Pharm 1 Exam 3 - Prostaglandins

Front 1

What is arachidonic acid (AA)?

Back 1

AA, a phospholipid, is the main precursor of eicosanoid.

Front 2

What are eicosanoid?

Back 2

They are signaling molecules made by oxygenation of twenty-carbon essential fatty acids (EFAs). They exert complex control over many bodily systems, mainly in inflammation or immunity, and as messengers in the central nervous system.

Front 3

What are the four main eicosanoids?

Back 3

Prostaglandins
Thromboxane
Prostacyclin
Leukotrienes

Front 4

What is the function of phospholipase A2 in eicosanoid sysnthesis?

Back 4

It cleaves AA from phospolipid.

Front 5

Cytosolic PLA2 activation initiates AA ( subsequently eicosanoid) production. How is cytosolic PLA2 activated?

Back 5

In response to signal transduction events triggered by many stimuli, such as thrombin action on platelets, C5a on neutrophils, bradykinin on fibroblasts, and antigen-antibody reactions on mast cells. General cell damage also triggers the activation process.

Front 6

What are prostaglandins?

Back 6

They are essential fatty acids from the eicosanoid subclass prostanoid. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring.
They are are autocrine and paracrine lipid mediators that act upon platelet, endothelium, uterine and mast cells producing varied physiological effects including modulation & mediation of inflammation.

Front 7

What is the rate limiting step in eicosanoid sysnthesis?

Back 7

The liberation of arachidonate from phospholipids by the enzyme phospholipase A2 (PLA2).

Front 8

Of the many species of the enzyme phospholipase A2 (PLA2), which is the most important?.

Back 8

Cytosolic PLA2.

Front 9

In addition to the generation of AA,what else does PLA2 generate from phospholipids?

Back 9

Lysoglyceryl-phosphorylcholine (lyso-PAF), the precursor of platelet activating factor, another inflammatory mediator.

Front 10

Map the pathway from cell membrane phospholipid to PGE2?

Back 10

Phospholipid ->(PLA2) ->AA -> Arachidonate -> cyclic endoperoxide -> PGE2 (vasodilator, hyperalgesia)

Front 11

Map the pathway from the cell membrane phospholipid to PGF2a?

Back 11

Phospholipid ->(PLA2) ->AA -> Arachidonate -> cyclic endoperoxide -> PGF2a (bronchoconstrictor, myometrial contractor)

Front 12

What is the role of COX-1 in the body?

Back 12

It is the "housekeeping enzyme" that regulates normal cellular processes - gastric cryoprotection, vascular homeostasis, platelet aggregation & kidney function.

Front 13

What are the two major pathways in the synthesis of eicosanoids from AA?

Back 13

The cyclooxgenase (COX) & lipogenase (LOX) pathways

Front 14

Via what pathway is prostaglandins, thromboxane & prostacyclins synthesized?

Back 14

COX

Front 15

What are the two isoforms of COX?

Back 15

COX-1 (responsible for the physiological production of prostanoids)
COX-2 (induced -> increases the production of prostanoids in diseased and inflammed sites).

Front 16

COX-2 is constitutively expressed in tissues like the brain, kidney & bone. What does its presence in other areas indicate?

Back 16

Inflammation

Front 17

How does the substrate channel between COX-I and COX-2 differ and how is this significant in the development of drugs that act on these substrates?

Back 17

Selectivity can be based on drugs that are able to block or fill one channel (the binding site for AA) but not the other because of the difference in their sizes.

Front 18

What are 5-HPETE, 12HPETE & 15HPETE?

Back 18

They are unstable peroxide derivatives that are converted to their corresponding hydroxylated derivatives (the HETES) or to leukotrienes or lipoxins. This is via the lypogenase pathway.

Front 19

What type of receptors are prostaglandin receptors?

Back 19

GPCR which subsequently activate or inhibit adenyl cyclase or stimulate PLC

Front 20

How many different types of prostaglandin receptors are currently known?

Back 20

Nine

Front 21

With regards to prostaglandins (PGAs),
how is relief from pain & inflammation provided?

Back 21

Thru the pharmacological inhibition of COX

Front 22

What is the naming system of prostaglandins?

