ZENKOF PAEDIATRICK

Indications

• Allergic rhinitis
• Allergic conjunctivitis
• Urticaria (hives)
• Anaphylactic reactions (as adjunctive therapy)
• Motion sickness
• Insomnia
• Pre-medication for sedation in surgical procedures

Dosage

Adults: For allergic symptoms, the usual dose is 25 to 50 mg taken by mouth every 4 to 6 hours as needed, not exceeding 300 mg per

Mechanism of action

Diphenhydramine predominantly functions as an inverse agonist at H1 receptors, thereby reversing histamine's effects on capillaries and reducing allergic symptoms. It also acts as a competitive antagonist of muscarinic acetylcholine receptors, contributing to its antimuscarinic activity. Additionally, it blocks intracellular sodium channels, which may enhance its therapeutic profile, particularly in certain neurological conditions.

Pharmacodynamics

Diphenhydramine exhibits anti-histaminic, anti-emetic, anti-vertigo, and sedative properties. Its anti-histamine effects occur by blocking histamine's spasmogenic and congestive actions at H1 receptor sites, which prevents responses mediated by histamine. The drug's anti-emetic action is attributed to its inhibition of the medullary chemoreceptor trigger zone, while its anti-vertigo effects arise from its antimuscarinic impact on the vestibular apparatus and vomiting centers in the brain.

Pharmacokinetics

Diphenhydramine is well absorbed following oral administration, with peak plasma concentrations occurring within 1 to 4 hours. It is extensively metabolized in the liver, primarily by cytochrome P450 enzymes, and has a half-life of approximately 4 to 8 hours. The drug is eliminated mainly through urine as metabolites, with a small fraction excreted unchanged.

Contra-indications

• Hypersensitivity to diphenhydramine or any of its components
• Severe asthma or other respiratory conditions where suppression of respiratory function may be dangerous
• Narrow-angle glaucoma
• Prostate enlargement
• Urinary retention

Adverse effects

• Drowsiness
• Dizziness
• Dry mouth
• Constipation
• Blurred vision
• Urinary retention
• Confusion (especially in the elderly)
• Paradoxical excitation in children

Interactions

• Other central nervous system depressants (e.g., alcohol, benzodiazepines) may enhance sedative effects
• Anticholinergic drugs may potentiate antimuscarinic effects
• MAO inhibitors may prolong and intensify anticholinergic effects
• Caution with medications that affect the QT interval, as diphenhydramine may contribute to cardiac arrhythmias

Precautions

• Use with caution in the elderly due to increased sensitivity to adverse effects
• Caution in patients with cardiovascular disease, hyperthyroidism, or hypertension
• May impair the ability to drive or operate machinery
• Not recommended for use in neonates or premature infants

Pregnancy

Diphenhydramine should be used during pregnancy only if clearly needed, as safety in human pregnancy has not been established.

Breast-feeding

Diphenhydramine is excreted in breast milk; caution is advised when administering to nursing mothers.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Tablets
• Liquid formulation
• Injectable solution

Mechanism of action

Diphenhydramine predominantly works via the antagonism of H1 (Histamine 1) receptors. Such H1 receptors are located on respiratory smooth muscles, vascular endothelial cells, the gastrointestinal tract (GIT), cardiac tissue, immune cells, the uterus, and the central nervous system (CNS) neurons. When the H1 receptor is stimulated in these tissues it produces a variety of actions including increased vascular permeability, promotion of vasodilation causing flushing, decreased atrioventricular (AV) node conduction time, stimulation of sensory nerves of airways producing coughing, smooth muscle contraction of bronchi and the GIT, and eosinophilic chemotaxis that promotes the allergic immune response. Ultimately, diphenhydramine functions as an inverse agonist at H1 receptors, and subsequently reverses effects of histamine on capillaries, reducing allergic reaction symptoms. Moreover, since diphenhydramine is a first-generation antihistamine, it readily crosses the blood-brain barrier and inversely agonizes the H1 CNS receptors, resulting in drowsiness, and suppressing the medullary cough center. Furthermore, H1 receptors are similar to muscarinic receptors. Consequently, diphenhydramine also acts as an antimuscarinic. It does so by behaving as a competitive antagonist of muscarinic acetylcholine receptors, resulting in its use as an antiparkinson medication. Lastly, diphenhydramine has also demonstrated activity as an intracellular sodium channel blocker, resulting in possible local anesthetic properties. Antihistamines used in the treatment of allergy act by competing with histamine for H1-receptor sites on effector cells. They thereby prevent, but do not reverse, responses mediated by histamine alone. Antihistamines antagonize, in varying degrees, most of the pharmacological effects of histamine, including urticaria and pruritus. Also, the anticholinergic actions of most antihistamines provide a drying effect on the nasal mucosa. /Antihistamines/ H1 antagonists inhibit both the vasoconstrictor effects of histamine and, to a degree, the more rapid vasodilator effects mediated by activation of H1 receptors on endothelial cells (synthesis/release of NO and other mediators). /H1 Receptor Antagonists/ H1 antagonists suppress the action of histamine on nerve endings, including the flare component of the triple response and the itching caused by intradermal injection. /H1 Receptor Antagonists/ The first-generation antihistamines are widely prescribed medications that relieve allergic reactions and urticaria by blocking the peripheral histamine H(1) receptor. Overdose of these drugs often results in serious neuronal toxic effects, including seizures, convulsions and worsening of epileptic symptoms. The KCNQ/M K(+) channel plays a crucial role in controlling neuron excitability. Here, we demonstrate that mepyramine and diphenhydramine, two structurally related first-generation antihistamines, can act as potent KCNQ/M channel blockers. Extracellular application of these drugs quickly and reversibly reduced KCNQ2/Q3 currents heterologously expressed in HEK293 cells. The current inhibition was concentration and voltage dependent. The estimated IC(50) (12.5 and 48.1 microM, respectively) is within the range of drug concentrations detected in poisoned patients (30-300 microM). Both drugs shifted the I-V curve of KCNQ2/Q3 channel to more depolarized potentials and altered channel gating properties by prolonging activation and shortening deactivation kinetics. Mepyramine also inhibited the individual homomeric KCNQ1-4 and heteromeric KCNQ3/Q5 currents. Moreover, mepyramine inhibited KCNQ2/Q3 current in an outside-out patch excised from HEK293 cells and the inhibitory effect was neither observed when it was applied intracellularly nor affected by blocking phospholipase C (PLC) activity, indicating an extracellular and direct channel blocking mechanism. Finally, in cultured rat superior cervical ganglion (SCG) neurons, mepyramine reduced the

Pharmacodynamics

Diphenhydramine has anti-histaminic (H1-receptor), anti-emetic, anti-vertigo and sedative and hypnotic properties. The anti-histamine action occurs by blocking the spasmogenic and congestive effects of histamine by competing with histamine for H1 receptor sites on effector cells, preventing but not reversing responses mediated by histamine alone. Such receptor sites may be found in the gut, uterus, large blood vessels, bronchial muscles, and elsewhere. Anti-emetic action is by inhibition at the medullary chemoreceptor trigger zone. Anti-vertigo action is by a central antimuscarinic effect on the vestibular apparatus and the integrative vomiting center and medullary chemoreceptor trigger zone of the midbrain.