1. Histamine. Antihistamines
Assoc. Prof. Jaroslav Chládek. Ph.D.
2013

2. Histamine An autacoid, „local hormone“.
Autacoids are compounds synthetized and released to exert local effects such as histamine, serotonin, endogenous peptides, prostaglandins, and leukotrienes.
Histamine is widely distributed throughout most tissues and is also present in many venoms, bacteria, and plants.
Histamine is an important mediator of immediate hypersensitivity reactions acting locally and causing smooth muscle contraction, vasodilation, increased vascular permeability, edema and inflammation.
The release of histamine is the most important positive regulation mechanism of the secretion of gastric acid in the stomach.
The parasympathetic nervous system, via the vagus nerve, and the hormone gastrin stimulate the parietal cell to produce gastric acid, both directly acting on parietal cells and indirectly, through the stimulation of the secretion of the hormone histamine from enterochromaffine- like cells.

3. Histamine
The formation of histamine occurs by the removal of a carboxyl group (decarboxylation) from amino acid  L-histidine
histidine
histamine
histidine decarboxylase

4. Histamine tissue and cell distribution
Preformed histamine is stored in granules of mast cells of the nose, mouth, feet, and internal body surfaces and basophils of the blood. Turnover of histamine in these cells is relatively slow and, if depleted, may take days to return to normal levels.
Mast cells are important in that they release histamine and other molecules in response to potential tissue injury.
Very high concentrations are found also in the lung, skin, CNS and peripheral nervous system and in the GIT (enterochromaffin-like cells of the gastric mucosa). Histamine in these sites exhibits a relatively rapid turnover rate.

5. Histamine When released from granules, its metabolism is very rapid.
Therefore, plasma concentrations are low nanoMolar and the effects are local.

6. Histamine importance
Histamine has a broad spectrum of activities in various physiological and pathological situations.
It has been shown to be involved in:
Histamine/aminergic neurotransmission and numerous brain functions (sleep/wakefulness, emotion, learning, memory, locomotor activity, nociception, food intake and aggressive behavior)
secretion of pituitary hormones
regulation of gastrointestinal and circulatory functions, as well as
inflammatory reactions and modulation of the immune response

7. Histamine release the immediate (type I) allergic reaction.
1/ Immunologic Release: 
Histamine is released from mast cells by exocytosis during inflammatory or allergic reactions (cell-fixed IgE antibodies interact with an antigen).
Mast cells, if sensitized by surface IgE antibodies, degranulate and rapidly release many active compounds including histamine when exposed to specific antigen. 
the immediate (type I) allergic reaction.

8. Histamine release
2/ Non-immune mechanisms: mechanical/chemical release
any physical or chemical agent that injures tissue,
skin or mucosa are particularly sensitive to injury and will cause the immediate release of histamine from mast cells. 
3/ Drugs and other foreign compounds:
morphine, dextran, quaternary ammonium compounds - d-tubocurarine, penicillins, tetracyclines
toxins, venoms…

9. Mechanism of Action
Histamine mediates its effects by interacting with G-protein coupled histamine receptors of H1, H2, H3 and H4 types.  
cAMP Cyclic adenosine monophosphate
inositol trisphosphate
and diacylglycerol
Second messengers
Enzymes: adenylate cyclase C and protein kinase A
Enzymes: phospholipase C and protein kinase C

10. Overview of histamine receptor-mediated effects
H1 receptor activation:
vasodilation
increased vascular permeability
irritation of neuronal endings
(itching, pain)
contraction of extravascular smooth muscle (bronchoconstriction)
H2 receptor activation :
cardiac stimulation
stimulation of gastric acid secretion
H3 receptors at presynaptic sites (autoreceptors) inhibit the release of a variety of neurotransmitters in the CNS
H4 receptors are expressed on immunocompetent cells and are involved in immune reactions

