Nonallergic Release
Several agents (certain drugs, radiocontrast media, plasma expanders) can act directly on mast cells to trigger histamine release. With these agents, no prior sensitization is needed. Cell injury can also cause direct release.
Physiologic and Pharmacologic Effects
Histamine acts primarily through two types of receptors, named histamine-1 (H1) and histamine-2 (H2). The response produced depends on which of these receptors is involved.
Effects of Histamine-1 Stimulation
Vasodilation
Activation of H1 receptors causes dilation of small blood vessels (arterioles and venules). Vasodilation is prominent in the skin of the face and upper body, causing the area to become warm and flushed. If extensive vasodilation occurs, total peripheral resistance declines and blood pressure falls.
Increased Capillary Permeability
Activation of H1 receptors increases capillary permeability. Receptor activation causes capillary endothelial cells to contract, creating openings between these cells through which fluid, protein, and platelets can escape. Escape of fluid and protein into the interstitial space produces edema. If loss of intravascular fluid is substantial, blood pressure may fall.
Bronchoconstriction
H1 activation causes constriction of the bronchi. If histamine is administered to an individual with asthma, severe bronchoconstriction will follow. However, although exogenous histamine can induce bronchial constriction, histamine is not the cause of bronchoconstriction that occurs during a spontaneous asthma attack. Consequently, antihistamines are of no use for treating asthma.
CNS Effects
In the CNS, H1 receptors have a role in cognition, memory, and the cycle of sleeping and waking. In addition, H1 receptors appear to have a role in seizure suppression, modulation of neurotransmitter release, and regulation of energy and endocrine homeostasis.
Other Effects
Activation of H1 receptors on sensory nerves produces itching and pain. H1 activation also promotes secretion of mucus.
Effects of Histamine-2 Stimulation
The major response to activation of H2 receptors is secretion of gastric acid. Histamine acts directly on parietal cells of the stomach to promote acid release. Although acetylcholine and gastrin also help regulate acid release, histamine has a dominant role. We know this because, in the presence of H2 blockade, acetylcholine and gastrin are unable to elicit acid secretion.
Role of Histamine in Allergic Responses
Allergic reactions are mediated by histamine and other compounds (e.g., prostaglandins, leukotrienes, tryptase). The intensity of an allergic reaction is determined by which mediator is involved. The symptoms of mild allergy (e.g., rhinitis, itching, localized edema) are caused largely by histamine acting at H1 receptors. As a result, mild allergic conditions (e.g., hay fever, acute urticaria, mild transfusion reactions) are generally responsive to antihistamine therapy.
The Two Types of Antihistamines: Histamine-1 Antagonists and Histamine-2 Antagonists
Antihistamines fall into two basic categories: H1 receptor antagonists and H2 receptor antagonists. The principal use of H1 blockers is treatment of mild allergic disorders. The principal use of H2 blockers is treatment of gastric and duodenal ulcers. Because H2 antagonists do not block H1 receptors, these drugs are of no use for treating allergies. In this chapter, we focus on H1 antagonists. The H2 blockers, which are widely used, are discussed in Chapter 62.
Histamine1 Antagonists
Basic Pharmacology
The H1 antagonists are the classic antihistamines. Because of its historical use, the term antihistamines is still employed as a synonym for the subgroup of histamine antagonists that produce selective H1 blockade. Here, we continue to use the term antihistamine interchangeably with H1 blocker and H1 antagonist.
Although all H1 antagonists available have similar antihistaminic actions, these drugs differ significantly in side effects. Because of these differences, selection of a prototype to represent the group is not feasible. Thus, rather than structuring discussion around one prototypic drug, we discuss the H1 antagonists collectively. Differences among individual antihistamines are addressed as appropriate.
Classification
The H1 antagonists fall into two major groups: first-generation H1 antagonists and second-generation H1 antagonists. The principal difference between the groups is that first-generation antihistamines are highly sedating, whereas second-generation antihistamines are not.
