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TuLE > Case 3 - Farmis (NSAIDs) > Flashcards

Case 3 - Farmis (NSAIDs) Flashcards

0
Q

How do thromboxanes and prostacyclins differ from prostaglandins?

A

They have different cyclic structures.

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1
Q

What fatty acid is the basis for all eicosanoids?

A

Arachidonic acid (20 C).

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2
Q

Where are prostaglandins synthesized and how is prostaglandin synthesis regulated in the body?

A

In almost all cells. COX-2 (prostaglandin synthase) releases ARA from the cell membrane where it is stored in an esterified form. Prodtanoid synthesis is activated by many hormones and transmittor substances. Inhibition ex. by glucocorticoids (inhibits phospholipase action).

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3
Q

What are prostanoids?

A

Eicosanoids that include products of cyclooxygenase enzyme products such as prostaglandins, -cyclins and thromboxanes.

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4
Q

What is PAF and what is its relation to prostanoid synthesis?

A

Platelet activating factor. Produced from phosphatidylcholine after separation of ARA.

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5
Q

Distinguish between COX-1 and COX-2.

A

COX-1: Constitutive (structural) enzyme produces small physiological quantities of prostanoids, ex. prostaglandins in thrombocytes (inhibits aggregation) and PGE_2 in gastric mucosal membrane (protects the lining).

COX-2: Normally not present in cells. Synthesized following bacterial infection-products such as cytokines, growth factors and some hormones. Synthesis inhibited by glucocorticoid steroids.

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6
Q

Distinguish between a selective and non-selective AID. What are partially stressed AIDs?

A

Selective AIDs target inhibit either COX-1 or COX-2 enzyme. Thus therapeutic benefits may be gained by inhibiting COX-2 without affecting COX-1 (causing pathological side effects, gastric).

Non-selective AIDs will affect both pathways.

Partially stressed AIDs affect one cyclo-oxygenase more than another.

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7
Q

What are endoperoxides?

A

Unstable compounds that metabolically break down into prostanoid products PGD, PDE, PGF, PGI, TXA.

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8
Q

Connect the correct tissue with the correct prostanoid: [activated thrombocyte, endothelial cells, mast cell, macrophage (in inflammation)] - [PGI2, PGD2, TXA2, PGE2].

A

Thrombocyte - TXA2
Endothelial cells - PGI2
Mast cell- PGD2
Macrophage - PGE2

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9
Q

What signifies the prostanoid therapeutic effect?

A

Local and short.

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10
Q

What are the main metabolic places for prostanoids?

A

All cells but especially liver and lungs.

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11
Q

Why is prostanoid erapeutic effect a two-stage process?

A

Because prostanoids initially have a direct affect on a target enzyme, followed by lingering non-specific effects by lingering β- and ω-oxidation.

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12
Q

What are the derived metabolic products of prostaglandins, TXA2 and prostacyclins?

A

Podtaglandins are metabolized first into ketones and then into 13,14-dihydro-derivative. TXA2 is metabolized into TXB2 (TXA2 testing through urine 2,3-dinor TXB2 and 11-dehydro-TXB2 screening). Prostacyclins are non-enzymatically inactivated into 6-keto-PGF_1α (2,3-dinor-6-keto-PGF_1α measured in urine).

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13
Q

How are prostanoid reactions conveyed intrecellularly?

A

Through specific GPCRs (g protein coupled rceeptors).

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14
Q

Describe the degree of specificity of prostanoid GPCRs.

A

The receptors are not especially specific; large quantities of other prostanoids may trigger a response in the receptor of any prostanoid receptor.

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15
Q

What characteristic of the secondary signal transduction of prostanoids explains the multitude of responses to them?

A

The fact that secondary signal transduction for prostanoids differs with receptor type (FP, EP1, Arp2 etc.) from activation of adenylate cyclase and increasing intracellular cAMP to inhibition of adenylate cyclase, thus increasing intracellular calcium levels and activating PKC (protein kinase C).

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16
Q

What effects of prostanoids are achieved on the circulatory system?

A

PGE2, PGI2 (iloprost=analog) and PGD2 relax smooth muscle of blood vessles.
TXA2 constricts blood vessles.

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17
Q

What are the effects of prostanoids on te heart?

A

PGE2, PGF2α and PGI2 induce a positive inotropic effect on a separately functioning heart. In vivo: increased contractional force, relflexive heart rate increase due to lowered resistance in periphery.

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18
Q

How can prostanoids affect BP?

A

Through changing vessle constriction, nephric B-flow and renin excretion. May thus affect effects of Bp-meds.

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19
Q

What roles do prostanoids play in atrial flow in fetuses?

A

PGE2 and PGI2 are partly responsible for keeping ductus arteriosus open pre-natally. Prostaglandin inhibitors may be used post-natally to treat non-closure of ductus arteriosus.

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20
Q

What are the roles of prostaglandins in blood clot formation?

A

Thrombocytic TXA2 contracts blood vessles and induces thrombocyte aggregation. Endothelial PGI2 and NO dilates blood vessles and decreases thrombocyte aggregation.