11. Symptoms of histamine excess
Pruritus (itching especially of the skin, eyes, ears, and nose)
Urticaria (hives)
Tissue swelling (angioedema) especially of facial and oral tissues and sometimes the throat, the latter causing the feeling of “throat tightening”
Hypotension (drop in blood pressure)
Tachycardia (increased pulse rate, “heart racing”)
Symptoms resembling an anxiety or panic attack
Chest pain
Nasal congestion and runny nose
Conjunctivitis (irritated, watery, reddened eyes)
Some types of headaches that differ from those of migraine
Fatigue, confusion, irritability
Very occasionally loss of consciousness usually lasting for only one or two seconds
Digestive tract upset, especially heartburn, "indigestion", and reflux

12. The effects of histamine on the cardiovascular system:
i.v. histamine: fall in blood pressure
vasodilation of arterioles and precapillary sphincters. Vasodilation may be due in part to nitric oxide (NO) liberation.
the heart rate increases by autonomic reflex mechanisms and by direct action of histamine
- increased contractility (positive inotropism)
- increased pacemaker rate (positive chronotropism)
Both H1 and H2 receptors are involved in cardiovascular responses.

13. Cutaneous reaction to histamine
Intra-dermal injection of histamine: skin effects
the effect on terminal vasculature
reddening at injection site due to vasodilation
wheal or disk of edema within 1 to 2 min (increased vessel permeability)
a large, bright crimson flare or halo surrounding the wheal
itching, increased skin temperature

14. The effects of histamine on various organs
Histamine-associated edema: H1 receptor-mediated effects affecting postcapillary vessels
Increase in vessel permeability due to separation of endothelial cells, allowing transudation of fluid and molecules as large as small proteins.
endothelial cell separation: secondary to histamine-induced calcium influx causing intracellular actin/myosin-mediated contraction.

15. The effects of histamine on various organs
Gastrointestinal tract:
histamine promotes intestinal smooth muscle contraction which is an H1 receptor-mediated effect
potent stimulation of gastric secretion (HCl & pepsin) H2 receptor-mediated

16. The effects of histamine on various organs
Bronchiolar smooth muscle activation by histamine causes bronchoconstriction (H1 receptor mediated ).
Inhaled histamine is a diagnostic, provocative test for bronchial hyperreactivity (used in asthma).
Nerve Endings: Sensory nerve endings are stimulated by histamine, especially those which mediate pain and itching. These effects are H1 receptor mediated effect and represent part of the local reaction to insect stings (urticarial responses).

17. The effects of histamine on various organs
Exocrine glands:
enhances salivary and lacrimal gland secretion (minimal unless large doses are given), stimulates chromaffin cells in adrenal medulla to secrete catecholamines.

18. Pharmacological modulation of histamine effects
H1- and H2-antihistamines: receptor antagonists, selective blockers of histamine receptors (H1, H2)
physiologic antagonists: agents that produce opposing effects, acting on different receptors:
Example – epinephrine causing bronchodilation and vasoconstriction by activation of adrenoreceptors
anti-IgE antibody decrease the intensity of allergic reaction and of histamine release
specific allergen immunotherapy: prophylactic treatment (hyposenzibilization, immune tolerance development)
histamine release inhibitors causing reduced mast cell degranulation:
Examples: mast cell stabilizers cromolyn and nedocromil, ketotifen

19. Antihistamines
pharmacological antagonism at histamine receptors = receptor blockers
Daniel Bovet (1907 –1992) was a Swiss-born Italian pharmacologist who won the 1957 Nobel Prize in Physiology or Medicine for his discovery of drugs that block the actions of specific neurotransmitters.
His work on drugs affecting the autonomic nervous system, the neuromuscular junction, and the actions of histamine. He is best known for his discovery in 1937, synthesis and testing of antihistamines.

20. Sir James Black ( )
Black studied the factors that regulated gastric secretion, which he knew involved histamine. He was also aware that excessive secretion of gastric acid was associated with peptic ulcers. His goal was to develop a drug that would decrease gastric acid secretion but would possess limited other effects, such as smooth muscle contraction.
Black had to address the question as to why antihistamines available at the time could not curtail the production and release of gastric acid, despite the fact that they blocked the allergenic responses to histamine (contractions of gut smooth muscle). Based upon this knowledge and his previous studies on β-adrenoceptors, Black postulated that histamine binds to two different types of receptors in the body.
Black's finding that H2 receptor antagonists blocked acid secretion (histamine-, meal-, and gastrin-stimulated) reinforced the relevance of histamine as a physiological mediator of acid secretion.
In 1975, Black's perseverance was eventually rewarded when he and his team developed a more clinically useful H2 receptor antagonist called cimetidine.
Cimetidine, which was marketed under the brand name Tagamet, became the world's first billion-dollar drug.
1988 Nobel Prize in Medicine

21. Antihistamines: Mechanism of action
Histamine receptors have basal activity which does not require the binding of an endogenous agonist histamine.
Histamine receptor blockers are inverse agonists. They stabilize the receptor in an inactive conformation making the excessive stimulation with histamine less possible.

