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DWT exam 1 > Pharmacology anti inflammatories > Flashcards

Pharmacology anti inflammatories Flashcards

1
Q

glucocorticoids clinical use

A

Most consistently effective drugs available for a wide variety of inflammatory/immune conditions
* Respiratory disease
* Dermatologic disease
* Gastrointestinal disease
* Ophthalmic disease
* Musculoskeletal disease
* Neurologic disease
* Immune-mediated and autoimmune disease

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2
Q

arachadonic acid pathway

A
  1. inflammation causes phospholipase A2 to break down phospholipids into arachodonic acid which breaks down into leukotrienes and prostoglandin H2
  2. glucocorticoids block phospholipase A2
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3
Q

glucocorticoid genomic pathway

A
  1. glucocorticoid binds to glucocorticoid receptor
  2. heat shock protein 90 is degraded
  3. glucocorticoid receptor + glucocorticoid move to nucleus and bind to and stim anti inflammatory genes, blocks expression of pro inflammatory genes
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4
Q

what cells have glucocorticoid receptors

A

a lot! almost every cell

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5
Q

mineralicorticoid affects

A

regulation of Na/K balance
use for treating adrenocortical insufficiency (addisons)

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6
Q

potency

A

Related to the affinity of the drug for the glucocorticoid receptor
Not related to plasma PK

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7
Q

duration of activity

A

Also related to receptor affinity
Also not related to plasma pharmacokinetics
* Half-life measured in minutes
* Effects measured in hours

Related to drug and formulation!

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8
Q

phosphate and succinate ester formulations

A

Highly soluble
Suitable for IV administration
Rapid onset of action
“ER” drugs
ex: sodium phosphate, sodium succinate

S= soluable

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9
Q

phosphate and succinate ester formulations

A

Highly soluble
Suitable for IV administration
Rapid onset of action
“ER” drugs
ex: sodium phosphate, sodium succinate

S= soluable

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10
Q

acetate and acetonide ester formulations

A

Poorly soluble
More lipophilic, less ionized
Onset of action is days to weeks
Prolonged absorption from injection site
Suitable for IM, SC or IA administration
ex: triamcinaline base (potencey 5, duration 24-36hr) triamcinaline acetonide (potency 30, duration 14-21 days)

act = for a long time

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11
Q

Aqueous suspension formulations

A

Rapidly absorbed after IM or SC administration
Some labeled for IA administration

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12
Q

solution formulations

A

Polyethylene glycol or alcohol vehicles
IV or IM administration
Polyethylene glycol vehicle – give slow IV, caution in cats

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13
Q

prednisone vs prednisalone

A

Prednisone is a prodrug
It is converted to prednisolone
Cats and horses have low bioavailability of prednisone (Low capacity to convert prednisone to prednisolone)

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14
Q

cats vs dogs glucocorticoid dosing

A

Cats require higher doses for the same effect
* Cats have Fewer GRs and Lower affinity GRs

Cats are more resistant to adverse effects

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15
Q

glucocorticoid effect on leukocytes

A

Affect the number of circulating immune cells
* Increased neutrophils and monocytes (Neutrophilia and monocytosis (+/-))

Decreased lymphocytes, eosinophils and basophils
* Lymphopenia, eosinopenia, basopenia
* Species differences

Affect the function as well
* Decreased release of inflammatory cytokines

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16
Q

glucocorticoid immunsuppression

A

High doses of corticosteroids= ‘Immunosuppressive dose’
* Inability to mount and immune response
* Inability to fight infection
* T cells > B cells
* Treats an overactive immune response!

