Regal- Prostaglandins, Thromboxane and NSAIDS

Question 1

How are leukotrienes synthesized?

Answer 1

Phospholipase A2 cleaves membrane phospholipids into AA

5 LPO converts AA to 5HPETE then LTA4

Question 2

What do LTC4 synthase or glutathione S transferase do to LTA4? What converts LTE4 to LTB4?

Answer 2

LTA4>
LTC4
LTD4
LTE4-->LTA hydrolase
LTB4

Question 3

Where does LT synthesis occur?

Answer 3

Many cells and tissues

Predominately synthesized in leukocytes

Question 4

What enzyme is associated w/ mast cells and basophils and what to they primarily make?

Answer 4

LTC4 synthase

peptido LTs

Question 5

What enzyme is associated with endothelial cells and smooth muscle cells?

Answer 5

Glutathione S transferase

Question 6

What are the 2 (4) types of leukotrienes?

Answer 6

LTB4

Peptidoleukotrienes
LTC4, LTD4, LTE4

Question 7

How is LTB4 degraded?

Answer 7

Oxidized to inactive compound by enzymes in PMNs and others

Question 8

What are the biological effects of LTB4?

Answer 8

Chemotactic for neutrophils
enhanced leukocyte adhesion

Decreased pain threshold–> hyperalgesia

Question 9

What receptors does LTB4 target?

Answer 9

Non mentioned specifically but they’re distinct from peptide LTs

Question 10

How is LTE4 degraded?

Answer 10

It is excreted in urine or acetylated and excreted in bile

Question 11

LTC4, LTD4, LTE4 act on what receptor?

Answer 11

Cys LTR1

Cyst LTCR2

Question 12

Interaction of peptido leukotriens w/ LTR1 leads to…

Answer 12

increased vascular permeability-> swelling
chemotactic for eosinophils and cytokine secretion
bronchoconstriction
increased mucous production
DC maturation and migration
smooth muscle proliferation

Question 13

Interaction of peptido leukotrienes w/ LTR2 leads to…

Answer 13

endothelial cell and macrophage activation

fibrosis

Question 14

What two peptido leukotrienes are important in asthma?

Answer 14

LTC4

LTD4

Question 15

What drugs are leukotriene modifiers?

Answer 15

Zileuton
Zafirlukast
Montelukast

Question 16

What is the therapeutic use of leukotriene modifiers?

Answer 16

bronchial asthma

CHRONIC not acute

Question 17

What is the MOA of zileuton?

Answer 17

Inhibits 5-LPO

prevents synthesis of LTB4 and peptido LT

Question 18

How is zileuton eliminated?

Answer 18

M: cyp450

Question 19

What are the toxicities associated with zileuton?

Answer 19

drug interactions
hepatic toxicity (req monitoring)

Question 20

What is a unique property of zileuton related to asthma?

Answer 20

It can decrease the need for beta agonists in asthma

Question 21

What is the MOA of zafirlukast and montelukast?

Answer 21

LTR antagonists (cys LTR1)

Question 22

What is a toxicity associated w/ zafirlukast?

Answer 22

inhibits cyp450–> drug interactions

Question 23

What is a unique property of montelukast?

Answer 23

it can be administered once daily w/out regard to meals

Question 24

What are prostanoids?

Answer 24

PGD2
PGE2
PGF2
PGI2- prostacylcin
TXA2

Question 25

How are prostanoids synthesized?

Answer 25

Phospholipase A2 cleave membrane bound phospholipids into AA> Cox acts on platelets to form products

Question 26

What cells produce cos?

Answer 26

numerous cells in response to different stimuli

Question 27

Where is COX1 found?

Answer 27

platelets | constitutively expressed in most cells and is thought to protect mucosa

Question 28

Where is cox 2 found? What products is it more involved inmaking?

Answer 28

not in platelets inducible more involved in production of PG and TXA in inflammation

Question 29

How does enzyme expression of PG synthases influence the type of PG produced?

Answer 29

Platelets--> thromboxane (vasoconstrictor) Endothelium--> prostacylcin (vasodilator) Mast cells--> PGD2 (bronchoconstrictor)

Question 30

How are prostanoids degraded?

Answer 30

spontaneous chemical hydrolysis or rapid enzyme degradation

Question 31

What type of molecules are prostanoids, do they have a long or short t1/2?