22. H1- antihistamines: pharmacological effects
H1-antihistamines block the effects of histamine on the H1-R, whereas little effects at H2 receptor sites and negligible effects of H3 sites are observed.
They do not inhibit antigen/antibody reaction, nor histamine release!!!
In addition to this antihistamine effect, the older derivatives have parallel pharmacological actions, for example antimuscarinic and adrenolytic effects which must be considered.
H1-antihistamines are used to suppress manifestations of allergy, especially cutaneous (urticaria) or on the mucous membranes (rhinitis, hayfever, conjunctivitis).
They prevent or decrease postcapillary vessel dilation and permeability (less penetration of inflammatory cells), itching, glandular secretion.
They have best effects if used early in the course of allergy. 

23. H1- antihistamines: pharmacological effects
H1-antihistamines prevent bronchiolar or gastrointestinal smooth muscle constriction to some extent but are not effective as monotherapy for allergic asthma neither as bronchodilators nor anti-inflammatory drugs!!! However, they are prescribed to patients with allergic asthma to decrease the need for antiasthma drugs (inhaled corticosteroids and other)
H1-antihistamines do not completely prevent cardiovascular effects of histamine (some of these effects are mediated by H2 receptors).
H1-antihistamines are insufficient alone to treat anaphylactic shock or edema of the larynx, they could prevent them. The drug to use in severe situations is adrenaline.
H1-antihistamines cannot affect gastric acid secretion or mast cell histamine release because these effects are H2 receptor-mediated.

24. H1- antihistamines
H1- antihistamines are typically separated into sedating (first generation) and nonsedating (second generation) drugs, based upon their central nervous system effects, the nonsedating agents being less likely to cross the blood-brain barrier.
The antihistamines are some of the most commonly used drugs in medicine, and most are available in multiple forms, both by prescription and in over-the-counter products, alone or combined with analgesics or sympathomimetic agents.
The nonsedating antihistamines are typically used in extended or long term treatment of allergic disorders, including allergic rhinitis (hay fever), sinusitis, atopic dermatitis, and chronic urticaria.

25. H1- antihistamines
H1 antihistamines are drugs of choice to treat allergic rhinitis and urticaria.
H1 antihistamines are effective for treating nasopharyngeal itching, sneezing,  watery rhinorrhea, and ocular itching, tearing, erythema.
Nasal congestion in rhinitis patients is unaffected by H1 antihistamines !!
Topical alpha-adrenergic agonists:
Phenylephrine or oxymetazoline reduce nasal congestion/obstruction.
Efficacy duration: limited due to rebound rhinitis and systemic effects which may include insomnia, irritability, and hypertension - the latter which is seen more commonly with oral alpha adrenergic agonists.
Intranasal glucocorticoids are the most potent drugs available for management of severe allergic rhinitis (seasonal or perennial) which reduce inflammation and nasal obstruction.

26. H1- antihistamines
By contrast, in asthma,  H1-histamine receptor blockers are ineffective.
Angioedema may be initiated by histamine but is maintained by bradykinins. In this clinical setting, H1 antihistamines are also ineffective.
For atopic dermatitis, diphenhydramine (first-generation) provides effective control of itching and sedation.

27. First-generation H1- antihistamines
First-generation H1 antihistamines cause effects mediated by many other receptor systems.
These other effects in the mediated by  muscarinic cholinergic receptors, alpha adrenergic receptors, serotonergic receptors and muscular nicotinic receptors for ACH.
Sedation is a common side effect of first-generation H1 antagonists and provided the rationale for these agents to be used has sleep-aids and to alleviate tension and anxiety.
They may produce a paradoxical excitement in children and toxic reactions can include stimulation, agitation, or even coma.
Antiemetic/antinausea effect: some first-generation H1 antagonists prevent motion sickness.

