Pharmacology I - Nsaids

Front 1

What are eicosanoids?

Back 1

includes all prostaglandins, leukotrienes, thromboxanes, etc. derived from anarchidonic acid

Front 2

What is the ANALGESIC mode of action of NSAIDs, and where are their principal sites of analgesic action?

Back 2

* inhibit synthesis of eicosanoids (prostaglandins) from arachidonic acid by blocking action of the cyclo-oxygenase enzymes
* have both peripheral and central actions

Front 3

Which NSAIDS are highly COX2 selective

Back 3

> With the exception of firecoxib (Previcox) no NSAID licensed for animal use is highly selective for COX-2

Front 4

What are the principal side effects of NSAIDs? (5)

Back 4

- GI ulceration
- Nephrotoxicity
- Risk of renal decompensation
- Depressed platelet aggregation
- Plasma protein binding

Front 5

List 5 key contraindications for NSAID administration

Back 5

- concurrent corticosteroid medication
- hypotension or hypovolaemia (b/c NSAIDs will vasodilate?)
- gastric ulceration or vomiting
- renal dysfunction
- coagulopathy (clotting disorder)

Front 6

Phospholipase A2 converts cell membrane phospholipids into ?

Back 6

phospholipase A2 converts cell membrane phospholipids into ARACHIDONIC ACID

Front 7

CYCLOOXYGENASE converts ARACHIDONIC ACID into ?

Back 7

CYCLOOXYGENASE (COX) converts ARACHIDONIC ACID into PGG2/H2
(fyi: i think PGG2 is called an endoperoxide; it is reduced to form PGH2)

Front 8

PG-ISOMERASES convert PGG2/H2 into?

Back 8

PGI2, PGE2, PGD2, PGF2

Front 9

Thromboxane synthetase converts PGG2/H2 into ?

What does it do?

Back 9

Thromboxane synthetase converts PGG2/H2 into TXA2 (not TXB2)
TXA2 (thromboxane) is a platelet activation factor

Front 10

NSAIDs are divided into ?

Back 10

1. carboxylic acids
2. enolic acids
-----
3. cox-2 inhibitors (Coxibs)
- but this group of NSAIDs no longer used due to

Front 11

different types of carboxylic acids NSAIDs?

SAP

Back 11

1. Salicylic acid and esters
2. Acetic acids (hetero-/carbocyclic and Phenylacetic acids)
3. Propionic Acids

Front 12

Carboxylic acids NSAIDs:
Examples of Salicylic acid and esters? (2)

SAAD

Back 12

1. Acetyl salicylic acid
2. Diflunisal

SAAD

Front 13

Diclofenac is what kind of drug?

Back 13

Diclofenac = Phenylacetic acid (NSAID -> carboxylic acid -> acetic acid)

PAD

Front 14

What group do these drugs fall into?
Tolmetin
Sulindac
Indomethacin
Ketorolac

Back 14

Carbo/Heterocyclic Acetic acids (NSAID -> carboxylic acid -> acetic acid):
CA
Tolmetin
Sulindac
Indomethacin
Ketorolac

CAT SIK

Front 15

Carboxylic acids NSAIDs:
Give examples of the propionic acid drugs?

Hint: these usually end with what?
Hint #2: KFC Tastes Incredible For N (sorry but it helps :\ )

Back 15

Propionic acid drugs:

* usually end with -profen (except 1 -proxen and 1 -profenic acid)
Ketoprofen
Flurbiprofen
Carprofen
Tiaprofenic Acid
Ibuprofen*
Fenoprofen
Naproxen*

Front 16

What group do these drugs fall into?
Firocoxib
Deracoxib
Rofecoxib
Valdecoxib
Celecoxib

Back 16

There are all Cox-2 inhibitors
Firocoxib
Deracoxib
Rofecoxib
Valdecoxib
Celecoxib

Front 17

Carboxylic acids NSAIDs:
Example of Acetic acid that is a Phenylacetic acid?

PAD

Back 17

Diclofenac <- a phenylacetic acid

PAD

Front 18

Carboxylic acids NSAIDs:
Examples of Acetic acids that are carbo-and hetero cyclic acetic acids? (4)

Back 18

Carbo-and hetero cyclic acetic acids:
Tolmetin
Sulindac
Indomethacin
Ketorolac

CAT SIK

Front 19

What pH are NSAIDs soluble in?
Are they soluble in plasma?
Are they acids or bases?

