Antiiflammatory drugs

pharmacology midterm 1-7

What are the five signs of inflammation?

heat, redness, swelling, pain, loss of function

vasodilation (not actually increasing the temperature, just feels warmer)- brings blood supply to the injured tissues for repair

heat

vasodilation - blood vessels are closer to the skin giving it a reddish appearance

redness

prevents movement of joints, reducing further injury

swelling

prevents using the affected part

pain

prevents using injured part

loss of function

goal of anti-inflammatories

decrease pain associated with inflammation

substances called __ are produced when tissue traumatized

Eicosanoids

what produces the signs of inflammation

Eicosanoids

Eicosanoids include:

prostaglandins, leukotrienes, and thromboxanes

How anti-inflammatory drugs reduce inflammation

by blocking formation of these eicosanoids

Decreased inflammation = fewer pain signals = reduced perception of pain

summary

Steroidal antiinflammatories

glucocorticoid (GC) or corticosteroids (CS) drugs

Non-steroidal antiinflammatories

NSAIDs

Hormones that are produced by the cortex of the adrenal

Adrenocorticosteroids

-regulate electrolyte and water balance have no anti-inflammatory effect

Mineralocorticoids

What is the natural mineralocorticoid- causes the kidney to reabsorb sodium from the urine back into the body

aldosterone

-participate in homeostasis

-maintain supply of blood glucose (mobilize fatty acids and amino acids for glucose production)

-Maintain microcirculation, normal vascular

-permeability and stability of lysosomal membranes

-suppress inflammatory reactions: this is mostly obtained with pharmacological doses, not with natural concentrations

• inhibit synthesis of cytokines (inhibit T-cell immunity) and arachidonic acid metabolites

• upregulate anti-inflammatory mediators (e.g.,TGF-beta)

glucocorticoids

Mineralocorticoid

-used to treat clinical signs of hypoadrenocorticism (Addison’s disease)

-Mimic’s aldosterone’s effect by increasing reabsorption of sodium from urine and retaining it in the body

-Reabsorption of sodium also pulls water osmotically along with it and increases blood volume (discussed in cardio under the effect of aldosterone in the renin-angiotensin system)

Desoxycorticosterone

the natural glucocorticoid released by the adrenal cortex

cortisol

what causes release of CRF from the hypothalamus

stress and CNS activity

CRF (Corticotropin-Releasing Factor) or CRH (Corticotropin-Releasing Hormone) stimulate what to release what?

stimulates pituitary to release ACTH

ACTH (Adrenocorticotropic Hormone) stimulates what to release what

adrenal gland cortisol production

Cortisol produces what kind of feedback

negative

When sufficient cortisol is present, what happens to the further release of CRF and ACTH

The negative feedback shuts down further release of CRF and ACTH

Decreased ACTH mean adrenal gland is no longer stimulated →

stops producing cortisol, Cortisol levels drop

When cortisol levels drop, this __ the inhibition on the hypothalmus and pituitary and CRF/ACTH start to be released again

removes

have the same negative feedback suppression on CRF and ACTH release that natural cortisol does →this decrease adrenal activity and cortisol

Exogenous glucocorticoids = glucocorticoid drugs

-short acting,12 hours

-intermediate acting 12-36 hours

-long acting 48+ hours

Longer the duration of action, the longer the anti-inflammatory benefit..

But the longer the duration, the longer the suppression of the hypothalamus and pituitary release of CRF and ACTH and the longer there is decreased adrenal gland production of natural cortisol…

…greater the risk for side effects

Types of glucocorticoid drugs

short acting glucocorticoids (<12 hr effect)

-used for topical medications

-very similar to natural cortisol

“Cortisone“ is a hormone, but it is NOT used in vet med as a drug because it must be activated by the liver to hydrocortisone - not going to happen if applied topically

Hydrocortisone

Intermediate acting glucocorticoids (12-36 hr effect)

-are ideally suited for alternate day dosing

“Preds“ = prednisone, prednisolone, methylprednisolone and triamcinolone

-these drugs are essentially the same in the dog

-conversion of prednisone to prednisolone is less efficient in the cat (metabolism) - so cat dose of prednisone is higher than cat dose of prednisolone to achieve the same degree of anti-inflammatory effect

Prednisone must be converted by the liver to prednisolone for its maximal effect

Long acting glucocorticoids (> 48 hrs effect)

-Longer anti-inflammatory effect BUT longer suppression of hypothalamus and pituitary with adrenal suppression

• greater risk for side effect related to 48 + hour continuous effect on many systems in the body

