Antihistamines (Second-half)

The second generation H1 blockers are also classified as to whether they can
cause a weak sedation or they are totally nonsedative. Example of the second
generation H1 blockers which have a weak potential for producing sedation are
Acrivastine and the Cetirizine. For the second generation H1 blockers which are
nonsedating, examples of these are Desloratadine, Fexofenadine and Loratadine.

Antihistamines - Classification
Generation I
Most sedative, most potent
Moderate sedative, moderate potent
Less sedative, less potent
Generation II
Mainly anti-allergic
Antivertigo, antimigraine
Examples
Diphenhydramine, Dimenhydrinate,
Hydroxyzine, Promethazine
Pheniramine, Meclizine, Buclizine,
Cyproheptadine, Cetrizine
Chlorpheniramine, Mebhydroline,
Dimethindone, Clemastine
Examples
Levocetrizine, Loratadine, Desloratadine,
Fexofenadine
Flunnarizine, Cinnarizine

The sedative effect of the first generation H1 blockers can be classified according
to their potency.

Therapeutic Uses of H1 Antihistamines

- In allergic and anaphylactic reactions (along with EPI). It is used for the treatment
of patients with allergic conditions and to reduce or ameliorate the effects due to
histamine. The conditions benefited from H1 antihistamines include urticaria and
pruritus, allergic reactions to drugs and anaphylaxis.
- Relief of bronchial asthma, laminitis, azoturia and pulmonary emphysema in
horses. Azoturia is a condition of horses that causes stiffness and pain in the
muscles of the hindquarters and back and the production of dark colored urine
containing myoglobin.
- In bloat, acetonemia, gangrenous mastitis, metritis, and retained placenta
- Dermatitis, pruritus and eczema
- Prevention of motion sickness. Diphenhydramine, Dimenhydrinate and Meclizine
are considered to be more effective in preveting motion sickness that other H1
antihistamines. It has also been used for the induction of sedation. Promethazine
and Diphenhydramine are considered to be more potent in inducing sedation.

Pharmacokinetics of H1 Antihistamines
 - The pharmacokinetics of wide variety of H1-antihistamines has not been studied
in domestic animals. Most information is derived from humans.
- All H1-antihistamines are effectively absorbed following oral administration and
Tmax (time to plasma concentration) = 1-3 hours.
- All H1-antihistamines that have been studied for PK are well distributed and
bound by plasma proteins (≥60%).
- The first generation antihistamines are excreted primarily by the kidneys as
metabolites.
- The second generation antihistamines are excreted more into feces.

Adverse Effects of H1 Antihistamines

- CNS depression (lethargy, somnolence, ataxia)

- Anti-muscarinic effects (dry mouth, urinary retention)
- In high doses, CNS stimulation.
- Allergy
- Drug tolerance

H1 vs. H2 Antihistamines

Differences between first and second generation H1 antihistamines

First-generation H1 Antihistamines Second-generation H1 Antihistamines

Usually administered in three to four daily
doses
Cross the blood-brain barrier (lipophilicity,
low molecular weight, lack of recognition by
the P-glycoprotein efflux pump)
Potentially cause side-effects
(sedation/hyperactivity/insomnia/convulsion
s , in the absence of drug interactions
Case reports of toxicity are regularly
published
No randomized, double-bind, placebo-
controlled trials in children
Lethal dose identified for infants/young
children
Usually administered once or twice a day
Do not cross the blood-brain barrier
(lipophobicity, high molecular weight,
recognition by the P-glycoprotein efflux
pump)
Do not cause relevant side-effects
(sedation/fatigue/hyperactivity/convulsion)
No reports of seri0ous toxicity
Some randomized, double-bind, placebo-
controlled studies in children
Do not cause fatality in overdose

Chemical Structure of H2-antihistamines

H2-antihistamines contain imidazole ring with uncharged side chains and are
smaller than H1-antihistamines.
 Examples: Cimetidine, Ranitidine, Nizatidine, Famotidine

*Cimetidine is considered to be the least potent among the four H2-

antihistamines. The lack of therapeutic effect of Cimetidine has been reported in
dogs.

Pharmacologic Effects of H2-antihistamines

- H2-antihistamines competitively inhibit histamines (H2-receptors) in parietal cell

and thereby decrease gastric acid production during basal conditions and when
stimulated by food vagal activity, pentagastrin, gastrin or histamine. The H2-
antihistamines have been reported to act as inverse agonist but further validation
of this observation is needed.

Therapeutic Uses of H2-antihistamines

- H2-antihistamines are administered orally to treat gastric, abomasal and

duodenal ulcers
- Drug-induced erosive gastritis
- Duodenal gastric reflux
- Esophageal reflux

Pharmacokinetics (PK) of H2-antihistamines

- Well absorbed when administered orally. T-max is 2-3 hours for all four drugs.
- All four drugs are well distributed in the body, with 10-20% bound by plasma
proteins.
- All four drugs are excreted by the kidneys as the primary route.

Adverse Effects of H2-antihistamines

Adverse effects are considered to be uncommon when recommended dosages

are used. Cimetidine possesses weak anti-atherogenic activity and can cause
gynecomastia and decreased libido in humans.

Inhibitors of Histamine Release

Cromolyn Sodium

- It differs in mechanism of action from the H1 and H2-antihistamines

- It inhibits the release of histamine and other autacoids from mast cells.
- It does not inhibit H1 and H2-receptors, but open chloride channel to
hyperpolarize the cells.
PK & Therapeutic Uses of Cromolyn Sodium

- Primarily used to treat pulmonary and nasal allergic reactions.

- It is not well absorbed from the gut and has no clinical use when given orally.
- It is used in prophylactic manner.
- It has been used in the horse where it is nebulized and delivered via a face
mask.
- The 4% eye drop is used to control allergic conjunctivitis.

Physiologic Antagonist to Histamine

- Epinephrine, phenylephrine, phenylpropanolamine and ephedrine antagonize the

actions of histamine by antagonizing histamine’s physiological function.
- These drugs either directly or indirectly activate alpha- and beta- adrenoceptors
to elevate blood pressure and relax the bronchi. This counters the blood pressure
lowering and bronchoconstrictive actions of histamine. Epinephrine is considered
to be the preferred drug to treat the immediate effects of anaphylaxis.