Histamine and Bradykinin Pharmacology

H1 receptors exist in an equilibrium between an inactive conformation and an active conformation. Histamine binds preferentially to the active conformation, stabilizing it and producing a signal. H1 antihistamines bind preferentially to the inactive conformation, stabilizing it and shifting the equilibrium away from active receptor — suppressing even the constitutive (baseline) receptor activity. This inverse agonist mechanism accounts for anti-inflammatory effects of H1 antihistamines beyond simple histamine blockade, and it is why they are more accurately termed inverse agonists than competitive antagonists, though the practical clinical consequence is the same: blockade of histamine-mediated responses.

First-generation H1 antihistamines are sufficiently lipophilic to cross the blood-brain barrier by passive diffusion. Once in the central nervous system they block H1 receptors on tuberomammillary nucleus neurons, disrupting the histaminergic arousal system and producing sedation ranging from mild drowsiness to pronounced somnolence. Additive central nervous system depression with alcohol, opioids, and benzodiazepines is a significant safety hazard.

Second-generation agents achieve central nervous system exclusion through two complementary mechanisms. First, they are less lipophilic than first-generation agents, reducing passive diffusion across the blood-brain barrier. Second, and more importantly, they are substrates for P-glycoprotein, an efflux transporter expressed at high density on the luminal surface of brain endothelial cells that actively pumps drug substrates back into the bloodstream. The net result is that second-generation antihistamines produce peripheral H1 blockade with negligible central nervous system activity and minimal sedation at therapeutic doses.

Duration of action also differs between generations. First-generation agents generally require dosing every four to six hours. Second-generation agents have longer durations of action suitable for once-daily dosing — an important practical advantage for chronic allergic conditions.

Diphenhydramine is the prototypical first-generation agent and the benchmark against which others are compared. It is the active ingredient in most over-the-counter sleep aids and allergy preparations. Promethazine is a phenothiazine-derived antihistamine with particularly pronounced antiemetic and sedative properties, widely used for motion sickness and postoperative nausea. Hydroxyzine has both antihistaminic and modest anxiolytic properties and is used for pruritus and preoperative anxiety. Chlorpheniramine has a relatively lower sedative and antimuscarinic burden than diphenhydramine and is a common component of combination cold preparations.

All first-generation agents cross the blood-brain barrier and block central nervous system H1 receptors, suppressing histaminergic arousal signals from the tuberomammillary nucleus. The resulting sedation, cognitive impairment, and psychomotor slowing are hazardous when patients need to drive or operate machinery. The sedation is additive with other central nervous system depressants — alcohol, opioids, benzodiazepines — and this combination can produce dangerous respiratory depression.

In young children, first-generation antihistamines can produce paradoxical excitation — restlessness, irritability, and hyperactivity rather than sedation — attributed to incomplete maturation of central nervous system inhibitory systems. Promethazine is contraindicated in children under two years of age due to risk of fatal respiratory depression.

First-generation antihistamines have significant affinity for muscarinic acetylcholine receptors in addition to H1 receptors. This off-target activity produces the classic anticholinergic adverse effect profile: dry mouth, urinary retention, constipation, blurred vision (cycloplegia), and tachycardia. In elderly patients, anticholinergic burden is a recognized contributor to cognitive impairment, confusion, falls, and urinary retention. First-generation antihistamines appear on the Beers Criteria list of drugs to avoid in older adults for this reason, and second-generation agents are the preferred alternative whenever antihistamine therapy is needed in this population.

Loratadine is a tricyclic piperidine antihistamine with negligible anticholinergic activity and very low sedation at standard doses. It undergoes extensive first-pass hepatic metabolism to its active metabolite desloratadine, which is also available as a standalone agent. Once-daily dosing is appropriate. Because elimination is hepatic rather than renal, loratadine does not require dose adjustment in renal impairment — a useful clinical distinction from cetirizine.

Cetirizine is the active metabolite of hydroxyzine (a first-generation agent) and is primarily eliminated unchanged by the kidney. This renal-dominant clearance makes cetirizine the second-generation agent most sensitive to renal impairment — dose reduction is required when renal function is significantly reduced. Among second-generation agents, cetirizine is slightly more sedating than loratadine or fexofenadine in clinical trials, attributed to modestly greater central nervous system penetration; it is nonetheless far less sedating than any first-generation agent. Levocetirizine is the pharmacologically active enantiomer of cetirizine and is available at half the standard cetirizine dose with a comparable clinical profile.

Fexofenadine is the active metabolite of terfenadine, a first-generation agent that was withdrawn from the market due to QT-prolonging cardiac arrhythmias when plasma concentrations rose. Fexofenadine lacks terfenadine's cardiac toxicity and is the least sedating of all second-generation antihistamines — its negligible central nervous system penetration results from both low lipophilicity and robust P-glycoprotein efflux. It undergoes minimal hepatic metabolism and is eliminated primarily unchanged in feces and urine, making it a reasonable choice in patients with hepatic impairment.

Fexofenadine is subject to a well-characterized food-drug interaction: grapefruit juice, orange juice, and apple juice reduce its oral absorption by inhibiting an intestinal uptake transporter. The practical instruction is to take fexofenadine with water rather than fruit juice. This is a tested pharmacokinetic interaction at the Step 1 level.

Second-generation antihistamines are the preferred oral agents for allergic rhinitis and chronic urticaria in ambulatory patients. They control sneezing, pruritus, watery rhinorrhea, and conjunctival symptoms without impairing daytime function. For persistent allergic rhinitis, intranasal corticosteroids provide superior control of nasal congestion — which is driven partly by prostaglandins and leukotrienes in addition to histamine — and are the first-line treatment in current guidelines. Second-generation oral antihistamines are an important adjunct, particularly for ocular symptoms and pruritus.

In chronic spontaneous urticaria, second-generation antihistamines are first-line. Standard doses are used initially; if control is insufficient, doses may be increased under physician guidance. First-generation agents are sometimes used at bedtime when sedation at night is acceptable, but second-generation agents remain the preferred daytime treatment.

Epinephrine is the first-line and life-saving treatment for anaphylaxis. Antihistamines — both H1 and H2 blockers — are useful adjuncts that reduce pruritus, urticaria, and flushing, but they do not reverse the bronchospasm, laryngeal edema, or cardiovascular collapse that makes anaphylaxis fatal. They are administered after epinephrine, never as substitutes for it. A Step 1 question asking for initial management of anaphylaxis has one correct answer: epinephrine.