Lecture 15 - NSAIDS Flashcards
List the sources of NSAIDs.
- Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat?
- Many NSAIDs are also available in combination with ?
- It is important to verify the ____ ingredients in over-the-counter products and
the presence of additional ingredients such as (3?) that might contribute to ____ effects. - NSAID toxicity is among the ____ most common toxicoses. __% of cases involve dogs, ___% of cases involve cats.
- pain and inflammation and to reduce fevers.
- antihistamines and/or decongestants in cold, flu, and allergy products.
- active, caffeine, antihistamines, or
decongestants, adverse - 10, 70, 20
Sources
* Antiinflammatories, analgesics and antipyretics.
Sources include:
* _________- acids
– Salicylic acids, e.g., aspirin, diflunisal
– Propionic acids, e.g., ibuprofen, carprofen
– Acetic acids, e.g., sulindac, indomethacin
– Fenamates, e.g., meclofenamic acid, mefenamic acid
– Aminonicotinic acids, e.g., flunixin, clonixin
* _________ acids
– Pyrazolones, e.g., phenylbutazone
– Oxicams, e.g., piroxicam, meloxicam
* Cox-__ _________ inhibitors, e.g., deracoxib
(Deramaxx for dogs), celecoxib (Celebrex,
Celebra), firocoxib (Equioxx and Previcox for
horses and dogs), Rofecoxib (Vioxx), Valdecoxib
(Bextra)
* Bextra and Vioxx withdrawn from market in 2004/05
Carboxylic, Enolic, 2, selective
What is the ADME of NSAIDs?
• NSAIDs (______ acids) are well absorbed from the _______ and __________ _____ intestine
• They are highly bound to ____ protein
(________). May be > ___% bound
• Metabolized in the ______ via phase __ & ___ reactions
• Excreted in the ______ by ________ filtration and _____ secretion, and in ___ (some NSAIDs)
• Some NSAIDs undergo ?
Peak plasma concentration occurs at what time?
NSAID excretion is dependent upon?
Low vol of distribution = ?
Which NSAIDs undergo enterohepatic circulation?
stomach, proximal small, plasma, albumin, 99, liver, I, II, kidney, glomerular, tubular, bile, enterohepatic recirculation
How are NSAIDs metabolized and excreted?
The main metabolic pathways (indicated by the bold arrows) leading to the inactivation and elimination of non-steroidal anti-inflammatory drugs (NSAIDs) are oxidation by the cytochrome P450 enzymes (P450), glucuronide conjugation by the uridine-5’-diphosphate (UDP)-glucuronosyltransferases
(UGTs) and, to a lesser extent, sulphate conjugation (sulphotransferases). Cats are more susceptible to NSAIDs/salicylates due to low glucuronidation capacity.
What are the NSAID risk factors?
- NSAIDs are prevalent in households –> high likelihood of accidental ingestion by pets
- Inappropriate administration to pets by owners
- Long term use (e.g., Tx orthopedic diseases)
- Older and younger animals are at greater risk
- Drug interactions, e.g., corticosteroids, diuretics, anticoagulants, aminoglycosides, phenobarbital, chloramphenicol, cimetidine, digoxin
- Dehydration
- Cardiac disease
- Diminished hepatic and/or renal functions
- Gastrointestinal disease
- Hypotension and hypovolemia
– Anesthesia, severe trauma, surgery - Species: dogs, cats, horses (foals)
NSAIDs show significant interactions with other drugs. Corticosteroids increase risk of ?
Diuretics ______ the effects of NSAIDs
Anticoagulants increase risk of ______
Aminoglycosides increase risk of _______ toxicity
Phenobarbital induces metabolic enzymes thereby speeding up ________ of NSAIDs
Chloramphenicol & cimetidine inhibit ____ metabolic enzymes thereby ______ clearance of NSAIDs
Digoxin becomes more toxic by being displaced from _______ _____ by NSAIDS
GI ulceration and renal toxicity
reduce
bleeding
renal
clearance
liver
reducing
plasma proteins
Dehydration decreases _______ circulation thus ______ NSAIDS excretion and promoting renal ______
In heart failure, the kidney is dependent upon _____________ prostaglandins to maintain renal ______ and _____ and ____ balance.