Mechanism of Action
H1 blockers bind selectively to H1-histaminic receptors, thereby blocking the actions of histamine at these sites. H1 antagonists do not block H2 receptors. Also, they do not block release of histamine from mast cells or basophils.
It should be noted that, although interaction of the classic antihistamines with histaminic receptors is limited to the H1 receptor subtype, these drugs can also bind to nonhistaminic receptors. Most notably, certain antihistamines can bind to and block muscarinic receptors. This action underlies several important side effects.
Pharmacologic Effects
Peripheral Effects
The major therapeutic effects of the H1 antagonists can be attributed to preventing the actions of histamine at H1 receptors. In arterioles and venules of the skin, H1 blockers inhibit the dilator actions of histamine and thereby reduce localized flushing. In capillary beds, the antihistamines prevent histamine-induced increases in permeability and thereby reduce edema. By blocking histamine at sensory nerves, H1 antagonists reduce itching and pain. Blockade of H1 receptors in mucous membranes suppresses secretion of mucus.
Effects on the CNS
Antihistamines can cause both excitation and depression of the CNS. At therapeutic doses, antihistamines produce CNS depression: reaction time is slowed, alertness is diminished, and drowsiness is likely. These effects are more pronounced with some antihistamines than with others. With most second-generation antihistamines (e.g., fexofenadine), CNS depression is negligible.
Overdose with antihistamines can produce CNS stimulation. Seizures frequently result. Very young children are especially sensitive to CNS stimulation by these drugs.
Other Pharmacologic Effects
Blockade of muscarinic cholinergic receptors by antihistamines can produce typical anticholinergic responses. These are discussed later under “Adverse Effects.” Several antihistamines can suppress nausea and vomiting, as discussed later under “Motion Sickness.”
PATIENT-CENTERED CARE ACROSS THE LIFE SPAN
Antihistamines
| Life Stage | Patient Care Concerns |
| Infants | Antihistamines can cause sedation in infants. Although they can be used in small doses in children older than 6 months, caution should be employed. |
| Children/adolescents | Antihistamines can be used safely in children, just in smaller doses. Side-effect profiles are similar to those of adults. Promethazine is contraindicated in children younger than 2 years because deaths have occurred in this population. |
| Pregnant women | There has been debate regarding whether antihistamines cause fetal harm when used in pregnancy. Many of these drugs are classified in U.S. Food and Drug Administration Pregnancy Risk Category C and should be avoided unless absolutely necessary. |
| Breastfeeding women | Occasional, small doses of antihistamines do not appear to cause sedation in infants. Caution should be used. |
| Older adults | Because antihistamines can cause sedation, smaller doses should be used initially and titrated up if needed. Also, these medications can make glaucoma or benign prostatic hyperplasia worse. |
Therapeutic Uses
All of the H1 antagonists are useful in treating allergic disorders. Some are also indicated for other conditions (e.g., motion sickness, insomnia).
Mild Allergy
Antihistamines can reduce symptoms of mild allergies. In people with seasonal allergic rhinitis, H1 blockers can reduce sneezing, rhinorrhea, and itching of the eyes, nose, and throat. In patients with acute urticaria, these drugs can reduce redness, itching, and edema. The antihistamines can also reduce symptoms of allergic conjunctivitis and urticaria associated with mild transfusion reactions. In all these conditions, benefits result from H1 receptor blockade—not from preventing allergen-induced release of histamine from mast cells and basophils. Because mild allergic reactions may be mediated by substances in addition to histamine, antihistamines often fail to produce complete relief.
Motion Sickness
Some antihistamines, such as promethazine [Phenergan] and dimenhydrinate [Dramamine], are labeled for use in motion sickness. Benefits derive from blocking H1 receptors and muscarinic receptors in the neuronal pathway leading from the vestibular apparatus of the inner ear to the vomiting center of the medulla. Motion sickness and its treatment are discussed in Chapter 64.
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