28. H1- antihistamines
Common uses include short term treatment of symptoms of the common cold, motion sickness, nausea, vertigo, cough, urticaria, pruritus and anaphylaxis.
Many antihistamines are also available in topical forms, as creams, nasal sprays and eye drops for local use in alleviating allergic symptoms.

29. H1- antihistamines General properties:
Both first-generation and second-generation H1-antihistamines
are orally active and are metabolized by the liver using the cytochrome P450 drug-metabolizing system
the average duration of pharmacological action of the first-generation drugs is about 4-6 hours
several second-generation drugs are longer acting, with effects lasting hours (once-daily dosing). 

30. First generation H1-antihistamines
Chemical structures
Alkylamines
Ethanolamines
Ethylenediamines
Piperazines
Phenothiazines
Piperadines
Side Effects
Sedating
Anticholinergic
Many available Over- the- Counter (OTC)
Inexpensive
Brompheniramine, chlorpheniramine, clemastine, cyclizine, chlorcyclizine, diphenhydramine, doxylamine, hydroxyzine, phenyltoloxamine, promethazine …

31. First generation H1-antihistamines
When used as systemic treatments, first-generation agents are relatively more sedating and exert antimuscarinic effects (blockade of cholinergic, muscarinic-type receptors)
fairly strong sedatives – promethazine
antiemetics – cyclizine, cinnarizine
with antiallergic potency – diphenhydramine
Local treatments: eye drops, emulsions, nasal solutions, sprays

32. Second generation H1-antihistamines
They are more H1-receptor specific and exhibit less CNS penetration, which accounts for reduced sedation. 
loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, ebastine, akrivastine, azelastine, mizolastine
Some available as OTC
Most of the second-generation agents are metabolized by a cytochrome P450. Therefore, plasma concentrations of certain second generation H1 antagonists may increase, if the patients also taking drugs – inhibitors of the same cytochrome P450 such as ketoconazole or erythromycin.

33. Formulations for local use:
Second-generation drugs as local treatments: eye drops, nasal solutions, sprays

34. H1-receptor and Non-Histamine Receptor-Mediated Effects of H1-Antihistamines

35. Non-histamine receptor-mediated adverse effects
Anticholinergic effects:
Some first-generation H1 antagonists have strong antimuscarinic actions (atropine-like effects).  Prominent anticholinergic effects include blurred vision (loss of accommodation) and urinary retention. 
Therefore patients who may have benign prostatic hypertrophy may exhibit significant worsening of their clinical state due to antimuscarinic effects. 

36. Non-histamine receptor-mediated adverse efects
Alpha adrenergic blocking effects: Some first-generation H1 antagonists block alpha adrenergic receptors. Alpha-adrenergic receptor blockade can cause orthostatic (postural) hypotension.  
Serotonergic blockade: Some first-generation H1 antagonists block serotonin receptors
Local Anesthetic effects:
Many first-generation H1 antagonists are local anesthetics, exhibiting sodium channel blockade (similar in general to that caused by procaine and lidocaine)
For example, diphenhydramine and promethazine are more potent than procaine as a local anesthetic

37. H1-antihistamines: cardiotoxicity
Second-generation H1-antihistamine terfenadine and astemizole
Non-sedating
Caused QTC interval prolongation and fatal cardiac arrhytmia by inhibition of potassium channels
when used with ketoconozole, erythromycin, grapefruit juice which interfered with the metabolism , increasing the concentration of both H1-antihistamines in the blood
Removed from the market
It is not the class effect of all H1-antihistamines!!!

38. Adverse effects of second-generation H1 antihistamines
second-generation H1-antihistamines induce only exceptionally drowsiness. This possibility, even rare, must however be taken into account, particularly at time of a first prescription
excessive excitation and convulsions in children (unfrequent)
orthostatic (postural) hypotension (unfrequent)
allergic responses are relatively common following topical use
body weight gain
second-generation overdosage may induce cardiac arrhythmias
liver toxicity is rare
All H1-antihistamines, including those which are intended for treatment of motion sickness, should not be used during the first three months of pregnancy, more for reasons of principle than for observations of malformations. Promethazine has been prescribed to pregnant women without inducing malformations.