Back 22

The letter that follows the PG (eg PGE) indicates the substitutions on the the 9th and 11th carbons of the cyclopentane ring. The number (eg PGE2) indicates the total number of double bonds in the two R-groups.

Front 23

What is the precursor of the PG2 (the two double bonds) series?

Back 23

AA

Front 24

What is the precursor of the PG1 (the one double bonds) series?

Back 24

Dihomo-gamma-linolenic acid (DLA)

Front 25

What is the precursor of the PG3 (the one double bonds) series?

Back 25

Eicosapentaenoic acid (EPA)

Front 26

What are cyclic endoperoxides(PGG2 and PGH2) ?

Back 26

Cyclic endoperoxides are from a group of compounds derived from AA by the action of cyclooxygenase that give rise to prostacyclin, thromboxanes and prostaglandins.

Front 27

Where is prostacyclin primarily formed?

Back 27

In endothelial cells (in response to shear stress, hypoxia, and other mediators of nitric oxide production).

Front 28

What does prostacyclin do?

Back 28

Prostacyclin causes relaxation of the vascular smooth muscle by activating adenylate cyclase and increasing the production of cAMP. It also inhibits the activation and aggregation of platelets.

Front 29

What is thromboxane A2 (TXA2)?

Back 29

Thromboxane A2 (TXA2) is a potent platelet aggregator formed by the action of the enzyme thromboxane A2 synthase on cyclic endoperoxides. It is primarily produced in the platelets, although smaller quantities are synthesized in macrophages, lungs, kidneys, and heart.

Front 30

What is the primary factor in the regulation of hemostasis?

Back 30

The balance between the production of TXA2 and the production of prostacyclin by the endothelial cell.

Front 31

What is the role of leukotrienes in the body?

Back 31

They are proinflammatory.
Leukotrienes can exacerbate the effects of asthma and allergies.

Front 32

What are leukotrienes?

Back 32

Leukotrienes (leuko because they are made by white cells, and trienes because they contain a conjugated triene system of double bonds) are synthesised from AA by the enzyme 5-lipoxygenase via the lipoxygenase pathway and they are mediators.

Front 33

Where are leukotrienes found?

Back 33

These soluble cytosolic enzymes are found in lung, platelets, mast cells and white blood cells.

Front 34

Map the pathway from AA to leukotrienes

Back 34

AA -> arachidonate -> 5-lypogenase -> 5HPETE-> LTA4-> LTC4->LTD4->LTE4.
LTA4 may also be converted into LTB4.

Front 35

What is LTA4?

Back 35

It is the unstable compound leukotriene, precursor of LTB4 and the cysteinyl-containing leukotrienes LTC4, LTD4, LTE4 and LTF4 (also referred to as the sulfidopeptide leukotrienes).

Front 36

What is the action of leukotrienes on the respiratory system?

Back 36

Cysteinyl-leukotrienes are potent spasmogens, causing dose-related contraction of human bronchiolar muscle in vitro.
LTE4 is less potent than LTC4 and LTD4, but its effect is much longer lasting.
All cause an increase in mucus secretion.
They contribute to the underlying bronchial hyperreactivity in asthmatics, and are among the main mediators of both the early and late phases of asthma.

Front 37

What is the action of leukotrienes on the CV system?

Back 37

Small amounts of LTC4 or LTD4 given intravenously cause a rapid, short-lived fall in blood pressure, and significant constriction of small coronary resistance vessels.
Given subcutaneously, they are equipotent to histamine in causing weal and flare.
Given topically in the nose, LTD4 increases nasal blood flow and increases local vascular permeability. Leukotrienes may also mediate the cardiovascular changes of acute anaphylaxis.

Front 38

What is the role of leukotrienes in inflammation?

Back 38

LTB4: chemoattraction of leukocytes, mainly neutrophils.
SRS-A's: increased vascular permeability, causes
bronchoconstriction & have
chemotactic (leukotactic)actions.

Front 39

What is the precursor of the series 3 prostaglandins & thromboxanes?

Back 39

EPA (via the COX pathway)

Front 40

What is the precursor of leukotrienes?

Back 40

EPA (via the LOX pathway)

Front 41

What are some of the inflammatory stimuli that induce COX-2?

