4. Anti-Inflammatory Drugs: Steroids

True or False: There are few side effects when using glucocorticoids.

False; the side effects of glucocorticoids can be dangerous.

What is the role of COX 1 prostaglandins?

*COX 1 prostaglandins are GOOD.* They are present at all times, in low levels, and they are systemic. They work to increase stomach mucus, and bicarb secretion to neutralize stomach acid. They increase gastric cell turnover and increase gastric cell perfusion to aid in quicker healing. They also assist in renal vasodilation in times of hypotension.

What is the role of COX 2 prostaglandins?

*COX 2 prostaglandins are BAD.* They are localized, and not detectable under normal conditions. They only increase with injury when signaled by cytokines, growth factors, and lipopolysaccharides. These prostaglandins are the cause of inflammation, and are associated with localized inflammatory reactions.

Long Acting Glucocorticoid

*Dexmethasone* *Betamethasone* *Flumethasone* Greater than 48 hours effect. These drugs provide a longer beneficial effect, however there is a long duration of CRF/ACTH suppression. These are usually used in emergency situations of severe inflammation and pain.

Short Acting Glucocorticoid

*Hydrocortisone* Less than 12 hour effect. *No topical medications in vet med. Cortisone is the actual hormone, but it must be converted to hydrocortisone to work. The drug is the converted, active form.

Intermediate Glucocorticoid

*Prednisolone* *Methlyprednisolone* 12-36 hour effect. These are ideally suited for alternate day dosing for diseases such as skin allergies.

What are the 4 most common signs of a Cushings patient?

1. Atrophy 2. Alopecia 3. Thin skin (bruising) 4. PU/PD/PP

What are the 5 rules to remember when using glucocorticoids?

1. If there is another anti-inflammatory that will work, use that one! (NSAIDs) 2. Avoid continuous use if possible. 3. Use smallest dose and titrate to effect. 4. Taper off the drug when withdrawing. 5. Dogs are much more sensitive than cats!

What are the 4 glucocorticoid dosages?

1. Physiological--> replaces endogenous cortisol 2. Anti-Inflammatory--> allergies, hives 3. Immunosupressive--> autoimmune disease (IMHA), immune mediated thrombocytopenia 4. Shock--> Very high doses, generally not recommended anymore

Name a common mineralocorticoid that plays a role in Addison's disease. Explain Addison's disease.

An example of a mineralocorticoid would be Aldosterone, which normally causes sodium reabsorption from urine back into blood. In Addison's disease (Hypoadrenocorticism), these patients lose the ability to reabsorb sodium, they lose sodium through their urine, and become hyponatremic.

In general, how do anti-inflammatory drugs use the inflammation pathway to relieve pain?

Anti-inflammatory drugs block Leukotrienes and Prostaglandins to decrease the number of pain signals sent to the brain, effectively reducing pain. Tissue is still traumatized, but there is less pain.

Glucocorticoid Aqueous Solutions vs. Alcohol Solutions

Aqueous solution indicates the drug is dissolved in water, and can be safely given IV in high doses. Drug + Sodium/Potassium Ex: Dexmethasone SP Alcohol solution indicated the drug is dissolved. These drugs can be given IV, but not as a high dose. Drug (without additional compound) Ex: Dexmethasone

Which of the four doses will you start to multiple body system side effects?

At anti-inflammatory doses, the side effects are not life threatening. At immunosupressive doses, the entire immune system is shut down just to stop the part that is targeted, and exacerbation of signs seen at anti-inflammatory doses will be seen. All supraphysiological doses cause CRH/ATCH suppression.

Where are corticosteroids produced?

Corticosteroids are also known as adrenocorticosteroids. i.e.: They are produced in the adrenal cortex. Zona Glomerulosa--> salt Zone Fasciculata--> sugar Zona Reticularis--> sex

*Corticosteroids* MOA

Corticosteroids reduce inflammation and pain by inhibiting Phospholipase A2, which blocks the formation of leukotrienes and prostaglandins. They also inhibit Cyclooxygenase (COX), which double inhibits prostaglandin (and thromboxane) formation.

What disease can veterinarians cause by long-term or high-dose glucocorticoid administration?

Cushings (Hyperadrenocorticism) AKA: Iatrogenic Cushings *Cats are resistant to this!

What is the goal of anti-inflammatory drugs?

Decrease pain associated with inflammation. For the most part, Corticosteroids and NSAIDs don't work at the conscious level of upper CNS to reduce pain like opioids do.

Glucocorticoid Suspensions

Drug + Acetate/Pivalate/Acetonide/Valerate These preparations exist as ester linked compounds that need to be activated by esterases, however this is a slow process. These are used as depot drugs, and should NEVER be given IV. Remember: Suspension crystals can be altered by extreme temperatures.

How does a "fast negative feedback" mechanism work?

