Pharm E3, VII NSAIDs
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What is the complex pathophysiologic response of vascularised tissue to an injury?
What is due to dilation of small blood vessels within the damaged area?
What is seen only in peripheral parts of the body such as the skin. Due to increased blood flow (hyperaemia) in the region, resulting in vascular dilation and the delivery of warm blood to the area?
What results from accumulation of fluid in the extravascular space as part of the fluid exudate (edema)
What results partly from the release of chemical mediators of acute inflammation, including histamine and bradykinin, that stimulate nociceptors, and by modulators such as prostaglandins that sensitize nerve endings to the action of mediators?
What happens when movement of an inflamed area is consciously and reflexly inhibited by pain, while severe swelling may physically immobilize tissue?
Loss of function
What are some causes of inflammation (4)?
- Microbial infections
- Hypersensitivity reactions
- Physical and chemical agents
- Tissue necrosis
What are mediators of inflammation released or formed de novo from cells (6)?
- Platelet activating factor
- Free radicals
- Cytokines (interleukin, interferon, tumor necrosis factor)
What is the progenitor NSAID
How are NSAIDS classified? What are the classifications?
- Carboxylic acids
- Enolic acids
- (Chemical Structure)
Carboxylic acids can be subdivided into what groups (3)?
- Salicyclic Acids and Esters
- Acetic acids
- Propionic Acids
What are examples of Salicyclic acids and esters (2)?
- Acetyl salicyclic acid
What are examples of Acetic acids(3)?
- Phenylacetic acids
- Carbo-cyclic acetic acids
- Hetero-cyclic acetic acids
What are examples of phenylacetic acids (1)?
What are examples of carbo and hetero-cyclic acetic agents (4)?
What are examples of proprionic acids (7)?
- Tiaprofenic acid
What are examples of Enolic Acids (2)?
What is an example of a pyrazolones (1)?
What are examples of oxicams (2)?
What are examples of COX-2 inhibitors (5)?
NSAID solubility in water varies with oH of the medium, when are the soluble and when are the insoluble?
- Insoluble at neutral pH
- More soluble in alkaline solutions (however more unstable at alkaline pH)
NSAIDS are what type of compounds?
NSAIDS are what type of acids?
- Weak acids
- (acidity due to acid carboxcylic group or enol group)
What is cyclooxygenase?
- Enzyme that catalyzes the conversion of arachadonic acid to cyclic endoperoxide, prostaglandin, to the eicosanoids PGE2 and PGI2
- (which have pro-inflammatory properties)
What is a constitutive enzyme expressed in most tissues and blood platelets?
COX-1 mediates the formation of constitutive prostaglandins which are involved in what (2)?
- (Cellular "housekeeping" functions)
- Coordination of circulating hormone Action
- Vascular homeostasis regulation
What are the most important functions of COX-1 (4)?
- Gastic protection
- Platelet function regulation
- Endothelial cell regulation
- Maintenance of renal blood flow during periods of shock and low systemic BP
What is the inducible cyclooxygenase, that is expressed only following cell activation, is upregulated in the CNS and plays an essential role in the mediation of pain and the febrile response?
COX-s can also be found as constitutive in what tissues (6)?
- Ciliary body
Complete inhibition of COX-2 can potentially lead to what (6)?
- Fetal deformities
- Delayed bone healing
- Delayed wound healing
- Cardiovascular events
- enal toxicity
Inhibition of cyclooxygenase can be of two types:
- 1. competive inhibition of the substrate binding site of COX (reversible)
- 2. Acetylation of a key serine within the active site (irreversible)
As a consequence of the inhibition of prostaglandin synthesis, NSAIDs produce what three main therapeutic effects (3)?
How are NSAIDs antipyretic (2)?
- PGE2 in the pathogenesis of fever
- PGE2 is the second messenger of IL-1 at the hypothalamus
How are NSAIDS analgesic?
Role of PGE2 in sensitizing sensory nerve endings to other mediators such as histamine and bradykinin
How are NSAIDS anti-inflammatory?
Role of PGE2 in inducing vasodilation
Is it advisable to give NSAIDs with food?
