Antihistamines By Dr. Saad Raheem Abed 2016

Antihistamines

Outline What is the antihistamines. What is histamine. What is the receptors. What is the clinical uses of antihistamines. Side effects of antihistamines. What is the contraindications. Classes of antihistamines.

What is an antihistamine? A drug that reduces or eliminates the effects mediated by the chemical histamine. Histamine is released by your body during an allergic reaction and acts on a specific histamine receptor True antihistamines are only the agents that produce a therapeutic effect that is mediated by negative modulation of histamine receptors (other agents may have antihistaminergic action but are not true antihistamines) The term antihistamine only refers to H1 receptor antagonists (actually inverse agonists) Antihistamines compete with histamine for binding sites at the receptors.

Histamine: Storage and Release Histamine Stored in complex with: Heparin Chondroitin sulphate Eosinophilic Chemotactic Factor Nnutrophilic Chemotactic Factor Proteases

Histamine: Storage and Release 1- Immunologic Release: The most important mechnism for histamine release is in to an immunological stimlus. In mast cells, if sensitized by surface IgE antibodies, degranulate when exposed specific antigen. After degranulation of mast cells lead to libration of the contents of the mast cell granules, histamines are located in mast cells in the tissues and basophils in the blood. Degranulation is involved in the immediate type1 hypersensitivity reaction. 2- Mechanical and Chemical Release: I is a second type of release histamine after injury to mast cells. 3- Drug and other foreign compounds: Morphine, dextran, antimalarial drugs, dyes, antibiotic bases, alkaloids, amides, toxins, venoms .

Synthesis of Histamine Formed from the amino acid Histadine in a decarboxylation reaction with the enzyme histadine decarboxylase Occurs primarily in mast cells and basophils

The different Histamine receptors Location Type of receptor Effect Treatment H1 Throughout the body, specifically in smooth muscles, on vascular endothelial cells, in the heart and the CNS G-protein coupled, linked to intercellular Gq, which activates phospholipase C Mediate an increase in vascular permeability at sites of inflammation induced by histamine Allergies, nausea, sleep disorders,urticaria,angioedema H2 In more specific locations in the body mainly in gastric parietal cells, a low level can be found in vascular smooth muscle, neutrophils, CNS, heart, uterus G-protein coupled, linked to intercellular Gs Increases the release of gastric acid Stomach ulcers H3 Found mostly in the CNS, with a high level in the thalamus, caudate nucleus and cortex, also a low level detected in small intestine, testis and prostate. G-protein coupled, possibly linked to intercellular Gi Neural presynaptic receptor, may function to release histamine Unknown H4 They were recently discovered in 2000. They are highly expressed in components of the immune system such as the spleen, thymus and leukocytes and peripheral haematopoitic cell and bone marrow. Unknown, most likely also G-protein coupled In addition to benefiting allergic conditions, research in the h4 receptor may lead to the treatment of autoimmune diseases. (rheumatoid arthritis and IBS)

Dermatological Indications for Treatment with H1 Antihistamines Acute urticaria Chronic idiopathic urticaria Physical urticarias and dermatographism Atopic dermatitis (less evidence) Urticaria Pigmentosea & Systemic mastocytosis Pruritus associated with other conditions

Other Clinical Uses of Antihistamines Allergic rhinitis (common cold) Allergic conjunctivitis (pink eye) Anaphylactic reactions (severe allergies) Nausea and vomiting (first generation H1- antihistamines) Sedation (first generation H1-antihistamines)

Side effects Associated with the first generation H1-antihistamines and due to their lack of selectivity for the H1 receptor and anti-cholinergic activity. Side effects are due to CNS depression: Sedation Dizziness Tinnitus (ringing in the ear) Blurred vision Euphoria Uncoordination Anxiety Insomnia Tremor Nausea/vomitting Dry mouth/dry cough Newer second generation H1-antihistamines are more selective for the peripheral histamine receptors and have far less side effects (drowsiness, fatigue, headache, nausea and dry mouth)

Special Patient Populations 1-CHILDREN Many of the sedating and low-sedating H1 antihistamines can be safely used in children with appropriate dosing. Children may be more susceptible to certain side effects associated with first-generation drugs, such as excitation and insomnia. Acute poisoning may develop but is rare; hallucinations, ataxia, incoordination, athetosis, and convulsions are the major features. 2-ELDERLY Caution should be used when treating elderly patients, and decreased creatinine clearance, co-morbid conditions, and potential drug interactions should be taken into account. Older individuals may also be more susceptible to anticholinergic effects, particularly urinary retention and hesitancy, constipation, and postural hypotension.