Fast negative feedback mechanisms are triggered by blood cortisol changes. Production of cortisol doesn't stop, but the release of CRF/ACTH is suppressed.

What are the two types of steroidal drugs?

Glucocorticoids (GC) Corticosteroids (CS)

Why are GC used to treat lymphosarcomas?

Glucocorticoids are able to induce apoptosis in lymphocytes with lymphosarcoma. This is not a stand-alone treatment, however.

What effects do glucocorticoids have on pregnant mares?

Glucocorticoids can stimulate onset of partition in near term mares. Normally: Progesterone (from corpus luteum usually maintains pregnancy. Decreased progesterone--> Increased natural cortisol--> placenta produces enzyme to make local prostaglandins--> corpus luteum lyses. Glucocorticoids: Decrease in progesterone removes quiescent effect on uterus--> increased estrogen effect dominates--> oxytocinn receptor expressed--> labor

What effects do glucocorticoids have on fibroblast activity?

Glucocorticoids decrease collagen synthesis, which can delay tissue healing. This can impact surgical patients. Positive: Decreases scar tissue formation--> good for tissues like the gut. Negative: Loss of collagen--> thin skin--> easily bruised, fragile capillaries.

What effects do glucocorticoids have on immune response?

Glucocorticoids decrease immune response. GCs effect over 2,000 genes involved in immune regulation. Primarily, GCs depress cell-mediated immunity against bacteria and fungi. Anti-inflammatory doses will suppress activation of T-cells and cause apoptosis. GCs also inhibit productino of TNF-alpha and many IL which decrease macrophage activity.

What effects do glucocorticoids have on liver enzymes?

Glucocorticoids increase an isozyme of ALP different from that of cholestasis ALP. You will see an increase in ALP in dogs, but not in cats. This does no reflect fatty liver or hepatic degeneration.

Why are glucocorticoids contraindicated for corneal ulcers?

Glucocorticoids increase the activity of collagenase (breakdown) in corneal matrix. this suppresses epithelial regeneration and inhibits fibroblast activity. The descemetocile keeps the eye intact which the ulcer is trying to push through, and this can rupture.

What effects do glucocorticoids have on laminitis in horses?

Glucocorticoids increase the response to Alpha 1 receptors, causing vasoconstriction in the hoof. Laminae hypoxia--> degeneration--> seperation--. rotation of P3 bone--> laminitis

How do glucocorticoids cause PU/PD/PP?

Glucocorticoids inhibit ADH (no aquaporins to excrete water), resulting in diuresis; polyuria. Polydypsia occurs to replace fluid loss. Polyphagia possible is due to imparing the action of leptin, so the animal does not reach satiety. EDUCATE YOUR CLIENTS ON THIS!

What effects do glucocorticoids have on glucose regulation?

Glucocorticoids stimulate gluconeogenesis and decrease responsiveness to insulin by down regulating the receptors. GCs also increase lipolysis to increase fatty acids that can be converted to glucose. High glucose levels result in increased glycogen formation, which may result in a fatty liver.

*Glucocorticoids* MOA

Glucocorticoids work as anti-inflammatories. They work by increasing lipocortin (annexin), a protein that inhibits phospholipase A2 and cyclooxygenase (COX 2). This prevents the production of arachidonic acid, which inhibits leukotriene, prostaglandin, and thromboxane production, decreasing pain. This also leads to a decrease in histamine/cytokine production by traumatized cells, which maintains capillary integrity and decreases swelling/edema.

For diabetic patients, at which does of glucocorticoids would you need to also adjust their insulin levels?

Immunosupressive doses and higher.

*Triamcinolone*

Intermediate to Long-Acting Glucocorticoid The therapeutic effect is of intermediate duration, however this drug suppresses CRF/ACTH like long-lasting drugs. This makes this drug less popular among vets.

Why is inflammation good?

It is a protective mechanism that includes: 1. Heat--> kills bacteria/viruses 2. Redness--> vasodilation--> increased O2 perfusion, WBCs, and cytokines 3. Swelling--> edema 4. Pain--> decrease use--> enable healing 5. Loss of function--> damaged cells stop contributing

How does the inflammation pathway induce pain?

Leukotrienes and Prostaglandins produce pain by increasing nociceptor activity. Nociceptors send signals to the brain to perceive pain.

What role do leukotrienes play in inflammation?

Leukotrienes are confined to the lung, platelets, and WBCs, They draw WBCs to the site of inflammation, and play an active role in anaphylaxis and asthma.

*Desoxycorticosterone*

Mineralocorticoid Used to treat Addison's disease (Hypoadrenocorticism). This drug reestablishes Na/K and water balance. Use caution when using this in CHF patients because increasing Na reabsorption will increase fluid retention, increasing blood volume.

What are the two groups of corticosteroids?

Mineralocorticoids Glucocorticoids

What is the role of mineralocorticoids?

