. Therapeutically useful antihistamine drugs are H
-antihistamines. At present there are no clinically useful H
-antihistamines were the first type of antihistaminic drugs discovered and are sometimes referred to as the classical antihistaminics. See Table 3-1
for examples of drugs in this class.
a. Mechanism of action. Traditionally, it was thought that H1-antihistamines act as competitive antagonists of histamine receptors. However, recently it has been demonstrated that most, if not all, of H1-antihistamines act as inverse agonists rather than the receptor antagonists. (See Chapter 1 for detailed information on inverse agonists.)
b. Classification of H1
. Histamine can be broadly classified into two groups based on usage: (1) first-generation H1
-antihistamines and (2) second generation H1
Most frequently used first-generation H1-antihistamines are diphenhydramine, dimenhydrinate, hydroxyzyline, chlorpheniramine, meclizine, promethazine, and cyproheptadine. These drugs are unionized drugs at physiological pH and easily cross the blood–brain barrier (BBB). Therefore, they produce CNS side effects, in particular, sedation.
Commonly used second-generation drugs are loratadine (Claritin®), cetirizine (Zyrtec®), and fexofenadine (Allegra®). This class of drugs is ionized at physiological pH and is difficult to cross BBB. See Table 3-2 for chemical classification of H1-antihistamines (Table 3-2).
effects of H1
(1) Relaxation of contracted bronchiolar smooth muscle.
(2) Relaxation of contracted intestinal smooth muscle.
(3) Inhibition of histamine-induced vasodilation and increased capillary permeability and thereby blocking formation of edema and wheals.
of itch sensation by prevention of stimulation of sensory nerves. Many H1
-antihistamines have a potent local anesthetic action
that may contribute to their inhibition of itching and pain.
Note: H1-antihistamines alone are not effective for treatment of systemic anaphylaxis because large amount of other autacoids are released during anaphylaxis.
Other pharmacologic effects of H1
-antihistamines (Table 3-2
(1) Sedation is a common effect of first-generation H1 -antihistamines but sedation does not correlate with their potency for inhibiting H1-receptors. Sedation may be a desirable/undesirable effect and can be expected to be additive to other CNS depressants.
(2) Antimuscarinic effects are prominent for some H1-antihistamines, for example, diphenhydramine and promethazine, which decrease secretions and relax smooth muscles.
(3) Antimotion sickness (antiemetic) effects. This effect is due to the inhibition of histaminergic signals from the vestibular nucleus to the vomiting center in the medulla. All H1-antihistamine have this effect, but some of them (diphenhydramine, dimenhydrinate, and meclizine) have more potent antimotion sickness effect than others in the group.
e. Therapeutic uses.
-antihistamines are administered orally, parenterally, or topically for the following conditions.
Treatment of patients with allergic conditions and to reduce or ameliorate the effects due to histamine. Conditions benefited from
(a) Urticaria and pruritus
(b) Allergic reactions to drugs
(2) Prevention of motion sickness. Diphenhydramine, dimenhydrinate, and meclizine are more effective in preventing motion sickness than other H1-antihistamines.
(3) Sedation induction. Promethazine and diphenhydramine are the most potent for inducing sedation.
(1) The pharmacokinetics of vast majority of H1-antihistamines have not been studied in domestic animals. Most information is derived from humans.
(2) All H1-antihistamines are effectively absorbed following oral administration and Tmax = 1–3 hours.
(3) All H1-anithistamines that have been studied for pharmacokinetics are well distributed and are bound by plasma proteins (≥60%).
(4) All H1-antihistamines are metabolized by cytochrome P450 enzymes, and these metabolites further undergo conjugation.
(5) The first-generation antihistamines are excreted primarily by the kidneys as metabolites.
(6) The second-generation antihistamines that cause least or no sedation are excreted more into feces when compared with the first-generation drugs: cetirizine (70% in urine, 30% in feces); loratadine (40% in urine, 40% in feces as metabolites); fexofenadine (11% in urine, 80% in feces).