“methasones” - dexamethasone, betamethasone, flumethasone

-drug dissolved in water

• drug name plus “sodium” “phosphate“ added

• can be given safely IV high doses

Aqueous solution

-drug dissolved in alcohol

• drug name without additional compound listed

• given IV but not as high a dose as aqueous solutions

alcohol solution

-drug floating in liquid, but not dissolved in it

• link between glucocorticoid and other molecule must be severed by tissue enzyme at injection site

• glucocorticoid is releases a little at a time over several days to week-drug acts as a depot or repositol drug

• provides long beneficial effect, but equally as long suppression of the adrenal gland activity and cortisol

• NEVER given IV

• suspension crystals can be altered by extreme temperatures →can cause painful injections or alter ability of molecule combination to release glucocorticoid molecule

suspensions

Glucocorticoid four dosages

-all dosages except physiological dosage are supraphysiological dosages meaning they introduce far greater levels and effects of glucocorticoids than could be achieved with natural production of cortisol

physiological, anti-inflammatory, immunosuppressive dosage, shock dosage

type of glucocorticoid dosage

-dose that replaces amount of natural endogenous cortisol in a 24 hour period (e.g., 0.2 mg/kg/d)

physiological dosage

type of glucocorticoid dosage

-dose that is used to control allergies, hives, injury inflammation (e.g., 1-2 mg/kg/d)

anti-inflammatory dosage

type of glucocorticoid dosage

-dose tat is used to suppress the immune system and to treat autoimmune disease like immune mediated hemolytic anemia, pemphigus (e.g, 2-6 mg/kg/d)

immunosuppressive dosage

type of glucocorticoid dosage

-very high doses - generally not recommended any more for treatment of shock, spinal trauma, etc. (e.g, 30 mg/kg/d)

shock dosage

Glucocorticoid effects

-decreases formation of prostaglandins, leukotrienes

-maintains capillary integrity (decreases swelling/edema)

anti-inflammatory effect (dousing the fire of inflammation) is by inhibition of phospholipase A2

Glucocorticoid effects

-decreases collagen fiber synthesis-can delay tissue healing (what impact might this have on recovery from surgery?)

-decreases scar formation (scar is not flexible, disfiguring)

decreased FIBROBLAST activity at anti-inflammatory and > dosages- fibroblasts produce strong collagen fibers

Glucocorticoid effects

-anti-inflammatory dosages will suppress activation of T-cell lymphocytes (T-cells) and its cell mediated immunity (CMI)

-cell mediated immunity is the major defense against bacteria and fungi - glucocorticoids increase risk of fungal infection

Decreased immune response (used to decrease allergies and destructive autoimmune responses)

Glucocorticoid effects

-at anti-inflammatory doses, have minimal effect on B cells

-B-cells’ humoral immunity is what generates antibodies against foreign antigens

-vaccine ability to produce Ab’s is mostly unaffected at anti-inflammatory doses

-immunosuppressive doses do suppress some B cell function

B-lymphocytes (B cell) response (humoral immunity) affected far less than T cell

Glucocorticoid effects

-glucocorticoids cause lymphocytes and eosinophils to become sequestered (taken up) by tissues → fewer of these cells remain in systemic circulation to be sampled (lymphopenia, eosinopenia)

-glucocorticoids cause neutrophils “parked” along the blood vessel walls (the marginating pool) to come off the walls and re-enter circulation (neutrophilia)

glucocorticoid stress response - reflects physiologic stress such as disease or trauma

Glucocorticoid effects

-Gastritis and ulcer risk increases when GC and NSAIDs are used together (both block COX 1 enzyme that normally produces increased mucus and decreases acid production)

Increased gastric acid secretion and decreased mucus production in humans - predisposes stomach and duodenum to injury from stomach acid (pH 2-3)

Glucocorticoid effects

-natural cortisol helps the body get through a physiological stress by increasing glucose available for use to the body

-breaks down protein (muscle protein, protein for hair, etc.) to amino acids which are converted by the liver into glucose for body energy

-muscle atrophy, “pot bellied“ appearance, alopecia, skin gets thin

Glucocorticoid drugs are catabolic- they break down body protein

Glucocorticoid effects

-GC drugs are absolutely contraindicated for use in the eye if a corneal ulcer is present (often added to ophthalmic drops to relieve inflammation)

-GC increases activity of enzyme called collagenase in corneal stroma that breaks down the middle stroma layer of cornea between two thin epithelial cell layers