Mineralocorticoids work to regulate electrolytes and water balance, and they have no anti-inflammatory effect.

*NSAIDs* MOA

NSAIDs inhibit Cyclooxygenase (COX) and Lipoxygenase (LOX) which blocks the formation of Prostaglandins, Thromboxanes, and Leukotrienes.

Describe the inflammation pathway.

Phospholipase A2 converts the phospholipids found in the cell membranes into arachidonic acid. In one pathway, Cyclooxygenase (COX 1 & COX 2) converts arachidonic acid into prostaglandins and thromboxanes. In another pathway, Lipoxygenase (LOX) converts arachidonic acid into Leukotrienes.

Prednisone vs. Prednisolone in Cats

Prednisone is converted by the liver to Prednisolone, which is quick in dogs, but not in cats. Therefore, we use Prednisolone in cats to avoid having to give a higher dose of Predisone to be effective. Both have mineralocorticoid effects as well, causing increased sodium retention leading to increased fluid retention. Therefore, be cautious with CHF patients.

What are the catabolic effects of glucocorticoids?

Protein breakdown--> AA converted to glucose--> gluconeogenesis--> energy for stressful situation. This results in an increased skeletal muscle breakdown, which could lead to atrophy.

How does a "slow feedback mechanism" work?

Slow negative feedback changes are triggered by the precise cortisol blood levels. The cell nuclei within the hypothalamus and anterior pituitary actually decrease CRF/ACTH production.

What are the two types of anti-inflammatory drugs?

Steroidal Non-Steroidal

What effects will you see on a CBC in a patient who was recently administered glucocorticoids?

Stress-like leukogram; 1. Lymphopenia 2. Neutrophilia--> wall is "less sticky" so they are able to marginate faster; 1st responders. 3. Monocytosis (dogs) 4. Eosinopenia (dogs)

What are the disadvantages of depot glucocoticoids?

The rate at which the drug is activated (released from ester) is unpredictable. Also, with the depot glucocorticoids, the suppression of CRH/ACTH is continuous, leading to a down regulation of lipocortin (GC) receptors, making it very difficult to withdrawl the drug.

What effects do glucocorticoids have on the GI tract?

There is increased risk for gastritis and ulcers when glucocorticoids and NSAIDs are used together due to combined COX 1 suppression effect. (NSAIDs decrease mucin and GCs decrease bicarb--> increase acid.) Glucocorticoids increase gastric acid secretion and decreas mucous production in humans, but this is not well documented in vet med.

How are glucocorticoid drugs classified?

They are classified by their duration of action on the body. There are short acting, intermediate acting, and long acting glucocorticoids. However, the longer DOA, the longer the suppression of CRF/ACTH, and the more potential for side effects.

What are the advantages of depot glucocorticoids?

They only need o be given every 2-6 weeks, depending on the drug used.

True or False: There are some mineralcorticoid effects seen when giving glucocorticoids. Therefore one should be cautious when treating heart disease patients with glucocorticoids.

True; In spite of polyuria, the mineralocorticoid effect can cause sodium and fluid retention. Do not use in CHF patients!

What are the effects of inhibited cell-mediated immunity?

This raises concern for fungal infections. This has been seen in uveitis horses that were treated with opthal GCs and contracted mycotic keratitis. Suppression of CMI decreases macrophage clean up of necrotic tissue.

What role do thromboxanes play in inflammation?

Thromboxane assists in platelet aggregation. Blocking this would lead to decreased platelet function, and petechia.

What is the pathway for thromboxane production?

Thromboxanes are produced when arachidonic acid is converted into prostaglandins by Cyclooxygenase. The resulting unstable prostaglandin is then converted into Thromboxane A2 by thromboxane synthase. Thromboxane A2 can then be further converted into Thromboxane B2.

True or False: There are two types of Cyclooxygenase enzymes: COX 1 and COX 2. These enzymes produce different types of prostaglandins.

True

True or False: B cells (humoral immunity) is affected far less than T cells.

True; Anti-inflammatory doses have minimal effect on B cells, however immunosupressive doses will effect some B cell function, so be careful when vaccinating these patients. Normal lymphocyte apoptosis still occurs.

How does the body naturally control cortisol levels?

When there is stress, the hypothalamus releases CRH. CRF stimulates the anterior pituitary to release ACTH. ACTH stimulates the adrenal gland to produce cortisol, and cortisol then produces a negative feedback.

In Cushings disease, why wouldn't you immediately stop giving glucocorticoids?

While on glucocorticoids, CRF/ACTH have been suppressed, causing the adrenal gland to atrophy. The adrenal gland can no longer produce normal levels of cortisol, causing a decrease in normal mineralocorticoids as well as natural glucocorticoids. This will cause an Addisonian crisis! You must taper off the glucocorticoids for 2+ weeks.