NSAIDs decrease __________ synthesis and, thus, may cause fluid retention in patients with heart failure.
Diminished hepatic and/or renal functions reduce _________ and _______ of NSAIDs
Gastrointestinal disease increases risk of __________
Hypotension and hypovolemia increase risk of ______ injury
Dehydration decreases renal circulation thus reducing NSAIDS excretion and promoting renal damage
In heart failure, the kidney is dependent upon vasodilating prostaglandins to maintain renal perfusion and salt and water balance.
NSAIDs decrease prostaglandin synthesis and, thus, may cause fluid retention in patients with heart failure.
Diminished hepatic and/or renal functions reduce metabolism and excretion of NSAIDs
Gastrointestinal disease increases risk of ulceration
Hypotension and hypovolemia increase risk of renal injury
She said to know one or two examples from each?
Describe the NSAID toxicity.
1. NSAID toxicity varies with?
2. In the case of Ibuprofen and dogs,
- 8 mg/kg/day causes ?
- 25-125 mg/kg as a single dose causes ?
- >100-175 mg/kg causes
- Acute MLD (LD50) for dogs is ____ mg/kg?
- In the case of Ibuprofen and cats,
- 50mg/kg causes ?
A rough rule of thumb for dogs is that GI toxicity may be seen at __-__ times the therapeutic dose of a given NSAID, and renal injury may occur at doses ___-__ times the therapeutic doses.
Cats are considered to be __-__ times more sensitive than dogs
- Varies with dose, length of exposure, drug and animal species
–> Ibuprofen
1. Dogs
* 8 mg/kg/day causes gastric lesions
* 25-125 mg/kg as a single dose causes gastric lesions
* >100-175 mg/kg causes renal damage
* Acute MLD for dogs is 600 mg/kg
Cats: 50mg/kg causes GI irritation & haemorrhage
* Indomethacin: MTD = 0.5mg/kg/day (dogs)
* Naproxen: MTD = 5mg/kg/day (dogs)
* Piroxicam: MTD = 0.3-0.8mg/kg/day (dogs)
* Ketoprofen: MTD = >20mg/kg (dogs)
* Etodolac: MTD = 10mg/kg; lethal dose =
>80mg/kg (dogs)
A rough rule of thumb for dogs is that GI toxicity may be seen at 4–5 times the
therapeutic dose of a given NSAID, and renal injury may occur at doses 8–10
times the therapeutic doses.
Cats are considered to be 2 – 4 times more sensitive than dogs
What is the MOT of NSAIDs
The mechanism of toxicity of NSAIDS is the inhibition of biosynthesis of __________. In this process, ___________ acid is released from a phospholipid molecule of cell membrane by the enzyme ______, which cleaves off the fatty acid. The ___________ acid is then converted to prostanoids by ___________ or to leukotrienes by ______________. Prostanoids and Leukotrienes are collectively known as _____________. NSAIDs compete with _____ acid for the active site of the COX enzyme thus
__________ the synthesis of prostanoids which include ?
Glucocorticoids on the other hand inhibit _____________ or reduce the induction of ____.
The mechanism of toxicity of NSAIDS is the inhibition of biosynthesis of prostanoids.
In this process, Arachidonic acid is released from a phospholipid molecule of cell membrane by the enzyme phospholipase A2 (PLA2), which cleaves off the fatty acid.
The arachidonic acid is then converted to prostanoids by cyclooxygenase or to
leukotrienes by 5-lipoxygenase.
Prostanoids and Leukotrienes are collectively known as Eicosanoids.
NSAIDs compete with arachidonic acid for the active site of the COX enzyme thus inhibiting the synthesis of prostanoids which include PGE2, PGF2, PGD2,
PGI2 (prostacyclin) and TXA2 (thromboxane A2).
Glucocorticoids on the other hand inhibit Phospholipase A2 or reduce the induction of COX.
What role does PGE2 play in NSAID toxicosis?
The physiological Roles of PGE2 are identified in this slide. The ones that are
relevant for the toxicosis are in boxes with font of different colours
differentiating the organs they influence.
