Pharm Autacoids (9)

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  1. Autacoids
    • chemical mediators that the body releases during responses to a disease that cause symptoms associated with said disease
    • such symptoms are not due directly to a pathogen, but rather to the body’s response to the pathogen
    • small quantities of autocoids typically have profound physiologic effects
    • eg. histamine, serotonin, kinins, prostaglandins, leukotrienes
    • (from the Greek for “self-remedy”)
  2. What are the most common triggers of allergic reactions?
    • plants (27%)
    • drugs (19%)
    • house dust mites (17%)
  3. Type I Hypersensitivity Reaction (IgE-mediated Hypersensitivity)
    1. allergen-derived peptides bind to MHC class II molecules expressed on the surface of antigen presenting cells

    2. TH2-cells detect this antigen & become activated

    3. activated T-cells release IL-4, which stimulates B cells to differentiate into plasma cells that secrete IgE

    4. upon 1st exposure to an antigen, IgE antibodies stick to mast cells through their Fc portion (mast cells & basophils have receptors for IgE Fc regions)

    • 2. upon 2nd exposure to the antigen, it cross-links 2 molecules of IgE on the surface of a mast cells causing it to degranulate
    • *it's the granules released which cause the allergic reaction: autacoids, cytokines, & proteases

    reaction occurs within minutes ("allergic reaction")
  4. What makes up the granules released from mast cells upon 2nd exposure to an antigen, causing cross-linking of 2 molecules of IgE on the cells' surface?
    • autacoids, cytokines, & proteases
    • these act on many different targets & cause vasodilatation, inflammation, & nociception
    • the degranulation is called exocytosis, & is a calcium-mediated, energy dependent process
    • the whole sequence is termed stimulus-secretion coupling
  5. What pre-stored molecules are released from mast cells upon activation?
    • histamine
    • tryptase
  6. What molecules can mast cells synthesize & release upon activation?
    • leukotrienes
    • prostaglandins
    • platelet activating factor
    • IL-6, 8, & 13
    • TNF-alpha
    • VEGF
  7. True or False: allergic reactions in their entirety can be prevented?
    False: there are no clinically available drugs capable of blocking the process of an allergic reaction in its entirety
  8. luteolin
    • a naturally occurring flavonoid found in chamomile that can inhibit mast cells
    • it must be given in liposomal preparations to achieve sufficient oral absorption
  9. What other stimuli cause mast cells to degranulate?
    • non-allergic triggers such as contrast media, neuromascular junction blockers (NMBs), neuropeptides, venoms, anaphylatoxins, opioids, & even stress hormones
    • it's possibly that mast cells can release specific mediators selectively without degranulation, indicating they participate in inflammation
  10. What molecules are responsible for the cardinal signs of inflammation?
    • histamine & kinins
    • such as swelling, heat, pain, & itching
  11. The Triple Response of Lewis
    caused by the release of histamine

    1. red spot: due to capillary dilatation

    2. flare: redness in the surrounding area due to arteriolar dilatation mediated by axon reflex