Back 41

Growth factors, tumor promotors, endotoxin (lipopolysaccharide) or cytokines (interleukin-1 or tumor necrosis factor-alpha)

Front 42

Where is TXA2 synthesized?

Back 42

In platelets via TXA2 synthase

Front 43

What are the major effects of PGD2?

Back 43

Vasodilation,inhibits platelet aggregation,
relaxes GI tone & relaxes uterine smooth muscle (via DP receptor)

Front 44

What are the major effects of PGI2?

Back 44

IP receptor - potent vasodilation, inhibits platelet aggregation, renin release & natriuresis

Front 45

What are the major effects of PGI2?

Back 45

(Via IP receptor)- vasodilation (potent), inhibits platelet aggregation, renin release & natriuresis.

Front 46

What are the major effects of PGF2a?

Back 46

Increase uterine tone, some bronchoconstriction & vasoconstriction (via FP receptor).

Front 47

What are the major effects of PGF2a?

Back 47

(Via FP receptor); increases uterine tone, some bronchoconstriction & vasoconstriction. Also contracts GI tract muscles.

Front 48

What are the effects of PGE2 on gastric acid production?

Back 48

Via EP receptor –reduces/inhibits gastric acid secretion.

Front 49

What are the pathological effects of prostaglandins?

Back 49

Inflammation, fever & pain (hyperalgesia synergism)
Peripherally – increased nociceptor sensitivity.
Centrally – enhance transmission of pain signals in spinal cord.

Front 50

What are the physiological (protective) effects of prostaglandins?

Back 50

Cytoprotective, vasodilatory, platelet aggregation and disaggregation and increase uterine tone and contraction.

Front 51

How does the PGs (PGE2 , PGI2 , PGD2) mediate inflammation?

Back 51

They cause:
increased local blood flow in the inflamed region; vasodilatation;
edema formation;
erythema (long-lasting up to 10 hrs);
leukocyte infiltration &
tissue-damaging free radical formation during endoperoxide synthesis.
They also potentiate the inflammatory effect of histamine and bradykinin.

Front 52

How does PG (PGE2 & PGI2) mediate pain?

Back 52

Hyperalgesic response by potentiating pain-producing activity of bradykinin and other autocoids via sensitization of afferent nerve endings (C-fibers) to chemical and mechanical stimulation;
increase nociceptor sensitivity peripherally;
enhance transmission of pain signals in spinal cord centrally (PGE2).

Front 53

How does PG (PGE2) mediate fever?

Back 53

Pyrogens release IL-1 to increase PGE2 synthesis & release in hypothalamus;
temperature-regulating activity is altered;
temperature set point is reset in the hypothalamus.

Front 54

What are the two major thromboxanes?

Back 54

Thromboxane A2 (TXA2)and thromboxane B2 (the inactive form of thromboxane).

Front 55

What is the function of TXA2?

Back 55

TXA2 is generated from prostaglandin H2 by thromboxane-A synthase. It is a platelet aggregator & vasoconstrictor.

Front 56

What is ASA's action on TXA2?

Back 56

Aspirin irreversibly inhibits COX-1 by bonding covalently with its serine reside. ASA therefore inhibits TXA2 production.

Front 57

What is the clinical use of PGs in obstetrics?

Back 57

To induce childbirth; for parturition or abortion (via PGE2/PGF2a receptors). Also stops postpartum hemorrhage.

Front 58

How is PGA used in the management of patent ductus arteriosus?

Back 58

It is used to prevent closure of patent ductus arteriosus in newborns with particular cyanotic heart defects (PGE1)

Front 59

What is the clinical use of PGAs in the tx of GI ulcers?

Back 59

It is used in the prevention and treatment of peptic ulcers (PGE).

Front 60

Which of these condition(s) is PGA used to tx?
a. Glaucoma
b. Raynaud's phenomenon
c. PAH
d. All of the above
e. a & b
f. None of the above

Back 60

d. All of the above

Front 61

How does prostaglandins manage platelet aggregation?

Back 61

Opposing effects are mainly from PGI2/PGD2 and TXA2.
PGI2 & PGD2 causes disaggregation via increased cAMP levels while TXA2 causes aggregation via increased IP3 levels and mobilization of intracellular calcium.

Front 62

How does COX-2 selective NSAIDs affect platelet aggregation?

