Antihistamine Drugs

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Histamine

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Histamine is stored in Mast cells, basophils and brain, gastric mucosa. It is released in allergy-anaphylaxis situations via antigen-antibody reaction. Effects of histamine include smooth muscle contraction, vasodilation, increased vascular permeability, platelet aggregation, complement activation, mucus secretion and eosinophil and neutrophil recruitment. --> Asthma, Hay fever, skin rashes, local anaphylaxis, systemic anaphlyaxis

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Normal roles of Histamine

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a. Normal physiology: has a role in gastric secretions and is involved in proliferation and differentiation of cells, hematopoiesis, embryonic development, regeneration, and wound healing.
i. In the mammalian CNS histamine has a role in the sleep-wake cycle, regulation of feeding and obesity, and in cognition and memory.
b. Pathology: histamine plays a role in allergy, inflammation, and anaphylaxis.
c. Organ distribution: skin, mucous membranes of the respiratory and GI tracts.

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Histamine formation, metabolism and storage.

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a. Histidine is converted to histamine by histidine decarboxylase.
b. Histamine is stored in mast cells and basophils. There is also a non-mast cell pool of histamine in the brain and gastric mucosa, and it is perhaps present in neural elements.

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Effects and Clinical Symptoms of Immediate hypersensitivity reaction

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c. Effects: smooth muscle contraction, vasodilation, increased vascular permeability, platelet aggregation, complement activation, eosinophil and neutrophil chemotaxis, mucus secretion
d. Clinical symptoms: asthma, hay fever, skin rashes, local anaphylaxis, systemic anaphylaxis

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non-immunological mechanisms for histamine release

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a. Any chemical that can cause frank tissue damage can release histamine.
b. Additionally, some organic bases such as morphine and other opiates, d-tubocurarine, and some antihistamines can release histamine.
i. The effects of histamine release are usually not observed unless the agents are administered IV in fairly large doses.

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H1 Receptors

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H1: smooth muscle, endothelium, brain (postsynaptic). These receptors are coupled to Gq/11 that lead to the activation of Phospholipase C -> increased IP3/DAG.

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H2 Receptors

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H2: gastric mucosa, cardiac muscle, mast cells, brain (postsynaptic). These receptors are coupled to Gs that leads to increased cAMP.

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Histamines effect on smooth muscle (bronchi)

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Smooth muscle (bronchi) – H1 receptors
Activation of Gq/11 ->increased Ca2+/Calmodulin Dependent Protein Kinase (aka Myosin Light Chain Kinase) -> phosphorylation of Myosin Light Chain -> enhanced cross bridge cycling and contraction -> bronchoconstriction

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Histamine's effect on cardiovascular system

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i.Blood pressure is decreased upon IV injection of histamine or massive internal release (anaphylaxis).
ii.H1 receptors in the arterioles cause release of NO via Gq/11. This results in dilation of the arterioles and decreased blood pressure. H2 receptors in arterioles also contribute to dilation via Gs (similar to the effect seen with a beta-2 agonist).
iii.H1 receptors cause vasoconstriction of large veins because the NO pathway is absent. Small venules have the NO pathway so they dilate like the arterioles.
iv.Heart rate is reflexively increased via baroreceptors in response to the decrease in blood pressure.
v.Histamine also stimulates H2 receptors in the heart, which causes positive ionotropic and chronotropic effects (similar to the effect seen with a beta-1 agonist).
vi.H1 stimulation causes an increase in vascular permeability.
Overall BP decreases, HR and contractility increase!

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Triple Response: seen when histamine is injected into human skin; is H1 mediated

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1.Localized red spot (a few mm wide) develops
2.Red Flush or Flare (1-5 cm) develops more slowly probably due to the stimulation of local sensory nerve endings by histamine with a local axon reflex (resulting in dilation).
3.Wheal – localized edema, same area as localized red spot.

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Pentagastrin

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a. Histamine doesn’t have any clinical use. In the past it was used in gastric function tests to assess the ability of the stomach to secrete acid. However, it caused a drop in blood pressure that was not desirable, so it has been replaced by pentagastrin in gastric function tests.
b. The most common side effects of pentagastrin are nausea, dizziness, abdominal pain, and the urge to defecate. Less common are flushing, faintness, and numbness in the extremities.

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Antihistamines

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Most antihistamines are Inverse Agonists rather than classical competitive antagonists of H1 receptors meaning that they cause inactive state. The result is the same - blocking of histamines effects.

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First generation Antihistamines

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Dimenhydrinate, Diphenhydramine, Chlorpheniramine, Promethazine
Relief of Allergy symptoms: sneezing, rhinorrhea, nasal itching, ocular symptoms. (Little relief of nasal congestion, post-nasal drip)

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Dimenhydrinate

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(Dramamine) - First gen Antihistamine
+++ Anticholinergic activity
Marked sedation
Anti-motion sickness activity.

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Diphenhydramine

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(Benadryl) - First gen Antihistamine
+++ Anticholinergic activity (Profound)
Marked sedation
Anti-motion sickness activity.

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Chlorpheniramine

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First gen Antihistamine
+ Anticholingeric activity
Slight sedation
Common component of OTC cold medication.

