Autacoid and Autacoid Antagonists Flashcards
Histamine receptors location and MOA
All are G-protein linked and have constitutive activity
H1: endothelium, smooth muscle cells and nerve endings (Gq linked)
H2: gastric mucosa, cardiac muscle cells and some immune cells (Gs linked)
Histamine synthesis and storage
Found in granules of mast cells and basophils and can be released due to certain stimuli
Mast cells - found in tissues where there is potential for tissue injury, pressure points, feet, mouth, bifurcations, blood vessels, internal body cavities.
Histamine can also be stored and released from the enterocromaffin-like-cell of the fundus of the stomach.
Formed by decarboxylation of the amino acid L-histidine, a reaction catalyzed by histidine decarboxylase. Once formed, histamine is stored or rapidly inactivated.
Effects of histamine on CVS
Vasodilation:
H1: endothelial cell stimulation leads to formation of NO
H2: located on vascular smooth muscle and vasodilation is mediated by cAMP
Heart:
H2 effect
Increased contractility and heart rate
Increased capillary permeability:
H1 action on blood vessels: histamine induced edema due to the separation of endothelial cells –> permits transudation of fluid into perivascular tissue –> responsible for urticaria (hives)
Histamine effects on extravascular smooth muscle, CNS and secretory tissue
Contraction of GI Tract smooth muscle (H1)
Bronchoconstriction (H1)
CNS: Stimulant of sensory nerve ending –> mediates pain and itching (H1)
Stimulates gastric acid secretion (H2)
Uses of histamine
Pulmonary function testing –> histamine aerosol is sometimes used as provocative test for nonspecific bronchial hyperactivity (like methacholine)
Physiological antagonist of histamine
Epinephrine
Opposite action of smooth muscle and acts on different receptors
DOC for anaphylaxis
Histamine release inhibitors and use
Cromolyn
Nedocromil
Reduce immunologic mast cell degranulation
b2 agonists - capable of reducing histamine release
H1 receptor antagonists 1st gen (7)
Chlorpheniramine Cyclizine Diphenhydramine Dimenhydrinate Hydroxyzine Meclizine Promethazine
H1 receptor antagonists 2nd gen
Fexofenadine
Loratadine
Cetirizine
H1 receptor antagonists 1st gen vs 2nd gen
1st gen - have sedative effects and are more likely to enter CNS and have anti-muscarinic effects
2nd gen - less sedating because they are less liposoluble. Substates for P-glycoprotein (limits brain penetration)
H1 antagonists are actually inverse
Uses of H1 receptor antagonists
Allergic conditions:
DOC for allergic rhinitis and urticaria
Motion sickness and nausea: First gen block central H1 and M1 receptors. Second gen are ineffective
Somnifacients - First gen used in treatment of insomnia
H1 receptor antagonists AE
Sedation - less common with 2nd gen
Dry mouth - due to anticholinergic effects
H2 receptor antagonists and MOA
Cimetidine
Ranitidine
Famotidine
Nizatidine
Inhibitors of gastric acid secretion from parietal cells by competitively blocking H2 receptors
Gastrin can stimulate parietal cells to secrete gastric acid in two ways:
1) Directly
2) Stimulate enterocromaffin cells which release histamine which binds to H2 receptors on parietal cells –> main action of gastrin
H2 receptor antagonists uses
Peptic ulcers
Acute stress ulcers
GERD
H2 receptor antagonists AE and PK
Extremely safe drugs
Headache, dizziness, diarrhea, muscular pain, constipation
Confusion, hallucinations and agitation may occur when given IV (esp in patients in ICU who are elderly or who have renal or hepatic dysfunction)
AE more common with cimetidine
Why are H2 receptor antagonists AE more common with cimetidine?
1) Inhibits cytochrome P450 and can slow metabolism of several drugs
2) Binds androgen receptor and has anti-androgenic effects: gynecomastia and reduced sperm count in men and galactorrhea in women
Serotonin MOA
Formed from the amino acid L-tryptophan by hydroxylation of the indole ring
followed by decarboxylation of the amino acid.