-suppress epithelial and endothelial regeneration and delays healing

-ulcer worsens tot he point the inner thin cell layer (descemet’s membrane) protrudes through the ulcer hole (descemetocele) and the eye can rupture

ophthalmic complications

Glucocorticoid effects

-increase in natural cortisol at end of gestation normally causes production of local prostaglandins that lyse the corpus luteum and stop the production of progesterone (the hormone that maintains pregnancy)→ labor starts

GC drugs can stimulate the onset of parturition in near term mares

Glucocorticoid effects

-catabolism of skeletal muscle → protein →amino acids → glucose by the liver (gluconeogenesis)

-elevated glucose may affect control of a diabetic patient

-usually short term anti-inflammatory doses of glucocorticoids do NOT warrant a change in insulin dosing

glucocorticoid drugs increase blood glucose (for body energy)

Glucocorticoid effects

-GC inhibit Antidiuretic hormone (ADH) → results in polyuria

-Polydipsia - needed to replace lost fluid

-Polyphagia - not clear cause - may be due to impairing action of satiety molecule leptin (they don’t feel satisfied - still have appetite)

Client education issue !!

PU,PD,PP at anti-inflammatory doses

Glucocorticoid effects

-increased water in the blood= increased blood volume to be pumped by the heart = increased work load on heart (bad in weakened hearts)

All glucocorticoids have some mineralocorticoid effects, there is often retention of sodium in the body and subsequent retention of water in the body in spite of the PU

-Hyperadrenocorticism (form any cause) = Cushing’s Disease

-Cushing’s disease caused long term or high dose of GC drug administration = iatrogenic Cushing’s (iatrogenic= iatros (healer) + genic (causing)

CAUTION: if this condition occurs due to GC drug administration, do NOT immediately stop the drug!

Iatrogenic Cushing’s Disease

Iatrogenic Cushing’s Disease

Signs relate to physiological changes previously described

-pot belly (abdominal muscle wasting), muscle atrophy

-hair loss on lower trunk and legs (high water line)

-PU,PD,PP

-drugs that decrease inflammation like glucocorticoids, but do not have the “steroid“ ring in their molecular makeup (hence are NONsteroidals)

-Blocks prostaglandin and leukotriene formation by blocking COX and LOX

-in the 1900’s research showed the COX (cycloogenase) enzyme came in two forms

Nonsteroidal Anti-inflammatories Drug (NSAIDs)

NSAIDs - two forms of COX

• what form of COX is an enzyme that produces PGs involved in many normal physiological process (vasodilation, secretions, cell replication, etc.)

COX 1

NSAIDs - two forms of COX

• what form of COX is an enzyme that produces PGs that are primarily involved with the physiological changes associated with inflammation

COX 2

Prostaglandins produced by COX1 and 2

-enzyme is normally always there

-location in many different systems throughout the body

-GI tract: increases stomach mucus and bicarbonate buffer secretion

-increases gastric cell turnover (healing) and perfusion (amount of blood flow)

-Causes renal vasodilation under conditions of hypotension

COX 1-produced PG (good)

Prostaglandins produced by COX1 and 2

-Inducible enzyme (increases in response to inflammation)

-localized to tissue location that injured

-causes signs associated with inflammation

COX 2-produced PG (bad)

Types of NSAIDs

classic NSAIDs and Selective COX 2 inhibitors (COXIBs)

Classic NSAIDs

Aspirin. Flunixin megulmine, phenylbutazone

Selective COX 2 inhibitors (COXIBs)

Carprofen, Etodolac, Meloxicam, Deracoxib, Firocoxib, Robenacoxib

NSAIDs all block “wind up” or “central sensitization” from injury

-increased pain signals being sent to spinal cord

Causes increased COX 2 enzyme production in dorsal horn of spinal column

NSAIDs all block “wind up” or “central sensitization” from injury

-COX 2 causes increased inflammatory PGs in the spinal cord

*This is “wind up” or “central sensitization“*

pain transmission becomes easier and overcomes the normal opioid dampening

NSAIDs all block “wind up” or “central sensitization” from injury

-Greater number of nociceptive (pain) impulses successfully reach the conscious level in brain

perceived as greater pain coming from region

-drug molecules are small enough to distributes from the blood to tissues

-proteins are very large molecules and they cannot distribute to the tissue (they are “trapped“ with the systemic circulation)

All NSAIDs are highly protein bound to proteins in the blood

-the dose of NSAID takes into account that a high percentage of drug molecules are going to be attached to protein and unavailable to distribute to tissue to produce the anti-inflammatory effect

Drugs that are highly protein bound have many of their molecules “stuck” on protein in the blood

