Autocoids

Question 1

1. What is an autacoid?

Answer 1

A biological factor that acts as a local hormone. Its activity is usually very brief and acts near their site of synthesis. Ex. histamine, serotonin, eicosanoid

Question 2

2. What is the mechanism of action of histamine?

Answer 2

H1, H2, H3, H4 receptors – G protein linked – all of these receptors have constitutive activity without being bound by histamine.

Question 3

3. Where is the H1 and H2 receptors found and what signaling pathway do they activate?

Answer 3

H1 → endothelium, smooth muscle cells, nerve endings [Gq]

H2 → gastric mucosa, cardiac muscle cells, some immune cells [Gs]

Question 4

4. How do histamines affect blood vessels?

Answer 4

H1 and H2 → vasodilation
H1 binding on endothelial cells stimulates formation of NO and vasodilation possible increasing capillary permeability causing histamine-induced edema. This histamine-induced edema is what is responsible for hives during allergic reaction with mast cell histamine release. H2 binding on vascular smooth muscle leads to cAMP formation (Gs) and vasodilation.

Question 5

5. How do histamines affect the heart, GI tract and respiratory system?

Answer 5

Heart → H2 receptors found on the heart leading to an increased contractility and pacemaker rate.
GI tract → H1 binding leads to contraction of the GI tract smooth muscle (increasing defecation?)
Respiratory system → H1 binding leads to bronchoconstriction due to contraction of bronchiolar smooth muscle

Question 6

6. How do histamines affect the nervous system and secretory tissue?

Answer 6

Nervous system → H1 binding causes powerful stimulation of sensory nerve endings that mediate pain and itching
Secretory tissue → histamine is a powerful stimulate of gastric acid secretion via H2 receptors on parietal cells

Question 7

7. What drug do you give when someone goes in to anaphylactic shock?

Answer 7

Epinephrine is needed within minutes

Question 8

8. What are the clinical uses of histamine?

Answer 8

Pulmonary function test → histamine aerosols cause nonspecific bronchial hyperactivity (constriction and secretion??)

Question 9

9. What is the physiological antagonist of histamine?

Answer 9

Epinephrine as it opposes the histamine smooth muscle actions by acting at different receptors. [B2 agonists may also reverse the actions of histamine]

Question 10

10. What are Cromolyn and Nedocromil?

Answer 10

Histamine antagonists that act as release inhibitors. They are capable of reducing immunologic mast cell degranulation.

Question 11

11. What is the difference b/t first and second generation H1 receptor antagonists?

Answer 11

First generation → sedative effects present and there is blocking of autonomic activity
Second generation → less sedating compared to 1st generation b/c they are less liposoluble therefore unable to cross BBB and act centrally [these could also be substrates for P-glycoproteins transporters that shuttle drugs out of the CNS and tissues]
[H1 Blocker = inverse agonist, NOT antagonist]

Question 12

12. What are the first generation H1 receptor antagonists?

Answer 12

1. Chlorpheniramine
2. Cyclizine
3. Diphenydramine
4. Dimenhydrinate
5. Hydroxyzine
6. Meclizine
7. Promethazine
   * *not only block H1 receptor but also acts on cholinergic, a-adrenergic, serotonin and local anesthetic receptor sites

Question 13

13. What are the second generation H1 receptor antagonists?

Answer 13

1. Fexofenadine
2. Loratadine
3. Cetirizine

Question 14

14. What are the uses of H1 receptor antagonists?

Answer 14

1. Allergic conditions → drug of choice (esp for uticaria and allergic rhinitis) due to histamine mediation, ineffective in bronchial asthma b/c of other control placed upon the lungs
2. Motion sickness and nausea → ex. Dramamine, Bonine
3. Somnifacients →sedative properties used to treat insomnia

Question 15

15. What are the adverse side effects of H1 receptor antagonists?

Answer 15

1. Sedation → less common with 2nd generation
2. dry mouth → due to anticholinergic effect
3. Drug interactions → ventricular arrhythmias when taking terfenadine or astemizole [block cardiac K+ channels that repolarize the heart] in combination with CYP3A4 inhibitors