Serotonin is stored or is rapidly inactivated, usually by oxidation catalyzed by MAO.
7 families of 5-HT subtypes: 6 are GPCRs
5-HT3: only monamine NT receptor that functions as a ligand gated ion channel
Sumatriptan MOA and uses
5-HT1d/1b receptor agonist
First line therapy for acute severe migraine attacks
MOA: Migranes involve trigeminal nerve. At nerve terminal, CGRP (calcitonin gene-related peptide) is released –> binds to receptor on blood vessels and causes vasospasms
5HT1dR on nerve terminal inhibits release of CGRP
5HT1bR on blood vessels mediates vasoconstriction
Sumatriptan contraindications
Patients with CAD or angina –> may cause coronary vasospasms
Cisapride MOA and use
5-HT4 receptor agonists use
Prokinetic agent
Prolongs QT interval –> serious cardiac effects therefore no longer generally available in US
Cyrproheptadine MOA and uses
5-HT2 receptor antagonist + potent H1 antagonist
Uses:
- allergic rhinitis
- vasomotor rhinitis
- management of serotonin syndrome
Ondansetron MOA and uses
5-HT3 receptor antagonist –> ligand gated receptor
Anti-emetic –> used for severe N/V that occurs due to cancer chemotherapy
Ergot alkaloids
Ergotamine Dihydroergotamine Bromocriptine Cabergoline Ergonovine Methylergonovine
Effects include:
Agonist, partial agonist, antagonist at a-adrenoceptor and 5-HT receptors
Agonist or partial agonists at CNS dopamine receptors
Ergot alkaloids used to treat migraines
Ergotamine
Dihydroergotamine
Ergot alkaloids used to treat hyperprolactinemia
Bromocriptine
Cabergoline
Reduce high levels of prolactin due to pituitary tumors
Drugs used to treat postpartum hemorrhage
Oxytocin - preferred agent
If it is ineffective: can use ergot alkaloids IM
Ergonovine
Methylergonovine
Ergonovine uses
IM for postpartum hemorrhage
IV for diagnosis of variant angina (it provokes coronary artery vasospasm)
Ergot alkaloids AE and contraindications
Causes vasospasm
Contraindications:
Pregnancy: may cause fatal distress and miscarriage
Peripheral vascular disease, CAS, hypertension, and impaired hepatic or renal function
Should not be used with other drugs that can cause vasoconstriction
Difference between COX1 and COX2
COX1 is found in most cells as a constitutive enzyme –> produces prostaglandins involved in normal homeostasis
COX2 is found mainly on inflammatory cells and is induced by inflammatory stimuli
Eicosanoids MOA
Act in autocrine and paracrine fashion
Activate GPCRs
Contractile effects: mediated by Ca2+
Relaxing effects: mediated by cAMP
Misoprostol MOA and uses
PGE1 analog
Prevention of peptic ulcers in patients taking high doses of NSAIDs
To ripen cervix at or near term
Management of postpartum hemorrhage
Abortion - used in combination with antiprogestin mifepristone or methotrexate
Dinoprostone MOA and uses
PGE2
To ripen cervix at or near term
Abortion
Alprostadil MOA and uses
PGE1
To maintain potency of ductus arteriosus in infants with transposition of the great vessels until surgical correction can be undertaken
For impotence
Epoprostenol MOA and uses
PGI2
Used in severe pulmonary hypertension
To prevent platelet aggregation in dialysis machines
Latanoprost MOA and uses
PGFa derivative
Used for glaucoma
Inhibitors of 5-lipoxygenase
Zileuton
Antagosis of LTD4 receptors
Zafirlukast
Montelukast
Glucocorticoids MOA
Inhibit PLA2 –> block release of arachidonic acid
Inhibit synthesis of COX2
