Antihistamines Drugs


Intended Learning Outcomes

At the end of the lecture, students will be able to

• Pharmacology, Chemistry, Biosynthesis of Histamine

• Categorize the antihistamines according to their chemical structure

• Outline the synthesis of some antihistamines

• Differentiate between 1st generation and 2nd generation H1 receptor antagonist

• Recognize the specific uses of the different antihistamines


Histamine –Pharmacology

• Histamine is an Autacoid, which are biological chemicals which act like local hormones, have a brief duration, and act near their site of synthesis.

• Histamines has various function in body such as:

– Mediator of inflamation and local immune responses

– regulating physiological function in the gut and

– acting as a neurotransmitter.

• During inflammation Histamine is produced by basophils and by mast cells, found in nearby connective tissues, which increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues

• In the gut it is produced by parietal cells and then promotes gastric acid secretion and thus aids in digestion. Here it acts like a local hormone

• As a neurotranmitter, it effects sleeping and waking, food intake, thermal regulation, emotions and aggressive behavior, locomotion, memory, and learning

Histamine – Chemistry

• Histamine is a Nitrogenous base. It is composed of an imidazole ring and ethylamine side chain. In Plasma pH of 7.4 is exists in exclusively monocationic form (96.6%). At lower pH higher levels of dication form exist.

• In solution form, 80% contain H in Nτ tautamer and 20% in Nπ tautamer

• But crystal form consist primarily of Nτ form

Histamine Biosynthesis

Note- There some drugs that can block Histidine Decarboxylase such as Floromethylhistine which in theory can act as direct acting antihistamine but clinically were found to be not useful.

Storage and release of Histamine

• Stored in mast cells in Complex with Heparin (anticoagulant)

• Stored in basophiles in Complex with Chondrotin

• Histamine as stored in mast cells are found almost everywhere: skin and the mucosal cells of the bronchi, intestine, urinary tract, and tissues adjacent to the circulation and within neurons of CNS

• It is released in response to a wide variety of immune (antigen and antibody) and nonimmune (bacterial products, xenobiotics, physical effects, and cholinergic effects) stimuli

Histamine receptors Location and function

H1, H2, H3, H4; they all are GPCR’s

• H1 Location: CNS neurons, the smooth muscle of respiratory, GIT, uterine tissues, epithelial and endothelial cells, immune cells

Function: vasodilation, vascular permeability, hypotension, flushing, pain, headache, tachycardia, nasal congestion, bronco-constriction, stimulation of cough receptors, allergic immune response

Therapeutic usage: H1 antihistamine are antiallergic, and anti-emetic drugs,

• H1 receptor is 40% similar to muscarinic receptors (thus some H1 antagonist shows unwanted antimuscaric side effect)

• H1 receptors belong to the superfamily of G protein coupled receptors (GPCRs), and are encoded for by chromosome 3

• These receptors exhibit spontaneous activation of their intracellular messengers, requiring no binding by an agonist at surface level

• It exists as a balance between activated (characterized by the production of intracellular second messengers) and inactive (no such intracellular signaling) state.

• If the ligand stabilizes the active receptor conformation, making it the predominant form, then the drug is referred to as an agonist, while if the inactive conformation is stabilized the drug is said to be a inverse agonist. In this way, histamine is an agonist, while the antihistamines are presently considered to be inverse agonists instead of antagonists as previously believed

• H2 function - gastric acid secretion, vascular permeability, hypotension, flushing, headache, tachycardia, broncho-dilation and respiratory mucus production

• Therapeutic use – H2 antihistamines are Anti-ulcer drugs

• H3 Location: CNS

• Function: adrenaline release and autoreceptor of Histamine in CNS

• Therapeutic use – potential application against obesity

• H4 function: differentiation of hematopoietic cells

• Therapeutic use – none yet


• It is a process by which a less specialized cell becomes a more specialized cell type

• When cells divide into daughter cells, they are the same exact cells. This is cell division/growth

• But differentiation means when cells “divide”, different cell types are formed.

