Exam III Antihistamines Flashcards
Antihistamines
Used for allergic rhinitis, eczema, uticaria
Insomnia
Motion sickness
GERD/PUD
Histamine
Vasoactive amine found in
Mast cells/Basophils -> defends against allergic reactions (immune) reactions
CNS -> Acts as Neurotransmitter
Gut -> regulates gastric acid production
Histamine release
Allergic / hypersensitivity reaction
Tissue injury
Direct mast cell destruction (drugs / chemicals)
Histamine receptors
**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
Cardiovascular effects of Histamine
More likely to be pronounced in preexisting cardiac disease
Inotropic effect
Hypotension secondary to vasodilation
Tachycardia
Histamine in immune modulation
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
Histamine in parietal cells
Gastric acid secretion mediated by:
Histamine
Gastrin
AcH
Histamine in the CNS
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
H1 Effects of agonism
Bronchoconstriction
Diarrhea
Stimulation of peripheral nerves
Urticaria / edema
H1 Effects of antagonism
Bronchodilation
Constipation
Anti-itch, reduction of pain
Reduce inflammatory/allergic reaction
H2 Effects of agonism
Gastric Acid production
H2 effects of antagonism
Suppression of gastric acid
Histamine antagonists
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
First gen H1 antihistamine Facts
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
First Gen H1 Antihistamines
Doxylamine
Diphenhydramine
Cyclizine
Meclizine
Chlorpheniramine
Brompheniramine
Hydroxyzine
Promethazine
Cyproheptadine
Doxylamine & Diphenhydramine Clin Use
Insomnia, allergies
Highly sedating, large doses can cause arrythmias (QTc prolong)
Avoid in elders
+++ Anticholinergic effect - OTC
Cyclizine & Meclizine Clin Use
Motion sickness
Vertigo
Mildly sedating
+ Anticholinergic effects – OTC/RX
Chlorpheniramine & Brompheniramine Clin Use
Allergies
Moderately sedating possible paradoxical CNS stimulation
Often found in combo w/cold products
Avoid elder use
++ Anticholinergic effects - OTC
Hydroxyzine Clin Use
HCL: allergies, urticaria
PAMoate: insomnia, anxiety
Mild-moderate insomnia, anxiety
+ And ++ Anticholinergic effects - RX
Promethazine Clin Use
Anti-emetic
Highly sedating
a-blockade ->hypotension
D2-blockade -> dystonic reactions, akathisia
+++ Anticholinergic effect - RX
Cyproheptadine Clin Use
Weight gain due to 5-HT2 blockade
+ Anticholinergic effect - OTC/RX
ADE/DDI of 1st gen antihistamines
ADE/DDI of 1st gen antihistamines DDIs
Metabolized via 2D6 and 3A4
Avoid:
- Alcohol
- Other Hypnotics and or Benzos
- Tricyclic antidepressants (TCAs)
- Acetylcholinesterase Inhibitors
Second Gen H1 Antihistamines
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
Second Gen H1 Antihistamines
Cetirizine
Azelastine
Levocetirizine
Fexofenadine
Desloratadine
Olopatadine
Loratadine
CALF LOD ine
Azelastine and Olopatidine
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—
Fexofenadine
Highest safety profile
No CYP 450 metabolism
–Oral-OTC–
Cetirizine
Most somnolence
Active metabolite of hydroxyzine
–Oral-OTC–
Levocetirizine
Active metabolite of Cetirizine
–Oral-OTC—
Loratadine
Metabolized via 3A4, 2D6 -> check for 3A4 inhibitors
–Oral-OTC—
Desloratadine
Least likely to cause somnolence
Active metabolite of Loratadine
–Oral-RX—
Potency of 2nd Gen H1 Antihistamines Most to Least
Desloratadine
Levocetirizine
Fexofenadine
2nd Gen H1 Antihistamine ADEs
Somnolence
- Usually at higher doses
- Highest with cetirizine & levocetirizine
Constipation
HA
No sig Cardiac Effect
2nd Gen H1 Antihistamine DDIs
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
H2 Receptor antagonist-Description
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.
H2 Receptor antagonist-Misc
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
Available H2 receptor antagonists
Ranitidine
Nizatidine
Cimetidine
Famotidine
-Pepcid Complete Famotidine variant
R NiCe Fam tidine
H2RA ADEs
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
H2RA DDIs
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
