AUTOCOIDS & AUTOCOID ANTAGONISTS Flashcards
Non neuronal site of histamine storage
Enterochromaffin-like cells of the fundus of the stomach —> release histamine, which activates acid-producing parietal cells of the mucosa.
Mast cells
Rich at sites of potential tissue injury: nose, mouth, feet, internal body surfaces, and blood vessels (esp @ pressure points and bifurcations)
Granules store histamine
H1 receptors
In brain, located on postsynaptic membranes.
Also present in endothelium, smooth muscle cells and nerve endings.
Coupled to PLC —>
activation causes IP3 and DAG formation —> IP3 = release of Ca2+ from ER
H2 receptors
In brain, located on postsynaptic membranes.
Also located in gastric mucosa, cardiac muscle cells and some immune cells.
Linked to stimulation of adenylyl cyclase —>
Activation of cAMP-dependent protein kinase in target cell
H3 receptors
Predominantly presynaptic receptors
Reduce transmitter release from histaminergic and other neurons.
H4 receptors
Mainly found on leukocytes in the bone marrow and circulating blood
Chemotactic effect on eosinophils and mast cells —> important role in inflammation and allergy
CVS Effects of Histamine
-Vasodilation (H1 & H2)
H1: higher histamine affinity, rapid and short response (located on endothelial cells; formation of NO)
H2: dilation develops slowly and is more sustained (located on vascular smooth muscle, vasodilation mediated by cAMP)
Dec BP usually leads to reflex tachycardia
-Inc contractility and rate (H2)
In atrial muscle, can also lead to dec contractility (H1)
-Inc capillary permeability (H1 on vessels of micro circulation, esp post capillary vessels)
The Triple Response
1) A localized red spot (direct histamine vasodilatory effects)
2) A brighter red flush or flare ( indirect vasodilatory effect d/t histamine induced stimulation of axon reflexes
3) A wheal seen in 1-2 minutes (histamine’s capacity to cause edema)
Extravascular smooth muscle
GI tract - contraction of intestinal smooth muscle (H1)
Bronchiolar - bronchoconstriction (H1)
Nervous System effect of Histamine
Powerful stimulant of sensory nerve endings, esp those mediating pain and itching ( H1)
Physiological histamine antagonist
Epinephrine
Act on different receptors than histamine
Injection can be life-saving in systemic anaphylaxis
Histamine release inhibitors
Cromolyn and Nedocromil
Reduce degranulation of mast cells that result from immunologic triggering by antigen-IgE interaction
Histamine effect on secretory tissue
Gastric acid secretion and, to a lesser extent, gastric pepsin and IF production (H2 mediated)
H2 receptor antagonists
- cimeTIDINE, raniTIDINE, famoTIDINE, nizaTIDINE
- inhibit gastric acid secretion (block H2 receptors = dec cAMP)
- uses: peptic ulcers, acute stress ulcers, GERD
-Adverse effects: less than 3% of cases; extremely safe drugs
Cimetidine inhibits CYP450; also binds to androgen receptors (antiandrogenic effects = gynecomastia and reduced sperm count in men, galactorrhea in women)
Serotonin
- rapidly oxidized by MAO
- over 90% found in enterochromafgin cells in GI tract
- in blood, found in platelets
- is a precursor of melatonin in the pineal gland
- Raphe nuclei of the brain stem: contain cell bodies of serotenergic neurons that synthesize, store and release serotonin as a NT.
