Flashcards in Histamine H2 antagonists, Serotonin Agonists/Antagonists, Eicosanoid Antagonist Deck (44)
Again the H2 receptor antagonists are cimetidine, ranitidine, famotidine, nizatidine. What is the main clinical use of these drugs?
To inhibit gastric secretion
--reduce cAMP and therefore reduce gastric secretions
--competitive, reversible inhibitors
What are the uses of H2 receptor antagonists?
1. Peptic ulcers: healing of duodenal and gastric ulcers; recurrence is common after treatment is stopped
2. Acute stress ulcers: associated with major physical trauma in high risk patients
3. GERD: prevention and treatment of heart burn. Stop acid secretion so they may not stop symptoms for up to 45 minutes but longer lasting action
Adverse effects occur in less than 3% of patients, what are these effects?
Headache, dizziness, diarrhea, muscular pain and constipation
When elderly patient take Cimetidine, what adverse effect is common/
Mental status change
--esp in elderly patients in the ICU or who have renal or hepatic dysfunction
Cimetidine inhibits cytochrome P450 and therefore does what?
Can slow metabolism of several drugs
Cimetidine binds to androgen receptors and has antiandrogenic effects, such as ?
Reduced Sperm count in men
Galactorrhea in women
No harmful effects have been shown on the fetus for H2 antagonists however the drug can cross the placenta as well as?
Rapid IV infusion may cause bradycardia and hypotension through blockage of H2 receptors, therefore IV injection should be given how?
Over 30 minutes
Now moving on to serotonin (5-hydroxytryptamine, 5-HT), It is stored or is rapidly inactivated by what?
Usually by oxidation catalyzed by MAO
serotonin in the body is found where?
Enterochromaffin cells in the GI tract: over 90%
Platelets in the blood
Serotonergic neurons are found in the enteric nervous system of the GI tract and around blood vessels
Pineal gland: precursor of melatonin
Raphe nuclei of the brain stem: which synthesizes, stores and releases serotonin
Brain serotonergic neurons are involved in various functions such as ?
Perception of Pain
Regulation of blood pressure and vomiting
What is the mechanism of action of serotonin?
G-protein coupled receptor (6) and Ligand gated (1)
--5-HT3 receptor is the only monoamine neurotransmitter receptor known to function as a ligand gated ion channel
What are the pharmacological effects of serotonin on the GI tract and CVS
GI: 5-HT increases GI motility due to activation of 5-HT2 smooth muscle receptors and to action on ganglion cells of the enteric nervous system. 5-HT4 causes increased AcH realse and mediated the prokinetic effect of serotonin agonist like cisapride.
CVS: Constricts large vessels, both arteries and veins due to activation of 5-HT2 receptors on vascular smooth muscle cells
What are the pharmacological effects of serotonin on platelets and the nervous system?
Platelets: 5-HT causes platelet aggregation via 5-HT2A receptors
Nervous: 5-HT excites some neurons and inhibits others
--5HT3 receptors in the GI tract and in the vomiting center of the medulla participate in the vomiting reflex
--5-HT is a potent stimulator of pain and itch sensory nerve endings, an effect mediated by 5-HT3 receptors. so insect and plant sting bite pain
Now we will discuss the serotonin agonists. There is no clincal application of the drug, however, there are receptor subtypes used clinically. First is 5-HT1D/1B receptor agonist (Triptans). The drug is called sumatriptan, what is this drug used for?
Almost exclusively for migraine headaches
--trigeminal nerve release peptide neurotransmitters, esp calcitonin gene related peptide, a powerful vasodilator
--substance P and neurokinin A may also be involved
What is the pathophysiology of migraine attacks?
Triptans cause vasoconstriction, opposing the vasodilation thought to be involved in migraine attacks
What is first line therapy for severe migraine attacks?
--vasoconstrictive so dont give to patients with coronary artery disease
What are other classes of drugs used for migraine prophylaxis?
The last two drugs to discuss are 5-HT4 receptor agonists. The first drug is Metoclopramide, what is its action?
1. Facilitates AcH release from enteric neurons
--facilitated by suppression of inhibitory interneurons by antagonism at 5-HT3 receptors and stimulation of excitatory neurons via activation of 5-HT4 receptors
2. Central and peripheral antidopamingeric actions
--central: antinauseant and antiemtic properties
--peripheral: counteracting the inhibitory effects of dopamine mediated via dopamine D2 receptors on cholinergic enteric neurons
What are the adverse effects of Metoclopramide?
Extrapyramidal and Tardive Dyskinesia: may occur but rare
The last 5-HT4 receptor agonist is Cisapride, what is the action of this drug?
Until recently most commonly used agent for
-GERD and gastroparesis
Why is Cisapride not commonly used anymore?
Serious cardiac adverse effects:
--extend the action potential and the QT interval
--serious cardiac arrhythmias and death from v-tach, v-fib, torsades de pointes and QT prolongation
--no longer available in the US
Moving on to the Serotonin Antagonists. First are the 5-HT2 receptor antagonists. The drug to discuss is Cyproheptadine, what is the action of this drug?
Prevents smooth muscle effects of both serotonin and histamine but has no effect on gastric secretion stimulated by histamine
--has significant antimuscarinic effects and causes sedation
What is the use for cyproheptadine?