Natriuresis: excretion of sodium in the urine
What is the role of PGI2 in NSAID toxicosis?
See below
What is the role of PGD2 in NSAID toxicosis?
Vasodilation
Inhibition of platelet aggregation
What are the actions of the following prostanoids:
- PGF2 alpha
- TXA2
- Bronchoconstriction and uterine contraction
- Platelet activation and aggregation, vasconstriction, bronchoconstriction
What systems are affected in a case of NSAID toxicosis? Which are the first and second most important?
Gastrointestinal - first most important
Renal - second most important
Blood
Hepatic
Cardiovascular
CNS
Immune
Describe the pathogenesis of NSAID-induced GI injury.
1. NSAIDs induce injury/bleeding via three key pathways. Name them.
2. Effects produced via only one of these pathways (e.g., selective inhibition of COX-1 or of COX-2) are ?
3. The suppression of ______ and ______ is the primary mechanism through which NSAIDs induce ulceration.
4. The suppression of COX-1 activity impairs several elements of _________ defense, including causing a reduction of mucosal _____ flow, mucus ______, and ________ secretion. By inhibiting __________ synthesis, suppression of COX-__ activity also promotes bleeding. While many of the anti-inflammatory effects of NSAIDs may be related to the suppression of COX-__, this also has implications for gastric mucosal integrity.
Suppression of COX-2 leads to ________ within the microcirculation, which contributes to ulcer formation.
Also, COX-2-derived PGs are essential for the _________ of mucosal injury, and this process is ________ when COX-2 is inhibited.
Some NSAIDs have the capacity to directly damage the ______ epithelium, through acid back-diffusion which impairs ?
NSAIDs induce injury/bleeding via three key pathways: inhibition of cyclooxygenase (COX)-1 activity, inhibition of COX-2 activity, and direct cytotoxic effects on the epithelium.
Effects produced via only one of these pathways (e.g., selective inhibition of COX-1 or of COX-2) are unlikely to produce significant damage.
The suppression of COX-1 and COX-2 is the primary mechanism through which NSAIDs induce ulceration.
The suppression of COX-1 activity impairs several elements of mucosal defense, including causing a reduction of mucosal blood flow, mucus secretion, and bicarbonate secretion.
By inhibiting thromboxane synthesis, suppression of COX-1 activity also
promotes bleeding.
While many of the anti-inflammatory effects of NSAIDs may be related to the suppression of COX-2, this also has implications for gastric mucosal integrity.
Suppression of COX-2 leads to leukocyte-endothelial adhesion within the microcirculation, which contributes to ulcer formation.
Also, COX-2-derived PGs are essential for the healing of mucosal injury, and
this process is impaired when COX-2 is inhibited.
Some NSAIDs have the capacity to directly damage the gastric epithelium, through acid back-diffusion which impairs platelet aggregation ad the healing process
List the GI consequences of COX Inhibition.
- Reduced mucosal defense
- Inhibition of repair processes
- Damage to blood vessels
- Inhibition of TXA2 production
Explain how reduced mucosal defense affects the GI.
The consequence of COX inhibition includes first, reduced mucosal defense and this is because virtually every component of GI tract mucosal defense is PG-dependent.
Prostaglandins maintain gastric mucosal integrity by inhibiting acid secretion, stimulating mucus and bicarbonate secretion, inhibiting mast cell activation, decreasing leukocyte adherence to the vascular endothelium, inhibiting apoptosis, increasing or maintaining mucosal blood flow and thus preventing ischemia.
Explain how inhibition of the repair processes affects the GI.
Normal repair/restitution and ulcer healing is impaired due to:
- Inhibition of ________
- Increased _______
- Reduced _______ ______
- inhibition of cell _________.
See below.
Explain how damage to blood vessels affects the GI.
- Stimulation of neutrophil adherence to vascular endothelium –> obstruction of normal blood flow thro’ capillaries –> iischemia
- Adherent neutrophils release proteases and free radicals –> injury to endothelial and epithelial cells –> cell death
Explain how inhibition of TXA2 production affects the GI.
TXA2, produced by activated platelets, has prothrombotic properties, stimulating activation of new platelets as well as increasing platelet aggregation.