• At conception we all were just a single cell but differentiation causes us to have diverse specialized cells that make up different organs

Undifferentiated cell, called stem cells differentiates into diverse functioning cells

Actions of Histamine by receptors

Adverse effects of Histamine

• Drowsiness

• Hypertension

• Urinary Retention

• Vertigo

• Tachycardia

• Dry Mouth

• Increased Appetite

Fig: Effects of H1 antihistamines at histamine, adrenergic, cholinergic, and serotonin-binding receptors. Many second generation antihistamines do not enter the brain and, therefore, show minimal CNS effects.

H1 antihistamines

• Their main application is as anti-allergic, anti-emetic and

• The first generation of H1 antihistamines has sedative effect due to effect on H1 receptor in brain.

• Structurally this effect is linked to their high lipophilicity induced BBB penetration and also they are poor substrate for brain’s endothelial Pglycoprotein efflux pumps, thus can’t exist the brain once they enter.

• They also antagonize cholinergic receptors which causes dry mouth, dizziness, fatigue and are alpha adrenergic blockers which can cause cardiotoxicity by prolonging the QT interval

• The second generation are more selective for H and don’t penetrate brain and thus has no sedation or cardiotoxicity

• MOA: They bind and stabilize the inactive form of H1 receptors onto which Histamine is not capable of binding.

Therapeutic Uses: H1 blockers

1. Dermatosis

2. Allergic rhinitis

3. Motion sickness & emesis

4. Parkinson’s disease

5. EPS

6. Insomnia

ECG of heart and prolonged QT interval

• The QT interval denotes time period taken by heart to empty it’s blood.

• Prolonged QT interval Suggests problem in cardiac muscle’s repolarization mechanism after each contraction.

• It is a dangerous side effect that can cause ‘Ventricular Fibrillation' which will lead to sudden death unless a   defibrillator is used to reset heart’s  normal rhythm

Classification of antihistamines

First Generation Antihistamines

1) Propylamines - Chlorpheniramine, Phenindamine

2) Ethanolamines - Diphenhydramine, Clemastine

3) Ethylenediamines - Pyrilamine, Tripelennamine

4) Phenothiazines - Promethazine, Trimeprazine

5) Piperazines - Cyclizine, Meclizine

6) Heptanes – Azatadine, Cyproheptadine

7) Phthalazinone – Azelastine

Second Generation (Peripherally Selective) Antihistamines 

1) Piperazine- Cetirizine/Levocetirizine

2) Piperidines - Fexofenadine, Loratadine /Desloratadine

Note: Antihistamines have a lot of structural diversity

Structures of antihistamines

SAR of H1 antihistamines (1st gen only)

General framework of AntiHistamine (Ethanolamine based)

General framework of Anticholinergics

Note the similarity in H1 antihistamines and Anticholinergics (this explains the origin of Anticholinergic side effect of H1 antihistamines)

1. It needs a tertiary amine which is mostly di-methyl substituted or part of cyclic ring

2. The methylene (-CH2-) groups can be about 2 or 3

3. The oxygen can be removed or replaced with C

4. The terminal carbon must have two aromatic groups and R group is mostly H but can be CH3 too

5)  Alkyl Substitution in these aromatic rings influence selectivity

• Increasing alkyl substituions at C4 increases anticholinergic activity and decreases antihistaminic activity

• Increasing alkyl substituions at C2 decreases anticholinergic activity and modestly increases antihistaminic activity

6) Presence of halogen at C4 position enhances potency

7) Replacement of one of the aromatic rings with

2-pyridyl group increases histaminic selectivity

8) For max potency, the terminal carbon must have R configuration. R/S configuration at amine is less important

Effect of increasing Alkyl group at C2 or C4

Alkyl position



At C2



At C4



Importance of stereomeric consideration

Configuration (C,N)

ED50 mg/kg









Clemastine has two chiral centres, terminal carbon and amine ED50 reflect potency. Entry 1st and 3rd are most potent. Both contain R configuration at terminal carbon. Conversely Entry 2nd and 4th with S configuration at terminal carbon are the least potent


