Drugs inflammator and relared disorder_ Eicosanoid pharmacology

Question 1

_______ are cell-regulating polyunsaturated fatty acids

Answer 1

Eicosanoids

Question 2

Eicosanoids is synthesized from ______ and released by actions of __________ from lipid membranes

Answer 2

Arachidonic acids; phospholipase A2

Question 3

Eiconsanoids are present in ______ concentration in most cells but synthesized and released on demand in response to stimuli

Answer 3

Low

Question 4

Stimulus that triggers release of eicosanoids

Answer 4

IgE-mediated reactions (HSR type I); inflammatory mediators, trauma, heat; and toxins

Question 5

eicosanoids interact with specific receptors, which are ________ effector systems

Answer 5

G-protein coupled to 2nd messenger

Question 6

membrane phosplipids “____________” ——> arachidonic acid which gives

1. cyclooxygenase (COX1, COX2) —->endoperoxides: giving PGI2; PGD2, PGE2, PGF2alpha
2. Lipooxygenase (LOX) —->hydroperoxides: giving Leukotrienes

Answer 6

phospholipase A2;

Question 7

Prostaglandins (PGs) are _________ in stomach, dilates renal vasculature, contracts uterus and maintains ductus arteriosus

Answer 7

Cytoprotective

Question 8

TxA2 causes

Answer 8

platelet aggregation

Question 9

GI PGs and platelets TxA2 are synthesized via

Answer 9

COX1 (constitutive)

Question 10

________ synthesizes PGS involved in inflammation; fever, and pain

Answer 10

COX2 (inducible)

Question 11

both enzymes _____ and ______ synthesizes renal PGs which increases RBF

Answer 11

COX1 and COX2

Question 12

_______ are formed via hydroperoxides from LOX on arachidonic acid

Answer 12

Leukotrienes (LTs)

Question 13

________ inflammatory mediator leading to neutrophil chemoattractant; activates PMNS(polymorphonuclear leukocytes); increase free radical formation - cell damage

Answer 13

LTB4

Question 14

LTB4 (inflammatory mediators)

Answer 14

neutrophil chemoattractant; activates PMNS(polymorphonuclear leukocytes); increase free radical formation - cell damage

Question 15

LTA4; LTC4 and LTD4 causes

Answer 15

anaphylaxis and bronchoconstriction (role in asthama)

Question 16

Leukotrienes are targets for ?

Answer 16

1. Glucocorticoids: decreases phopholipase A2 activity leading to both antiinflammatory and immunosuppressive actions
2. Zileuton: inhibits lipooxygenase leading to decrease LTs used in Rx of asthma
3. Zafirlukast and “lukasts” : LT-receptor antagonists used in Rx of asthma

Question 17

inhibits lipoxygenase leading to decrease LTs used in Rx of asthma

Answer 17

Zileuton

Question 18

ecreases phopholipase A2 activity leading to both antiinflammatory and immunosuppressive actions

Answer 18

Glucocorticoids

Question 19

LT-receptor antagonists used in Rx of asthma

Answer 19

Zafirlukast and “lukasts”

Question 20

__________ are formed via endoperoxides from actions of cyclooxygenases (COXs)

Answer 20

Prostaglandins

Question 21

_______ is expressed in most tissues: platelets, stomach; and acts to synthesize TxA2 and cytoprotective PGs

Answer 21

COX1

Question 22

_______ is expressed in brain and kidney and sites of inflammation

Answer 22

COX2

Question 23

_______ are drugs of PGE1

Answer 23

Misoprostol: ( used previously in Rx of NSAID induced ulcers; protective action on gastric mucosa)

Alprostadil: ( maintains patency of ductus arteriosus; vasodilates, used in male impotence) - CI in preg unless used as abortifacient (misoprostol + miferprsitone combined)

Question 24

used previously in Rx of NSAID induced ulcers; protective action on gastric mucosa

Answer 24

Misoprostol

Question 25

maintains patency of ductus arteriosus; vasodilates, used in male impotence) - CI in preg unless used as abortifacient (misoprostol + miferprsitone combined)

