Pharm - Histamine/ Histamine Antagonists

Question 1

Histamine is synthesized from what?

Answer 1

L-histadine

Question 2

Name 2 most important sites of histamine synthesis? Key distinguishing difference between these sites and others within the body?

Answer 2

Mast cells and Basophils. These are the only 2 sites that can store large amounts of histamine. All others (epidermal cells, intestinal mucosa, CNS neurons, rapidly dividing cells) produce histamine as needed

Question 3

Describe mechanism of time release that occurs with histamine?

Answer 3

Mast cells/basophils have granules that are - charged. These granules contain tons of histamine that are + charged. As granules fuse with mast cell membrane, the + charged histamine is slowly exchanged with Na+, essentially producing a long, slow release process.

Question 4

What prevents histamine from having a systemic effect vs the local, regionalized effect it does have?

Answer 4

short 1/2 life of histamine.

Question 5

Immunoglobulin associated with histamine? Mechanism?

Answer 5

IgE, binds to mast cells (along with allergen) triggers release of histamine

Question 6

Histamine effect on capillary beds?

Answer 6

No effect, no histamine receptors

Question 7

Increased “capillary” permeability via histamine occurs primarily at what sites?

Answer 7

Metarterioles, venules

Question 8

Histamine binding to H1 receptors of arterioles and venules produces what effect?

Answer 8

rapid onset, short term dilation

Question 9

Histamine binding to H2 receptors of arterioles and venues produces what effect?

Answer 9

slow onset, persistent dilation

Question 10

Net effect of histamine on large vessels?

Answer 10

Vasoconstriction (via smooth muscles cells)

Question 11

Net effect of histamine in lungs?

Answer 11

bronchoconstriction

Question 12

Main MOA of histamine antagonists?

Answer 12

Histamine receptors occur in active and inactive confirmation. H antagonists simply bind to histamine receptors and increase # of inactive receptors, thus decreasing total receptor activity

Question 13

Key difference(s) b/t 1st gen and 2nd gen H1 antagonists

• structure?
• 1/2 life?
• dosing regimen?
• sedation qualities?
• Anti-cholinergic side effects?

Answer 13

1st generation
- based on structure of histamine
- short lived
- multiple dosing
- highly sedative
- anticholinergic side effects (which can be beneficial)
The last 3 are the key differences between 1st and 2nd generation H1 antagonists

Question 14

1st generation H1 antagonists sedative effects due to what MOA? Key important fact about this?

Answer 14

H1 antagonists sedative effects ARE NOT due to antimuscarinic effects.
- sedative quality bc histamine antagonists cross BBB and act on H1 receptors in hypothalamus, causing sedative traits.

Question 15

What key feature allows 1st gen H1 antagonists to have effect in brain.

Answer 15

Can cross BBB and evade p-glycoprotein (which is in charge of drug efflux)

Question 16

1st gen H1 antagonist are contraindicated in what patients? Why?

Answer 16

Asthmatics, b/c these 1st gen drugs actually increase production of dry, thickened mucus secretions via anticholinergic effects.

Question 17

Cardiac effects of 1st gen H1 antagonists?

Answer 17

QT prolongation, ventricular arrhythmias

Question 18

Key point regarding selectivity of 1st gen H1 antagonists?

Answer 18

They can, in some cases, bind to other receptors besides H1, producing adverse effects (i.e. M receptors - hence the anticholinergic effects seen in 1st gen)

Question 19

1st gen H1 antagonists can produce antiemetic effects via what mechanism?

Answer 19

through anticholinergic effects, but can cause sedation as well. (he gives his story of working on a fishing vessel)

Question 20

Main structural difference b/t 1st and 2nd generation H1 antagonists? Why is this important? Hint: charge

Answer 20

2nd gen H1 antagonists have much greater + charge. Do not cross BBB as easily, thus do not have sedative effects. Key difference

Question 21

H1 blockade effects b/t 1st and 2nd generation antagonists?

Answer 21

Essentially the same, again main difference is lack of sedative effects seen with H2

Question 22

Asthmatics and 2nd generation H1 antagonists. Contraindicated? Why/Why not

Answer 22

Not contraindicated, 2nd gen doesn’t have anticholinergic effects. Won’t produce increased dry, thickened mucus (seen with 1st gen). Safe for asthmatics to take

Question 23

Which has greater duration of action, 1st or 2nd gen H1 antagonists?

Answer 23

2nd generation, much longer duration of action. single dosing.

Question 24

Main 2 goals of 3rd generation H antagonists

Answer 24

1. Increase specificity and binding for H1 receptor (thus lower dose and more potent)
2. Targe multiple receptor types in addition to anti-histamine functions (potentially having anti asthmatic function and histamine release inhibition)

Question 25

Allergic Rhinitis: 1st or 2nd/3rd generation H1 antagonists?

Answer 25

1st: ++ | 2nd/3rd: ++ (better compliance)

Question 26

Urticaria: 1st or 2nd/3rd generation H1 antagonists?

Answer 26

1st: ++ | 2nd/3rd: ++ (better compliance)

Question 27

Atopic dermatitis or itching dermatosis: 1st or 2nd/3rd generation H1 antagonists?

Answer 27

1st is better, Symptoms are due to adrenergic pathway effects (in which muscarinic receptors play a role)

Question 28

Asthmatics: 1st or 2nd/3rd generation H1 antagonists?

Answer 28

2nd/3rd better. No antimuscarinic effects (as seen with 1st)

Question 29

Anti-motion/antiemetics/appetite stimulation/insomnia: 1st or 2nd/3rd generation H1 antagonists?

Answer 29

1st is better. b/c of antimuscarinic effects

Question 30

List 1st generation H1 antagonists?

Answer 30

``` Brompheniramine [Dimetane] chlorpheniramine [Chlor-Trimeton] Clemastine [Tavist] cyclizine [Marezine] Dimenhydrinate [Dramamime] Diphenhydramine [Benadryl] Hydroxyzine [Atarax] Meclizine [Antivert] Promethazine [Phenergan] Tripolidine [Actidil] ```

Question 31

List 2nd generation H1 antagonists

Answer 31

Acrivastine [Semprex] Cetirizine [Zyrtec] Fexofenadine [Allegra] Loratadine [Claritin]

Question 32

List 3rd generation H1 antagonists

Answer 32

``` Azelastine [Astelin,Astepro] Desloratidine [Clarinex] Emedastine [Emadine] Levocabastine [Livostin] Mizolastine [Mistamine] Olopatadine [Patanol] ```

Question 33

Main dif b/t loratadine (2nd gen) and desloratadine (3rd gen)

Answer 33

Desloratadine: | - 14-17x greater binding to H1 receptor

Question 34

Which 3rd gen drug is given ocularly for allergic rhinitis?

Answer 34

olopatadine

Question 35

Which 3rd gen drug inhibits release of histamine from mast cells?

Answer 35

olopatadine

Question 36

Olopatadine inhibits the release of what 2 mediators from inflammatory cells?

Answer 36

tryptase, PGD2

Question 37

Most specific 3rd gen H1 antagonist?

Answer 37

Levocabastine

Question 38

Azelastine key features

Answer 38

1. inhibits histamine and leukotriene activity 2. blocks Ca2+ and 5-lipooxygenase pathway 3. Inibits PAF through receptor antagonism.