GI tract effect of serotonin
Increases GI motility (5HT2 smooth muscle receptors)
Overproduction of serotonin in carcinoid tumor results in severe diarrhea
CVS effect of serotonin
-constricts large vessels (both arteries and veins) (5HT2 receptor activation on vascular smooth muscle cells)
Serotonin effect on platelets
Platelet aggregation (via 5HT2a receptors)
Nervous system effect of serotonin
- excited some and inhibits other neurons
- 5HT3 receptors in GI tract and vomiting center in medulla participate in vomiting reflex
- 5HT3 receptor effect involved in pain and itch sensation
Sumatriptan
5HT1D/1B receptor agonist (triptans)
Used almost exclusively in migraines
MOA: activation of postsynaptic 5HT1b = vasoconstriction. Activation of presynaptic 5HT1D = inhibit release of CGRP (a powerful vasodilator). Inhibition of pain transmission by inhibiting trigeminal neurons
Adverse: triptans may cause coronary vasospasm, this are contraindicated in pts with CAD or angina
Metoclopramide
5HT4 receptor agonist
Prokinetic (enhances GI motility)
—>Facilitates ACh release from enteric neurons
Cisapride
5HT4 agonist
Prokinetic agent
*No longer generally available in the US d/t adverse cardiac effects (extends AP, prolong mA QT interval, serious cardiac arrhythmia sand deaths from VT, VF, torsades de pointes)
Cyproheptadine
5HT2 receptor antagonist
Prevents smooth muscle effects of both serotonin and histamine (but has no effect on gastric secretion by histamine)
Uses: allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis. Treatment of serotonin syndrome (caused by overstimulation if 5HT1a and 2 receptors - may be fatal, causes hyperthermia, muscle rigidity and myoclonus)
Ondanestrone
5HT3 receptor antagonist
Anti-emetic drug, particularly for controlling severe N/V in pts on chemo
Ergot alkaloids
- ergotamine, dihydroergotamine, bromocriprome, cabergoline, ergonovine, methylergonovine
- MOA: act on several types of receptors. Effects include agonist, partial agonist, and antagonist action @ alpha-adrenoreceotors and 5HT receptors; and agonist or partial agonist @ CNS dopamine receptors
Uses:
- migraine
- hyperprolactinemia
- postpartum hemorrhage
- dx of variant angina
Adverse:
-N/V
Eicosanoids
Principal subgroups: prostaglandins, prostacyclin, thromboxanes and leukotrienes
Not preformed in tissue, are generated de novo from phospholipids (mainly arachidonic acid, which is found esterified in phospholipids, usually in the 2nd position)
2 major pathways of eicosanoid synthesis:
- Cyclo-oxygenate: prostaglandins, prostacyclins and thromoxanes
- Lipoxygenase: leukotrienes, and other compounds
MAO of Eicosanoids
- act in autocrine and paracrine fashion
- bind to receptors on cell surface, all which are G protein coupled
- some coupled to activation of PLC, some to activation of adenylyl cyclase, some to inhibition of adenylyl cyclase
- contractile effects on smooth muscle mediated by release of Ca2+, relaxation medicated by elevations in cAMP
Dinoprostone
PGE2
Used to ripen the cervix @ or near term
Can be used as an abortifacient
Misoprostol
Synthetic derivative of PGE1
Used to ripen the cervix @ or near term
Can be used for the management of postpartum hemorrhage
Approved for the prevention of peptic ulcers in pts who must take high doses of NSAIDS
Alprostadil
PGE1
Given IV to maintain latency of ductus arteriosus in infants with transposition of the great vessels until surgical correction can be undertaken
Used in the treatment of impotence
Preparations available for injection into the penis as well as for insertion into the urethra.
Prostacyclin
PGI2
Lowers peripheral, pulmonary and coronary resistance
Epoprostenol
Commercial preparation of PGI2
Severe HTN & to prevent platelet aggregation in dialysis machines
Latanoprost
A PGF2alpha derivative used for the treatment of glaucoma
Increases the outflow of aqueous humor, thus reducing intraocular pressure
Zileuton
5-lipooxygenase inhibitor
Prevents leukotriene synthesis
Zafirlukast, Montelulast
LTD4 receptor antagonists
Prevent LTD4 from binding to its receptor in target tissues, thereby preventing its action
Glucocorticoids
Inhibit cytosolic phospholipids A2, this blocking the release of arachidonic acid from phospholipids, and its subsequent conversion to eicosanoids.
Also inhibit COX-2 synthesis
NSAIDS
Act primarily by inhibiting COX enzymes
Group of agents with antipyretic, analgesic, and anti-inflammatory activities.
Cimetidine
H2 receptor antagonist
Inhibits cytochrome P450 and can slow metabolism of several drugs
Antiandrogenic efffects
