Lecture 15: Autacoids Flashcards
1
Q
AUTACOIDS
A
- Histamine: **Formed by decarboxylation of the amino acid L-histidine, a reaction catalyzed by histidine decarboxylase. **
- Serotonin
- Eicosanoids
2
Q
HISTAMINE: MOA
A
- Four histamine receptors: H1, H2, H3 & H4; only focus no H1 & H2
- All are G protein-linked.
- All four receptors have constitutive activity in some systems.
- thus, some antihistamines previously considered to be antagonists are actually inverse agonists
Toxicity
- Adverse effects are dose-related. Flushing, hypotension, tachycardia, headache, wheals, bronchoconstriction, GI upset.
- Histamine should not be given to asthmatics or to patients with active ulcer disease or GI bleeding.
3
Q
H1 AND H2 RECEPTORS
A
- H1 receptors are present in endothelium, smooth muscle cells and nerve endings.
- H1 receptors are coupled to activation of PLC.
- H2 receptors are present in gastric mucosa, cardiac muscle cells and some immune cells.
- H2 receptors are linked to activation of adenylyl cyclase.
- H4 receptors are mainly found on leukocytes in the bone marrow and circulating blood. They appear to have important chemotactic effects on eosinophils and mast cells. They may play an important role in inflammation and allergy.
4
Q
H1 & H2 in CVS
A
Vasodilation
- involves both H1 and H2 receptors.
- H2 receptors are located on vascular smooth muscle and the vasodilation is mediated by cAMP .
- H1 receptors are on endothelial cells and their stimulation leads to formation of NO.
Heart
- Increased contractility and increased pacemaker rate.
- Mainly due to H2 receptors.
Increased Capillary Permeability
- Histamine-induced edema results from the action of histamine on H1 receptors in blood vessels.
- The effect is due to separation of the endothelial cells which permits the transudation of fluid and molecules into the perivascular tissue.
- This effect is responsible for the urticaria (hives) that signals the release of histamine in the skin.
5
Q
H1 & H2: Extravascular smooth muscles
A
- GI Tract Smooth Muscle: Contraction (H1 effect).
- Bronchiolar Smooth Muscle: Bronchoconstriction (H1 effect).
6
Q
H1 & H2: Pain & Secretory tissues
A
- Histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain and itching (H1 effect).
- Histamine is a powerful stimulant of gastric acid secretion (H2 receptors in gastric parietal cells).
7
Q
HISTAMINE ANTAGONISTS
A
PHYSIOLOGICAL ANTAGONISTS
- Epinephrine.
- Epinephrine has smooth muscle actions opposite to those of histamine, but acting at different receptors.
RELEASE INHIBITORS
RECEPTOR ANTAGONISTS
8
Q
Cromolyn and nedocromil
A
RELEASE INHIBITORS
- Reduce immunologic mast cell degranulation.
- BETA2-agonists also appear capable of reducing histamine release.
9
Q
H1 ANTAGONISTS
A
- H1-blockers were considered H1 receptor antagonists; They are now known to be inverse agonists.
- First-generation H1 antagonists have additional effects due to blocking of cholinergic, alpha- adrenergic, serotonin and local anesthetic receptor sites.
- Second-generation are less sedating because of their less complete distribution into the CNS (they are less liposoluble). Additionally, they are substrates of the P-glycoprotein transporter, which further limits their brain penetration.
- The first-generation H1 antagonists have additional effects unrelated to their blocking of H1 receptors. These effects reflect binding of the H1 antagonists to cholinergic, α- adrenergic, serotonin and local anesthetic receptor sites.
Uses
- Drugs of choice for allergic rhinitis and urticaria because histamine is the principal mediator.
- Ineffective in bronchial asthma because histamine is only one of several mediators.
- Motion sickness and nausea: Ex. Dramamine/dimenhydrinate & Bonine/Meclizine
- Somnifacients
Adverse
- Sedation: less common with second generation agents.
- Dry mouth: due to **anticholinergic effects. **
- Urinary retention
10
Q
H1 antagonists: drug interactions
A
- Ventricular arrhythmias occurred in several patients taking terfenadine or astemizole in combination with inhibitors of CYP3A4.
- Terfenadine and astemizole block cardiac K+ channels responsible for repolarization of the action potential because they induced the potentially fatal arrhythmia, torsades de pointes
- Both drugs were withdrawn from the US market due to these problems.
11
Q
Chlorpheniramine
A
First Generation H1 receptor antagonist
12
Q
Cyclizine
A
First Generation H1 receptor antagonist
13
Q
Diphenhydramine
A
First Generation H1 receptor antagonist
14
Q
Dimenhydrinate
A
First Generation H1 receptor antagonist
15
Q
Hydroxyzine
A
First Generation H1 receptor antagonist
16
Q
Meclizine
A
First Generation H1 receptor antagonist
