Exam III Antihistamines

Question 1

Antihistamines

Answer 1

Used for allergic rhinitis, eczema, uticaria

Insomnia

Motion sickness

GERD/PUD

Question 2

Histamine

Answer 2

Vasoactive amine found in

Mast cells/Basophils -> defends against allergic reactions (immune) reactions

CNS -> Acts as Neurotransmitter

Gut -> regulates gastric acid production

Question 3

Histamine release

Answer 3

Allergic / hypersensitivity reaction

Tissue injury

Direct mast cell destruction (drugs / chemicals)

Question 4

Histamine receptors

Answer 4

**H1 – bronchial smooth muscle, CNS, Cardiac muscle – Sleep/Wake cycle, learning, memory, stimulate nerve endings, bronchoconstriction, vasodilation of blood vessels, contraction of smooth muscle.

**H2 – Parietal cells of stomach, cardiac muscle CNS – Gastric Acid production

H3 – CNS, peripheral tissue – Modulation of neurotransmitter release

H4 – Basophils, bone marrow, small intestine, colon, spleen, thymus – Facilitates mast cell chemotaxis

Question 5

Cardiovascular effects of Histamine

Answer 5

More likely to be pronounced in preexisting cardiac disease

Inotropic effect

Hypotension secondary to vasodilation

Tachycardia

Question 6

Histamine in immune modulation

Answer 6

Vasodilation -> capillaries permeable -> allows WBC to move in to site threat

• Leads to Facial flushing and edema
• Separation of endothelial cells -> urticaria
• Induces fluid secretion – Gives rise to classic allergy symptoms —“Runny” nose, watery eyes etc

Question 7

Histamine in parietal cells

Answer 7

Gastric acid secretion mediated by:

Histamine

Gastrin

AcH

Question 8

Histamine in the CNS

Answer 8

Considered a Neurotransmitter

-H1,H3 receptors located in brain, some H2

Modulates:

• ACH release -> learning & cognition
• Alertness -> sleep wake cycle
• Serotonin -> mood
• Food intake -> suppression of appetite
• Emesis center -> nausea / vomiting

Question 9

H1 Effects of agonism

Answer 9

Bronchoconstriction

Diarrhea

Stimulation of peripheral nerves

Urticaria / edema

Question 10

H1 Effects of antagonism

Answer 10

Bronchodilation

Constipation

Anti-itch, reduction of pain

Reduce inflammatory/allergic reaction

Question 11

H2 Effects of agonism

Answer 11

Gastric Acid production

Question 12

H2 effects of antagonism

Answer 12

Suppression of gastric acid

Question 13

Histamine antagonists

Answer 13

Epinephrine -> works quickly/emergent

• SM relaxation
• A&B receptor stim

Cromolyn sodium -> works over weeks

-Stabilize mast cells, prevent degran

Antihistamines

• H1 blockers-> txt allergies, insomnia, motion sickness
• H2 blockers -> txt GERD/PUD

Question 14

First gen H1 antihistamine Facts

Answer 14

Allergic symptoms / motion sickness / insomnia

-OTC & RX

Poor receptor selectivity

-Often interact with other receptors of other amines

–Anti-muscarinic, anti-alpha adrenergic, and anti-serotonin

Highly lipophilic!

-Crossees BBB to interfere with histaminergic transmission]

–Leads to many ADEs limiting use

Not preferred in elders

Question 15

First Gen H1 Antihistamines

Answer 15

Doxylamine

Diphenhydramine

Cyclizine

Meclizine

Chlorpheniramine

Brompheniramine

Hydroxyzine

Promethazine

Cyproheptadine

Question 16

Doxylamine & Diphenhydramine Clin Use

Answer 16

Insomnia, allergies

Highly sedating, large doses can cause arrythmias (QTc prolong)

Avoid in elders

+++ Anticholinergic effect - OTC

Question 17

Cyclizine & Meclizine Clin Use

Answer 17

Motion sickness

Vertigo

Mildly sedating

+ Anticholinergic effects – OTC/RX

Question 18

Chlorpheniramine & Brompheniramine Clin Use

Answer 18

Allergies

Moderately sedating possible paradoxical CNS stimulation

Often found in combo w/cold products

Avoid elder use

++ Anticholinergic effects - OTC

Question 19

Hydroxyzine Clin Use

Answer 19

HCL: allergies, urticaria

PAMoate: insomnia, anxiety

Mild-moderate insomnia, anxiety

+ And ++ Anticholinergic effects - RX

Question 20

Promethazine Clin Use

Answer 20

Anti-emetic

Highly sedating

a-blockade ->hypotension

D2-blockade -> dystonic reactions, akathisia

+++ Anticholinergic effect - RX

Question 21

Cyproheptadine Clin Use

Answer 21

Weight gain due to 5-HT2 blockade

+ Anticholinergic effect - OTC/RX

Question 22

ADE/DDI of 1^st gen antihistamines

Answer 22

Question 23

ADE/DDI of 1^st gen antihistamines DDIs

Answer 23

Metabolized via 2D6 and 3A4

Avoid:

