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Histamine and Antihistamines

Almost everyone has taken an antihistamine to treat hay fever, itching, to relieve nausea and vomiting, in tablets and syrups used to treat cough and cold symptoms, or as an aid to sleep. The popularity of antihistamines is a mute testimony to the diverse negative effects of histamine. To get a good idea of what histamine can do, let us imagine the effects of an injection of a small amount of histamine:

Histamine symptoms might include:

Headache is felt as a pulsating, whole-head pain, often with a sense of pressure.

Fast heart, blood pressure falls, irregular beats with alarming palpitations.

Skin sensations
  local itching or burning sensation, flushing and a disagreeable heat.

Stomach pain
acid secretion increases;  small intestine contracts with crampy pain

Respiratory - nose swelling, congestion, sneezing and wheezing.

Anxiety and agitation
with diffuse, deep, odd body sensations:"...my bones are on fire", "I feel weird all over", "...a deep pricking, crawling sensation...".

Histamine carries its message to a large number of cells by attaching to a special receptor on the cells' surfaces. There are two kinds of histamine receptors, H1 and H2. These receptors both receive histamine as a messenger, but the meaning conveyed is different.

H1 receptors tend to produce the symptoms already listed and activate allergic reactions.

H2 receptors tend to act as negative feedback receptors and turn the allergic reaction off. They also activate the acid-producing, parietal cells of the stomach lining.

Histamine dilates blood vessels and acts with prostaglandins, PGE2 and PGI2, to produce the early swelling, redness and heat of an inflammatory response. The same mediators may sensitize nerve endings to other pain-producing mediators such as bradykinin. An initial burst of mediator activity will often set a series of cell responses in motion which will amplify and prolong disturbances. Once inflammation is established in tissues by immune cell invasion and mediator release, recovery may take several days to weeks.

Antihistamines are drugs which block the receptors so that the histamine messages are not received. We have drugs that selectively block both kinds of histamine receptors. The common antihistamines (Benadryl, Chlortripalon, Atarax, Claritin,Seldane, and Hismanal) are H1 blockers. The H1 block is useful to treat allergic reactions. The older sedating antihistamines have been used for years and are cheap and effective. 

The sedating group also act on brain H1 receptors where they cause the sedative effect, a dangerous effect if you are driving, operating machinery, or otherwise need to be alert and vigilant. Antihistamine sedative effects are increased by concurrent alcoholic beverage ingestion. The powerful sedative effects of some foods such as milk and wheat in susceptible people is not blocked, but enhanced by antihistamines.

The classic antihistamines are represented by chlorpheniramine ( Chlor-Tripalon), brompheniramine (Dimetane), diphenhydramine ( Benadryl) and dimenhydrinate (Gravol). All have been in common use for 40  years with an enviable safety record. These antihistamines have been marketed as allergy preparations for the relief of hay fever and itchy skin conditions. Antihistamines are included in over-the counter cold and cough preparations even though there is little evidence of benefit and unwanted side effect such as sedation may be undesirable or risky. 

Gravol is marketed as an anti-nausea drug although it is a typical antihistamine. Benadryl has been used as a sedative infants and children, although the occasional child will become restless or hyperactive after taking it. A single bedtime dose of 8.0 mg of chlopheniramine will block allergy symptoms for 24 hours and is often adequate for hay fever relief or relief from skin itching. The sedating antihistamines are grouped into groups according to their chemical structure. Here are some examples:

Class Generic (Proprietary) with Usual Adult Dose

Ethanolamines   

Dimenhydrinate  (Gravol) 50-100 mg qid 

Diphenhydramine (Benadryl) 25-50 mg qid  


Alkylamines  

Chlorpheniramine (chlortipalon)  4 mg tid  

 Dexchlorpheniramine  2-4 mg tid 


Phenothiazines
  

Promethazine (Phenergan)    10-25 mg bid  


Piperazines 

 Hydroxyzine (Atarax)    10-25 mg tid  


Piperidines 

 Cyproheptadine (Periactin)    4 mg tid  

 Azatadine (Zadine)    1-2 mg tid  

Unwanted effects are common with these antihistamines, the commonest being sedation, dizziness fatigue, insomnia and dry mouth. Paradoxical hyperactivity occurs in some children. Alcohol  increases the sedative effects of these drugs and users are advised to abstain from drinking while on antihistamine therapy. The ability to drive and operate machinery is impaired  and should be avoided. An anticholinergic action may cause urinary retention and can precipitate glaucoma.

Non- Sedating Antihistamines

Seldane, Claritin and Hismanal * were likely to cause drowsiness than the older H1 blockers. Seldane and Hismanal have run into big problems with adverse effects. The following drugs are shown with generic name, trade name, common dose, onset and duration of action.

Terfenadine  (Seldane) *    60 mg bd    1-2 hours   >12 hours   

Astemazole  (Hismanal) *   10 mg daily  1-2 hours   4 weeks 

Loratadine (Claritin)    10 mg daily   1-2 hours    24 hours   

Cetirizine   (Reactine)    10 mg daily    1-2 hours    24 hours  

Fexofenadine ( Allergra)

* Seldane and Hismanal have been withdrawn from the US market and placed on prescription drug status in Canada because of rare fatal ventricular arrythmias  reported with larger than normal doses, in patients with liver disease and when the drugs were administered along with erythromycin, ketoconazole and other drugs. 

Seldane has been replaced by Fexofenadine ( Allergra), a metabolite of terfenadine with no know cardiac effects. It is non-sedating.  Claritin remains a top selling drug.

Other antihistamines and related drugs :

Ketotifen.  Adult dosage : 1-2 mg bd.
Tricyclic antidepressants -  most of the first and second generation antidepressant
s have antihistaminic activity.
Doxepin - a tricyclic antidepressant with marked antihistamine activity. Suitable for administration at night. There is drug interaction with MAOIs, and can cause cardiac arrthythmia. Dosage : 10 mg

H2-Receptor Blockers

The H2 receptor blocker, cimetadine, first marketed as "Tagamet", joins Valium as one of the best-selling drugs of all time. The H2 block reduces stomach acid secretion. This acid reduction helps to prevent and to heal peptic ulcers. Cimetadine may be thought of as an allergy reaction modifier and antacid combined.

Cimetidine - 400 mg bd
Ranitidine - 150 mg bd

 

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