Perennial and seasonal allergic rhinitis
Allergic Conjunctivitis: due to inhalant allergens and foods, cold urticaria, dermatographism
Tx of smooth muscle manifestations of carcinoid tumor
Used to tx serotonin syndrome
Finally the last serotonin antagonists is a 5-HT3 receptor antagonist called Ondansetron, what is the use of this drug?
Anti-emetic drug for controlling severe nausea, vomiting
Moving on to the Ergot Alkaloids what are they?
--Produced by Claviceps Purpurea, a fungus that infects grain
What is the mechanism of action of Ergot Alkaloids?
--Act on several types of receptors: effects include agonist, partial agonist, and antagonist actions at alpha adrenoceptors and 5-HT receptors, and agonist or partial agonist actions at CNS dopamine receptors
What are the various clinical pharmacology for Ergot Alkaloids?
1. Migraine: can be quite effective when given during the prodrome of an attack
2. Hyperprolactinemia: bromocriptine and cabergoline reduce high levels of prolactin that result from pituitary tumors
3. Post-partum hemorrhage: oxytocin in preferred for control of postpartum hemorrhage, if ineffective, ergonovine or methylergonovine
4. Diagnosis of Variant Angina: ergonovine provokes coronary artery spasm
Moving on the Eicosanoids, what are the subgroups?
Eicosanoids are not found preformed in tissues, they are generated?
de novo from phospholipids
The main source of eicosanoids is arachidonic acid, a 20-carbon unsaturated fatty acid containing four double bonds. Arachidonic acid is found??
Esterified in phospholipids
What are the two major pathways in the synthesis of eicosanoids from arachidonic acid?
1. Cyclo-oxygenase: which initiate the biosynthesis of prostaglandins, prostacyclins and thromboxanes
2. Lipo-oxygenase: which initiate the synthesis of leukotrienes, and other compounds
The anti-inflammatory action of glucocorticoids is due largely to what?
Inhibition of induction of cyclooxygenase
--these drugs may also stimulate production of the phospholipase A2 inhibitor, lipocortin
The anti-inflammatory action of non-steroidal anti inflammatory drugs (NSAIDs) is due mainly to ?
the fact that they inhibit the action of the fatty acid cyclo-oxygenase
Describe the cyclo-oxygenase pathway
Cyclo-oxygenase exists in 2 forms: COX-1 and COX-2
--Cox-1: is found in most cells as a constitutive enzyme and it is thought that the prostaglandins it produces are involved in normal homeostasis
--Cox-2: is found primarily in inflammatory cells. Induced by inflammatory stimuli. Expressed by growth factors, tumor promoters, and cytokines. Lipopolysaccharide is particularly potent
Describe the lipoxoygenase pathway
Metabolism of arachidonic acid by lipooxygenases results in the production on leukotrienes and lipoxins.
---leukotrienes produced by 5-lipooxygenase are present in inflammatory cells
--this pathway is associated with asthma, anaphylactic shock and cardiovascular disease
--stimulation of these cells elevates intracellular Ca2+ and releases arachidonate
--Leuotrienes LTC4 and LTD4 are potent bronchoconstrictors and are reorganized as primary components of the slow reacting substance of anaphylaxis, this is secreted in asthma.
What are the mechanism of action of eicosanoids?
1. Act in autocrine and paracrine fashion
2. Bind to receptors in cell surface
3. Some are adenylyl cyclase (activation/inhibitio) and some are PLC
4. contractile effects are mediated by release of Ca2+, while relaxing effects are mediated by elevation in cAMP
What are the obstetric uses of eicosanoids?
1. Dinoprostone (PGE3) and Misoprostol (PGE1) ripen the cervix at or near term
2. Carboprost tromethamine and Misoprostol can be used for management of postpartum hemorrhage
3. Dinoprostone and Carboprost tromethamine can be used as abortifacients in the second trimester of pregnancy
4. Misoprostol in combo with mifepristone or methotrexate as an abortifacient
What are the pediatric uses of eicosanoids?
1. Alprostadil (PGE1): is given as an infusion to maintain patency of the ductus arteriosus in infants with transposition of the great vessels
What are the pulmonary hypertension and dialysis uses of eicosanoids?
Prostacyclin (PGI2): lowers peripheral, pulmonary and coronary resistance
--a commercial preparation called epoprostenol is approved for use in severe HTN to prevent platelet aggregation in dialysis
What are the gastric cytoprotection, urology and ophthalmology uses of eicosanoids?
GI: Misoprostol prevention of peptic ulcers in patients who take high doses of NSAIDS
Urology: Alprostadil (PGE1): used to treat impotence
Ophtho: Latanoprost: tx of glaucoma
Finally the last topic deals with Eicosanoid antagonists. Which consists of Leukotriene pathway inhibitors, what two approaches are used to interrupt this pathway?
1. Inhibition of 5-lypoxygenase, thereby preventing leukotriene synthesis (zileuton)
2. Inhibition of the binding of LTD4 to its receptor in target tissues, thereby preventing its action (zafirlukast, montelukast)
--these drugs are used in the tx of moderate to severe asthma in patients who are poorly controlled by conventional therapy
The second eicosanoid pathway antagonist is Glucocorticoids, how does this work?
--Inhibits cytosolic phospholipase A2, thus blocking the release of arachidonic acid from phospholipids
--Inhibit synthesis of COX-2
--important for anti-inflammatory action of corticosteroids