Chronic low doses
* Effects on innate and cell-mediated immunity

Immunosuppression related to dose AND/OR duration of dosing
Cumulative dose is a factor in humans

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17
Q

glucocorticoids and metabolic effects

A

Stimulate glucose and lipid production (regional adiposity)
* Hyperglycemia
* Increase triglycerides, cholesterol, glycerol

Mobilization of amino acids from extrahepatic tissues
* Muscle breakdown

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18
Q

glucocorticoids effect on blood vessels

A

Stabilize membranes and decrease vascular permeability

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19
Q

endocrine effects glucocorticoids

A

Diabetes mellitus (cats)
* Gluconeogenic
* Antagonize insulin

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20
Q

glucocorticoids Hyper- and hypoadrenocorticism

A

when giving glucocorticoids, you can give too much and be in a hyperadrenocorticism state (cushings)
body stops producing its own cortisol because it is supplemented
drug administration stops > hypoadrenocorticism
TAPER OFF STEROIDS

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21
Q

glucocorticoid hepatopathy/hepatomegaly

A

Stimulate production of the steroid-specific isoenzyme of alkaline phosphatase (ALP) - dogs
(increased ALP)

22
Q

glucocorticoid GI ulceration effect

A

Slow turnover of enterocytes
**Inhibition of protective prostaglandins **
Potentiate the ulcerogenic effects of NSAIDs

23
Q

fluid/electrolyte balance glucocorticoid effects

A

Sodium and fluid retention and hypokalemic alkalosis

24
Q

Polyuria/polydipsia

A

Glucosuria
glucose in urine from hyperglycemia

25
Q

glucocorticoids mood/behavioral changes

A

“roid rage”

26
Q

glucocorticoids and laminitis

A

Recognized clinically
* Temporal relationship
* Unable to reproduce experimentally

Most likely related to insulin dysregulation
Horses may need to be predisposed
* Fat horses with cresty necks (EMS)

Osteopenia

27
Q

alternate day therapy of glucocorticoids

A

with Intermediate-acting glucocorticoids
give a higher dose every other day
body produces its own cortisol every other day

28
Q

glucocorticoids tapering the dose

A

When discontinuing treatment
To prevent signs of hypoadrenocorticism
Not necessary with short-term (< 2 wk) GC therapy
Necessary after long-term (>2 wk) GC therapy
* Allow for recovery of the HPA axis
* Takes 2 weeks after cessation of daily therapy
* Takes 1 week after cessation of alternate day therapy
* Based on prednisone/prednisolone in dogs

29
Q

if you can continue a glucocorticoid completely:

A

Lowest possible dose at the longest possible dosing interval

30
Q

when to administer glucocorticoids

A

morning

31
Q

using alternative routes of exposure to mitigate glucocorticoid effects

A

Local therapy results in less systemic exposure
Intra-articular
Inhalant
Topical (Includes ocular)

32
Q

NSAID pathway

A
  1. inflammation causes phospholipase A2 to break down phospholipids into arachodonic acid
  2. cyclooxygenase 1 and 2 convert arachidonic acid to prostaglandin H2
  3. NSAIDS block COX 1 and/or 2
33
Q

PGI2 prostanoid

A

antiplatelet, vasodilatory

34
Q

TXA2 prostanoid

A

pro platelet, vasoconstriction

35
Q

PGE2 prostanoid

A

pro inflammatory, pain, vasodilation, GI motility, fever

36
Q

PGF 2alpha prostanoid

A

vasocontriction, smooth muscle constriction (uterus, GIT)

37
Q

COX 1 vs COX 2

A

COX 1
* Constitutively expressed (expressed constantly)
* Cytoprotective to the GI tract (decrease acid and increase mucus)

COX 2
* induced by inflammation
* pro inflammatory effects (heat, swelling, pain, fever)

37
Q

COX 1 vs COX 2

A

COX 1
* Constitutively expressed (expressed constantly)
* Cytoprotective to the GI tract (decrease acid and increase mucus)

COX 2
* induced by inflammation
* pro inflammatory effects (heat, swelling, pain, fever)

38
Q

Wht cant we only block COX 2 and have no adverse effects?

