Pharmacology Tutoring Anti-inflammatory drugs

What is the goal of anti-inflammatories?

decrease pain associated with inflammation

What are produced when tissues are traumatized (they produce the signs of inflammation)?

Eicosanoids

What do eicosanoids include?

prostaglandins, leukotrienes, thromboxanes

What do anti-inflammatory drugs do to the eicosanoids?

block formation of the eicosanoids overall reducing inflammation

What are the 2 types of anti-inflammatory drugs?

Steroidal and NON-steroidal

What makes up mammaliam cellular membranes?

Phospholipids

What happens when cellulcar trauma occurs?

Phospholipase A2 breaks down phospholipids which releases arachidonic acid

What is Cyclooxygenase (COX)?

an enzyme that converts arachidonic acid into prostaglandins and thromboxanes

What is Lipoxygenase (LOX)?

an enzyme that converts arachidonic acid into leukotrienes

What are nociceptors?

pain receptors

What part of the pathway do corticosteroids inhibit/block?

phospholipase A2 (prevents arachidonic acid from being released)

What part of the pathway do NSAIDs inhibit/block?

COX and LOX

What are hormones produced by the adrenal cortex called?

adrenocorticosteroids/corticosteroids

What are the 2 types of corticosteroids?

mineralcorticoids and glucocorticoids

What is the natural mineralcorticoid?

aldosterone

What does aldosterone do?

causes the kidney to reabsorb sodium from the urine back into the body

What do mineralcorticoids do?

regulate electrolytes and water balance

Do mineralcorticoids have anti-inflammatory effects?

No

Name all the functions of glucocorticoids.

-homeostasis

-maintain supply of blood glucose

-maintain microcirculation

-permeability and stability of lysosomal membranes

-suppres inflammatory reactions

What is the ONLY mineralcorticoid used in vet med?

Desoxycorticosterone

What is desoxycorticosterone used for?

treat clinical signs of hypoadrenocorticism (addison's disease) by mimicking aldosterone's effect

What is the natural glucocorticoid released by the adrenal cortex?

cortisol

What does CRF stand for?

Corticotropin-Releasing-Factor

What does CRF do?

stimulates pituitary to release ACTH

What is ACTH? what does it do?

Adrenocorticotropic Hormone- stimulates adrenal gland cortisol production

What causes release of CRF from hypothalamus?

stress and CNS activity

What does it mean when it says that cortisol produces negative feedback?

cortisol tells brain/pituitary gland to stop releasing CRF/ACTH

decreased ACTH means...

adrenal gland is no longer stimulated and it stops producing cortisol

When cortisol levels drop what happens?

it removes the inhibition on the hypothalamus and pituitary and CRF/ACTH startes to be released again

Duration of short acting glucocorticoids

Duration of intermediate acting glucocorticoids

12-36 hours

Duration of long acting glucocorticoids

48+ hours

What occurs with use of longer acting glucocorticoids?

the longer the duration, the longer the suppression of hypothalamus and pituitary release of CRF/ACTH, which means there is a longer decrease of adrenal gland production of natural cortisol = greater side effects

Name the short acting glucocorticoid drugs

hydrocortisone

Why is "cortisone" not used in vet med as a drug

it must be activated by the liver to hydrocortisone-which won't happen if applied topically

Name they intermediate acting glucocorticoicds

prednisone, prednisolone, methylprednisolone, triamcinolone

What is special about prednisone?

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

**cats can't do this efficiently so we normally just give them prednisolone

Name the long acting glucocorticoids

"methasones"- dexamethasone, betamethasone, flumethasone

aqueous solution

-drug dissolved in water

-can be given IV safely

-drug name plus "sodium" "phosphate"

alcohol solution

-drug dissolved in alcohol

-can be given IV but lower doses

-drug name WITHOUT additional compound listed

suspensions

-drug floating in liquid, but not dissolved in it

- drug name + acetate, pivalate, acetonide or valerate

What form of glucocorticoid should you NEVER give IV? Why?

suspensions, suspension crystals can be altered by extreme temperatures and can cause painful injections

What are the 4 glucocorticoid dosages?

-physiological

-anti-inflammatory

-immunosuppressive

-shock

Physiological dosage

dose that replaces amount of natural endogenous cortisol in a 24 hours period

Anti-inflammatory dosage

dose that is used to control allergies, hives, injury inflammation

Immunosuppressive dosage

dose that is used to suppress the immune system and to treat autoimmune diseases like IMHA or pemphigus

Shock dosage

very high dosages-generally not recommented any more for treatment of shock or spinal trauma

true or false: all doses except shock dosages are supraphysiological dosages

False: physiological dosages

What does supraphysiological dosage mean?

they introduce far greater levels and effects of glucocorticoids than could be achieved with natural production of cortisol

Glucocorticoids stop inflammation by inhibition of what?

phospholipase A2

What some of the effects of glucocorticoids?

-anti-inflammatory

-decrease formation of prostaglandins and leukotrienes

-decrease fibroblasts activity

-decrease collagen fiber synthesis

-decreases scar formation

-decrease immune response

At anti-inflammatory doses, which cell do glucocorticoids have more of an effect on, T cells or B cells?

T cells

anti-inflammatory dosages will suppress activation of the T-cells and its ____

CMI (cell-mediated immunity)

What is the major defense against bacteria and fungi.

