AUTOCOIDS & AUTOCOID ANTAGONISTS

Question 1

Non neuronal site of histamine storage

Answer 1

Enterochromaffin-like cells of the fundus of the stomach —> release histamine, which activates acid-producing parietal cells of the mucosa.

Question 2

Mast cells

Answer 2

Rich at sites of potential tissue injury: nose, mouth, feet, internal body surfaces, and blood vessels (esp @ pressure points and bifurcations)

Granules store histamine

Question 3

H1 receptors

Answer 3

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

Question 4

H2 receptors

Answer 4

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

Question 5

H3 receptors

Answer 5

Predominantly presynaptic receptors

Reduce transmitter release from histaminergic and other neurons.

Question 6

H4 receptors

Answer 6

Mainly found on leukocytes in the bone marrow and circulating blood

Chemotactic effect on eosinophils and mast cells —> important role in inflammation and allergy

Question 7

CVS Effects of Histamine

Answer 7

-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)

Question 8

The Triple Response

Answer 8

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)

Question 9

Extravascular smooth muscle

Answer 9

GI tract - contraction of intestinal smooth muscle (H1)

Bronchiolar - bronchoconstriction (H1)

Question 10

Nervous System effect of Histamine

Answer 10

Powerful stimulant of sensory nerve endings, esp those mediating pain and itching ( H1)

Question 11

Physiological histamine antagonist

Answer 11

Epinephrine

Act on different receptors than histamine

Injection can be life-saving in systemic anaphylaxis

Question 12

Histamine release inhibitors

Answer 12

Cromolyn and Nedocromil

Reduce degranulation of mast cells that result from immunologic triggering by antigen-IgE interaction

Question 13

Histamine effect on secretory tissue

Answer 13

Gastric acid secretion and, to a lesser extent, gastric pepsin and IF production (H2 mediated)

Question 14

H2 receptor antagonists

Answer 14

• 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)

Question 15

Serotonin

Answer 15

• 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.

Question 16

GI tract effect of serotonin

Answer 16

Increases GI motility (5HT2 smooth muscle receptors)

Overproduction of serotonin in carcinoid tumor results in severe diarrhea

Question 17

CVS effect of serotonin

Answer 17

-constricts large vessels (both arteries and veins) (5HT2 receptor activation on vascular smooth muscle cells)

Question 18

Serotonin effect on platelets

Answer 18

Platelet aggregation (via 5HT2a receptors)

Question 19

Nervous system effect of serotonin

Answer 19

• 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

Question 20

Sumatriptan

Answer 20

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

Question 21

Metoclopramide

Answer 21

5HT4 receptor agonist

Prokinetic (enhances GI motility)
—>Facilitates ACh release from enteric neurons

Question 22

Cisapride

Answer 22

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)

Question 23

Cyproheptadine

Answer 23

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)

Question 24

Ondanestrone

Answer 24

5HT3 receptor antagonist

Anti-emetic drug, particularly for controlling severe N/V in pts on chemo

Question 25

Ergot alkaloids

Answer 25

- 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

Question 26

Eicosanoids

Answer 26

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: 1. Cyclo-oxygenate: prostaglandins, prostacyclins and thromoxanes 2. Lipoxygenase: leukotrienes, and other compounds

Question 27

MAO of Eicosanoids

Answer 27

- 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

Question 28

Dinoprostone

Answer 28

PGE2 Used to ripen the cervix @ or near term Can be used as an abortifacient

Question 29

Misoprostol

Answer 29

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

Question 30

Alprostadil

Answer 30

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.

Question 31

Prostacyclin

Answer 31

PGI2 Lowers peripheral, pulmonary and coronary resistance

Question 32

Epoprostenol

Answer 32

Commercial preparation of PGI2 Severe HTN & to prevent platelet aggregation in dialysis machines

Question 33

Latanoprost

Answer 33

A PGF2alpha derivative used for the treatment of glaucoma Increases the outflow of aqueous humor, thus reducing intraocular pressure

Question 34

Zileuton

Answer 34

5-lipooxygenase inhibitor Prevents leukotriene synthesis

Question 35

Zafirlukast, Montelulast

Answer 35

LTD4 receptor antagonists Prevent LTD4 from binding to its receptor in target tissues, thereby preventing its action

Question 36

Glucocorticoids

Answer 36

Inhibit cytosolic phospholipids A2, this blocking the release of arachidonic acid from phospholipids, and its subsequent conversion to eicosanoids. Also inhibit COX-2 synthesis

Question 37

NSAIDS

Answer 37

Act primarily by inhibiting COX enzymes Group of agents with antipyretic, analgesic, and anti-inflammatory activities.

Question 38

Cimetidine

Answer 38

H2 receptor antagonist Inhibits cytochrome P450 and can slow metabolism of several drugs Antiandrogenic efffects