The Clinical Indications And Therapeutic Actions Of Antihistamines Biology Essay

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The word allergy was coined in 1906 by two Austrians; Clemens Von Pirquet and Bela Schick, from the Greek words allos and ergos which mean other and work respectively. This was used to describe anaphylactic reactions observed in patients who received diphtheria anti-toxin.

1907 the biological amine Histamine was isolated and in 1927 it was identified in human tissue. Histamine was labeled as the causative agent of these reactions.

This association led to a scientific search to counteract the effects of histamine. Antergan was the first antihistamine used successfully in man. Diphenhydramine a first generation antihistamine followed in 1945.

Fig. 1.1. Diphenhydramine

A recurring side-effect of these Antihistamines was sedation and it was only in 1980 that non-sedative antihistamines were introduced such as Loratadine a 2nd Generation antihistamine (FDA approved in 2001) and Levocetirizine a 3rd Generation antihistamine (Launched in 2001 as Xyzal®)

Fig.1.3. Desloratadine

Fig. 1.2. Loratadine

The clinical indications and therapeutic actions

Diphenhydramine, Loratadine and Desloratadine belong to the pharmacological class of H1-receptor antagonists (Antihistamines). Their aim is to antagonise the H1-Histamine receptors, thus keeping the effect of Histamine on the body under control.


Diphenhydramine is a 1st generation antihistamine. It is indicated in the symptomatic relief of nasal and non-nasal symptoms of Seasonal Allergic Rhinitis (SAR) (Hay fever) such as sneezing and rhinorrhea, and in the symptomatic relief of common cold (Runny nose and Sneezing) above the age of 6 months.

It can be used as an alternative to adrenaline injections in anaphylaxis caused by bee stings and peanut allergy and in the treatment of extra pyramidal side effects caused by 1st generation antipsychotics and as an addition to OTC sleep aids due to its sedating properties.

The injectable form is used in the prevention of motion sickness and where oral Anti-parkinsonism therapy is contraindicated.

Diphenhydramine is available as Benadryl® Allergy capsules (25mg) and Benadryl® injection (0.1mg/ml for IV/IM administration)


Loratadine on the other hand is a 2nd generation antihistamine; this means that unlike Diphenhydramine it has non sedating properties.

It is indicated in the symptomatic relief of nasal and non-nasal symptoms of SAR and in the treatment of Chronic Urticaria of unknown cause (CIU) (Idiopathic) (Hives/nettle rash) in patients above the age of 2 years.

Unlike Diphenhydramine, Loratadine is not to be used as a substitute for prescribed adrenaline injections, as Loratadine is merely a symptomatic relieving agent and not a preventive/curative one.

The use of Montelukast (A leukotriene receptor antagonist) and Loratadine simultaneously was shown to enhance the symptomatic relief of seasonal allergic rhinitis more than when one of the drugs is used on its own.

Fig.2.1. Montelukast

Loratadine is available as a non propriety formulation in tablet form (10mg) and syrup form (5mg/ml).


Desloratadine is a 3rd generation antihistamine and thus is a metabolite of a 2nd generation antihistamine, in this case Loratadine. Being its metabolite it has a higher efficacy whilst having a reduction in its side-effects profile.

Desloratadine is indicated in the symptomatic relief of nasal and non-nasal symptoms of SAR in patients above the age of 2 years, and in the treatment of CIU and Perennial Allergic Rhinitis (PAR) in patients 6 months or older.

Desloratadine is available as Neoclarityn® and Clarinex® oral solution

(0.5 mg/mL) and as tablets (5 mg/tablet)

Loratadine and Desloratadine have the advantage over Diphenhydramine of being non-sedating hence can be used in patients who need to operate machinery or drive. This is due to the former drugs not acting on the Central Nervous System (CNS). Diphenhydramine however has been used for its sedative property to help in sleeping.

Desloratadine is the major active metabolite of Loratadine, it has been reported that the anti-histaminic effect of Loratadine is due to the presence of this metabolite, thus one can note the advantage of using one Desloratadine over Loratadine.

Mode of Action at the molecular level

The mode of action of 1st generation antihistamines action is believed to be competitive blocking (Antagonism) of the H­1-histamine receptors present on smooth muscle tissue and nerve endings.

This antagonism prevents histamine from exerting its effect on the receptors also leading to an increase in the contraction of vascular smooth muscles which decreases edema in inflammation.

Sedative effects have been demonstrated to occur with this class of anti-histamines and anti-muscarinic activity has been noticed. Serotonin reuptake inhibition also occurs this may aid in the symptomatic relief of allergic rhinitis. This low level of selectivity is the main cause of Diphenhydramine's (and other 1st generation antihistamines) side-effects.

Second and Third generation antihistamines on the contrary present with a higher selectivity towards the peripheral H1-receptors hence side-effects are less common. Both Loratadine and Desloratadine lead to the inhibition of Granulocyte macrophage colony-stimulating factor (GM-CSF) and Interleukin 8 (IL-8) released by macrophages and endothelial cells, apart from the H1-receptor antagonism mentioned for the 1st generation antihistamines.