    3. wheal: due to exudation of fluid from capillaries & venules
  12. Mast Cell Activation Syndrome
    characterized by a normal number of mast cells, but all the symptoms and in some cases the genetic markers of systemic mastocytosis
  13. Autocoid Classes
    • 1. Prostaglandins, Prostacyclin, Thromboxanes
    • 2. Leukotrienes
    • 3. Platelet Activating Factor
    • 4. Kinins
    • 5. Histamine
    • 6. Serotonin
  14. Arachidonic Acid (AA) Metabolism (Eicosanoids)
    • after mechanical, physical, or biochemical cell stimulation phospholipase A2 is activated & cleaves arachidonic acid (a polyunsaturated fatty acid) from phospholipids (eg. phosphatidylcholine) in the plasma membrane
    • AA is precursor for both inflammatory mediators PG & LT as well as PAF
  15. What inhibits phospholipase A2?
    • corticosteroids
    • therefore no arachidonic acid is cleaved from the phospholipids of the PM, & neither PGs or LTs are made
  16. What are the two pathways by which AA can be metabolized by?
    • 1.Cyclooxygenase pathway: produces prostaglandins
    • 2. Lipoxygenase pathway: produces leukotrienes & lipoxins
  17. Prostaglandins (PG)
    • in general cause vasodilation & increased vascular permeability
    • made from arachidonic acid via the cyclooxygenase pathway
  18. What 2 enzymes mediate the cyclooxygenase (COX) pathway?
    • 1. COX 1
    • 2. COX 2
    • make prostaglandins
  19. COX-1
    • cyclooxygenase pathway enzyme constitutively expressed in most tissues (principally by endothelium and to a lesser extent, vascular smooth muscle)
    • is thought to be involved in the production of physiologic levels of prostaglandins
  20. COX-2
    • cyclooxygenase pathway enzymes produced principally by endothelial cells & vascular smooth muscle WITHIN sites of inflammation and tissue trauma
    • only produced at sites of trauma because it's upregulated BY WBCs
  21. Prostaglandin F (PF)
    • acts as a bronchoconstrictor & vasoconstrictor
    • is made by COX-2
    • AA → PGG2 → PGH2 → PF
    • [exacerbate gastric acid secretion, contract both the nonpregnant and pregnant uterus, and causes corpus luteum regression. Additionally, it promotes drainage of ocular fluid (aqueous humor) via the uveoscleral pathway]
  22. Latanoprost
    • a PF analogue that treats glaucoma by increasing the outflow of vitrous humor reducing intraocular pressure which if left untreated can cause blindness
    • off-label use: lengthens eye lashes & darkens eye color
  23. Glaucoma
    • a major cause of blindness in the US
    • the most common type is “wide-angle” glaucoma
    • treatment may include prescription eye drops or surgery to lower the pressure in the eye & prevent further damage to the optic nerve
    • there is no cure but early diagnosis + continuing treatment can preserve eyesight
    • treatment = carbachol, pilocarpine, drugs that increase drainage (outflow) of intraocular fluid
  24. Prostaglandin E2 (PGE2)
    • acts as a bronchodilator & decreases BP by acting as a vasodilator
    • made by COX-1 from arachidonic acid
    • is more potent than histamine or ACh but less potent than bradykinin
    • AA → PGG2 → PGH2 → PGE2
    • [inhibits gastric acid secretion, maintains the integrity of the gastric mucosa, constricts the pregnant uterus (relaxes the non-pregnant one), increases luteal progesterone secretion, induces hyperalgesia (increased sensitivity to pain), induces hyperpyrexia (fever), & inhibits T cells + other lymphocytes]
  25. How is PGE2 used clinically?
    • used acutely to include labor
    • used prophylactic against gastric ulcers
  26. Misoprostol (Cytotec)
    a PGE1 analogue that reduces the incidence of gastric ulcers in patients on chronic NSAIDs
  27. Thromboxane A2 (TXA2)
    • induces platelet aggregation
    • made in platelets
    • AA → PGG2 → PGH2 → TXA2 → TXB2
  28. Prostacyclin (PGI2)
    • the most potent inhibitor of platelet aggregation
    • opposes action of thromboxanes that make clots
    • made in endothelial cells by COX-2 from arachidonic acid
    • AA → PGG2 → PGH2 → PGI2
  29. What could happen if PGI2 was inhibited?
    serious complications, such as myocardial infarctions, could result due to aberrant clot formation
  30. Drugs designed to inhibit COX enzymes
    • ns-NSAIDS
    • s-NSAIDS
  31. Non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDS)
    • block BOTH COX-1 & COX-2
    • eg. aspirin, indomethacin, ibuprofen
    • take care of inflammation, but also decrease physiologic amounts of PGs
  32. Selective NSAIDS (s-NSAIDS)
    • Specific for COX-2 and have the benefit of relieving symptoms of acute inflammation WITHOUT the undesirable side effects of gastrointestinal ulceration & potential renal damage