Back 19

- NSAIDs are weak acids
- insoluble in plasma at neutral pH (more lipid soluble)
- more soluble in alkaline solutions (when ionized?, but this decreases absorption)

note: acidity due to the presence of acid carboxcylic group or an enol group

Front 20

Are NSAIDs readily absorbed when admin. orally?

Back 20

NSAIDs are lipid soluble, weak organic acids and generally well absorbed when admin. orally, b/c not ionized at LOW pH of stomach

Front 21

Are NSAIDs ionized in plasma/physiological pH?

Are injectables a good route of admin.?

Back 21

Yes, being weak acids they are ionized in blood; therefore capacity to penetrate mem. decreases

No, tend to be alkaline, cause pain, necrosis if perivascular leakage occurs

Front 22

Are NSAIDs highly protein bound?

Back 22

Yes, mainly albumin - for most of NSAIDs % of plasma protein binding is greater than 90%

Front 23

Which NSAIDs is not 90% PP bound?

Back 23

Aspirin only 50% PP bound

also salicylate

Front 24

Ketorolac is a ?

Back 24

carbo/heterocyclic acetic acid

CAT SIK

Front 25

How does fact that NSAIDs are highly protein bound facilitate function?

Back 25

facilitates passage into inflammatory exudate; therefore more concentrated at site of inflammation

fyi: exudate carries proteins, cells, fluid from local blood vessels to damaged area to mediate local defenses

Front 26

What can inhibit absorption/ bioavailability of NSAIDs?

Back 26

food, drugs bind to food e.g. hay

Front 27

Ketoprofen is ?

Back 27

Propionic acid drugs:

KFC Tastes Incredible For N

Front 28

T/F NSAIDs are:
Optical activity
- optically active
- chiral compounds

Back 28

True

Front 29

Diclofenac is a ?

Back 29

Diclofenac <- it is the only phenylACETIC acid

PAD

Front 30

What anti-platelet drug is Acetyl salicyclic acid, irreversibly inhibits cyclooxygenase enzyme, and therefore synthesis of prostaglandins and thromboxane A2?

Back 30

Aspirin

Front 31

Another name for aspirin?

What group does it fall into?

Back 31

Aspirin = Acetyl salicylic acid

Example of Salicylic acid and esters

Front 32

What are mediators of inflammation released or formed de novo from cells?

Back 32

histamaine, 5-hydroxytryptamine, the eicosanoids, platelet activating factor, free radicals and cytokines (interleukin, interferon, tumor necrosis factor)

Front 33

Diflunisal is a ?

Back 33

Examples of Salicylic acid and esters? (2)
1. Acetyl salicylic acid
2. Diflunisal

SAAD

Front 34

What are examples of Enolic Acids?

Back 34

pyraxolones and oxicams

Front 35

Tolmetin is a ?

Back 35

Carbo/Heterocyclic Acetic acids (NSAID -> carboxylic acid -> acetic acid):

caT sik

Front 36

What is an example of a pyrazolones?

Back 36

Phenylbutazone

Enolic Acid -> pyrazolones -> **Phenylbutazone**

Front 37

What are examples of oxicams?

Back 37

piroxicam and MELOXICAM

Front 38

Are NSAIDs chiral?

Back 38

Yes

Front 39

What is cyclooxygenase?

Back 39

enzyme that catalyzes the conversion of arachadonic acid to cyclic endoperoxide, prostaglandin, to the eicosanoids PGE2 and PGI2 which have pro-inflammatory properties

Front 40

What is a constitutive enzyme expressed in most tissues and blood platelets?

Back 40

COX-1

Front 41

COX-1 mediates the formation of constitutive prostaglandins which are involved in what?

Back 41

cellular "housekeeping" functions such as coordinating the action of circulating hormoned and regulating vascular homeostasis.

Front 42

What are the most important functions of COX-1?

Back 42

gastic protection, platelet function regulation, endothelial cell regulation, maintenance of renal blood flow during periods of shock and low systemic BP

Front 43

What is the inducible cyclooxygenase, that is expressed only following cell activation, is upregulated in CNS and plays an essential role in the mediation of pain and the febrile response?

Back 43

COX-2

Front 44

COX-2 can also be found as constitutive in what tissues?

Back 44

brain, kidney, OVARY, UTERUS, ciliary body and bone

Front 45

Complete inhibition of COX-2 can potentially lead to what?

Back 45

abortion, fetal deformities, delayed bone healing, delayed wound healing, cardiovascular events, renal toxicity
~ that is why a lot of COX-2 inhibitors (coxibs) have been taken off market

Front 46

Inhibition of cyclooxygenase can be of two types:

(which is irreversible?)