(7) Elimination t½ :
See Table 3-2
for information in humans. The t½
information for animals is mostly not available.
g. Adverse effects
(see also Table 3-2
(1) CNS depression (lethargy, somnolence, ataxia) are the most common but they may diminish with time. The performance of working dogs may be adversely affected.
(2) Antimuscarinic effects (dry mouth, urinary retention) occur with many H1-antihistaqmines. They should be used with caution in patients with angle closure glaucoma.
(3) In high doses CNS stimulation is possible, for example, pyrilamine in the horse.
(4) Some individuals could develop allergy to the use of H1-antihsitamines.
(5) Drug tolerance. The decrease in efficacy and sedation (also called subsensitivity) can develop during the use of H1-antihistamines for days or weeks. The mechanisms underlying this phenomenon are not understood.
. These drugs are inhibitors of gastric acid secretion. They have little action on H1
-antihistamines contain imidazole ring with uncharged side chains and are smaller than H1
-antihistamines. See Figure 3-2
for an example of drugs in this class.
b. Pharmacologic effects. H2-antihistamines competitively inhibits histamine (H2-receptors) in parietal cell and thereby decreases gastric acid production during basal conditions and when stimulated by food, vagal activity, pentagastrin, gastrin, or histamine. H2-antihistamines have been reported to act as inverse agonists, but further validation of this observation is needed.
c. Therapeutic uses. H2-antihistamines are administered orally to treat gastric, abomasal and duodenal ulcers, drug-induced erosive gastritis, duodenal gastric reflux, and esophageal reflux. Cimetidine is least potent among the four H2-antihistamines. Lack of therapeutic effect of cimetidine has been reported in dogs.
(1) All four drugs are well absorbed when administered orally. T max is 2–3 hours for all four drugs. The bioavailability for cimetidine, ranitidine, nizatidine, and famotidine is 95%, 81%, >70%, and 40–50%, respectively.
(2) All four drugs are well distributed in the body, with 10–20% bound by plasma proteins.
(3) Cimetidine, ranitidine, and famotidine are metabolized by cytochrome P450 enzymes. Only < 10% of nizatidine is metabolized by CYP450 enzymes.
(4) All four drugs are excreted by the kidneys as the primary route. The majority of cimetidine, ranitidine, and famotidine is excreted as metabolites and 30– 50% is excreted as the unchanged drug. A total of ≥60% of nizatidine is excreted as the unchanged drug.
(5) Plasma t½ of cimetidine, ranitidine, and famotidine are 2–3 hours for all three drugs. The t½ for cimetidine and ranitidine in dogs are 1.3 hours and 2.2 hours, respectively. Plasma t½ of nizatidine is 1–2 hours in humans; no information is available for animals.
e. Adverse effects
are uncommon when recommended dosages are used. Cimetidine possesses weak antiandrogenic activity and can cause gynecomastia and decreased libido in humans. The antiandrogenic effect is, in part, due to decreased testosterone synthesis.
Ranitidine, famotidine, and nizatidine seem to be very well tolerated. Rarely, agranocytosis has been seen with the use of ranitidine and famotidine.
f. Drug interactions. Cimetidine can inhibit the hepatic cytochrome P450 enzymes. It may reduce the metabolism of other drugs, which undergo hepatic metabolism, thereby elevating and prolonging their concentration in the plasma.
3. Inhibitors of histamine release
. The one drug in this category, cromolyn sodium, differs in mechanism of action from the H1
– and H2
-antihistamines discussed above.
a. Cromolyn sodium
inhibits the release of histamine and other autacoids from mast cells. It does not
– and H2
-receptors, but opens chloride channel to hyperpolarize the cells.
(1) It is primarily used to treat pulmonary and nasal allergic reactions.
(2) It is not well absorbed from the gut and has no clinical use when given orally.
(3) It is used in a prophylactic manner.
(4) It has been used in the horse where it is nebulized and delivered via a face mask.
(5) The 4% eye drop is used to control allergic conjunctivitis.
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