Part 9

-Histamine&Antihistaminics

-Hyperacidity

-NSAIDS

-Gout

-Opioids

-Allergy

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 are common 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, and sneezing.

An asthmatic attack may be provoked.

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. The H1 and H2 receptors both receive histamine as a messenger, but the meaning taken by the different receptors 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 and 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 show 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 antidepressants 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 hs

 Antihistamine

Background: Antihistamines comprise a broad class of pharmacologic agents that include the first-generation, centrally acting, H1-receptor antagonists (eg, diphenhydramine) and the newer, second-generation, nonsedating H1 blockers (eg, loratadine). Other antihistaminic agents, such as cimetidine, work primarily at H2 receptors causing inhibition of gastric secretion; still other experimental antihistamines act on presynaptic H3 receptors.

While first-generation H1-receptor antagonists are responsible for the vast majority of poisonings, all antihistamine classes have been associated with serious toxicity.

Pathophysiology: H1, H2, and H3 receptors are the 3 histamine receptors that have been identified.

All H1 histamine antagonists are reversible competitive inhibitors of histamine receptors. First-generation H1-receptor blockers also are potent competitive inhibitors of muscarinic receptors and may cause anticholinergic syndrome (eg, sinus tachycardia, dry skin, dry mucous membranes, dilated pupils, ileus, urinary retention, agitated delirium). In addition, antihistamines disrupt cortical neurotransmission and block fast sodium channels. These effects exacerbate sedation and seizure activity and may cause cardiac conduction delays manifested by widening of the QRS interval. The phenothiazine class of antihistamines (eg, promethazine) has alpha-adrenergic blocking activity and may cause hypotension.

The 6 structural classes of antihistamines are as follows:

1.    Alkylamines (eg, brompheniramine, triprolidine, pheniramine)

2.    Ethanolamines (eg, clemastine, diphenhydramine, doxylamine)

3.    Ethylenediamines (eg, tripelennamine)

4.    Phenothiazines (eg, promethazine)

5.    Piperidines (eg, fexofenadine and loratadine; terfenadine and astemizole (recalled from US market)

6.    Piperazines (eg, cetirizine, meclizine)

Fexofenadine, loratadine, astemizole, and cetirizine are peripherally selective H1-receptor antagonists. They have a distinct advantage because they bind much more selectively to peripheral H1 receptors and have a lower binding affinity for the cholinergic and alpha-adrenergic receptor sites than other antihistamines. This group of antihistamines is popular because specificity for the peripheral histamine receptor site eliminates many adverse effects, including central nervous system (CNS) depression, blurred vision, dry mouth, and tachycardia.

Two nonsedating antihistamines, terfenadine and astemizole, are known to inhibit the potassium rectifier currents, which slows repolarization. This is manifested clinically as prolongation of the QT interval and torsade de pointes. Astemizole and terfenadine have been removed from the US market. Terfenadine has been replaced by fexofenadine, which is the pharmacologically active metabolite of terfenadine. Fexofenadine has not been associated with torsade de pointes in volunteer and animal studies. Diphenhydramine is known to prolong the QT interval on ECG by presumed inhibition of the delayed potassium rectifier channel. Torsade de pointes has not been documented with diphenhydramine, most likely because of the concurrent sinus tachycardia created by the anticholinergic-induced tachycardia, which shortens repolarization.

A new class of selective nonsedating H1 antagonists, the norpiperidine imidazoazepines, is currently in clinical trials. Current in vitro and in vivo safety studies show no increase in incidence of cardiac dysrhythmia.

