Antihistamincs

8/7/2019 Antihistamincs

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HISTAMINE ANTAGONISTS

Dr. Anil Kumar Saxena



H1 ANTAGONISTSThe finding that histamine is a major mediator of the allergic hypersensitivity reaction led to thediscovery of the first H 1 receptor antagonist in1937.

The term ³H 1 receptor antagonist´ was proposedto replace the term ³antihistamine´ when it wasfound that the early drugs were ineffective ininhibiting histamine-induced gastric acidsecretion.

Currently, H 1 receptor antagonists are of twotypes:

A. First Generation H 1 receptor antagonistsB. Second Generation H 1 receptor antagonists



First generation H 1 antagonists were the initial

³antihistamines´ to be used clinically.They are highly lipid soluble so easily penetratethe BBB & exert inhibitory effects on H 1 receptorsin the CNS (especially hypothalamus) & periphery.

The high CNS penetration accounts for thesedating effects of these drugs.

The sedating effect can be used to treat insomnia.

They have weak anti-cholinergic side effects(dryness of nasal mucosa & xerostomia).



Second generation H 1 antagonists have little CNSpenetration compared to first generation H 1antagonists.

Thus, these drugs do not posses the sedating sideeffects observed with first generation antagonists.

No anti-cholinergic side effects.

Have additional antiallergic action apart fromhistamine block. Some also inhibit late phase

allergic reaction by acting on leucotrienes or PAF.



Classification of H 1 antagonists

A. First Generation Antihistaminics:

I. Highly sedative: Diphenhydramine, Dimenhydrinate,Promethazine, Hydroxyzine.

II. Moderately sedative: Pheniramine, Cyproheptadine,Meclizine, Buclizine, Cinnarizine

III. Mild sedative: Chlorpheniramine, Mepyramine,Cyclizine, Triprolidine, Clemastine

B. Second Generation Antihistaminics:TerfenadineFexofenadineAstemizole

Loratadine

DesloratidineCetrizineAzelastine

Ebastine



PHARMACOLOGICAL ACTIONS

1. Antagonism of histamine

They effectively block histamine inducedbronchoconstriction, contraction of intestinal &other smooth muscle and triple response.

Fall in BP by low doses of histamine is blocked,but additional H 2 antagonists are required for complete blockade of higher doses.

Pre-treatment with these drugs protects animalsfrom death caused by i.v. histamine.

Release of adrenaline from adrenal medulla inresponse to histamine is blocked.



Constriction of larger blood vessels by histamine isalso antagonized.

Action of histamine on gastric secretion is notaffected by these drugs.

2. Antiallergic action

Many manifestations of immediate hypersensitivity(type I reaction) are suppressed. Urticaria, itching& angioedema are well controlled.

Anaphylactic fall in BP is only partially prevented.

Asthma in man is practically unaffected(leucotrienes ± C 4 & D4 & PAF are more importantmediators for human asthma).



3. CNS

The older antihistaminics produce variabledegree of CNS depression because of BBBpenetrability.

Some individuals also experience stimulanteffects like restlessness & insomnia. Excitement& convulsions are seen at toxic doses.

Second generation antihistaminics are practicallynon-sedating.

Certain H 1 antihistamines are effective inpreventing motion sickness. It is not certainwhether this is due to histamine antagonism inthe brain or antimuscarinic property of thesedrugs.



Promethazine also controls vomiting of pregnancy& vomiting due to other causes.

Promethazine & few other antihistaminics reducetremor, rigidity & sialorrhea of Parkinsonism.Anticholinergic & sedative properties underlie thebenefit.

Some of them are effective antitussives.

4. Local anesthetic

Some drugs like mepyramine, have strong whileothers have a weak membrane stabilizingproperty. However, they are not used clinically aslocal anesthetic due to irritation on s.c. inj.



5 . Blood Pressure

Most antihistaminics cause a fall in BP on i.v. inj.(direct smooth muscle relaxation). However, thisis not evident on oral administration.

6. Uptake of NA

Many of these drugs inhibit neuronal uptake of NA & potentiate it like cocaine.



PHARMACOKINETICS

The classical H 1 antihistaminics are well absorbedfrom oral & parenteral route, metabolized in theliver & excreted in urine.

They are widely distributed in the body & enter brain (newer compound penetrate brain poorly).

Duration of action of most agents is 4-6 hours,some acts for 12-24 hours or more.

On repeated use many histamines induce their own metabolism.



SIDE EFFECTS & TOXICITY

Side effects with first generation H 1 antihistaminicsare frequent, but are generally mild.

Sedation, diminished alertness & concentration,light headedness, motor incoordination, fatigue &

tendency to fall asleep are the most common.Patients should be cautioned not to operate motor vehicles or machinery requiring constant attention.Alcohol synergies in producing these effects as doother CNS depressants. Second generation

compound are largely free of CNS effects.

Dryness of mouth, alteration of bowel movement,urinary hesitancy & blurring of vision can be due toanticholinergic property.



CLINIACL USES

1. Allergic disorders.

2. Other conditions involving histamine like:Block effects produced by histamine liberators,Symptomatic relief in insect bite & ivorypoisoning. They have prophylactic value in blood /saline infusion induced rigor.

3. Pruritis: many conventional antihistamines haveantipruritic action independent of H 1 antagonism.Though relief is often incomplete, they remain thefirst choice drugs for idiopathic pruritis.



4. Common cold: They do not affect the course of the

illness but may afford symptomatic relief byanticholinergic & sedative actions. The newer nonsedative antihistamines are less effective in thisrespect.

5 . Motion sickness: Promethazine etc have prophylacticvalue in milder types of motion sickness; should betaken one hour before starting journey. Promethazinecan also be used in morning sickness, drug induced& post operative vomiting, radiation sickness.

6. Vertigo: Cinnarizine has been widely used in vertigo.



H2 RECEPTOR ANTAGONISTS

They inhibit histamine-induced gastric acidsecretion.

They act as competitive antagonists of histaminebinding to H 2 receptors on gastric parietal cells.

This antagonism reduces acid secretion inheartburn & peptic ulcer disease.

H2 receptors are also present in the CNS & cardiacmuscle, but the therapeutic dose of H 2 receptor antagonists are sufficiently low thereforecardiovascular & CNS side effects are negligible.

Cimetidine, Ranitidine, Famotidine, Nizatidine



Secretion of HCl by gastric parietal cell & its regulation



H3 RECEPTOR ANTAGONISTS

Recently, H 3 receptors have been shown tomediate certain CNS & gastrointestinal effects.

Though a selective H 3 antagonist thioperamidehas been developed, it has not found any clinicalutility.

Pharmacological agents selective for thesereceptors are in development, with potentialapplications in the treatment of obesity &attention-deficit disorders.

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