Question 16

16. What are the H2 receptor antagonists?

Answer 16

1. Cimetidine [Tagamet]
2. Ranitidine [Zantac]
3. Famotidine [Pepside AC]
4. Nizatidine [AXID AR]

Question 17

17. What is the mechanism of H2 receptor antagonists?

Answer 17

H2 receptor antagonists competitively bind H2 receptors reducing secretion of gastric acid. Therefore the main clinical use is to inhibit the gastric acid secretion to treat peptic ulcers, acute stress ulcers, and GERD.

Question 18

18. What are the adverse side effects of H2 receptor antagonists?

Answer 18

These are actually fairly safe drugs that rarely (only 3%) show adverse side effects. Some side effects may include headache, dizziness, diarrhea, muscular pain and constipation. On the other hand, when given via IV the pt may experience hallucinations, confusion and agitation (esp elderly and pts with renal dysfunction). [side effects are usually associated with Cimetidine b/c it inhibits cytochrome P450 therefore slowing metabolism of drugs]

Question 19

19. What are specific side effects seen with the H2 receptor antagonist Cimetidine?

Answer 19

Cimetidine can block H2 receptors as well as bind androgen receptors causing antiandrogenic effects. This leads to gynecomastia and reduced sperm count in men and galactorrhea in women.

Question 20

20. What is the mechanism of action for Serotonin?

Answer 20

Serotonin is a monoamine neurotransmitter that may bind to 7 different 5-HT receptors: 6 GPCRs and 1 ligand-gated ion channel (5-HT3). Serotonin itself has no clinical application as a drug, but there are several agonists against the serotonin receptors that are used clinically.

Question 21

21. What is a 5-HT1D/1B receptor agonist?

Answer 21

Sumatriptan (prototype) – this is a first line therapy for acute severe migraine attacks – not a prophylactic but rather to abort current episodes. It is thought that binding of CGRP to the CGRP receptor on blood vessels in the brain cause vasodilation leading to migraines. Triptans come along and bind 5-HT1DR on the trigeminal nerve terminal preventing CGRP release as well as 5-HT1BR on the blood vessels in the brain causing vasoconstriction therefore preventing migraines.

Question 22

22. What is metoclopramide?

Answer 22

5-HT4 receptor agonist used as a prokinetic agent. Its administration results in coordinated contractions that help constrict lower esophageal sphincter.

Question 23

23. What is Cisapride?

Answer 23

5-HT4 receptor agonist that acts as a prokinetic agent. Due to tis serious cardiac adverse effects it is no longer available in the US.

Question 24

24. What is Cyproheptadine?

Answer 24

5-HT2 receptor antagonist that is a potent H1 blocking agent. It is used for allergic rhinitis, vasomotor rhinitis and management of serotonin syndromes.

Question 25

25. What is Ondansetron?

Answer 25

5-HT3 receptor antagonist used as an anti-emetic. This is one of the most powerful anti-emetic drugs and is for severe nausea and vomiting that occurs with cancer chemo, not for motion sickness.

Question 26

26. What are ergot alkaloids?

Answer 26

Chemical compound produced by Claviceps purpurea (fungus that infects grain). It acts as an agonist, partial agonist and antagonist at the a-adrenoreceptors and 5-HT receptors as well as an agonist or partial agonist at CNS dopamine receptors. The functions differ due to high affinity of some alkaloids for presynaptic receptors whereas others are more selective for postsynaptic receptors. Ex. Ergotamine, Dihydroergotamine, bromocriptine, cabergoline, ergonovine, methylergonovine]

Question 27

27. How are Ergot alkaloids used clinically?

Answer 27

1. Migraine → ergots are highly specific for migraine pain. [note: triptans are preferred, but therapy with ergotamine or dihydroergotamine is effective] 2. Hyperprolactinemia → bromocriptinea nd cabergoline effective at reducing high levels of prolactin resulting from pituitary tumors 3. Postpartum hemorrhage → oxytocin is preferred agent, but if it is ineffective, ergonovine or methylergonovine intramuscular can be useful 4. Diagnosis of variant angina → ergonovine IV provokes coronary artery spasms in patients with variant angina

