Pharm Autacoids (9)

• 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”)

• plants (27%)
• drugs (19%)
• house dust mites (17%)

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")

• 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

• histamine
• tryptase

• leukotrienes
• prostaglandins
• platelet activating factor
• IL-6, 8, & 13
• TNF-alpha
• VEGF

False: there are no clinically available drugs capable of blocking the process of an allergic reaction in its entirety

• a naturally occurring flavonoid found in chamomile that can inhibit mast cells
• it must be given in liposomal preparations to achieve sufficient oral absorption

• 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

• histamine & kinins
• such as swelling, heat, pain, & itching

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

characterized by a normal number of mast cells, but all the symptoms and in some cases the genetic markers of systemic mastocytosis

• 1. Prostaglandins, Prostacyclin, Thromboxanes
• 2. Leukotrienes
• 3. Platelet Activating Factor
• 4. Kinins
• 5. Histamine
• 6. Serotonin

• 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

• corticosteroids
• therefore no arachidonic acid is cleaved from the phospholipids of the PM, & neither PGs or LTs are made

• 1.Cyclooxygenase pathway: produces prostaglandins
• 2. Lipoxygenase pathway: produces leukotrienes & lipoxins

• in general cause vasodilation & increased vascular permeability
• made from arachidonic acid via the cyclooxygenase pathway

• 1. COX 1
• 2. COX 2
• make prostaglandins

• 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

• 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

• acts as a bronchoconstrictor & vasoconstrictor
• is made by COX-2
• AA → PGG₂ → PGH₂ → PF_2α
• [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]

• a PF_2α 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

• 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

• 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]

• used acutely to include labor
• used prophylactic against gastric ulcers

a PGE1 analogue that reduces the incidence of gastric ulcers in patients on chronic NSAIDs

• induces platelet aggregation
• made in platelets
• AA → PGG₂ → PGH₂ → TXA₂ → TXB₂

• 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

serious complications, such as myocardial infarctions, could result due to aberrant clot formation

• ns-NSAIDS
• s-NSAIDS

• block BOTH COX-1 & COX-2
• eg. aspirin, indomethacin, ibuprofen
• take care of inflammation, but also decrease physiologic amounts of PGs

• 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)

• 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

• 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

• 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

• 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]

• 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

• 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

• a leukotriene receptor blocker (antagonist) best used prophylactically once a day for treating asthma, especially for allergic asthma
• adverse side effects: GI upset, laryngitis

• 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

• 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

• 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

• 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

• 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

• 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

• 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

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

• 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)

• 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

• found blood vessels, especially veins
• when activated, the vascular endothelium is stimulated to generate nitric oxide → vasodilatation

• 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

severe hypotension, diminished blood volume, reduced venous return, low cardiac output during anaphylaxis can be caused by histamine binding to H1 receptors on veins

• 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

• 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

• 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)

• many are able to antagonize H₁ receptors in the central nervous system
• eg. tricyclic antidepressants & phenothiazine (a compound in some antipsychotic drugs)

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)

• 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

• drugs used to treat gastritis, peptic ulcers, & reflux esophagitis
• eg. Famotidine, Ranitidine

• 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)

a proton pump inhibitor used to treat dyspepsia, peptic ulcer disease, & gastroesophageal reflux disease [not an H2 antagonist, just treats similar conditions]

found in the brain & act as autoinhibitory receptors; when activated, they decrease NT release

• found on immune cells
• activation inhibits immune responses

• a sympathomimetic drug that is the most commonly used nasal/sinus decongestant
• it is abused as the starting material for making methamphetamine

a decongestant that has been banned in the USA because it's been associated w/ hemorrhagic stroke, especially in women

• 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

• 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