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21
Q

How does TXA2 compare to TXA3 in terms of thromboaggregatory affect?

A

TXA3 has a lesser affect than TXA2.

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22
Q

How and why does recovery of endothelial cells and thrombocytes differ after ASA exposure?

A

Endothelial cells recover immediately after exposure as they can produce nuevo PGI2 and because ASA affects PGI2 as a competitive inhibitor. TXA2 of the thrombocytes on the other hand is not renewed and furthermore is irreversibly acetylated on the cyclo-oxygenase.

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23
Q

Why do selective COX-2 inhibitors pose a risk for patients with ischemic heart disease, encephalic vascular disease or pripheral arterial disease?

A

Because hypoxia naturally produces PGI2 in tissues. Inhibition of this mechanism through inhibition of COX-2 makes the PGI2/TXA2 ratio unfavourable and exposes to risk of thrombosis.

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24
Q

What tasks do prostanoids have in the kidneys?

A

PGE2 and PGI2 increase perfusion and excretion of Na, K and water. PGE2 decreases resorption of water excreted by diuretics. PGE2, PDE2 and PGI2 increase renin excretion. TXA2 decreases nephric blood flow and gomerulal filtering. Macula densan expresses COX-2 physiologically, regulating prostanoid synthesis in the kidneys.

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25
Q

How are the lungs affected by eicosanoids?

A

PGE2 and PGI2 dilate the pulmonary airways. PGD2, PGF2α and TXA2 constrict them.

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26
Q

What effects do eicosanoids have on the alimentary canal?

A

Both PGE2 and PGF2α constrict the longitudinal muscle layer, whilst PGF2α constricts and PGE2 relaxes the transverse one. Analogs may cause diarrhea.

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27
Q

Which prostaglandins protect the stomach lining and how?

A

PGE2 and PGI2 increase bicorbonate and mucus production whilst decreasing pepsin and gastric acid secretion.

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28
Q

Which types of eicosanoids are less harmful for the stomach lining?

A

COX-2-selective eicosanoids.

29
Q

In what reactions of the CNS do eicosanoids play a role?

A

Found in liquor during inflammation or post epileptic seizure. Cause fever.

30
Q

What endocrine effects do eicosanoids have?

A

PGE2 increases secretion of ACTH, HGH, gonadotropin and prolactin. It also increases steroid secretion from suprarenal glands and increases insulin secretion.

31
Q

What are the roles of prostaglandins in male reproduction?

A

They promote erection and smooth muscle contraction during ejaculation. Semen has the highest concentration of prostaglandins in the body.

32
Q

What are the roles of prostaglandins in female reproduction?

A

PGE and PGF promote fertilization by changing mucosal concistency and smooth muscle contraction. Prostaglandins also regulate the menstrual cycle (COX-2 mediated) and are responsible for mesntrual cramps. PGE2 and PGF2α derivatives are used for induced labour/termination. Pre-eclampsia results from prostaglandin imbalance in favour of TXA2.

33
Q

What is the main prostaglandin product of mast cells?

A

PGD2.

34
Q

What are the roles of prostaglandins in the inflammatory response?

A

Vasodilation. They do not per se affect permeability, but instead aid in plasma extravacation into parenchyme. They cause hyperalgesia by altering nerve signaling.

35
Q

Which prostaglandin mediate the fever response? How is this response activated by infection?

A

PGE2 mediated the fever response. Infection products such as interleukines and cytokines induce PGE2 production, thus causing fever.

36
Q

What kind of immunosuppressive properties does PGE2 have?

A

It inhibits granulocyte, lymphocyte and macrophage activity and some cytokine synthesis. The anti-inflammatory properties of prostaglandins are very limited compared to glucocorticoid steroids and rheumatic specific drugs.

37
Q

What is misoprostoli?

A

PGE1 analog that similarly protects gastric lining. Induces uterine contractions so is not fit for pregnant patients.

38
Q

What therapeutic use is there for PGE/PGF analogs (gemeprosti, sulprostoni, dinoprostoni)?

A

They may be used as labour-inducing drugs together with mifepristoni (progesterone antagonist sensitizes the uterus to the effects of progesterones).

39
Q

What is iloprost?

A

Prostacyclin analogue used for treating peripheral arterial obstructive disease (dilates peripheral blood vessles).

40
Q

What is alprostadiili?

A

Synthetic PGE1 used for erectyle dysfunction/weak erection.

41
Q

Nem synthetic analogs of PGF2. What are their usage?

A

Bimatoprosti, latanoptosti, travoprosti. Decrease ocular pressure by increasing outflow.

42
Q

What are the three main qualities of NSAIDs?

A

Anti-analgetic, anti-pyretic and slightly anti-inflammatory.

43
Q

Give examples of non-selective, COX-2 partially stressed (painotteisia) and COX-2 selective NSAIDs.

A

Most NSAIDs such as ASA and ibuprofen, ketoprofeeni, naproxen; Etodolaakki, Meloksikaami, Nabumetoni; All coxibs (koksibit) Etorikoksibi, Selekoksibi.