Answer 25

Alprostadil

Question 26

_______ used to close ductus arteriosus

Answer 26

Indomethacin

Question 27

PGE2 causes

Answer 27

uterine smooth muscle contraction

Question 28

uses of PGE2

Answer 28

dinoprostone used for "Cervical ripening" and as abortifacient

Question 29

abortifacient means

Answer 29

combination of misoprostol + miferprsitone

Question 30

used for "Cervical ripening" and as abortifacient

Answer 30

dinoprostone

Question 31

PGF2-alpha actions

Answer 31

causes uterine and bronchiolar smooth muscle contraction

Question 32

drugs of PGF2-alpha are

Answer 32

Carbopros (used as abortifacient) | latanoprost (Rx glaucoma (decrease intraocular pressure)

Question 33

_______Rx glaucoma (decreases intraocular pressure

Answer 33

latanoprost

Question 34

PGI2 (prostacyclin) uses

Answer 34

pulmonary HTN

Question 35

PGI2 actions

Answer 35

platelet stabilizer and vasodilators

Question 36

Drugs of prostacyclin (PGI2) include

Answer 36

epoprostenol

Question 37

Prostacylin

Answer 37

Vasodilator (PGI2)

Question 38

PGE2 and PGF2-alpha

Answer 38

both increases in primary dysmenorrhea | Therapeutic effects of NSAIDs may be due to inhibition of their synthesis

Question 39

Thromboxanes (TxAs) (TxA2)

Answer 39

platelet aggregator (inhibition of synthesis underlines protective role of acetylsalicylic acid (ASA) post-MI))

Question 40

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Answer 40

most are non-selective inhibitors of cyclooxygenases, acting on COX 1 and COX2 isoforms to decrease formation of PGs and TxA2

Question 41

most are non-selective inhibitors of cyclooxygenases, acting on COX 1 and COX2 isoforms to decrease formation of PGs and TxA2

Answer 41

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Question 42

______ are analgesic, antipyretic and antiinflammatory and have anti-platele effects

Answer 42

NSAIDs

Question 43

Acetylsalicylic acid (ASA) is prototype of ________ which includes more than 20 individual drugs

Answer 43

NSAIDs

Question 44

Platelet stabilization via PGI2

Answer 44

activation of PGI2 receptors --->stimulation of adenylate-cyclase ----->increase cAMP ---> increase activity of internal Ca2+ "pumps" ---> decrease free Ca2+ => platelet stabilization

Question 45

Platelet aggregation via TxA2

Answer 45

activation of TxA2 receptors --->stimulation of phospholipase C ---> increase PIP2 hydrolysis ---> PIP3 ------>mobilization of bound Ca2+ ----> increase free ca2+ => platelet aggregation

Question 46

Acetylsalicylic acid (ASA: Aspirin) causes

Answer 46

irreversible inhibition of COXs; covalent bond via acetylation of Serine hydroxyl group near the active site

Question 47

covalent bond via acetylation of Serine hydroxyl group near the active site

Answer 47

Acetylsalicylic acid (ASA: Aspirin)

Question 48

Actions of ASA is dose dependent:

Answer 48

1. antiplatelet aggregation: low dose, used in post-MI prophylaxis to reduce risk of transient ischemic attack (TIAs) 2. analgesia and antipyresis: moderate dose 3. antiinflammatory: high doses 4. uric acid elimination: - Low to moderate doses --> decreases tubular secretions ---> hyperuricemia - High-doses: decrease tubular reabsorption =>uricosuria 5. Acid-Base and Electrolyte balance: - High therapeutic: mild uncoupling of oxidative phosphorylation ---> increase respiration ---> decrease PCO2 ----> respiratory alkalosis ----> renal compensation -----> increase HCO3- elimination ---> compensated respiratory alkalosis (pH = normal; decrease HCO3- ; decrease PCO2) - Adults: stable condition but in children it increases toxicity - Toxic dose: inhibits respiratory center ---> decrease respiration ----> increase PCO2 ----> respiratory acidosis (decreased pH, decrease HCO3- and normalization of PCO2) plus inhibition of Krebs cycle and severe uncoupling of oxidative phosphorylation (decreases ATP)----> metabolic acidosis, hyperthermia and hypokalemia (decrease K+)

Question 49

Side effects of ASA (aspirin)

