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
17
Q
Promethazine
A
First Generation H1 receptor antagonist
18
Q
Fexofenadine
A
Second Generation H1 receptor antagonist
19
Q
Loratidine
A
Second Generation H1 receptor antagonist
20
Q
Cetirizine
A
Second Generation H1 receptor antagonist
21
Q
H2 RECEPTOR ANTAGONISTS
A
- Main clinical use: inhibitors of gastric acid secretion.
- By competitively blocking H2receptors, these agents reduce secretion of gastric acid.
Uses
- Peptic ulcers: promote healing of duodenal and gastric ulcers.
- Acute stress ulcers
- GERD: effective in prevention and treatment of heart-burn.
Adverse
- H2 antagonists are extremely safe drugs.
- Adverse effects occur in less than 3% of patients.
- Include: headache, dizziness, diarrhea, muscular pain, constipation.
- Confusion, hallucinations and agitation may occur when given IV, especially in patients in the ICU who are elderly or who have renal or hepatic dysfunction.
- These adverse effects may be more common with cimetidine.
- Cimetidine inhibits cytochrome P450 and can slow metabolism of several drugs.
- Cimetidine binds to androgen receptors and has antiandrogenic effects: gynecomastia and reduced sperm count in men and galactorrhea in women.
- Exam Q: Cimetidine inhibits warfarin metabolism
22
Q
SEROTONIN: MOA
A
- Seven families of 5-HT receptor subtypes have been characterized.
- Six are G protein-coupled receptors.
- One is a ligand-gated ion channel.
- The 5-HT3 receptor is the only monoamine neurotransmitter receptor known to function as a ligand-gated ion channel.
23
Q
Sumatriptan
A
- prototypical 5-HT 1D/1B receptor agonist
- 1st-line therapy for acute severe migraine attacks
- may cause coronary vasospasm
24
Q
METOCLOPRAMIDE
A
- 5-HT4 RECEPTOR AGONISTS
- Prokineticagent.
- Its administration results in coordinated contractions that enhance transit -> treats lazy gut
25
Q
CISAPRIDE
A
- 5-HT4 RECEPTOR AGONISTS
- Prokinetic agent.
- Due to serious cardiac adverse effects it is no longer generally available in the US.
- The drug is available only on a limited basis.
26
Q
CYPROHEPTADINE
A
- 5-HT2 RECEPTOR ANTAGONISTS
- Also has potent H1 blocking actions.
USES
- Allergic rhinitis
- Vasomotor rhinitis
- Management of serotonin syndrome.
27
Q
ONDANSETRON
A
- 5-HT3 RECEPTOR ANTAGONISTS
- Anti-emetic.
- Particularly for the severe nausea and vomiting that occurs with cancer chemotherapy.
28
Q
ERGOT ALKALOIDS
A
Produced by Claviceps purpurea, a fungus that infects grain.
These alkaloids affect alpha-adrenoceptors, 5-HT receptors and CNS dopamine receptors.
29
Q
ergotamine or dihydroergotamine
A
Ergot derivatives are highly specific for migraine pain.
30
Q
Bromocriptine and cabergoline
A
- DA agonists
- effective in reducing the high levels of prolactin that result from pituitary tumors.
31
Q
ergonovine or methylergonovine
A
- ERGOT ALKALOIDS
- Postpartum Hemorrhage: Oxytocin is the preferred agent for control of postpartum hemorrhage, but if it is ineffective, ergonovine or methylergonovine IM can be tried.
32
Q
Ergonovine
A
ERGOT ALKALOIDS
Diagnosis Of Variant Angina: IV provokes coronary artery spasm in patients with variant angina.
33
Q
EICOSANOIDS: MECHANISM OF ACTION
A
- The contractile effects of eicosanoids on smooth muscle are mediated by Ca2+.
- Their relaxing effects are mediated by cAMP.
34
Q
Dinoprostone (PGE2), and misoprostol
A
- EICOSANOIDS
- to ripen the cervix at or near term.
- Misoprostol: for prevention of peptic ulcers in patients taking high doses of NSAIDs.
35
Q
Carboprost tromethamine (15-methyl-PGF2alpha), and misoprostol
A
- EICOSANOIDS
- for management of postpartum hemorrhage.
36
Q
Dinoprostone & carboprost tromethamine:
A
- EICOSANOIDS
- used as abortifacients.
- Misoprostol: used in combination with the antiprogestin mifepristone or with methotrexate as abortifacient.
37
Q
Alprostadil (PGE1):
A
- EICOSANOIDS
- used for impotence.
- used to maintain patency of the ductus arteriosus.
- Exam Q: Baby w problems in artery
38
Q
Epoprostenol (PGI2):
A
- EICOSANOIDS
- used in severe pulmonary hypertension and to prevent platelet aggregation in dialysis machines.
39
Q
zileuton
A
Inhibition of 5-lypoxygenase
40
Q
zafirlukast, montelukast
A
Inhibition of the binding of LTD4 to its receptor in target tissues