40. These drugs:
have week effects in allergic asthma
were used in children in the past because of the safety concerns about inhaled corticosteroids
no longer recommended

41. H2-antihistamines = H2 Receptor Antagonists
H2 receptor antagonists inhibit histamine-induced stomach acid secretion
The incidence of peptic ulcer disease (and related gastrointestinal disease) is high.

42. H2-antihistamines
The H2 antihistamines act by binding to histamine type 2 receptors on the basolateral (antiluminal) surface of gastric parietal cells interfering with pathways of gastric acid production and secretion.
The most important effect is a reduction in gastric acid secretion (acidity and volume) and decreased pepsin concentration
The selectivity of H2 blockers is of key importance, as they have little or no effect on the histamine type 1 receptors, which are blocked by H1- antihistamines that are used to treat allergic diseases and have little effect on gastric acid production.
The effect of H2 blockers is largely on basal and nocturnal acid secretion which is important in peptic ulcer healing.

43. The effects of histamine on various organs: H2-receptors in GIT
Gastric acid production is regulated by both the autonomic nervous system and several hormones. The parasympathetic nervous system, via the vagus nerve, and the hormone gastrin stimulate the parietal cell to produce gastric acid, both directly acting on parietal cells and indirectly, through the stimulation of the secretion of the hormone histamine from enterochromaffine-like cells (ECL). Vasoactive intestinal peptide, cholecystokinin, and secretin all inhibit production.
The production of gastric acid in the stomach is tightly regulated by positive regulators and negative feedback mechanisms. Four types of cells are involved in this process: parietal cells, G cells, D cells and enterochromaffine-like cells. Besides this, the endings of the vagus nerve (CN X) and the intramural nervous plexus in the digestive tract influence the secretion significantly.
Nerve endings in the stomach secrete two stimulatory neurotransmitters: acetylcholine and gastrin-releasing peptide. Their action is both direct on parietal cells and mediated through the secretion of gastrin from G cells and histamine from enterochromaffine-like cells. Gastrin acts on parietal cells directly and indirectly too, by stimulating the release of histamine.
The release of histamine is the most important positive regulation mechanism of the secretion of gastric acid in the stomach. Its release is stimulated by gastrin and acetylcholine and inhibited by somatostatin.
Wikipedia

44. H2-antihistamines
The selective H2 blockers are less potent in inhibiting acid production than the proton pump inhibitors (which block the common, final step in acid secretion) but, nevertheless, suppress 24-hour gastric acid secretion by about 70%.

45. H2-antihistamines
The initial H2-antihistamine approved for use was cimetidine (1977), which was followed by ranitidine (1983), famotidine (1986), and nizatidine (1988).
All four of these agents are available by prescription and as over-the- counter oral formulations. Intravenous and intramuscular forms are available for cimetidine, ranitidine and famotidine.

46. H2-antihistamines: pharmacokinetics
The elimination is mainly renal
However, H2-antihistamines are also metabolized in the liver by the cytochrome P450 system.
Among the four agents, cimetidine is distinctive in its potent inhibition of the P450 system, which can result in significant drug interactions.
Cimetidine and ranitidine inhibit renal clearance of basic drugs that use renal secretory transport systems.

47. Clinical uses of H2-antihistamines
 Peptic Ulcer Duodenal Disease:
H2 receptor antagonists by reducing gastric acidity have significantly advanced treatment of peptic ulcer disease
 Other agents that reduce gastric acid include:
Antimuscarinic drugs (at high dosages required, side effects are significant)
Antacids which require frequent dosing and may be associated therefore with  poor patient compliance
Proton pump inhibitors (omeprazole, esomeprazole, lansoprazole…) are very effective in reducing gastric acid by directly inhibiting an enzyme-pump which produce hydrogen ions (protons) in the stomach thus decreasing pH
Sucralfate (a coating agent), promotes healing
Antibiotics are prominent in current therapy because of the importance of H. pylori in gastric ulcer disease.  