Back 62

COX-2 selective NSAIDs do not inhibit COX-1 so TXA2 is more expressed than PG12 or PGD2 which therefore leads to increased platelet aggregation

Front 63

Where in the body is COX-2 found?

Back 63

In vascular lining

Front 64

Where in the body is COX-1 found?

Back 64

In platelets

Front 65

Where is prostacyclin synthase & thromboxane synthase found?

Back 65

In vascular lining & in platelets, respectively.

Front 66

COX-1 is continuously stimulated. True or false?

Back 66

True. COX-1 is continuously stimulated by normal body physiology.

Front 67

Prostaglandins are paracrine secretions (hormones). What does this mean?

Back 67

They are released from cells and bring about changes in neighboring cells that carry specific prostaglandin receptors in their membranes.

Front 68

The COX active site lies at the end of a long narrow, hydrophobic tunnel or channel that has three of the alpha helices of the membrane-binding domain lying at the entrance of this channel. How is this significant in the mode of action of COX inhibitors?

Back 68

In various ways, inhibitors act by blocking or filling the channel, hence preventing AA attachment to the COX enzyme.

Front 69

Inhibitors, except ASA, temporariy block AA attachment to the binding site of COX enzymes. ASA block is not temporary (it is irreversible). Why is this so?

Back 69

When ASA acetylates COX-1, it covalently bonds to the residue of the enzyme & a new enzyme must be produced to replaced the altered ones.

Front 70

Explain why only COX-1 is blocked by ASA?

Back 70

The channel for COX-1 is smaller than that of COX-2 so ASA is able to block AA's entry from COX-1 but not from COX-2

Front 71

A major side effect of NSAIDs is varying degrees of stomach irritation/damage. Why is this so?

Back 71

The lining of the stomach contains lipid for protection against acids. Most NSAIDs are weakly acidic lipid soluable compounds that are able penetrate the stomach lining.

Front 72

What is the drug prostaglandin analogue cytotec (misoprostol) used for & how does it work?

Back 72

It prevents NSAID-induced ulcers by stimulating mucus secretion and at higher doses (=/> 200mcg), reduce gastric acid secretions. It is therefore cryoprotective.

Front 73

Why would you instructed a pt to hold ASA for at least 7-10 days before a surgical procedure?

Back 73

ASA inactivates the constitutive form COX-1-by irreversibly acetylating a serine residue in its active site.
This reduces both TXA2 synthesis in platelets and PGI2 synthesis in endothelium.
Vascular endothelial cells can synthesise new enzyme via regeneration of COX-1 and via COX-2, whereas platelets (which contain only COX-1 and have no nuclei) cannot.
After administration of ASA, TXA2 synthesis does not recover until the affected cohort of platelets is replaced in 7-10 days.

Front 74

What is the daily dose of ASA recommended for thromboprophylaxis (decreased platelet aggregation)?

Back 74

81 mg

Front 75

Why must ASA for antiplatelet therapy be given daily (and not for example), every other day?

Back 75

For ASA’s antiplatelet aggregation effects, ASA must inactivate majority of platelets & inhibit > 90% TXA2 production;
1/7 of circulating platelets are renewed Q24 hr, so up to 30% of platelets could circulate with uninh TXA2 production after 48 hr without ASA; thus – ASA must be used daily rather than every other day.

Front 76

What are prostaglandins action on the GI system?

Back 76

Stimulation of intestinal motility - longitudinal muscle is contracted by PGE2 & PGF2a;
circular muscle is relaxed by PGE2.
They are cryoprotective, increase bicarb & mucus production, inhibit acid production.

Front 77

What is prostaglandin action on uterine muscles?

Back 77

Increases tone and uterine contractions;
levels of PGEs and PGFs increased during labor

Front 78

How does prostaglandin provide cryoprotection to the GI system?

Back 78

Mainly thru PGE2 & PGI2 by inhibition of gastric acid secretions, stimulation of mucus secretion, increased bicarbonate secretion & increased mucosal blood flow.
Its effect is to enhance resistance of gastric mucosal cells to damage & accelerate ulcer healing.

Front 79

What class of drug is misoprostol?

Back 79

It is an analogue of PGE1
It is often administered with NSAID to provide cryoprotection.

Front 80

What is the role of prostaglanins in the renal system?