CMI (cell-mediated immunity)

What will you see on a CBC for a dog that has the "glucocorticoid stress response"?

decrease in lymphocytes and eosinophils, increase in neutrophils

What does it mean when glucocorticoids are catabolic?

they break down body protein

What is 1 risk of giving glucocorticoids and NSAIDs together?

increased risk of gastritis and stomach ulcers

What are some of the symptoms of glucocorticoids that have a catabolic effect?

-muscle atrophy

-"pot-belly" appearance

-alopecia

-thin skin

Why are glucocorticoids absolutely contraindicated in patients with corneal ulcers?

-increase activity of enzyme collagenase which breaks down collagen. collagen makes up cornea's structure so if we are breaking that down, then ulcer gets worse/deeper

-also slows healing of ulcers

How can glucocorticoids simulate onset of parturition in mares?

-natural rise in cortisol leads to release of prostaglandins. this breaks down corpus luteum.

-corpuse luteum makes progesterone, when this is stopped, labor starts

How do glucocorticoids increase blood glucose levels?

-break down muscle protein which releases amino acids. the liver then converts the amino acids into glucose through gluconeogenesis

-liver releases new glucose into bloodstream causes hyperglycemia

What are the 3 P's side effects of glucocorticoids

polyuria, polydipsia, polyphagia

What does it mean when all glucocorticoids have SOME mineralcorticoid activity?

they can cause kidneys to retain sodium --> increases blood volume --> increases blood pressure

What does iatrogenic mean?

that "WE" caused it, meaning the medical treatment we used for the patient caused that disease

If a patient develops iatrogenic cushing's disease due to glucocorticoids, should you immediately stop the drug?

NO, always taper down

What are the 5 rules of safe use of glucocorticoids?

1. in you can use an NSAID, use it

2. avoid continuous use

3. use smallest dose, and decrease dose when possible

4. always taper gradually

5. dogs are more sensitive to effects than cats

Where in the inflammation pathway do NSAIDs work?

COX and LOX

True or False: there are 2 forms of cyclooxygenase (COX)

true

What is an enzyme that produces PGs involved in many normal physiological processes (vasodilation, secretions, cell replication)

COX 1

What is an enzyme that produces PGs that are primarily involved with the physiological changes associated with inflammation?

COX 2

Which form of COX is good?

COX 1

Which form of COX is always present?

COX 1

Name the classic NSAIDs.

-aspirin

-flunixin megulmine

-phenylbutazone

Name all the selective COX 2 inhibitors (COXIBS)

-carprofen

-etodolac

-meloxicam

-deracoxib

-firocoxib

-robenacoxib

Discuss the NSAID "wind up"

When there are increased pain signals being sent to spinal cord --> increase of COX 2 enzyme which increases inflammtory PGs in spinal cord. Spinal cord becomes hyper actice and greater pain is perceived

True or False: All NSAIDs are highly protein bound to proteins in the blood

True

Dose of highly protein-bound NSAIDS may need to be (increased/decreased) under hypoproteinemia conditions to prevent toxic concentrations from reaching tissues?

decreased

If a patient has low blood protein are they at risk for toxicity or non-therapeutic concentrations?

toxicity

What is the most frequent side effect of NSAIDs

GI irritation (due to COX 1 inhibition)

Inhibition of COX 1 enzyme results in:

-decreased bicarb-rich mucus production

-increased acid production

-decreased perfusion of GI tisssue

-decrease cell turnover (healing)

Why are non-selective NSAIDS more prone to produce gastritis and ulcers than COX-2 selective NSAIDS?

because non-selectives block both COX 1 (good) and COX 2

Name 3 treatments for ulcers?

-sulcralfate to protect open ulcer site

-H2 blocker antacids and omeprazole antacids

-misoprostol to provide synthetic prostaglandin to counteract

Nsaids inhibit COX that produces renal ?

vasodilating PGs (protect kidney flow under hypotension)

What drugs will block renal vasodilating COX?

NSAIDS

If a patient has a low blood pressure and is given NSAIDs what will happen?

decreased blood flow to kidney

What are the key ways to decrease risk of renal papillary necrosis?

-maintain blood pressure while on NSAIDs

-IV fluids during surgery

-prevent dehydration

-avoid using drugs that cause hypotension

Name the 3 toxic side effects of NSAIDs in order of occurence

1. GI side effects

2. Renal side effects

3. Hepatotoxicity

-This drug is safe to use in dogs AND cats

-primarily for chronic joint inflammation

-blocks formation of thromboxane

-removed via hepatic metabolism

aspirin (salicylate)

What drug do we have to make sure patients have been off of a week prior to surgery?

aspirin (salicylate)

What does aspirin decrease?

spontanenous clot formation

What do cats have a limited amount of? why does this matter?

-glucuronyl transferase, glycine, glucuronic acid

-salicylates take longer to leave cat's body and can accumulate in their body

What species has the longest half life of elimination for salicylates?

cats

Flunixin meglumine also known as?

Banamine

This drug is approved for use in horses, cattle for laminitis and colic

flunixin meglumine

Which drug has a stronger analgesia effect than aspirin, but there is concern is may mask colic signs?

flunixin meglumine

What drug has a high incidence of hemorrhagic gastritics in dogs when used extra label?

flunixin meglumine

When should you avoid using flunixin meglumine in horses?

If they have Equine Gastric Ulcer Syndrome

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

phenylbutazone

What NSAID is highly protein bound and you need to reduce dose if patient has hypoproteinemia to avoid toxic side effects

phenylbutazone

What are the ONLY routes that phenylbutazone can be administered? Why?

IV and PO ONLY

-IM and SQ can cause necrosis and skin sloughing