Back 46

1. competive inhibition of (arach.acid) substrate binding site of COX (reversible)
2. Acetylation of key serine w/in active site (irreversible)

Front 47

As consequence of inhibition of prostaglandin synthesis, NSAIDs produce what three main therapeutic effects?

Back 47

Antipyretic (lower febril state), analgesic, anti-inflammatory

Front 48

How are NSAIDs antipyretic (fever suppression)?

Back 48

the role of PGE2 in the pathogenesis of fever, PGE2 is the second messenger of IL-1 at the hypothalamus

Front 49

How are NSAIDS analgesic (reduction of inflammatory pain)?

Back 49

role of PGE2 in sensitizing sensory nerve endings to other mediators such as histamine and bradykinin

Front 50

How are NSAIDS anti-inflammatory?

Back 50

role of PGE2 in inducing vasodilation

Front 51

Is it advisable to give NSAIDs with food?

Back 51

? no, food can impair the oral absorption of some NSAIDS

Front 52

Why is it better to give NSAIDs orally, then administering injectable preparations?

Back 52

injectibles are alkaline and can cause necrosis or pain if perivascular leakage occurs

Front 53

Being weak acid, NSAIDs are ___ in blood, therefore their capacity to penetrate membrane is _____.

Back 53

ionized in blood; decreased

Front 54

NSAIDs are metabolized in the liver and and generally undergoes what two reactions?

Back 54

oxidation (a phase I reaction) followed by conjugation (a phase II reaction)

Front 55

Phenylbutazone is metabolized to the active metabilite _______?

What kind of NSAID is it again?

Back 55

Phenylbutazone (an enolic acid and pyrazolone) is metabolized to the active metabilite OXYphenbutazone!!!

Front 56

Aspirin is metabolized to the active metabolite __________?

Back 56

salicylic acid

Front 57

NSAIDS are mainly excreted in the urine, but what compounds are excreted in bile?

Back 57

tolfenamic acid and naproxen

Front 58

Why is excretion of NSAIDS faster in herbivores?

Back 58

* NSAIDs are ionized in alkaline urine; therefore reabsorption in renal tubules is decreased (opposite in carnivores)

Front 59

The toxicity of NSAIDs on the GIT is a consequence of what?

Back 59

the inhibition of gastric mucosal PG synthesis

Front 60

Because of the affects of NSAIDs on the GIT, it is always advised to administer NSAIDS with a what?

Back 60

cytoprotectant/ misoprostol (PGE replacement)

Front 61

Inhibition of cyclooxygenase by NSAIDs in renal compromised patients induces what?

Back 61

renal vasoconstriction, thereby decreasing renal blood flow and glomerular filtration rate

Front 62

NSAIDs interfere with platelet activity due to what?

Back 62

impaired thromboxane synthesis

Front 63

What are factors that increase or predispose NSAID toxicity?

Back 63

* if administered to patients with GIT inflammation or ulceration, inadequate dose regimens, age

* if administered to hypotensive , dehydrated, hyponatremic patients (low sodium - electrolyte inbalance), administration with highly plasma protein bound drugs or corticosteroids

Front 64

NSAIDs can be indicated for the treatment of what medical conditions?

Back 64

joint disease, bone tumors (e.g. meloxicam COX-2 inhibitor), intervertebral disc lesions, pancreatitis, external otitis, inflammatory eye conditions

Front 65

DO NOT use NSAIDs in patients with what problems?

Back 65

GIT inflammation or ulcerative disease, hyperchlorhydria, renal insufficiency, patients with reduced CO, patients receiving corticosteroids

Front 66

What is the mechanism of action of Aspirin?

Back 66

irreversible inhibition of cyclooxygenase enzyme activity, inhibits the formation and release of kinins, stabilize lysosomes

Front 67

How is aspirin (salicylic acid) eliminated?

Back 67

by glucuronide conjugation

Front 68

What are signs of acute toxicity of aspirin?

Back 68

depression, vomiting, hyperthermia, electrolyte imbalance

Front 69

What drug is approved by the FDA in horses and dogs, administered IV/oral, metab. in liver to form active oxyphenbutazone, prolonged duration of action with long half-life?

Back 69

phenylbutazone

Front 70

What are some adverse affects of phenylbutazone?

Back 70

GI toxicity, bone marrow hypoplasia, hepatotoxicity and renal papillary necrosis

Front 71

When should you use phenylbutazone?