Answer 31

unstable molecules short t 1/2 limited systemic effects

Question 32

What does PGD2 do?

Answer 32

Bronchoconstriciton

Question 33

What receptor does PGD2 act on?

Answer 33

DP

Question 34

What does PGE2 do?

Answer 34

vasodilation> redness and heat increased vascular permeability> swelling decreased pain threshold, sensitize pain receptors, synergy w/ other receptors > pain fever

Question 35

What receptors does PGE2 act on?

Answer 35

EP subtypes EP1-4

Question 36

What receptors does PGF2 act on?

Answer 36

FP

Question 37

What does prostacyclin (PGI2) do?

Answer 37

1. Vasodilation → redness & heat & opposes platelet aggregation 2. increased vascular permeability → swelling 3. increased pain threshold, sensitize pain receptors, synergy w/ other mediators→ pain

Question 38

What receptors does PGI2 act on?

Answer 38

IP

Question 39

What does TXA2 do?

Answer 39

1. Vasoconstriction → platelet aggregation

Question 40

What receptor does TXA2 act on?

Answer 40

TP

Question 41

What drugs are NSAIDS?

Answer 41

acetylsalicylate ibuprofen naproxen ``` ketorolac idomethacin sulindac petoprofen piroxicam ```

Question 42

What is the MOA of NSAIDS?

Answer 42

Inhibit COX

Question 43

How are NSAIDS eliminated?

Answer 43

renal

Question 44

What are toxicities associated w/ NSAIDS?

Answer 44

``` Gastric ulcers prolonged gestation impaired renal function increased bleeding aspirin hypersensitivity ```

Question 45

What is the generic name for acetylsalicylate and it's MOA?

Answer 45

Aspirin irreversibly inhibits COX 1 and 2

Question 46

What are SE associated w/ aspirin?

Answer 46

reye syndrome fatty liver tinnitus low TI

Question 47

What are SE associated w/ ibuprofen?

Answer 47

Fewer GI SE than aspirin

Question 48

What is a unique property associated with naproxen?

Answer 48

Primary algesia | anti-inflammatory

Question 49

What is a toxicity associated w/ indomethacin?

Answer 49

severe frontal lobe head ache

Question 50

What is the most potent NSAID?

Answer 50

indomethacin

Question 51

What is a SE associated w/ piroxicam?

Answer 51

Dose related GI bleeding

Question 52

What is the only cox inhibitor?

Answer 52

celecoxib

Question 53

What is the MOA of celecoxib?

Answer 53

selective cox 2 inhibitor

Question 54

What are toxicities associated w/ celecoxib?

Answer 54

Increased risk of thrombotic vascular events Gastric ulcer (less likely than for NSAIDS) Altered renal function Hypersensitivity (less likely)

Question 55

What is the MOA of acetaminophen?

Answer 55

Weak inhibitor of COX

Question 56

How is acetaminophen distributed?

Answer 56

D: highly effective on COX in brain, but not inflammatory sites

Question 57

What is a SE of acetaminophen?

Answer 57

Overdose> | serious hepatic injury

Question 58

What MUST you know about acetaminophen?

Answer 58

It is NOT anti-inflammatory used as anti-pyretic and analgesic

Question 59

What are the two types of kinins?

Answer 59

bradykinin | kalldin

Question 60

Where are kinins synthesized?

Answer 60

extracelluar in blood or interstitial fluid

Question 61

How is kinase I degraded?

Answer 61

carboxypeptidase N or anaphylatoxin inactivator removes carboxy terminal arg--> des arg kinins

Question 62

How is kinase II degraded?

Answer 62

Angiotensin converting enzyme (ACE) OR | dipeptide hydrolase

Question 63

What kinins act on B-2 receptor and what does that do?

Answer 63

kallidin & braykinin more active 1. Vasodilation → redness & heat 2. VERY strong vasodilators → hypotension 3. increased vascular permeability → swelling, edema 4. cause pain 5. Bronchoconstriciton 6. Release catecholamines & PGs

Question 64

What kinins act on the B1 receptor? and what effect does that have?

Answer 64

des-arg kinins (lack terminal ARG) more active 1. chronic inflammatory effects 2. induced after trauma 3. cytokine production & long term effects 4. hypotension & pain