-normal protein binding (shown above) of NSAIDs means that only a small percentage of drug dose is free to sistribute to the tissues

-Hypoproteinemia=fewer protwins in the blood for the drug dose to bind to

-Causes of hypoproteinemia: liver disease (liver produces the proteins), protein losing enteropathy (GI disease), protein losing nephropathy (renal disease)

Hypoproteinemia effect on NSAIDs

-With less blood protein, there are fewer bound molecules and more free molecules

-More drug molecules can distribute to the tissue and produce a greater effect than normal

-Dose of highly protein-bound NSAIDs may need to be decreased under hypoproteinemia conditions to prevent toxic concentrations from reaching tissues

Hypoproteinemic Blood and Binding

Side effects of NSAIDs

-Inhibition of COX 1 enzyme results in:

• decreased bicarb-rich mucus production

• increased acid production

• decreased perfusion of GI tissue

• decreased cell turnover (healing)

Most frequent side effect: GI irritation (due to COX 1 inhibition)

Side effects of NSAIDs

specific to GI tract: V/D

Gastritis and ulceration produce signs of vomiting, hematemesis (vomiting of blood), and melena (black, tarry stool from digested blood)

Side effects of NSAIDs

-COX 2 selective NSAIDs will produce COX 1 inhibition at higher doses (these drugs lose their COX selectivity at higher doses)

Non-selective (classic) NSAIDs are more prone to produce gastritis and ulcers than the COX-2 selective NSAIDs because non-selective NSAIDs block COX 2 and COX 1 (“good“ COX)

Side effects of NSAIDs

Treatment for ulcers include:

-Sucralfate to protect open ulcer site

-H2 blocker antacids (cimetidine, famotidine, ranitidine) and omeprazole antacids to reduce acid production

-misoprostol to provide synthetic prostaglandin to counteract

Side effects of NSAIDs

NSAIDs also inhibit COX that produces renal ___ PGs that protect kidney flow under low arterial blood pressure conditions (hypotension)

vasodilating

Side effects of NSAIDs

-alpha receptor stimulation causes vasoconstriction of renal arterioles (along with vasoconstriction of GI tract and skin)

Hypotension normally activates sympathetic nervous system to bring the arterial blood pressure back to normal

Side effects of NSAIDs

-vasodilation offsets vasoconstriction and maintains flow

Vasodilation → decreased renal blood flow → kidney activates COX to produces PGs that causes renal vasodilation

Side effects of NSAIDs

-NSAIDS will block renal vasodilating COX

-Low blood pressure + NSAID = marked decrease blood flow to the kidney (some parts of kidney will be deprived of adequate oxygen)

• the renal “papilla“ are where the renal tubules come together at the tip of the renal pyramids to dump urine into renal pelvis

• Pappillae have poor blood supply anyway so the cells at the tips of the renal papillae begin to die from inadequate oxygen supply → renal papillary necrosis

NSAID induced Renal Papillary Necrosis

Side effects of NSAIDs

-no drop in arterial blood pressure → no activation of sympathetic nervous system → no renal vasoconstriction

• maintain arterial pressure with IV fluids duringsurgery (rehydrate prior to Sx)

• prevent dehydration (e.g., have water available for animals at all times- especially hot day)

• avoid using drugs that produce hypotensive effects (e.g., vasodilators used to treat cardiac disease or acepromazine)

Key to decreasing renal papillary necrosis risk is to maintain normal blood pressure while on NSAIDs

Side effects of NSAIDs

NSAIDs hepatotoxicity has been reported with some COX 2 selective inhibitor NSAIDs

*this is RARE, IDIOSYNDRACTIC reaction* (discussion w/ carprofen)

Toxic side effects ranked in order of occurence are:

1. GI side effects (most common)

2. renal side effects (can be prevented by maintaining arterial BP)

3. hepatotoxicity (rare and idiosyncratic-not predictable)

Classic NSAIDs (inhibit both COX 1 and 2) - SALICYLATE

-one of the few safe in both dogs AND cats

-primary use in vet med is for chronic joint inflammation (arthritic hip w/ hip dysplasia)

NOTE: make sure surgical patients have been off this for a week before having the surgery

Aspirin

Effects regarding ASPIRIN

-Net effect of aspirin blocking TBX → decreases platelet aggregation → decreases platelet plug formation → get small hemorrhages (visible on mucus membranes)

COX inhibition also blocks formation of thromboxane (TBX-A2 causes platelets to clump together to form a platelet plug)

Aspirin effects:

__ → thickened ventricular wall → less flexibility prevents ventricle from contracting properly → normal smooth blood flow through the heart is disrupted

-disrupted blood flow creates turbulence

-turbulence creates clots

-clots can aggregate at distal bifurcation of femoral arteries (produce saddle thrombus)

-Aspirin decreases spontaneous clot formation

feline cardiomyopathy

Aspirin Metabolism:

• primarily removed via ___ (most NSAIDs are metabolized via this)

• This conjugates aspirin (combines it with another molecule)

hepatic metabolism

Cats are not very good at conjugating salicylate (or other NSAIDs)

-Salicylates and other NSAIDs take longer to leave the cat’s body - can accumulate in body if dose not adjusted for cat

-Cats have limited amount of what?