44
Q

Which of the two functional reactions of COX-enzymes do NSAIDs inhibit?

A

The cyclo-oxygenase reaction where ARA is turned into PGG2 (as opposed to the later reaction: PGG2->PGH2).

45
Q

Why does COX-2 selective inhibition pose a risk for patients suffering from asthma?

A

Since if ARA doesn’t proceed to be metabolized by cyclo-oxygenase it enter lipid metabolism path leading to leukotriene formation (ca 20% of asthmatics are over-sensitive to leukotrienes).

46
Q

Outline the pyretic reaction path blocked by prostaglandin synthase inhibitors.

A

Cytokines produced by infection start PGE2 production in hypothalamus.

47
Q

What form of inflammatory response do prostanoids mainly mediate?

A

Acute inflammation,

48
Q

Where and how can fairly selective COX-2 inhibitors inhibit also COX-1 cyclooxygenases?

A

In the gastric lining through ion trapping. Prostanoids are usually weak acids that are non-polar in the acidic conditions of the stomach. They thus diffuse into the cells, where they polarize, thus leading to increased intracellular concentration.

49
Q

Can COX-2 inhibitors cause gastric distress?

A

Yes, during gastritis or other IBDs. In these cases some of the protective actions of the lining are COX-2 mediated.

50
Q

Suggest three AID cocktails that are stomach lining friendly.

A

1) paracetamol + mild opiate, 2) COX-2 stressed/selective AIDs in smaller doses or 3) AID + misoprostol/PPI.

51
Q

What are the effects of prostaglandins on bone formation?

A

Positive. Inhibition of their synthesis decreases bone formation rate and may inhibit ectopic bone formation (therapeutic usage).

52
Q

What is the relationship between thrombocyte TXAs and endothelial prostacyclins?

A

Antagonistic.

53
Q

Why is ASA so effective for TXA inhibition?

A

It is specific for TXAs, as opposed to other AIDs that affect both TXAs and prostacyclins.

54
Q

What is it in the metabolism of ASA that makes it so effective at low doses?

A

ASA affects thrombocytes already in the portal vein circulation. Also, thrombocytes do not recover from the inhibition of their COX enzymes so the affect lasts until their renewed 5-9 days.

55
Q

What properties differ between ASA and salicylate (post-metabolic ASA)?

A

ASA is more COX-1 selective whilst salicylate is more COX-2 selective.

56
Q

name some propionic acid derivative AIDs.

A

Ibuprofen, ketoprofeeni and naproxen.

57
Q

What signifies propionic acid derivatives in terms of therapeutic usage?

A

Rather large dose needed for analgesic properties. Even higher dose needed for anti-inflammatory response.

58
Q

Compare ASA and propionic acid derivative AID pharmacokinetics.

A

ASA: peak serum concentration after 15 min, halfing-time 3-5 hrs.
Propionic acid derivatives: peak concentration after 1,5 h. Naproxen half time 12-15 hrs.

59
Q

Name some ethinoic acid derived NSAIDs.

A

Indometasiini (COX-1 partial), diklofenaakki (COX-2 partial, increased liver values, eye drops post op), ketorolaakki (injection, post op).

60
Q

Name some oxicames (oksikaami) and their properties.

A

Meloksikaami, COX-2 partial. Piroksikaami, non-selective. Oxicames have long half lives so can be administered once/day.

61
Q

Why might fenematea (fenemaatit) be appropriate for asthmatics?

A

Because they inhibit COX enzymes non-selectively and amongst others release of leukotrienes.

62
Q

What is charachteristic of coxibs (etorikoksibi, selekoksibi and parekoksibi)?

A

They are COX-2 selective.

63
Q

What is the mechanism of action of paracetamol?

A

Conjugation with ARA in brain and spinal chord (AM404) makes for effective COX-1/2 ingibitor, affecting the endocannabinoid system and TRP-channels.

64
Q

What is the mechanism of paracetamol toxicity?

A

Its reactive metabolites are conjugated with glutathione. When gluthatione storages run out the reactive metanolites react with glutathione groups on proteins in the liver, causing liver dammage.

65
Q

What drug is mainly used for gout?

A

Allopurinol (inihibits urate formation).

66
Q

Why are all but ASA NSAIDs suitable for treating pain associated with gout?

A

ASA decreases urate excretion in the kidneys.

67
Q

What is the mechanism of action of allpurinol?

A

It inhibits xanthine oxidase from changing hypoxanthine into xanthine and further into urate/uric acid.

68
Q

What is rasburicase?

A

A urateoxidase enzyme which oxidizes uric acid to allantoin (easily excreted). It is reverse engineered from refombinant DNA.

69
Q

What is the use of probenesidi?

A

Against gout. Inhibits reabsorption of excreted urate from primary urine. Adverse effect: inhibits paracetamol glukuronidation and thus increases their plasma concentrations.

70
Q

Why might colchisine be used against gout?

A

It arrests chromosomal reproduction at metaphase, inhibiting neutrophile aggregation to site of inflammation.

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