Adrenergic antagonist drug

• Autacoide is divided into 3 sections, and they are

1. Decarboxylated amino acid
2. Vasoactive peptide
3. Eicosanoid

• Decarboxylated amino acid is divided into two types

1. Histamine
2. Serotonin

Today we will talk about histamine and histamine-inhibiting drugs, their benefits, therapeutic effects and side effects.

histamine

• Histamine is formed by decarboxylation of L-histidine, a reaction catalyzed by histidine decarboxylase enzyme.

• Histamine exerts powerful effects on smooth and cardiac muscle, on certain endothelial and nerve cells, on the secretory cells of the stomach, and on inflammatory cells.

Histamine Receptors

H1 (Gq): found in smooth muscles, endothelium and brain, Main effects, Spasmogenic on smooth muscle, VD and skin itching.

H2 (Gs): found in gastric mucosa, cardiac muscles mast cells and brain, Main effects; Increase HCI secretion & cardiac stimulation.

H3 (Gi): Decrease neurotransmitter release.

H4 (Gi): Plays a role in chemotaxis.

Pharmacological Action of Histamine

• Nervous System:

Powerful stimulation of sensory nerve endings which lead to pain and itching (H1).

• CVS:

1) Direct VD (H1) (via NO production)

2) increase HR Due to

         i) Direct stimulatory on the heart (H2),

        ii) Reflex tachycardia (due to VD).

Triple Response of Lewis

Intradermal histamine injection cause:

1) Red spot; by direct VD of small vessels.

2) Flare; by axon reflex.

3) Edema formulation by increase capillary permeability. 

• Lung: Bronchoconstriction (H1).
• GIT: Intestinal smooth muscle contraction (H1).
• Stomach: Powerful stimulant of HCI secretion (H2).
• Nose: Runny nose, Sneezing & Nasal congestion.
• CNS: increase wakefulness and prevent sleep (H1).

Antihistamines

First Generation (Sedating Antihistamines)

1. Chlorpheniramine
2. Brompheniramine Hydroxyzine
3. Triprolidine
4. Dimethindene
5. Clemastine
6. Pheniramine
7. Mequitazine
8. Diphenhydramine
9. Dimenhydrinate
10. Cyclizine
11. Meclizine
12. Doxylamine
13. Promethazine
14. Cyproheptadine

• Penetrate CNS (lipophilic) which lead to Sedation.
• Short duration of action (4 to 6 hours).
• Some of these have another actions e.g. Anticholinergic, Antiemetic, Antiserotonin and local anesthetic effects.
• Diphenhydramine, Dimenhydrinate, Cyclizine, Meclizine, Doxylamine and Promethazine are the most effective for motion sickness and vertigo.
• Doxylamine; strong sedation, used in insomnia.
• Cyproheptadine also acts as a serotonin antagonist used off- label as an appetite stimulant.

Second Generation (Non-sedating Antihistamines)

1. Cetirizine
2. Loratadine
3. Acrivastine
4. Ebastine
5. mizolastine 

• less penetrate CNS (more polar) which lead to less or no sedation.
• Long duration of action (12 to 24 hours).
• More selective for H1-receptors.

[Ophthalmic Antihistamines)

1. Ketotifen
2. Alcaftadine
3. Bepotastine
4. Emedastine
5. Azelastine
6. Olopatadine

• used for allergic conjunctivitis.
• Azelastine and Olopatadine: have intrahasal formulations
• Ketotifen: has oral formulations.
• Azelastine and Ketotifen: have mast cell stabilizing effects.

Third Generation (Non-sedating Antihistamines)

1. Levocetirizine
2. Desloratadine
3. Fexofenadine

• They are active enantiomer or metabolite derivatives of second-generation which lead to increase efficacy with fewer adverse reactions.
• Long duration of action (24 hours).
• Pure selective for H1-receptors.

Therapeutic Uses of Antihistamines

1. Allergic Reactions: Allergic rhinitis (hay fever), Urticaria, Atopic dermatitis & (asthma; ineffective alone).
2. Motion Sickness and Vestibular Disturbance.
3. Nausea and Vomiting of Pregnancy (NVP):
4. Somnifacient (Hypnotic): Especially Doxylamine and Diphenhydramine.

• Meclizine, Cyclizine and Doxylamine are combined with vit.B, to control of NVP.

Toxicity

• Systemic Acute Toxicity are common in young children; hallucinations, excitement, ataxia, and convulsions.

Drug Interaction

1. First generation antihistaminic interact: with anxiolytic hypnotic drugs and MAO inhibitors (increase anticholinerpic).
2. Second generation Terfenadine interact, Wilth LMEIS, inhibit metabolism of Terfenadine, lead to increase concn. of Terfenadine in the blood which lead to Block K channels in the heart cardiac arrhythmia (QT interval prolongation).

H2-receptor Antagonists

1. Cimetidine
2. Ranitidine
3. Nizatidine
4. Famotidine

• Duration of action depend on the dose given.

Mechanism of action

1. H2 receptor antagonists block the actions of histamine at parietal cell H2 receptors and suppress basal and meal stimulated acid secretion.
2. H2 receptor antagonists inhibit 60-70% of total 24-hours acid secretion.

Therapeutic Uses

1. Peptic Ulcer Disease (PUD)
2. Zollinger-Ellison Syndrome (ZES)
3. Gastroesophageal Reflux Disease (GERD)
4. Non-ulcer Dyspepsia
5. Acute Stress Ulcers (IV).

Side Effects

• Cimetidine has Anti-androgenic effect and increase serum prolactin, long term use may cause: Impotence, Gynecomastia, Galactorrhea and amenorrhea.
• Cimetidine inhibits several cytochrome P450 (is a LME inhibitor), interfere with the metabolism of many drugs 

H3-receptor Antagonists

Betahistine

Is an anti-vertigo drug used in balance disorders or relieve vertigo symptoms associated with Ménière's (men-YEERS) disease.

Mechanism of Action

Betahistine seems to dilate the blood vessels within the inner ear which can relieve pressure from excess fluid and act on the smooth muscle.

References 

1) pubmed

2) pharmaguide

3) medscape

4) drugbank