Glucuronyl transferase, glycine and glucuronic acid

• Man- 1.5 hours

• Ruminant - 1 hour

• Horse - 5 hours

• Dog - 8 hours

• Cat - 1 to 1.5 DAYS

• Aspirin IS safe to use in cats if dosed properly (e.g., baby aspirin given every 2 days)

Half life of elimination for salicylates in mammals

Classic NSAIDs (inhibit both COX 1 and 2) - BANAMINE

-approved in EQ, BO for laminitis and colic

• stronger analgesia effect then aspirin

• concern that analgesic effect may mask colic signs delaying owner seeking veterinary help

-Horses tolerate drug better than dogs

• high incidence of hemorrhagic gastritis in dogs when used (extra label) - within 3 days

Flunixin Meglumine

You should avoid Flunixin Meglumine in horses with what?

Equine Gastric Ulcer Syndrome (EGUS)

Classic NSAIDs (inhibit both COX 1 and 2)

-Old, non-selective NSAID used for years to treat equine lameness and musculoskeletal inflammation

-Highly protein-bound (99%) - reduce dose if patient has hypoproteinemia to avoid toxicity side effects

-FDA may eventually ban the drug from any food-producing animals due to aplastic effects in humans

• Jockey died from this self-administration a dozen times over 3 years

Phenylbutazone (“bute”)

Classic NSAIDs (inhibit both COX 1 and 2) - Phenylbutazone

Why do you not use this in dogs?

Hepatotoxic effect and aplastic anemia

Classic NSAIDs (inhibit both COX 1 and 2) - Phenylbutazone

-IV and PO only!

What happens if you give this SQ or IM

necrosis and skin sloughing

-selective for BLOCKING COX 2 - doesn’t readily bind to COX 1 at normal doses

• “coxib“ describes any selective COX 2 inhibitor

• “COX 1 sparing“ “COX 2 specific“ means the drug has affinity for binding to COX 2 enzyme site over COX 1

COX 2 selective inhibitors

COX 2 selective inhibitor drugs are __ ___ to cause stomach upset because less COX 1 activity is inhibited → “good“ prostaglandins can still be produced (GI, kidney)

less likely

But COX 2 selectives DO or DO NOT totally protect against gastritis (they just decrease the risk for GI toxic side effects)

-AVOID complacency in using COX 2 inhibitors - we must still be vigilant and educate clients to watch for signs of GI upset

Do NOT

Selective COX 2 inhibitor - Rimadyl

-First, approved in US for dogs ONLY

-does NOT inhibit thromboxane like aspirin

-RARE! few cases of adverse reaction (less than 0.02%)- death even less

Carprofen

Selective COX 2 inhibitor - Carprofen (Rimadyl)

Hepatic toxicity appears to be idiosyncratic

what does this mean?

can’t predict which patients

Selective COX 2 inhibitor - Carprofen (Rimadyl)

what breed disproportionately reported (25%) - reflects breed popularity and incidence of hip problems

Labrador Retrievers

Selective COX 2 inhibitor

-Approved in US for dogs to treat osteoarthritis

-used less than carprofen, but still effective once-daily drug relief from canine hip dysplasia

-Preferentially inhibits COX-2, but less selective than other COX-@ selective NSAIDs (some argue)

-Appears NOT to be very specific for COX-2 in horses (reflects variability between species)

Etodolac

Selective COX 2 inhibitor - Etodolac

-is chemically similar to sulfa antibiotics - has had reports of ___

KCS (keratoconjunctivitis sicca or “dry eye“)

Selective COX 2 inhibitor — Deramaxx

-approved in US for dogs only for osteoarthritis pain

-Anti-inflammatory, analgesic, and antipyretic (reduces fever) like all the rest of the COX 2 selective NSAIDs

-Higher dose approved for Post-op surgical pain

-incidence of GI side effects is about the same as other COX 2 selective NSAIDs

Deracoxib