    • eg. Rofecoxib (vioxx) & Celecoxib (celebrex)
  33. Why does selective inhibition of COX-2 by s-NSAIDS (eg. Rofecoxib) lead to an increased risk of MI?
    • because PGI2 (prostacyclin) - a natural anti-clotting agent - is synthesized BY COX-2 from arachidonic acid
    • inhibiting COX-2 → no PGI2 → blood clots form → MI
  34. Leukotrienes (LT)
    • the key mediators in asthma
    • are 10,000x more bronchoconstrictive than histamine
    • made from arachidonic acid via the lipoxygenase pathway
    • also cause vasoconstriction
    • only class of molecules of where a phospholipid backbone is covalently attached to a tripeptide
    • increase the production & decrease the clearance of airway mucous
  35. 5 lipoxygenase
    • enzyme responsible for inducing the lipoxygenase pathway resulting in leukotriene production from arachidonic acid
    • blocking it's activity doesn't completely get rid of asthma because it's a complex disease
  36. LTB4
    • one of the most potent chemotactic molecules known
    • is chemotactic for neutrophils, eosinophils, & mononuclear cells
    • can also activate neutrophils
    • AA → 5-HPETE → LTA4 → LTB4
    • [can compare it to IL-1]
  37. LTC4 & LTD4
    • potent bronchoconstrictors
    • IV injection results in contraction of small airways & decreases pulmonary compliance
    • are 1,000x more potent in contracting strips of the human lung tissue than histamine
    • AA → 5-HPETE → LTA4 → LTC4, LTD4
  38. What do non-steroidal drugs for the treatment of asthma target?
    • Leukotrienes
    • they can either block the receptors leukotrienes act on to promote bronchoconstriction OR prevent their synthesis
    • corticoSteroids inhibit the action of phospholipase A2, preventing both leukotrienes & prostaglandins from forming
  39. Montelukast (Singulair)
    • a leukotriene receptor blocker (antagonist) best used prophylactically once a day for treating asthma, especially for allergic asthma
    • adverse side effects: GI upset, laryngitis
  40. How might taking NSAIDs induce asthma?
    • NSAIDs inhibit the cyclooxygenase (PG forming) pathway, but NOT the lipoxygenase (LT forming) pathway
    • if phospholipase A2 is still cleaving AA from plasma membranes at the same rate, their use may lead to increased or preferential synthesis of leukotrienes
    • in other words, cyclooxygenase inhibitors can shift precursors (AA) to the lipoxygenase pathway & exacerbate asthma
    • known as “aspirin-induced asthma”, or Samter’s Syndrome/triad
  41. Kinins
    • peptides that can cause vasodilatation, capillary permeability, bronchial & intestinal smooth muscle contraction, and pain
    • are generated from precursors called kininogens
    • have a very short half-life in the plasma (less than 25 seconds b/c they're rapidly inactivated by kininases)
    • eg. bradykinin
  42. kininases
    • enzymes responsible for degrading kinins
    • therefore they prevent further vasodilation & promote vasoconstriction
    • *kininase II is identical to angiotensin converting enzyme (ACE), the enzyme that converts angiotensin I → angiotensin II
    • angiotensin II is a potent vasoconstrictor
    • the other type, kininase I, acts mostly in the blood
  43. Hageman Factor (Clotting Factor XII)
    • its fragments activate the enzyme pre-kallikrein & convert it to kallikrein
    • kallikrein then acts on the precursor kininogen to generate kinins
    • kallikrein can also convert tissue kininogens to kallidin; THIS kallidin can then be converted to bradykinin via an aminotransferase
  44. Kinins are the most potent vasodilators of ______ _______ however, they tend to constrict _____ __________& most _____
    • dilate: small arteries
    • constrict: LARGE arteries & most veins
    • only small concentrations are needed for kinins to produce all the cardinal signs of inflammation:
    • 1. increased capillary permeability
    • 2. edema
    • 3. pain
  45. bradykinin
    • acts directly through specific receptors to activate calcium-dependent nitric oxide synthase (NOS)
    • NOS generates nitric oxide & NO induces smooth muscle relaxation & vasodilatation
    • a protein that causes vasodilation and PAIN at a site of inflammation
    • made from the cleavage of HMWK by Kallekrein
  46. Direct Vasodilators
    • also generate NO which stimulates production of cyclic GMP (cGMP), which in turn induces smooth muscle relaxation & vasodilation
    • are used to treat angina
    • eg. Isosorbide (oral & sublingual)
    • Nitroglycerine (sublingual)
    • Nitropaste (adhesive)
    • Nitroprusside (IV)
    • side effects: throbbing headaches
  47. Histamine
    richest sources are mast cells & basophils (is also found in eosinophils, lungs, skin, & intestinal mucosa)