• Alcohol
• Other Hypnotics and or Benzos
• Tricyclic antidepressants (TCAs)
• Acetylcholinesterase Inhibitors

Question 24

Second Gen H1 Antihistamines

Answer 24

Used to treat allergic symptoms only

Highly Selective for H1 receptor with no other receptor effects

Limited penetration of BBB

-Minimally or non-sedating

Preferred in elders

Rapid onset of action

Longer duration of action

Question 25

**Second Gen H1 Antihistamines**

Answer 25

**C**etirizine **A**zelastine **L**evocetirizine **F**exofenadine **D**esloratadine **O**lopatadine **L**oratadine **CALF LOD** ine

Question 26

**Azelastine and Olopatidine**

Answer 26

Dual MOA: **Mast Cell Stabilizer + H1 blocker** Local application -\> less systemic effect - **Local Irritation** can occur (irritation, nosebleed, bitter taste/smell) - Avoid use in nasal passage damage --RX – Nasal Spray—

Question 27

**Fexofenadine**

Answer 27

**Highest safety profile** No CYP 450 metabolism --Oral-OTC--

Question 28

Cetirizine

Answer 28

**Most** **somnolence** Active metabolite of hydroxyzine --Oral-OTC--

Question 29

**Levocetirizine**

Answer 29

Active metabolite of Cetirizine --Oral-OTC—

Question 30

**Loratadine**

Answer 30

Metabolized via 3A4, 2D6 -\> check for 3A4 inhibitors --Oral-OTC—

Question 31

Desloratadine

Answer 31

**Least** likely to cause **somnolence** Active metabolite of Loratadine --Oral-RX—

Question 32

**Potency of 2^nd Gen H1 Antihistamines Most to Least**

Answer 32

Desloratadine Levocetirizine Fexofenadine

Question 33

**2^nd Gen H1 Antihistamine ADEs**

Answer 33

Somnolence - Usually at higher doses - Highest with cetirizine & levocetirizine Constipation HA No sig Cardiac Effect

Question 34

**2^nd Gen H1 Antihistamine DDIs**

Answer 34

Fexofenadine - NOT metabolized via CYP450 –\> highest safety profile - Avoid grapefruit, orange, or apple juice --Must separate by at least 4 hours Loratadine, desloratadine -Metabolized via 3A4 and 2D6 – Watch for DDIs Ketoconazole/grapefruit etc Cetirizine, levocetirizine - Not metabolized via CYP450, but both are **PgP substrates** -\>watch for DDI with **Grapefruit juice** - Avoid other sedative drugs -\> additive effects

Question 35

**H2 Receptor antagonist-Description**

Answer 35

Reversibly decreases fasting and food stimulated acid secretion by inhibiting histamine at H2 receptor of parietal cell Indicated for the treatment of mild-moderate, infrequent, episodic heartburn -Good for on-demand, meal provoked symptoms H2RA – onset:30-45 mins – Duration 4-10 Hrs.

Question 36

**H2 Receptor antagonist-Misc**

Answer 36

All H2Ras are equally efficacious – interchangeable All are both OTC and RX -OTCs about half strength Well absorbed: absorption can be delayed by antacid but not food -Bioavailability of cimetidine and ranitidine reduced with simultaneous high-dose antacid

Question 37

**Available H2 receptor antagonists**

Answer 37

**R**anitidine **Ni**zatidine **C**imetidine **Fam**otidine -Pepcid Complete Famotidine variant **R NiC**e **Fam** tidine

Question 38

**H2RA ADEs**

Answer 38

Well tolerated Most common are CNS related: -HA, dizzy, fatigue, confusion --Incident increased in elderly / renal impairment **Dose related gynecomastia occurs with cimetidine** Tolerance reported with prolonged use -PRN

Question 39

**H2RA DDIs**

Answer 39

Drugs that **depend on acid for proper absorption:** **-Ketoconazole, itraconazole, protease inhibitors**, calcium carbonate, iron salts **Cimetidine inhibits CYP450** (3A4, 2D6, 1A2, 2C9) -Substrates: Cyclosporine, theophylline, warfarin, phenytoin. Amiodarone, antidepressants