Histamine, 5-HT, and Antagonists

Question 1

autacoids are …

Answer 1

substances produced by neural and non-neural tissues which act locally to modulate activity of smooth muscle, nerves, glands, platelets, etc; regulate aspects of GI, uterine, renal function and involved in pain, fever, inflammation, allergic reactions, asthma, thromboembolic disorders, etc

Question 2

Where is the largest concentration of histamine found?

Answer 2

skin, lungs, GI, nasal mucosa, blood

Question 3

Where is histamine stored and synthesized? Ie what types of cells.

Answer 3

storage - bound to proteoglycan in granules in mast cells and basophils
synthesis - rapidly in response to correct stimuli in paracrine cells of gastric fundus and histaminergic neurons

Question 4

What stimuli cause mast cells to degranulate? Examples?

Answer 4

1. antigens and anaphylatoxins (via crosslinking of IgE; Ca mediated)
2. certain basic drugs (probably dec GTP; examples codeine, morphine, tubocurarine, Ach)
3. chemical or mechanical injury (increased Na; insect, snake venom, cuts)

Question 5

Distribution and mechanism of H1 receptor.

Answer 5

smooth muscle, endothelium, brain

Gq

Question 6

Distribution and mechanism of H2 receptor.

Answer 6

gastric mucosa, cardiac muscle, mast cells, brain

Gs

Question 7

Distribution and mechanism of H3 receptor.

Answer 7

presynaptic: brain, myenteric plexus, other neurons

Gi

Question 8

Distribution and mechanism of H4 receptor

Answer 8

eosinophils, neutrophils, CD4 T cells

Gi

Question 9

What’s the really important physiologic effect of histamine in the cardiovascular system?

Answer 9

fall in BP due to vasodilation - pronounced drop, anaphylactic shock
there’s also an increase in vascular permeability and decrease in HR

Question 10

What effect does histamine have in the lungs? Who does this affect most?

Answer 10

bronchoconstriction; hyperreaction in asthmatics

Question 11

Effects of histamine in GI tract? Which receptors?

Answer 11

contraction of sm muscle - diarrhea H1

secretion of acid, pepsin, intrinsic factor H2

Question 12

Effects of histamine on sensory nerve endings in the skin?

Answer 12

pain (dermis) and itching (epidermis) H1

Question 13

What’s the role of H3 receptors in the brain?

Answer 13

autoreceptors; feedback inhibition on histaminergic neurons to stop synthesis and release

Question 14

What are the three ways to reduce the effects of histamine?

Answer 14

1. physiological antagonists (epi) that have opposite actions (on diff receptors)
2. release inhibitors - reduce degranulation of mast cells
3. histamine receptor antagonists

Question 15

Class and action of diphenhydramine.

Answer 15

H1 antagonist; ethanolamine derivative

antimuscarinic effects; sedation

Question 16

Class and action of tripelennamine.

Answer 16

H1 antagonist; ethylenediamine derivative

moderately sedating, OTC sleep aids

Question 17

Class and action of cyclizine.

Answer 17

H1 antagonist; piperazine derivative

dramamine; anti-motion sickness

Question 18

Class and action of promethazine.

Answer 18

H1 antagonist; phenothiazine derivative

antimuscarinic effects, marked sedation, antiemetic

Question 19

Class and action of chlorpheniramine.

Answer 19

H1 antagonist; alkylamine derivative
less sedating (daytime) cold meds

Question 20

Class and action of loratidine and fexofenadine

Answer 20

H1 antagonist; piperadine derivatives
newest class; 2nd generation
don’t cross BBB - no sedation
longer duration - once a day dosing

Question 21

Class and action of azelastine

Answer 21

H1 antagonist; 2nd generation
intranasal for allergic rhinitis
ophthalmic solution for allergic conjunctivitis

Question 22

Class and action of cetirizine.

Answer 22

H1 antagonist; 2nd generation

high grossing - zyrtec

Question 23

Clinical uses of H1 antagonists.

Answer 23

1. allergic reactions - allergic rhinitis, urticaria, conjunctivitis, topically for insect stings
2. motion sickness
3. nausea and vomiting of pregnancy
4. ‘sleep aids’

Question 24

Adverse effects of H1 antagonists

Answer 24

1. sedation (impaired cognitive function)
2. anti-muscarinic (blurred vision, dry mouth, urinary retention, constipation)
3. poisoning - esp children; convulsions at high doses
4. allergy (esp with topical)
5. local anesthesia (high conc)
6. ventricular tachycardia with high dose of piperadines

Question 25

What are the H2 antagonists?