No, food can impair the oral absorption of some NSAIDS
Why is it better to give NSAIDs orally, then administering injectable preparations?
Injectibles are alkaline and can cause necrosis or pain if perivascular leakage occurs
Being a weak acid, NSAIDs are ionized in the blood, therefore their capacity to penetrate membrane is _____.
For most NSAIDs the percentage of plasma protein binding is what?
>90% (aspirin is the exception with a 50% plasma protein binding)
Why is the high percentage of protein binding for NSAIDs an advantage (2)?
- They show a long-lasting effect
- Have a relatively short elimination half-life
NSAIDs are metabolized in the liver and and generally undergoes what two reactions?
- Oxidation (a phase I reaction)
- Followed by conjugation (a phase II reaction)
Phenylbutazone is metabolized to the active metabilite _______?
Aspirin is metabolized to the active metabolite __________?
NSAIDS are mainly excreted in the urine, but what compounds are excreted in bile (2)?
Why is excretion of NSAIDS faster in herbivores?
- NSAIDs are ionized in alkaline urine => Decreased reabsorption in renal tubules
- (opposite in carnivores)
The toxicity of NSAIDs on the GIT is a consequence of what?
Inhibition of gastric mucosal PG synthesis
Because of the affects of NSAIDs on the GIT, it is always advised to administer NSAIDS with a what?
Cytoprotectant/Misoprostol (PGE replacement)
Inhibition of cyclooxygenase by NSAIDs in renal compromised patients induces what?
Renal vasoconstriction=> decreases renal blood flow and glomerular filtration rate
NSAIDs interfere with platelet activity due to what?
Impaired thromboxane synthesis
What are factors that increase and/or predispose NSAID toxicity(7)?
- GIT inflammation or ulceration
- Inadequate dose regimens
- Administration with highly plasma protein bound drugs or corticosteroids
NSAIDs can be indicated for the treatment of what medical conditions (6)?
- Joint disease
- Bone tumors
- Intervertebral disc lesions
- External otitis
- Iinflammatory eye conditions
NSAIDS can be indicated for the treatment of what surgical conditions (4)?
- Orthopedic Sx
- Crossed ligament reparation
- Abdominal Sx
DO NOT use NSAIDs in patients with what problems (5)?
- GIT inflammation or ulcerative disease
- Renal insufficiency
- Reduced CO
- With Corticosteroids
What is the mechanism of action of Aspirin (3)?
- Irreversible inhibition of cyclooxygenase enzyme activity
- Inhibits the formation and release of kinins
- Stabilize lysosomes
How is aspirin (salicylic acid) eliminated?
What are signs of acute toxicity of aspirin(4)?
- Electrolyte imbalance
What drug is approved by the FDA in horses and dogs, administered IV/oral, metabolized in liver to form active oxyphenbutazone, has prolonged duration of action with long half-life?
What are some adverse affects of phenylbutazone(4)?
- GI toxicity
- Bone marrow hypoplasia
- Renal papillary necrosis
When should you use phenylbutazone (2)?
- Osteoarthritic/Osteoporotic conditions
- Equine colic
What is a nicotinic acid derivative, approved for use in hoses, a potent analgesic agent, and also possesses antiendotoxic effects?
When should you use flunixin meglumine(2)?
What can accidental intra-arterial administration in horses of flunixin meglumine cause(2)?
- CNS stimulation
What is flunixin meglumine used to treat in ruminants (2)?
- Acute mastitis
- Acute bovine pulmonary emphysema
What can flunixin meglumine used to treat in dogs?
What is the mechanism of action for carprofen (3)?
- Inhibition of COX2
- Inhibition of phospholipase
- Impaired release of arachidonic acid
When should you use carprofen?
- Post-Op pain
What is an adverse affect of carprofen?
What drug is approved by FDA for use in horses, and is used to treast myositis and soft tissue inflammation?
What animals are more sensitive to naproxen, and extensive enterohepatic recycline leads to prolonged elimination?
What is a less effective analgesic compared to aspirin, commonly used in humans, dogs are sensitive to GI toxicity (use is not recommended in dogs)
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