    subcutaneous skin injections cause local itching while intradermal injections cause wheal & flare reactions, characterized by local redness, edema (wheal), & diffuse redness (flare)

    • 1st 2 are due to vasodilatation + fluid extravasation b/c of histamine’s effect on capillary permeability
    • the last reaction is due to local nerve-ending stimulation by histamine

    acts of 4 receptors: H1 → 4
  48. How is histamine made?
    • de novo from dietary histidine via histidine decarboxylase.
    • most is metabolized by methylation to methylhistamine (which is then converted to 1-methylimidazole-4-acetic acid by monoamine oxidase (MAO))
    • (some histamine is eventually converted to imidazole acetic acid ribolase)
  49. Methylhistamine
    • the major metabolite of histamine
    • it can be measured in the urine after anaphylaxis OR to test for systemic mastocytosis, a condition characterized by an unusual number of mast cells in the skin, lungs, & other organs
  50. H1 Receptor
    • found blood vessels, especially veins
    • when activated, the vascular endothelium is stimulated to generate nitric oxide → vasodilatation
  51. What are the effects of intravenous injection of histamine?
    • burning, itching sensation followed by intense warmth, flushing, hypotension, tachycardia, headache, crops of hives on the skin, nausea.
    • may also result in flushing of the face, cerebrospinal fluid pressure elevations, & bronchial asthma in asthmatics
  52. Histamine Shock
    severe hypotension, diminished blood volume, reduced venous return, low cardiac output during anaphylaxis can be caused by histamine binding to H1 receptors on veins
  53. Diphenhydramine (Benadryl)
    • an older H1 receptor antagonists that is anti-inflammatory by preventing histamine from binding to H1 receptors
    • used to treat allergic rhinitis, urticaria, hay fever, insomnia, motion sickness, & vertigo
    • causes sedation because it crosses the BBB
  54. Cyclizine (Marezine)
    • an antihistamine (H1 receptor antagonist) used to treat nausea, vomiting, & dizziness caused by motion sickness
    • Meclizine (Antivert) is another example of an antihistamine that treats motion sickness
  55. Hydroxyzine (Atarax, Vistaril)
    • an antihistamine that has strong anxiolytic properties (relieves symptoms of anxiety)
    • in addition, if given with morphine it enhances its analgesic effects & blocks morphines side-effects (win-win)
  56. Why do many antidepressant & antipsychotic medications produce sedation as a side effect?
    • many are able to antagonize H1 receptors in the central nervous system
    • eg. tricyclic antidepressants & phenothiazine (a compound in some antipsychotic drugs)
  57. Newer H1 receptor Antagonists
    allergy medications that do NOT cross the blood-brain barrier as readily, which means they are much less sedating

    • Fexofenadine (Allegra)
    • Loratadine (Claritin)
    • Desloratadine (Clarinex)
    • Cetirizine (Zyrtec)
  58. H2 Receptor
    • found on exocrine glands, especially gastric & parietal ones
    • binding of histamine stimulates glands to secrete their contents
    • activation of H2 receptors in the stomach's gastric glands causes increased gastric acid secretion
    • H2 receptor activation of parietal cells in the stomach leads to increased HCl & intrinsic factor secretion
  59. H2 Receptor Antagonists
    • drugs used to treat gastritis, peptic ulcers, & reflux esophagitis
    • eg. Famotidine, Ranitidine
  60. Cimetidine
    • an H2 receptor antagonist aimed at inhibiting stomach acid production to treat heartburn & peptic ulcers
    • it's different from other H2 antagonists in that it inhibits the liver microsomal CYP450 system
    • therefore it has a high probability of interacting with other medications that use the CYP450 system
    • side effects include anti-androgenic effects (reversible impotence, loss of libido, gynecomastia in men, & galactorrhea in women)
  61. Omeprazole
    a proton pump inhibitor used to treat dyspepsia, peptic ulcer disease, & gastroesophageal reflux disease [not an H2 antagonist, just treats similar conditions]
  62. H3 Receptors
    found in the brain & act as autoinhibitory receptors; when activated, they decrease NT release
  63. H4 Receptors
    • found on immune cells
    • activation inhibits immune responses
  64. Pseudoephedrine
    • a sympathomimetic drug that is the most commonly used nasal/sinus decongestant
    • it is abused as the starting material for making methamphetamine
  65. Phenylpropanolamine
    a decongestant that has been banned in the USA because it's been associated w/ hemorrhagic stroke, especially in women
  66. Platelet activating factor (PAF)
    • causes vasodilation and increased vascular permeability
    • is also a powerful bronchoconstrictor
    • Rupatadine (Rupafin) is a new H1 receptor antagonist that also specifically blocks PAF receptors
  67. Serotonin
    • causes skeletal muscle vasodilatation, flushing, constricts bronchial & gastrointestinal smooth muscle, and constricts extra & intracranial vessels (which might play a role in the pathophysiology of migraines)
    • it also stimulates sensory nerve endings
    • aberrant levels are associated w/ Carcinoid syndrome, depression, & migraines
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Pharm Autacoids (9)
Exam 2
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