Their antiallergic property is due to the reduction in the synthesis and release of arachidonic acid metabolites and down-regulating Intercellular adhesion molecule (ICAM_1) expression on epithelial cells during inflammation.

Pharmacokinetic Parameters

Diphenhydramine shows good absorption from the GI tract after oral administration.

The oral availability is 61% and 78% is plasma-bound and due to its relatively high 1st pass effect only about 40% to 60% bioavailability. Peak plasma concentrations are reached in 2 to 3 hours having plasma ½ life of 6.7 hours.

Its active metabolite (metabolized via cytochrome P450 2D6 isoenzyme); nor-Diphenhydramine and non-active metabolites di-nordiphenhydramine and diphenylmethoxyacetic acid are excreted in urine with 1.9% of unchanged Diphenhydramine. (Metabolism pathway is shown below)

Fig.4.1. Metabolism of Diphenhydramine

Loratadine also shows a good absorption rate from the GI tract after oral administration.

Bioavailability of Loratadine is about 40%. Peak plasma concentrations of 24.3µg/L to 30.5µg/L are reached in 1 to 1.5 hours having average plasma ½ life of 9 hours meaning it exerts a longer effect than Diphenhydramine.

Its active metabolite (which is 70% of the total metabolites) (metabolized via CYP3A4, CYP2D6); descarboethoxy-loratadine (Desloratadine) is inactivated through conjugation and excreted in urine with minimal amounts of unchanged Loratadine.

Fig.4.2. descarboethoxy-loratadine or DESLORATADINE

Desloratadine unlike its parent molecule Loratadine and Diphenhydramine does not need to be metabolised to increase its pharmacological activity.

Bioavailability of Desloratadine is much higher about 70%. Peak plasma concentrations are reached in 3 hours with very long plasma ½ life of around 27 hours indicating a longer lasting effect then Loratadine and Diphenhydramine.

Desloratadine is metabolized to 3-hydroxydesloratadine, however the enzyme responsible for this has not yet been identified, which is then glucoronidated to 3-Hydroxy Desloratadine glucuronide.

Fig.4.3. 3-hydroxydesloratadine

Side-Effect profiles

Diphenhydramine side effects include anti-muscarinic SE and CNS depression such as dry mouth, confusion, dizziness, drowsiness, blurring of vision for near objects, sedation and fatigue, with drowsiness and sedation being the most common. Dilation of the pupils (Mydriasis) was also observed.

The patient can develop Photosensitivity with the use of such 1st generation antihistamine.

Rarely, patients being treated with diphenhydramine may develop dermatitis.

One must note however that Gastro-Intestinal disturbances were less common with the use of diphenhydramine compared to the other H1 antagonists.

A case of a 34-year old woman who developed dependence and thus experienced withdrawal symptoms with urinary incontinence and increased blood pressure (Hypertension) from has been reported.

A severe interaction with metronidazole presenting with; an acute vesicular and erythematosus eruption around the mouth has been reported. Such interaction is highly unlikely as their chemical structures are different.

Loratadine being a 2nd generation anti-histamine presents with diminished effects on the cholinergic system, leading to lower sedative effects when compared to diphenhydramine however drowsiness has been reported to occur. Blurring of vision and dryness of mouth are common side-effects however.

Unlike diphenhydramine, Loratadine presents the patient with a higher chance of encountering Gastro-Intestinal disturbances, these include:

Gastric discomfort

Loss of appetite

Bitter taste

Two separate cases (Two women one 42 years and another 49 years of age) of hepatitis after Loratadine administration both being treated for multiple environmental allergies have been reported.

Desloratadine being a 3rd generation antihistamine is expected to have fewer incidences of side-effects than its 1st and 2nd generation predecessors.

The occurrence of dry mouth, fatigue and sedation is lower than those of diphenhydramine and Loratadine; however an increase in the incidence of headaches was noted when compared to Loratadine.



Children above 6 months:

5 mg/kg/24 hr with a maximum dose of 300 mg.

This is divided into four doses, administered intravenously at 25mg/min or intramuscularly.


10  50 mg (up to 100 mg if required) with a maximum dose of 400mg

Administered intravenously at 25 mg/min or deep intramuscularly



Adults and children above 6 years:

10 mg once daily

Children 2  5 years:

5 mg once daily

Adults and children above 6 years [with liver failure or renal insufficiency]:

10 mg every other day

Children 2  5 years [with liver failure or renal insufficiency]:

5 mg every other day



Adults and children above 12 months:

5 mg once daily

Children 2  5 years:

2.5 mg once daily

Children 12  48 months:

1.25 mg once daily

Children 6  11 months:

1 mg once daily


"In nothing do men more nearly approach the gods than in giving health to men."

~ Cicero