48. Gastroesophageal Reflux Disorder (erosive esophagitis)
Gastric Ulcer:
H2 receptor antagonists reduce symptoms and promote healing for benign gastric ulcers
 Gastroesophageal Reflux Disorder (erosive esophagitis)
H2 receptor antagonists, at higher dosages than for management of peptic or gastric ulcer disease, are used as one component of treatment. Proton pump blockers (e.g. omeprazole) are usually also administered.
Hypersecretory Disease:
 Zollinger-Ellison syndrome is associated with acid hypersecretion which is caused by gastrin-secreting tumor. This disorder is often fatal; however, H2 receptor antagonists often control symptoms.
 Systemic mastocytosis and multiple endocrine adenomas are hypersecretory conditions in which H2 receptor antagonists often control symptoms.

49. Adverse effects of of H2-antihistamines
These drugs are generally well tolerated.
Side effects are uncommon, usually minor and include diarrhea, constipation, fatigue, drowsiness, headache and muscle aches.
Cimetidine had the most adverse effects and drug interactions and was, therefore, replaced by newer drugs.
CNS effects are uncommon. However, in the elderly confusional of states, delirium, and slurred speech may occur. These effects are often associate with cimetidine and are unusual with ranitidine.
Endocrine effects are also relatively uncommon. However cimetidine does exhibit antiandrogenic effects because the drug blinds to androgen receptors and therefore can cause gynecomastia (men) and galactorrhea (women). Endocrine effects not associated with famotidine, ranitidine, nizatidine.
Other uncommon side effects include (cimetidine): granulocytopenia, thrombocytopenia, neutropenia, aplastic anemia which is extremely rare, hepatotoxicity  with reversible cholestatic effects, reversible hepatitis, liver enzyme test abnormalities.

50. Anaphylaxis
Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death.
It can be either Ig-E or non-IgE mediated (anaphylactoid reaction)
Common causes include insect bites/stings, foods, and medications.
It typically causes a number of symptoms including an itchy rash, throat swelling, low blood pressure (mainly in adults) and dyspnea (in all ages).
Anaphylactic shock is the term used when consciousness is lost as a result of hypotension from an anaphylactic reaction.
Symptoms usually spread beginning with the skin, followed by the eyes, nose, and gastrointestinal system and then the respiratory system; finally, cardiovascular symptoms develop.
Angioedema

51. Anaphylaxis

52. Anaphylaxis
Histamine is a primary mediator of anaphylaxis and signs and symptoms of anaphylaxis can be reproduced by histamine infusion.
Histamine triggers a cascade of inflammatory mediators and modulates its own release.
H1-antihistamines are only adjunctive treatment with limited importance in the therapy for acute anaphylaxis and anaphylactoid reactions, in which many mediators of inflammation are involved.
Compared with epinephrine, the first-response medication of choice, antihistamines have a slow onset of action, and they cannot block events that occur subsequent to histamine binding to its receptors.
Antihistamines are an important component of regimens for the prevention of anaphylaxis and anaphylactoid reactions in patients at risk

53. Therapy of anaphylaxis
1/ Adrenaline: i.m., i.v. injection or i.m. autoinjector, NOT subcutaneously
10 mcg (tj. 0,01 ml) / kg, maximum single dose of 0,5 mg (i.e. Adrenaline inj. 1:1000 in 0,5 ml volume)
multiple injections at min if no symptom improvement
In adults with hypovolemia and collaps

54. Therapy of anaphylaxis
2/ antihistamine i.m. or i.v. – e.g. Dithiaden inj.
3/ corticosteroid i.m. or i.v. e.g. hydrocortisone 200 mg, methylprednisolone 40 mg, dexamethasone 8 mg

55. Therapy of anaphylaxis
oxygen in severe dyspnea and hypotension
volume replacement with crystaloids (F1/1 20 ml/kg in minutes, repeat)
salbutamol (Ventolin dos. aer.) if respiratory symptoms are severe (asthma attack)
4 doses, pMDI + spacer , if no improvement up to 4-times in the first hour (20-min intervals)
glucagon in patients on betablockers
transport to hospital