A

Not that simple
A lot of overlap btwn COX 1 and 2
COX-2 constitutively expressed in kidney
COX-2 is needed for mucosal healing
Specificity of most drugs is overcome at high doses

39
Q

COX selectivity

A

Varies by drug and species (Don’t extrapolate between species!)
Carprofen is not selective in people
Appears to be selective in dogs
Another drug, the opposite may be true

40
Q

clinical uses of NSAIDS

A

Antipyresis
* Including fevers caused by infection
* Not all fevers need treatment

Analgesia
* Pain associated with inflammation (chronic osteoarthritis, soft tissue injury, post-operative pain)
* Pain independent of inflammation = Less effective

Endotoxemia/sepsis
* Prostaglandins are responsible for many of the clinical signs

Anticoagulant (platelet) activity
* Low dose aspirin is best understood
* All NSAIDs affect coagulation
* Clinical significance varies with species
* COX-2 and thrombosis

41
Q

NSAIDS are not appropriate for treating:

A
  • Immune-mediated diseases (IMHA/IMTP)
  • Autoimmune diseases (Pemphigus, Systemic Lupus Erythematosus)
  • Allergic diseases (atopy)
  • Inflammatory respiratory diseases (asthma, chronic bronchitis)

Need steriods or alternative drugs

42
Q

NSAID pharmacokinetics

A

High bioavailability (active transport)
Small volume of distribution (0.15 - 0.3 L/kg)
High protein binding (70-99%) therefore:
Hepatic metabolism predominates
* Capacity-limited – nonlinear PK
* Species differences
* Neonates

Dosing in one species is UNLIKELY correct for another

43
Q

human NSAIDs for animals

A

“Human NSAIDs will make your pet die a horrible death”
Tylenol (acetaminophen)
* Atypical NSAID
* Cats
* Dogs – OK up to a point
* Horses - OK

Ibuprofen
* TOXIC to Dogs and Cats

44
Q

NSAIDS and GI ulcers

A

Weak acids trapped in the basic environment of the gastric surface epithelial cells resulting in cell death

GI tract part depends on species
* Dogs & cats – stomach and SI
* Horses – stomach and colon
* Ruminants - abomasum

PGE2 effects
* NOT about oral administration – injections can cause
* PGE2 is necessary for healing with pre-existing damage
* COX-2 inhibitors can delay healing or cause progression of disease
* COX2 ARE SAFER BUT NOT ENTIRELY SAFE!!!

45
Q

nephrotoxicity with NSAIDS

A

Inhibition of PGE2 and PGI2
* Causes vasoconstriction, decreased renal BF, possible toxicity

Effects greatly exacerbated in dehydrated patients
* Already compromised renal blood flow

PGE2 constitutively expressed in the kidney
* COX-2 inhibitors probably not safer

Lesions are characterized by medullary crest or papillary necrosis
* Normally receive less blood flow =More vulnerable to insult
* Areas that concentrate urine

46
Q

NSAIDs hemorrhage

A

Effect on platelets
* Drugs that inhibit COX-1 activity
* Thromboxane A2

Aspirin irreversibly binds COX-1
* Effects last for the life of the platelet (7-10 days)

Most NSAIDs can induce prolonged bleeding
* Less of an issue in large animals

47
Q

hepatotoxicity and NSAIDs

A

ALL NSAIDS, fairly low incidence – mainly dogs
Toxic principle (mechanism) is not clear
* Idiopathic
* Not reproducible

Anorexia, vomiting, icterus
Hepatomegaly
Increased bilirubin, ALT, ALP, AST

48
Q

IMHA/IMTP and NSAIDS

A

Up to 12% of drug-induced IMHA/IMTP cases in humans attributed to NSAIDs
RARE in animal species
1 published case report in a dog with carprofen
Second exposure
48 hours after initiating therapy

49
Q

Blood dyscrasias and NSAIDs

A

Pancytopenic marrow failure
Non-regenerative anemia and thrombocytopenia
People and dogs
Not used in either species anymore

50
Q

NSAIDs and injection site reactions

A
  • Heat, pain, swelling
  • Abscess formation
  • Tissue necrosis
  • Clostridial myositis (anaerobic injection)

Prevention
* Both the injectable formulations of phenylbutazone and flunixin can be given orally
* Bioavailability similar to commercially available preparations
* Tastes terrible and can be irritating
* Mix with corn syrup and rinse mouth with water

DWT exam 1 (13 decks)

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