Answer 49

GI irritation, ulcer and bleeding; salicylism ( tinnitus, vertigo, decrease hearing ---often 1st sign of toxicity) Brochoconstriction : exacerbates asthma Hypersensitivity, especially "triad": asthma, nasal polyps, rhinitis Reye Syndrome: encephalopathy increase bleeding time (antiplatelet) ``` chronic use: - associated with renal dysfunction Drug interactions: - ethanol (increase GI bleeding) - OSUs and warfarin (increase effects) - uricosurics (decrease effects) ```

Question 50

aspirin overdose management

Answer 50

extensions of the toxic actions, + at high dose vasomotor collapse occurs, with respiratory and renal failure management: no antidote; managed via gastric lavage (+/- activated charcoal); + ventilatory support and symptomatic manangement of acid-base/ electrolyte imbalance and hyperthermia and resulting dyhration increase urine volume and its alkalinization facilitates ASA renal elimination; ASA follows zero-order elimination at toxic doses

Question 51

ASA follows _______elimination at toxic doses

Answer 51

zero-order

Question 52

other examples of NSAIDs that are reversible inhibitors of COX 1/2 with analgesic, antipyretic, and antiinflammatory actions include

Answer 52

``` Ibuprofen Naproxen indomethacin ketorolac sulindac ``` comparison with ASA: analgesia: ketorolac > ibuprofen/naproxen> ASA GI irritation: < ASA(but still occurs use misprostol) minimal effects on acid-base balance, no effect on uric acid elimination allergy: common (cross HS with ASA) Renal: chronic use, nephritis, nepheritic syndrome, acute failure (via decrease PGE2 and PGI2, which normally maintains GFR and RBF) does not occur with sulindac

Question 53

which PGs normally maintains GFR and RBF

Answer 53

PGE2 and PGI2

Question 54

toxicities of Indomethacin

Answer 54

thrombocytopenia, agranulocytosis and >CNS effects

Question 55

toxicities of sulindac

Answer 55

Steven-johnson syndrome, hematotoxcity

Question 56

Selective COX 2 inhibitors

Answer 56

Celecoxib

Question 57

_______ not as effective as antiflammatory compare to other NSIADs; less GI toxicity; less antiplatelet actions

Answer 57

Celecoxib

Question 58

may possibly exert prothrombotic effects via inhibition of endothelial cell function (MI and strokes)

Answer 58

Celecoxib

Question 59

Cross-hypersensitivity between ________ and _________

Answer 59

Celecoxib and sulfonamides

Question 60

NSAIDs are associated with _________?

Answer 60

increased risk of thrombotic events such as MI and stroke

Question 61

_________ has no inhibition of COX in peripheral tissues and lacks sign. antiinflammatory effects

Answer 61

Acetaminophen

Question 62

Equivalent analgesic and antipyretic activity to ASA due to inhibition of cyclooxygenases in CNS

Answer 62

Acetaminophen

Question 63

Comparison of Acetaminophen to ASA

Answer 63

no antiplatelet action; no Reye syndrome; no effects on uric acid; not bronchospastic (safe in NSAID HS and asthmatic) and GI distress is minimal at low-moderate dose

Question 64

Acetaminophen toxicity effects

Answer 64

Hepatotoxicity: - its metabolized mainly by liver glucuronyl transferase to form inactive conjugate - at P450 it results in formation of reactive metabolite (N-acetylbenzoquinoneimine), which is inactivated by glutathione (GSH) - in overdose: finite stores of GSH is depleted resulting in metabolite reacting with hepatocyte causing nausea and vomiting, abdominal pain, liver failure due to centrilobular necrosis - chronic use of ethanol enhances liver toxicity via induction of P450 management of hepatotoxicity: N-acetylcysteine (supplies -SH groups), preferably within 1st 12 hrs

Question 65

________ (supplies -SH groups), preferably within 1st 12 hrs in hepatotoxicity

Answer 65

N-acetylcysteine

Question 66

N-acetylcysteine also used as

Answer 66

mucolytic in CF disease

Question 67

"Tot" toxicity

Answer 67

young children are gustatory explorers; therefore compounds responsible for toxicity in children age of 3 years are : aspirin, acetaminophen (ppl know about reye syndrome), supplementary iron tablets

Question 68

aspirin, acetaminophen (ppl know about reye syndrome), supplementary iron tablets

Answer 68

"Tot" toxicity