Histamine H2 antagonists, Serotonin Agonists/Antagonists, Eicosanoid Antagonist

Question 1

Again the H2 receptor antagonists are cimetidine, ranitidine, famotidine, nizatidine. What is the main clinical use of these drugs?

Answer 1

To inhibit gastric secretion

• -reduce cAMP and therefore reduce gastric secretions
• -competitive, reversible inhibitors

Question 2

What are the uses of H2 receptor antagonists?

Answer 2

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

Question 3

Adverse effects occur in less than 3% of patients, what are these effects?

Answer 3

Headache, dizziness, diarrhea, muscular pain and constipation

Question 4

When elderly patient take Cimetidine, what adverse effect is common/

Answer 4

Mental status change

–esp in elderly patients in the ICU or who have renal or hepatic dysfunction

Question 5

Cimetidine inhibits cytochrome P450 and therefore does what?

Answer 5

Can slow metabolism of several drugs

Question 6

Cimetidine binds to androgen receptors and has antiandrogenic effects, such as ?

Answer 6

Gynecomastia
Reduced Sperm count in men
Galactorrhea in women

Question 7

No harmful effects have been shown on the fetus for H2 antagonists however the drug can cross the placenta as well as?

Answer 7

Breast milk

Question 8

Rapid IV infusion may cause bradycardia and hypotension through blockage of H2 receptors, therefore IV injection should be given how?

Answer 8

Over 30 minutes

Question 9

Now moving on to serotonin (5-hydroxytryptamine, 5-HT), It is stored or is rapidly inactivated by what?

Answer 9

Usually by oxidation catalyzed by MAO

Question 10

serotonin in the body is found where?

Answer 10

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

Question 11

Brain serotonergic neurons are involved in various functions such as ?

Answer 11

Mood 
Sleep
Appetite 
Temp 
Regulation 
Perception of Pain 
Regulation of blood pressure and vomiting

Question 12

What is the mechanism of action of serotonin?

Answer 12

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

Question 13

What are the pharmacological effects of serotonin on the GI tract and CVS

Answer 13

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

Question 14

What are the pharmacological effects of serotonin on platelets and the nervous system?

Answer 14

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

Question 15

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?

Answer 15

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

Question 16

What is the pathophysiology of migraine attacks?

Answer 16

Triptans cause vasoconstriction, opposing the vasodilation thought to be involved in migraine attacks

Question 17

What is first line therapy for severe migraine attacks?

Answer 17

Triptans

–vasoconstrictive so dont give to patients with coronary artery disease

Question 18

What are other classes of drugs used for migraine prophylaxis?

Answer 18

Beta-Adrenergic blockers 
Tricyclic Antidepressants 
Valproic acid 
Topiramate 
Gabapentin 
Verapamil 
Ace inhibitors 
ARBs 
Botulism Toxin

Question 19

The last two drugs to discuss are 5-HT4 receptor agonists. The first drug is Metoclopramide, what is its action?

Answer 19

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

Question 20

What are the adverse effects of Metoclopramide?

Answer 20

Somnolence
Nervousness
Dystonic reaction
Extrapyramidal and Tardive Dyskinesia: may occur but rare

Question 21

The last 5-HT4 receptor agonist is Cisapride, what is the action of this drug?

Answer 21

Until recently most commonly used agent for

-GERD and gastroparesis

Question 22

Why is Cisapride not commonly used anymore?

Answer 22

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

Question 23

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?

Answer 23

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

Question 24

What is the use for cyproheptadine?

Answer 24

Perennial and seasonal allergic rhinitis
Vasomotor 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

Question 25

Finally the last serotonin antagonists is a 5-HT3 receptor antagonist called Ondansetron, what is the use of this drug?

Answer 25

Anti-emetic drug for controlling severe nausea, vomiting

Question 26

Moving on to the Ergot Alkaloids what are they?

Answer 26

``` Ergotamine Dihydroergotamine Bromocriptine Cabergoline Ergonovine Methylergonovine --Produced by Claviceps Purpurea, a fungus that infects grain ```

Question 27

What is the mechanism of action of Ergot Alkaloids?

Answer 27

--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

Question 28

What are the various clinical pharmacology for Ergot Alkaloids?

Answer 28

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

Question 29

Moving on the Eicosanoids, what are the subgroups?

Answer 29

Prostaglandins Prostacyclins Thromboxanes Leukotrienes

Question 30

Eicosanoids are not found preformed in tissues, they are generated?

Answer 30

de novo from phospholipids

Question 31

The main source of eicosanoids is arachidonic acid, a 20-carbon unsaturated fatty acid containing four double bonds. Arachidonic acid is found??

Answer 31

Esterified in phospholipids

Question 32

What are the two major pathways in the synthesis of eicosanoids from arachidonic acid?

Answer 32

1. Cyclo-oxygenase: which initiate the biosynthesis of prostaglandins, prostacyclins and thromboxanes 2. Lipo-oxygenase: which initiate the synthesis of leukotrienes, and other compounds

Question 33

The anti-inflammatory action of glucocorticoids is due largely to what?

Answer 33

Inhibition of induction of cyclooxygenase | --these drugs may also stimulate production of the phospholipase A2 inhibitor, lipocortin

Question 34

The anti-inflammatory action of non-steroidal anti inflammatory drugs (NSAIDs) is due mainly to ?

Answer 34

the fact that they inhibit the action of the fatty acid cyclo-oxygenase

Question 35

Describe the cyclo-oxygenase pathway

Answer 35

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

Question 36

Describe the lipoxoygenase pathway

Answer 36

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.

Question 37

What are the mechanism of action of eicosanoids?

Answer 37

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

Question 38

What are the obstetric uses of eicosanoids?

Answer 38

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

Question 39

What are the pediatric uses of eicosanoids?

Answer 39

1. Alprostadil (PGE1): is given as an infusion to maintain patency of the ductus arteriosus in infants with transposition of the great vessels

Question 40

What are the pulmonary hypertension and dialysis uses of eicosanoids?

Answer 40

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

Question 41

What are the gastric cytoprotection, urology and ophthalmology uses of eicosanoids?

Answer 41

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

Question 42

Finally the last topic deals with Eicosanoid antagonists. Which consists of Leukotriene pathway inhibitors, what two approaches are used to interrupt this pathway?

Answer 42

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

Question 43

The second eicosanoid pathway antagonist is Glucocorticoids, how does this work?

Answer 43

- -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

Question 44

Finally the last eicosanoid pathway antagonist is NSAIDS, how does this work?

Answer 44

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