Question 28

28. What are the adverse effects of ergot alkaloids?

Answer 28

1. nausea and vomiting 2. vasospasms (contraindicated in pts with peripheral vascular disease, CAD, HTN, impaired hepatic or renal function) 3. may cause fetal distress and miscarriage (contraindicated in pregnant women) 4. Do not use with other drugs that also cause vasoconstriction

Question 29

29. What is an Eicosanoid?

Answer 29

Eicosanoids stem from arachidonic acid (20 carbon, unsaturated fatty acid with 4 double bonds) producing prostaglandins, prostacyclins, thromboxanes and leukotrienes. Arachidonic acid is found esterified in phospholipids @ position 2 (arachidonate). There are two major pathways in synthesis of eicosanoids from arachidonic acid.. 1. cyclo-oxygenase (COX) – which initiates the biosynthesis of prostaglandins, prostacyclins and thromboxans 2. Lipoxygenase (LOX) – which initiates the synthesis of leukotrienes and other compounds

Question 30

30. What are the 2 COX enzymes?

Answer 30

1. COX-1 → found in most cells as constitutive enzymes, prostaglandins it produces are involved in normal homeostasis 2. COX-2 → found in inflammatory cells, induced by inflammatory stimuli

Question 31

31. What is the effect of Leukotrienes?

Answer 31

Leukotrienes are associated with asthma, anaphylactic shock and CV disease. LTC4 and LTD4 are potent bronchoconstrictors and are secreted in asthma and anaphylaxis.

Question 32

32. What is the mechanism of action of eicosanoids?

Answer 32

1. Eicosanoids act in autocrine and paracrine fashion 2. Eicosanoids bind to receptors on cell surface and activate GPCR (Gs, Gi, Gq) 3. Increase in Ca2+ → SM contraction 4. Increased cAMP → SM relaxation

Question 33

33. What is the role of Eicosanoids in obstetrics?

Answer 33

1. Dinoprostone (PGE2) and Misoprostol (PGE1 analog) → ripen cervix at or near term 2. Carboprost tromethamine (15-methyl-PGF2a) and Misoprostol → manage postpartum hemorrhage 3. Dinoprostone & carboprost tromethamine → abortifacients (causes abortion) 4. Misoprostol → used with antiprogestin Mifepristone or Methotrexate as abortifacient

Question 34

34. What is the role of Eicosanoids in pediatrics?

Answer 34

Alprostadil (PGE1) → maintain patency of ductus arteriosus

Question 35

35. What is Epoprostenol (PGI2)?

Answer 35

Eicosanoid that is used in severe pulmonary HTN and to prevent platelet aggregation in dialysis machines.

Question 36

36. What is Misoprostol?

Answer 36

Eicosanoid used to prevent peptic ulcers in pts taking high doses of NSAIDs

Question 37

37. What is Alprostadil (PGE1)?

Answer 37

Eicosanoid used for impotence

Question 38

38. What is Latanoprost?

Answer 38

Eicosanoid used for glaucoma. It is a PGF2a derivative.

Question 39

39. What are the two ways to interrupt the leukotriene pathway?

Answer 39

1. inhibition of 5-lypoxygenase (Zileuton) | 2. inhibition of binding of LTD4 to its receptor in target tissues (Zafirlukast, Montelukast)

Question 40

40. What is the effect of glucocorticoids on eicosanoids?

Answer 40

Glucocorticoids inhibit PLA2 thus blocking the release of arachidonic acid and inhibiting synthesis of COX-2.

Question 41

41. What is the role of NSAIDs?

Answer 41

NSAIDs are antipyretic, analgesic, and anti-inflammatory drugs that act primarily by inhibiting cyclooxygenases.