H2 receptors are primary regulators of gastric acid secretion. In the CNS, histamine (H1, H2) modulates activities such as arousal, thermoregulation, neuroendocrine, and vegetative functions. H2-receptor antagonists are considered relatively benign in overdose; as observed with cimetidine, the primary adverse reaction is confusion. Cimetidine also inhibits hepatic oxidative metabolism by most cytochrome P450 enzymes and, thus

1)-antacids

Oral-Local

Aluminum hydroxide: 78

Calcium carbonate: 100.09

Magnesium hydroxide: 58.32

Magnesium oxide: 40.30

Sodium bicarbonate: 84.01

Indications

-Hyperacidity (treatment) Ulcer, duodenal (treatment) or Ulcer, gastric (treatment)

-Antacids are indicated for relief of symptoms associated with hyperacidity (heartburn, acid indigestion, and sour stomach). In addition, antacids are used in hyperacidity associated with gastric and duodenal ulcers. However, there have been reports of increased gastrin levels and increased gastric secretion (acid rebound) associated with the use of antacids.

-Some of the antacid combinations contain other ingredients that have no antacid properties. Simethicone, an antiflatulent, has been added as an aid in those conditions in which the retention of gas may be a problem; however, in the treatment of peptic ulcer diseases, the advantage of using antacid and simethicone combinations rather than antacids alone has not been clearly established.

-Hypersecretory conditions, gastric (treatment adjunct) Zollinger-Ellison syndrome (treatment adjunct) Mastocytosis, systemic (treatment adjunct) or Adenoma, multiple endocrine (treatment adjunct)

-Antacids are indicated in conjunction with histamine H 2 -receptor antagonists or omeprazole for transient symptomatic relief in the treatment of pathological gastric hypersecretion associated with Zollinger-Ellison syndrome (alone or as part of multiple endocrine neoplasia Type-I), systemic mastocytosis, and multiple endocrine adenoma.

-Reflux, gastroesophageal (treatment)

-Antacids are indicated in the symptomatic treatment of gastroesophageal reflux disease.

-Stress-related mucosal damage (prophylaxis and treatment)

-Antacids are indicated to prevent and treat upper gastrointestinal, stress-induced ulceration and bleeding, especially in intensive care patients.

-[Hyperphosphatemia (treatment)]

-Aluminum carbonate and aluminum hydroxide may be used in conjunction with a low-phosphate diet to reduce elevated phosphate levels and demineralization of bones in patients with renal insufficiency. However, use of aluminum-containing antacids as phosphate binders may lead to aluminum toxicity in patients with renal insufficiency. Other agents may be preferable for treating hyperphosphatemia in patients with renal insufficiency.

-Hypocalcemia (treatment)

-See .

[Aluminum hydroxide has been used in the treatment of neonatal hypocalcemia and diarrhea; however, it generally has been replaced by other agents. Aluminum carbonate and aluminum hydroxide have been used along with a low-phosphate diet to prevent formation of phosphatic (struvite) urinary stones; however, their use has been replaced by other agents. Magnesium hydroxide has been used to prevent recurrence of calcium stones; however, it has been replaced by other agents. Use of aluminum-containing antacids in young children and premature infants may lead to aluminum toxicity, especially in those patients with renal failure. ]

Contraindications

The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

* Aluminum hydroxide has the ability to form the insoluble complex of aluminum phosphate, which is excreted in the feces. This may lead to lowered serum phosphate concentrations and phosphorus mobilization from the bone. If phosphate depletion (e.g., malabsorption syndrome) is already present, osteomalacia, osteoporosis, and fracture may result, especially in patients with other bone disease. In such patients predisposed to phosphate depletion, other aluminum-containing antacids (except aluminum phosphate) will be of concern only in relation to their ability to form an aluminum phosphate complex

† Antacids containing more than 5 mEq (115 mg) of sodium per total daily dose should not be used without first checking with physician. The usual amount of sodium allowed in restricted diets is 3 grams or less per day

‡ In patients with renal function impairment, use of antacids containing more than 50 mEq (608 mg) of magnesium per total daily dose should be carefully considered

Mechanisms Of Action

BACKGROUND: #e2e2e2; MARGIN: 0in 0in 0pt; DIRECTION: ltr; unicode-bidi: embe