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Antihistamine was discovered more than a century ago by AnneMarie Staub and Daniel Bovet. Antihistaminic drugs were made by doing primarilymodifications in cholinergic antagonists and are formed from diverse chemicalentities such as piperazines, piperidines, ethanolamine’s, ethylene diamines,alkylamines, and phenothiazines.
These first-generation antihistamines have poor receptorselectivity and thus cause significant unwanted side effects. Histaminereleased from the mast cells during the inflammatory process including type Ihypersensitivity allergic reactions is antagonized by antihistamines. Although,antihistamines do not antagonize histamine binding on all types of histaminereceptors. Antihistamines are H1-receptor antagonists.
Antihistamines include some of the most commonly prescribeddrugs in the primary health care system for the symptomatic relief of allergicdiseases, the common cold, seasonal rhinitis, conjunctivitis, urticaria,dermatitis, and asthma and insomnia.
Classification of Antihistamines
First generation H1-antihistamine
Chlorpheniramine
Cyclizine
Diphenhydramine
Dimenhydrinate
Doxylamine
Hydroxyzine
Meclizine
Promethazine
Doxepine
Second-generation H1-antihistamines
Cetirizine
Acrivastine
Desloratadine
Fexofenadine
Loratadine
Pharmacokinetics
Absorption
H1 receptor blockers are well absorbed after oraladministration. Time to reach peak plasma level is 1 to 2 hours. The durationof onset of action of these drugs is often similar to the rate of its oralabsorption. Onset of action is 1 to 3 hours. Duration of action is at least 24hours after once daily dosing.
Distribution
These drugs have high bioavailability and are readilydistributed in body tissue as well asin CNS.
Metabolism
Cetirizine and levocetirizine are the drugs that are notmetabolized and are excreted primarily unchanged in the urine. Desloratadineundergoes extensive metabolism in the liver.
Most antihistamines act upon the substrate of CYP3A4,grapefruit juice increases the bioavailability of the drugs by inhibiting drugmetabolism in intestinal mucosa. Most of antihistamines undergo hepaticmetabolism by several cytochrome p450 (CYP) isoenzymes, with exceptions such ascetirizine, levocetirizine that undergo urinary excretion, and fexofenadinethat is excreted through feces.
Elimination
The average half-life is 4 to 6 hours expect for meclizinewhich is 12 to 24 hours.
Fexofenadine is also minimally metabolized and is excretedprimarily in the feces after its active secretion into the intestine under theinfluence of active drug–transporting molecules.
Pharmacodynamics
Therapeutic indications
Antiallergic conditions
The primary mechanism of action of antihistamines in thetreatment of allergic diseases is by binding to H1-receptors that are presenton nerve endings, smooth muscles, and glandular cells. So they are competitiveantagonists of histamine binding to cellular receptors.
Antiallergic conditions
Inflammatory condition
Majority of research on H1-antihistamines is focused on thehistamine dependent early symptoms of the allergic response. It is now clearlyevident that these drugs have anti-inflammatory effects.
Histamine activates NF-B, which is transcription factor thatis involved in the synthesis of a lot of pro-inflammatory cytokines andadhesion molecules involved in the initiation and maintenance of allergicinflammation process.
Motion sickness
Diphenhydramine, dimenhydrinate, cyclizine, meclizine andpromethazine are highly effective against prevention of the symptoms of motionsickness.
Somnifacients
Many first-generation antihistamines, such asdiphenhydramine and doxylamine are used as sedative agents.
Drug interactions
Antihistamines are not metabolized and are excretedunchanged that’s why no pharmacokinetic drug-drug interactions occur. Althoughthere are chances of pharmacodynamics drug-drug interaction but no significantinteractions have been reported.
Potentiation of effects of other CNS depressants, includingalcohol.
Patients taking MAOIs should not take antihistamines.
1st generation antihistamines with anticholinergic actionsmay decrease effectiveness of cholinesterase inhibitors.
Adverse drug reactions
H1 receptor blocker are usually non selective, they not onlybind to histamine receptor but also with other receptors. So, they have variousside effects.
When acting on H1 receptors Sedation
Decrease CNS neurotransmission
Decrease cognitive function
Increase apatite
When acting on muscarinic receptors
Sinusoidal tachycardia
Urinary retention
When acting on alpha adrenergic receptors
Hypotension
Dizziness
Reflex tachycardia
Serotonergic receptors
Increase apatite
When acting on cardiac channels
QT prolongation
Cardiac arrhythmias
Over dose
The safety margin of H1-receptor blockers is relativelyhigh, and chronic toxicity is rare. Acute poisoning is relatively common,especially in young children.
The side effects of acute poisoning are caused due to effect on the CNS, which includeshallucinations, excitement, ataxia, and convulsion that may leads to coma andcollapse of the cardiorespiratory system, if remain untreated.
