of phenylbutazone
- Animals with bleeding disorders
- Animals prone to GI ulcers
(e.g., those receiving glucocorticoids)
what species is carprofen approved in
dogs
selective nature of carprofen
Somewhat selective for COX 2, therefore fewer GI adverse effects compared to other NSAIDs (incl. meloxicam)
what is a rare but serious ADR for carprofen and how to avoid it
Rare but serious Type B ADR: idiosyncratic acute hepatotoxicity in <1 in 2,000 dogs; can be fatal -> monitor hepatic function before & during therapy
therapeutic margin for carprofen
narrow
when to use/avoid carprofen and side effects
-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
what species is ketoprofen approved in
most of them
selective nature of ketoprofen
Inhibits COX enzymes non-selectively, and to some extent LOX enzymes = inhibits leukotriene & bradykinin production in addition to inhibiting PG synthesis
half life vs duration of action for ketoprofen
Short serum half life (~ 2 h) but long duration of action (~24 h) because it distributes to inflamed tissue well
what species if flunixin approved for
horses and cattle
most common adverse effect of ketoprofen
vomiting
selective nature of flunixin
Inhibits COX enzymes non-selectively,
also inhibits some leukocyte functions
what is the result of high doses/long duration of flunixin
High dosages or prolonged use cause
GI ulceration
does flunixin have a long or short duration of action
long
meloxicam inhibition
Inhibits both COX1 & COX2 (COX2 more so)
what species is meloxicam used in to alleviate musculoskeletal pain and inflammation
dogs, cats, pigs, & cattle
adverse effects of meloxicam
-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)
contraindications of meloxicam
-Animals with bleeding disorders
-Animals prone to GI ulcers (e.g., those receiving glucocorticoids)
what are the adverse effects of meloxicam most commonly associated with and how can you prevent them
Most often these problems are associated with overdose or coadministration of another NSAID or a corticosteroid
=Monitor GI and renal parameters during tx
most common adverse effect with non selective NSAIDS
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)
what is an example of a coxib (3)
deracoxib, firocoxib, rovenacoxib (onsior)
what species and use is deracoxib approved for
-Approved for dogs only
-Approved for osteoarthritis, post-op pain
-Little effect on platelets/bleeding because platelet COX1 not inhibited
significantly
what is long term coxib use associated with in humans
increased MI risk
what is the mechanism behind long term coxib use and intravascular coagulation
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
why isnt acetaminophen considered an NSAID anymore
-Inhibits PG synthesis centrally (in CNS) = antipyretic, analgesic
-Little peripheral activity so poor anti-inflammatory effect and no effect on blood clotting
where are steroid hormones produced
adrenal cortex
what are mineralocorticoids required for
Na+ & water conservation
what are glucocorticoids required for
-increase blood glucose levels
-inhibit inflammation
-inhibit leukocyte function
two types of corticosteroids
glucocorticoids and mineralocorticoids
what are corticosteroids synthesized from
cholesterol
what indirectly inhibits phospholipase A2 and what is the outcome of that
glucocorticoids = This inhibits the synthesis of AA, and therefore the synthesis of not only PGs, but also
leukotrienes= inhibits inflammation & essentially all WBC functions
what do glucocorticoids do to acheive elevated blood glucose levels (4)
-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
what is the effect of glucocorticoids on leukocytes and the outcome of that
they inhibit virtually all leukocyte functions which leads to higher susceptibility to infection
what do high levels of glucocorticoids lead to? and what are the catabolic effects of that
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.
what is a common adverse effect of CHRONIC glucocorticoid administration
osteoporosis
absorption, distribution, metabolism and elimination of glucocorticoids
absorption = Oral; IM / SQ; intra-articular; topical
distribution = Carried in blood by albumin & transcortin
metabolism = Hepatic ADRs possible
excretion = Urine / feces
when do you tend to see adverse effects with glucocorticoid use
Serious adverse effects are usually only seen after ~2 weeks of continuous therapy (dose-dependent)
what are some adverse effects of glucocorticoid use
- 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
therapeutic principles for glucocorticoid use (8)
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
what must you do when stopping glucocorticoid use
MUST wean patient off drug GRADUALLY
what is secondary to abrupt glucocorticoid cessation
HYPOadrenocorticism
why does HYPOadrenocorticism happen after glucocorticoid use
-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!
clinical use of glucocorticoids for arthritis
-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)