What is the role of COX1 and COX2 in GI tract injury?
COX-1 Tract toxicity
COX-2 tract toxicity
What are the benefits of COX-2 for the kidneys?
NSAIDs have a direct GI mucosal irritant effect. Explain the ways in which this occurs.
NSAIDs can cause gastroduodenal ulcers when administered parenterally, topical irritant properties of these drugs make an important contribution to their overall ulcerogenic properties.
- Acidic NSAIDs have topical irritant properties. The unionized forms of these drugs can enter epithelial cells in the stomach and duodenum where, within the neutral intracellular environment, they become ionized and get trapped in the epithelial cells (ion trapping). As the drug accumulates within the epithelial cell, osmotic movement of water results in cellular swelling, eventually to the point of lysis.
- NSAIDs may also damage the gastro-duodenal epithelium via uncoupling of
mitochondrial respiration in epithelial cells leading to a depletion of ATP and therefore a reduced ability to regulate normal cellular functions, such as maintenance of intracellular pH and ion gradients. The ability of NSAIDs to uncouple oxidative phosphorylation may also be related to some extent to acidic moieties (carboxylic acid residues) because substitutions at these sites interfere with the ability of the compounds to act as uncouplers.
3). NSAIDs may exert topical irritant effects on the mucosa is by decreasing the hydrophobicity of the mucus gel layer in the stomach. The mucus layer is the primary barrier to acid-induced damage in the stomach and gastric mucosal surface is hydrophobic which retards diffusion of hydrophilic toxicants
What can be seen here?
Indomethacin toxicosis in dog
–> Gastric mucosal hemorrhage
and ulceration
What can be seen here?
Indomethacin toxicosis in dog
–> Small intestinal mucosal ulceration
What is the role of prostaglandins in renal function –> toxicity?
Under basal conditions, PGs do not have much effect on the kidney. When vasoconstrictor agents Angiotensin II and noradrenaline are generated and released, vasodilator PGE2 and PGI2 modulate their effect on the kidney by causing compensatory vasodilation. PGS control renin release under basal conditions and under conditions of volume depletion. Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin I, which is further converted into angiotensin II by ACE, the angiotensin-converting enzyme primarily within the capillaries of the lungs. Angiotensin II then constricts blood vessels, increases the secretion of ADH and aldosterone, and stimulates the hypothalamus to activate the thirst reflex, each leading to an increase in blood pressure. Renin’s primary function is therefore to eventually cause an increase in blood pressure, leading to restoration of perfusion pressure in the kidneys.
What are the renal effects of COX inhibition?
Acute interstitial nephritis (AIN) is rapidly developing inflammation that occurs within the interstitium due to an acute allergic reaction to NSAIDs. It can produce a variety of clinical symptoms, depending upon the severity and extent of kidney involvement.
Older and younger animals are more at risk to renal syndromes
Indomethacin toxicosis in dog
–> Papillary Necrosis
How could COX inhibition lead to
Hematological toxicity?
How does the uncoupling of oxidative phosphorylation –> aspirin toxicity?
- Reduces ATP synthesis via OXPHOS thus
promoting anaerobic metabolism leading to
elevations of lactate, ketones and pyruvate –> metabolic acidosis - Salicylates stimulate the respiratory center
in the medulla –> hyperventilation –> primary respiratory alkalosis
Part of the process of ATP production in the mitochondria involves pumping of protons (H+) from the _____ into to the _________ to create a proton gradient known as a ________ force.
This proton gradient is the utilized by the ATP synthase to phosphorylate ____ to _______.
Aspirin short-circuits this process by transporting the protons from the ____________ _____ back to the ______.
Therefore, the energy that was trapped in the proton gradient is __________ as _____ which manifests clinically as ?
Part of the process of ATP production in the mitochondria involves pumping of protons (H+) from the matrix into to the intermembrane space to create a proton gradient known as a protonmotive force.
This proton gradient is the utilized by the ATP synthase to phosphorylate ADP
to ATP.
Aspirin short-circuits this process by transporting the protons from the intermembrane space back to the matrix.
Therefore, the energy that was trapped in the proton gradient is dissipated as heat which manifests clinically as elevated body temperature.