Back 71

osteoarthritic and osteoporotic conditions (porous bones), equine colic

Front 72

What is a nicotinic acid derivative, is approved for use in horses, is a potent analgesic agent, and also possesses antiendotoxic effects?

Back 72

flunixin meglumine

Front 73

When should you use flunixin meglumine?

Back 73

colic and treatment of endotoxic shock

Front 74

What can accidental intra-arterial administration in horses of flunixin meglumine cause?

Back 74

CNS stimulation, ataxia, and hyperventilation

Front 75

What is flunixin meglumine used to treat in ruminants?

Back 75

acute mastitis and acute bovine pulmonary emphysema

Front 76

What can flunixin meglumine used to treat in dogs?

Back 76

septic shock

Front 77

What is the mechanism of action for carprofen?

Back 77

Mechanism of action for carprofen (propionic acid)?
~inhibition of COX2 (reversible), inhibition of phospholipase A2, impaired release of arachidonic acid

Front 78

When should you use carprofen?

Back 78

to treat osteoarthritis, and for post-operative pain

Front 79

What is an adverse affect of carprofen?

Back 79

hepatotoxicity

Front 80

What drug is approved by FDA for use in horses, and is used to treast myositis and soft tissue inflammation?

Back 80

naproxen

Front 81

What animals are more sensitive to naproxen, and extensive enterohepatic recycling leads to prolonged elimination?

Back 81

dogs (cats) sensitive to naproxen

infact not recommended in either of these animals; no safe dose for cats

Front 82

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)

Back 82

Ibuprofen

Front 83

What is a derivative of anthranilic acid, an analogue of salicyclic acid, has a slow onset of action, thus clinical efficacy requires 2-4 days?

Back 83

meclofenamic acid is a derivative of anthranilic acid, an analogue of salicyclic acid, has a slow onset of action

used for joint and muscular pain.
It inhibits the synthesis of prostaglandins.[1]
No other complications

Front 84

What is a proprionic acid NSAID approved for use in humans, horses, and small animals, it is a strong inhibitor of COX, so has powerful anti-inflammatory, analgesic and antipyretic properties.

Back 84

Ketoprofen

Front 85

How does ketoprofen interfere with the formation of leukotrienes?

Back 85

inhibits lipooxygenase

Front 86

What are side effects of ketoprofen?

Back 86

GI upset, CNS reactions, nephritis

Front 87

When is piroxicam used?

Back 87

for treating osteoarthritis in dogs, for reducing the size of transitional cell TUMORS in dogs, and a potent anti-inflammatory for treating musculoskeletal conditions

also evidence of antitumor activity in squamous cell carcinoma of oral cavity and skin in dogs (Schmidt et al. 2001)

Front 88

What is an effective analgesic and antipyretic agent, but has weak anti-inflammatory activity, does not inhibit COX, but interferes with endoperoxidase intermediates formed during the arachidonic acid metabolism?

Back 88

Acetaminophen

Front 89

For what animal is acetaminophen toxic?

Back 89

cats

Front 90

What are the adverse effects of acetaminophen?

Back 90

hepatotoxicity, methemoglobinemia

Front 91

How do you treat acetaminophen toxicity?

Back 91

antioxidants, a precursor of glutathione and ascorbic acid, cimetidine administration

Front 92

What enzyme converts cell membrane phospholipids into ARACHIDONIC ACID?

Back 92

phospholipase A2 converts cell membrane phospholipids into arachidonic acid

Front 93

What enzyme converts ARACHIDONIC ACID into PGG2/H2?

Back 93

CYCLOOXYGENASE (COX) converts arachidonic acid into eicosanoids PGG2/H2

(fyi: i think PGG2 is called an endoperoxide; it is reduced to form PGH2)

Front 94

What enzyme converts PGG2/H2 into PGI2, PGE2, PGD2, PGF2?

Back 94

PG-ISOMERASE converts PGG2/H2 into PGI2, PGE2, etc.

Front 95

What enzyme converts PGG2/H2 into TXA2?

Back 95

Thromboxane synthetase converts PGG2/H2 into TXA2 (platelet/clotting factor)

Front 96

How aspirin affect clotting factor thromboxane synthesis?

Back 96

Aspirin irreversibly inhibits platelet cyclooxygenase 1 preventing the formation of prostaglandin H2, and therefore thromboxane A2.

TXA2 is generated from prostaglandin H2 by thromboxane-A synthase.