Back 80

They act via PGE2 and PGI2 to cause:
vasodilation & increased glomerular filtration; modulation of renal blood flow;
increased medullary blood flow;
natriuretic effect caused by vasodilation/increased glomerular filtration or direct inhibition of sodium;
reabsorption in distal tubule.
They modulate renin secretion (although the major effect on renin secretion is beta 1 receptor). They block ADH effects on adenylate cyclase to increase water clearance.

Front 81

What is the potential effect of chronic COX-2 induced PGA release on the kidneys?

Back 81

Over secretion of renin ->
HTN

Front 82

Map the pathway from stimuli to the results of PGF2 activation

Back 82

Stimuli-> Cell membrane phosholipids -> PLA2 -> AA -> COX-1 -> PGG2 -> PGH2 ->PGF2 -> bronchoconstriction, increased uterine contraction, vasoconstriction

Front 83

Map the pathway from stimuli to the results of TXA2 activation

Back 83

Stimuli -> Cell membrane phosholipids -> PLA2 -> AA -> COX-2 -> PGG2 -> PGH2 -> TXAs -> TXA2 -> vasoconstriction, increased plt aggregation

Front 84

Map the pathway from stimuli to the results of PGI2 activation

Back 84

Stimuli -> Cell membrane phosholipids -> PLA2 -> AA -> COX-2 -> PGG2 -> PGH2 -> PGI2 -> decreased plt aggregation, vasodilation.

Front 85

Map the pathway from stimuli to the results of PGE2 activation

Back 85

Stimuli -> Cell membrane phosholipids -> PLA2 -> AA -> COX-2 -> PGG2 -> PGH2 -> PGE2 -> vasodilation, naturesis, increased renal blood flow.

Front 86

Map the pathway from stimuli to the results of PGD2 activation

Back 86

Stimuli -> Cell membrane phosholipids -> PLA2 -> AA -> COX-2 -> PGG2 -> PGH2 ->PGD2 -> increased renal blood flow, decreased gastric production

Front 87

What are the actions of prostaglandins on the reproductive system?

Back 87

PGE2 & PGF2a have potent oxytocic actions. They can: stimulate uterine contractions;
increase endometrial synthesis during mensturation -> increased menstrual pain;
Administered PGs can terminate pregnancy at any stage & increase collagenase activity to soften cervix.

Front 88

What are PGs action on the eye?

Back 88

Via the action of PGF2a:
it increases aqueous humor outflow
via trabecular meshwork pathway -> decreased intraocular pressure.
PGs are useful in tx'ing open angle glaucoma.

Front 89

LTC4, LTD4 and LTE4 are also called SRS-A (substance of slow release anaphylaxis). What are their main effects?

Back 89

Increased vascular permeability;
bronchoconstriction &
chemotactic (leukotactic)

Front 90

What is the role of LTB4 in inflammation mediation?

Back 90

Chemoattraction of leukocytes, mainly neutrophils;
release of lysosomal enzymes and toxic oxygen radicals;
extremely potent effect on plasma exudation;
promotes neutrophil adhesion to vascular endothelium and subsequent migration across cells;
stimulates synthesis of proinflammatory cytokines from macrophages and lymphocytes.

Front 91

What are the effects leukotrienes on the CV system?

Back 91

They are 1000 x more potent than histamine, causing vasodilation in most vessels.
They:
(1)reduce myocardial contractility;
decrease coronary blood flow &
cause coronary artery vasoconstriction.
(2) Plasma exudation from postcapillary venules.
The net effect is decreased cardiac output.

Front 92

What is the pathogenesis of the ASA sensitivity,ASA Induced Asthma (AIA)?

Back 92

By inhibiting the COX pathway, ASA diverts AA metabolites to the lipogenesis pathway, leading to a decrease in PGE2 & an increase in cysteinyl leukotrienes (LTs). An increase in production of LTs is associated with an increase in the activity of LTC4 synthase, the rate limiting enzyme in cysteinyl LT synthesis. This promotes inflammation.

Front 93

What LT-modifying drugs used for?

Back 93

They are used to tx AIA by preventing the bronchoconstriction provoked by ASA.

Front 94

What limits the usefulness of PGs as drugs?

Back 94

They have a wide range of activities & they have short duration of action.