Antihistamines – do they have a downside?

Antihistamines are a pharmaceutical class of drugs that act to treat histamine-mediated conditions. There are two main classes of histamine receptors: H-1 receptors and H-2 receptors.

Antihistamine drugs that bind to H-1 receptors are generally used to treat allergies and allergic rhinitis.

Drugs that bind to H-2 receptors can treat upper gastrointestinal conditions that are caused by excessive stomach acid. This article looks at the indications, contraindications, activity, adverse events, and other vital elements of antihistamines.

What are antihistamines used for?

H-1 antihistamines are further classified according to first and second-generation agents. First-generation H-1 antihistamines more easily cross the blood-brain barrier into the central nervous system (CNS), whereas second-generation H-1 antihistamines do not.

The first-generation drugs will bind to both central and peripheral histamine-1 receptors, whereas second-generation drugs selectively bind to peripheral histamine-1 receptors; this leads to different therapeutic and side effect profiles.

First-generation antihistamines have several indications that primarily include nausea and vomiting secondary to motion sickness and vertigo, but also are useful for allergic rhinitis, insomnia, allergic reactions, parkinsonism, and as an antitussive. This class of drugs includes:

Diphenhydramine

For nasal allergies, allergic dermatosis, anaphylaxis in combination with epinephrine, insomnia, prevention of motion sickness, antiemetic, management of parkinsonian symptoms.

Off-label use: Oral mucositis

Meclizine

For motion sickness and vertigo

Promethazine

For allergic conditions, antitussive, motion sickness, surgical analgesic/hypnotic, sedation

Off-label: Nausea and vomiting associated with pregnancy

Doxylamine Succinate

For nausea and vomiting of pregnancy

Other H-1 antihistamines include; Cetirizine, Chlorpheniramine, Cyclizine, Dimenhydrinate, and Hydroxyzine.

In summary, H-1 Antihistamines are used for:

• Allergic rhinitis
• Allergic conjunctivitis
• Allergic dermatological reaction(s)
• Sinusitis
• Urticaria
• Angioedema
• Atopic dermatitis
• Bronchitis
• Motion sickness
• Nausea
• Vomiting

H-2 Antihistamine are used for:

• Peptic ulcer
• Acid reflux
• Gastritis
• Zollinger Ellison syndrome

H-2 Antihistamine drugs are:

• Cimetidine
• Famotidine
• Raniditine
• Nizatidine
• Roxatidine

How do they work?

Histamine (a chemical messenger) induces an increased level of vascular permeability, which leads to fluid moving from capillaries into the surrounding tissues. The overall outcome of this is increased swelling and dilation of vessels. Antihistamines stop this effect by acting as antagonists at the H-1 receptors. The clinical benefit is a reduction in allergy symptoms and any related symptoms.

First-generation antihistamines easily cross the blood-brain barrier into the central nervous system and antagonize H-1 receptors, leading to a different therapeutic and adverse effect profile in contrast to second-generation antihistamines that selectively bind to peripheral histamine receptors.

The duration of action of first-generation antihistamines is about 4 to 6 hours. In contrast, second-generation antihistamines work for 12 to 24 hours. They are both metabolized by the liver using the P450 cytochrome system. If you take this type of antihistamine daily, it is a good idea to support the P450 cytochrome detoxification pathway in the liver.

Parietal cells in the gastrointestinal tract secrete hydrochloric acid. They are regulated by acetylcholine, gastrin, and also histamine. Increased histamine leads to increased stomach acid, e.g., hydrochloric acid secretion.

The use of antihistamines specific to the H-2 receptor blocks the entire process and reduces stomach acid secretion.

Adverse Effects

Antihistamine medications carry a broad range of adverse effects depending on the specific class of drugs utilized.

H-1 receptor antihistamines will generally cause clinically noticeable adverse effects that are dose-dependent.

These side effects are far more commonly seen in first-generation antihistamines.

Second-generation antihistamines do not easily cross the blood-brain barrier, and therefore their side effect profile is far more limited. In contrast to H-1 receptor antihistamines, H-2 receptor antihistamines do not commonly cause adverse effects, except for cimetidine.

H-1 receptor antihistamines have anticholinergic properties, which are adverse effect-inducing; this principally occurs only in the first generation category of antihistamines. As a whole, they are sedating but may cause insomnia in some users. Due to their anticholinergic properties, dry mouth is a relatively common adverse effect. Some users experience dizziness and tinnitus. Antihistamines may also be cardio-toxic in some users.

H-2 receptor antihistamines are generally well tolerated by users but do carry the risk of uncommon side effects. Gastrointestinal changes can be seen, including both diarrhoea and constipation. Reports exist of fatigue, dizziness, and confusion.

One specific drug in this category that may cause a range of adverse effects is cimetidine. Its anti-androgenic effects correlate with the possible occurrence of gynecomastia (increased breast tissue) in men. In women, it can cause galactorrhoea. Other H-2 receptor antihistamines do not exhibit the same properties as cimetidine. Ranitidine was previously removed from the market in the United States due to concerns of potential contamination with a carcinogen.

H-2 receptor antihistamines can cause inhibition of the cytochrome system, especially cimetidine, thereby leading to drug toxicity and interactions with other medications.

Patients who present with haemodynamic alterations, increased intra-ocular pressure or increased urinary retention should use antihistamines with caution as these conditions can become exacerbated.

Contraindications

Given the potential cardio-toxic effects of certain antihistamines, they are relatively contraindicated in any patient with QTc prolongation. Patients using other QTc-prolonging drugs require careful monitoring for further prolongation of the QTc interval due to the risk of potentially fatal cardiac arrhythmias.

Usage in pregnant women is a relative contraindication. Additionally, women who are lactating should also avoid usage of antihistamines.

Patients with impaired renal or hepatic function should use antihistamines with caution.

Hypertension, cardiovascular disease, urinary retention, increased ocular pressure are relative contraindications to the use of antihistamines.