Answer 25

cimetidine, ranitidine, famotidine, nizatidine

Question 26

Mechanism of H2 antagonists?

Answer 26

compete at H2 receptors in parietal cells; block gastric acid secretion (effect more pronounced on nocturnal than post meal)

Question 27

Clinical use of H2 antagonists?

Answer 27

dyspepsia (OTC) duodenal and gastric ulcers hypersecretory conditions (zollinger-ellison syndrome caused by gastrin-secreting tumor)

Question 28

Adverse effects of H2 antagonists?

Answer 28

``` very rare (1-3% of pts) CNS dysfunction (slurred speech, confusion; elderly) antiandrogen (cimetidine - gynecomastia, impotence) liver toxicity (ranitidine) P450 inhibition (cimetidine - potentiates action of other drugs; nizatidine doesn't do this!!!) ```

Question 29

What amino acid is 5-HT derived from?

Answer 29

tryptophan

Question 30

Distribution of 5-HT in the body?

Answer 30

GI tract (90% enterochromaffin cells) platelets (8%) CNS (2%)

Question 31

There are a lot of 5-HT receptors. What are most of them? What's the one exception?

Answer 31

most are GPCRs; 5HT-3 is a ligand-gated cation channel

Question 32

Actions of 5-HT in GI tract?

Answer 32

contraction of smooth muscle; | not carcinoid syndrome - enterochromaffin tumors release large amounts

Question 33

Actions of 5-HT in cardiovascular?

Answer 33

vasoconstrictor in smooth muscle, vasodilate in skeletal muscle and heart reflex bradycardia platelet aggregation

Question 34

Actions of 5-HT in nervous system?

Answer 34

peripheral - pain and itching; activator of chemosensitive endings in coronary vascular bed central - mood, food intake, sleep, regulation of pituitary secretions; presynaptic autoreceptors

Question 35

Cyproheptadine is both antihistaminic and antiserotinergic. What are its uses and side effects?

Answer 35

Use: skin allergies, urticaria (anti-H1) diarrhea of carcinoid (anti-5HT2) Side effects - sedation, antimuscarinic

Question 36

Ketanserin isn't marketed in the US yet, but what is it used for in other countries?

Answer 36

antihypertensive (relaxes vascular and tracheal sm muscle) | antagonizes platelet aggregation

Question 37

What receptor does ondansetron block? What's it used for?

Answer 37

5-HT3 antagonist; | prevention of N/V associated with chemo

Question 38

Ergot alkaloids work at a whole bunch of receptor types - what are they?

Answer 38

agonist and antagonist at serotonin and alpha-adrenergic; some dopamine agonists too

Question 39

In general, ergot alkaloids have actions in the CNS, vascular sm muscle, and uterine sm muscle. What are these effects?

Answer 39

CNS - powerful hallucinations Vascular sm muscle - vessel constriction - prolonged and powerful Uterine sm muscle - prolonged contraction

Question 40

What ergot alkaloids are used in the Tx of migraines?

Answer 40

ergotamine and methysergide | triptans (not ergot)

Question 41

When can ergotamine be helpful? Side effects?

Answer 41

given during prodrome of migraine; | side effects - N/V, prolonged vasoconstriction

Question 42

Methysergide is only used for migrain prophylaxis. What are it's side effects?

Answer 42

GI disturbances, inflammatory fibrosis fr chronic use, occasional hallucinations

Question 43

The triptans are also useful for migraine treatment, but aren't ergot alkaloids. What are the possible mechanisms for how they work?

Answer 43

1. activate 5-HT1B,D receptors - vasoconstriction of cerebral vessels, relieving the dilation that contributes to throbbing HA 2. stimulate presynaptic receptors (same type) on trigem nerve endings, inhibiting release of pro-inflammatory neuropeptides

Question 44

What is ergonovine used for?

Answer 44

sustain uterine contraction to treat postpartum hemorrhage

Question 45

Bromocriptine is an ergot alkaloid that acts as a D2 dopamine agonist in the treatment of what?

Answer 45

hyperprolactinemia - suppresses prolactin secretion from pituitary cells