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Promethazine

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(Phenergan) - First gen Antihistamine
+++ anticholinergic activity
Marked sedation
Antiemetic (anti nausea and vomiting)

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Second Generation Antihistamines

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Cetirizine, Desloratidine, Fexofenadine, Levocetirizine, Loratadine. Do not cause as much sedation at their recommended doses because they don’t cross the BBB very well. A number of 2nd gen antihistamines appear to possess several anti-allergic (anti- inflammatory) effects that cannot be explained by H1 receptor antagonism (inhibition of inflammatory cell migration, mediator release, and adhesion molecule expression).
Relief of Allergic Symptoms: Sneezing, Nasal itching, ocular symptoms and some nasal congestion. (little relief of rhinorrhea, post-nasal drip)

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Cetirizine

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(Zyrtec) - Second Gen Antihistamine
Less sedation than first gen but more sedation than the rest of the second gen drugs

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Desloratidine

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(Clarinex) - Second Gen Antihistamine
Less sedation

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Fexofenadine

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(Allegra) - Second Gen Antihistamine
Less sedation
Orange, grapefruit, and apple juice can decrease absorption of fexofenadine by inhibiting the organic anion transporter (OATP).

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Levocetirizine

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Second Gen Antihistamine
Less sedation

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Loratadine

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(Claritin) - Second Gen Antihistamine
Less sedation

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Pharmacokinetics of 1st and 2nd generation Antihistamines

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Readily absorbed from the GI tract and from parenteral sites. (Oral or IV). Take effect within 1-3 hrs. Average duration 4-24 hrs. 2nd gen have longer half lives (24h) and usually only require one dose a day.

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Clinical Uses of Antihistamines

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1. Allergy: Oral antihistamines are useful in allergic rhinitis, conjunctivitis, and urticaria. They are best used prophylactically.Some preparations are also available for topical use for treatment of allergic conjunctivitis or rhinitis (eye drop, nasal spray). These preparations act more quickly than the oral ones, but must be used several times a day.

2. Anaphylaxis: The antihistamines are generally not useful in anaphylaxis. H1 and H2 blockers may have some additional benefit to the preferred treatment for anaphylaxis (epinephrine) on shock.
3. Bronchial asthma - Second generation antihistamines may play a limited adjunctive role, but are not the treatment of choice.
4. Motion sickness: Are effective; best given prophylactically 30 minutes before exposure. First generation: dimenhydrinate, promethazine, others
5. Sedation/Insomnia and Peri-operative sedation: First generation drugs are effective: diphenhydramine, promenthazine, others
6. OTC cold remedies: May have some nasal drying effect. First generation
7. Local anesthesia: First generation drugs effective
8. Ulcers: H2 blockers

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Azelastine

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Antihistamine - Nasal spray. For allergic rhinitis and non-allergic vasomotor rhinitis.
Adverse Effects: Headache, Somnolence, Bitter/sweet taste/taste perversion
Contraindicated in pregnant women - teratogenic

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Olopataine

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Antihistamine - Eye Drops. For allergic conjunctivitis.
Adverse Effects: Transient stinging, headache.

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Side Effects of First vs Second gen Antihistamines.
(Second gen is nearly free of side effects).

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1.CNS: first generation drugs may cause sedation, drowsiness, and impairment of psychomotor performance. They may interfere with learning and decrease work productivity. Second generation drugs don’t cross the BBB well and so have little CNS effect.
Less likely CNS effects: disturbed coordination, fatigue, confusion, restlessness, excitation, nervousness, tremor, irritability, insomnia, euphoria, paresthesias, vertigo, tinnitus, acute labyrinthitis, hysteria, neuritis, convulsion. Children are more likely to show excitation than adults.
2. Gastrointestinal: epigastric distress, anorexia, nausea, vomiting, diarrhea, constipation.Also largely restricted to first generation drugs.
3. Respiratory: dry nose, mouth and throat, nasal stuffiness, possible thickened bronchial secretions, tightness in the chest and wheezing (first generation – typical of anticholinergic activity).
4.GU: exacerbate symptoms of Benign Prostatic Hyperplasia (first generation – typical of anticholinergic activity).
5.Ophthalmic: blurred vision, possible exacerbation of narrow angle glaucoma (first generation – typical of anticholinergic activity).
6. Cardiovascular: Seldane; Williams will cover more about cardiovascular side effects

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Teratogenic Antihistamines

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Azelastine, Cyclizine, Meclizine
These are contraindicated in pregnant women.

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Overdosage of Antihistamines

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a. Overdose is rare.
b. Varies from CNS depression to CNS stimulation. May include dizziness, tinnitus, ataxia, blurred vision, and hypotension.
c. CNS stimulation and atropine-like signs and symptoms (dry mouth, fixed/dilated pupils, hyperthermia, flushing, GI disturbances) are particularly likely in children.

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Drug interactions of Antihistamines

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Sedating antihistamines may interact with alcohol, sedatives and other CNS depressants.

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Contraindications of Antihistamines

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Elderly patients (over 60) may experience dizziness, sedation and hypotension more frequently.