• It is a propylamine based 1st generation H1 antihistaminic

• It is chlorinated pheniramine which improves potency 10 times and changing toxicity

• It’s Dextro isomer has S configuration and called DexChlorpheniramine is more potent

• It also acts as serotonin-norepinephrine reuptake inhibitor or SNRI

• It is combined with opiods for cough medicine because it can potentiate action of opiods

• It causes drowsiness by penetrating into brain and acting on H1 receptor

• Uses

– Allergic rhinitis, in cough medicines


• It is an ethanolamine based 1st generation H1 antihistaminic

• This class has a longer duration of action (10-12 hrs)

• It causes drowsiness by penetrating into brain and acting on H1 receptor

• Uses

– Allergic rhinitis, urticaria (itchy skin rash), anti-emetic


• It is an ethylenediamine based 1st generation H1 antihistaminic

• They are among the weakest antihistamines

• It is combined with opiods for cough medicine because it can potentiate action of opiods

• It causes drowsiness by penetrating into brain and acting on H1 receptor

• Uses

– Allergic rhinitis, incest bites (topically)


• It is a phenothiazine based 1st generation H1 antihistaminic

• It’s sedative action is strong to be used clincally

• It causes drowsiness by penetrating into brain and acting on H1 receptor

• Uses

– Allergic rhinitis, motion sickness, anti-emetic, sedative


• It is a Piperazine based 1st generation H1 antihistaminic

• It has weak antihistaminic activity

• It causes drowsiness by penetrating into brainand acting on H1 receptor

• Uses

– Anti-emetic and motion sickness


• It is a Heptane based 1st generation H1 antihistaminic

• It possesses both antihistamine and antiserotonin activity and is used as an anti-itch agent

• It causes drowsiness by penetrating into brain and acting on H1 receptor

• Uses

– Allergic rhinitis, allergic conjunctivitis, allergic skin urticaria, hypersensitivity reactions


• Uses

• Antipruritic

– it prevents itching caused by eczema or poison ivy

• It also acts as a sedative,hypnotic

• Antiemetic for prevention of motion sickness

Tripelennamine Hydrochloride

• First ethylene diamine developed

• Absorbed when given orally

• 2-[benzyl[2-dimethylamino)-ethyl]amino] pyridine

• Allergic rhinitis

• Allergic conjuctivitis

2nd generation H1 antihistamines

• They don’t act on H1 receptor in brain because their lower lipophilicity doesn’t allow them to penetrate the BBB

• They have low lipophilicity due to addition of hydrophilic groups OH, and COOH in the 1st gen molecules. (Other hydrophilic groups can be NH2,NO2,SO4,PO4)

• They have low affinity for off-targets such as muscarinic, adrenergic, and serotonergic receptors

• Advantage – negligible sedation, no cardiotoxicity

• Limitation – high selectivity for H1 prevents their use as anti-emetic, during motion sickness, potentiate cough medicines


• It is a piperadine based 2nd gen H1 antihistaminic

• It produces no clinically significant Anticholinergic or α1-adrenergic blocking or sedative effect at therapeutic doses and is safe even in higher doses

• It needs only single dosing daily

• Uses

– Allergic rhinitis, chronic urticarial


• It is a Piperazine based 2nd gen H1 antihistaminic

• It produces no clinically significant Anticholinergic or α1-adrenergic blocking or sedative effect at therapeutic doses

• It needs only single dosing daily

• It’s R-enantiomer, called Levocetrizine, has 30 fold higher affinity than the S-enantiomer

• Uses

– Allergic rhinitis, relief from urticaria, water eyes caused by hay fever



• Hay fever

• To treat cold or allergy symptoms such as sneezing, itching, watery eyes, or runny nose

• Relieve itching from hives


• Both the 1st generation drugs and the 2nd generation drugs are used to treat allergy, hay fever and symptoms of allergy such as sneezing, itching, watery eyes, or runny nose

• 1st generation drugs have side effects- mainly it causes drowsiness

• 2nd generation drugs are modified and hence are mostly devoid of the side effects

• Synthesis of some antihistamines have been outlined

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