4-BREAST-FEEDING WOMEN 3-PREGNANT WOMEN There are limited guidelines for the use of H1 antihistamines to treat pregnant women. Most H1 antihistamines are classified as U.S. Food and Drug Administration (FDA) pregnancy category B or category C. Based on earlier reports linking H1 antihistamines to fetal malformations, particularly cleft palate defects, H1 antihistamines are customarily avoided in the first trimester of pregnancy. 4-BREAST-FEEDING WOMEN No formal studies have been performed on the safety of H1 antihistamines during breast-feeding. Theoretically, first-generation drugs may diminish milk supply via anticholinergic effects. Clemastine, diphenhydramine, promethazine, triprolidine, cetirizine, loratadine, fexofenadine, and desloratadine are all known to be excreted in breast milk; their effects on the nursing infant are not known.

Drug Interactions of of H1 Antihistamine Therapy The H1 antihistamines may interact with other drugs metabolized by the hepatic CYP system, such as imidazole antifungals, cimetidine, and macrolide antibiotics. Diphenhydramine, chlorpheniramine, clemastine, promethazine, hydroxyzine, and tripelennamine inhibit the hepatic enzyme CYP 2D6 in vitro. In vivo, diphenhydramine has been noted to increase levels of other drugs metabolized by the CYP 2D6 system, including metoprolol and venlafaxine. H1-type antihistamines are contraindicated for patients receiving monoamine oxidase inhibitors. Central depressive effects may be accentuated when H1-type antihistamines are combined with alcohol or other CNS depressants, such as benzodiazepines. These interactions are generally not observed with second-generation H1 antihistamines. In rare circumstances, antihistamines of the phenothiazine group may block and reverse the vasopressor effect of epinephrine. If individuals receiving a phenothiazine require a vasopressor agent, norepinephrine or phenylephrine should be used.

Factors for Risk-Benefit Assessment of H1 Antihistamine Therapy Risks History of cardiac arrhythmias, particularly ventricular arrhythmias First trimester of pregnancy Prostatic hypertrophy Contraindications Narrow-angle glaucoma Concomitant use of monoamine oxidase inhibitors

Classes of First generation H1 receptor antagonist antihistamines Ethylenediamines Ethanolamines Alkylamines Piperazines Tricyclics Piperadines

Common Structural Features of classical First generation antihistamines 2 aromatic rings, connected to a central carbon, nitrogen, or oxygen Spacer between central atom and the amine, usually 2-3 carbons in length. (Can be linear, ring, branched, saturated or unsaturated) The amine is substituted with small alkyl groups Chirality at X and having the rings in different planes increases potency of the drug

Mechanism of Action H1 antihistamines are inverse agonists that reversibly bind and stabilize the inactive form of the H1 receptor, thereby favoring the inactive state. So the H1 receptor antihistamines decrease production of pro- inflammatory cytokines, expression of cell adhesion molecules, and chemotaxis of eosinophils and other cells H1 antihistamines may also decrease mediator release from mast cells and basophils through inhibition of calcium ion channels. In addition to having antihistamine actions, first-generation H1 antihistamines can also act on muscarinic, α-adrenergic, and serotonin receptors and cardiac ion channels

1-Ethylenediamines These were the first group of clinically effective H1- antihistamines Mepyramine (Pyrilamine)

2-Ethanolamines Diphenhydramine (Benedryl) This class has significant anticholinergic side effects and sedation, however reduced the gastroinestnal side effects Diphenhydramine (Benedryl) Oldest and most effective antihistamine on the market Available over the counter Because it induces sedation, it’s used in nonprescription sleep aids such as Tylenol PM Also inhibits the reuptake of serotonin, which led to the search for viable antidepressants with similar structures (prozac) The anticholinergic side effects may include: motor impairment, dry mouth/throat, flushed skin, rapid or irregular heart beat, blurred vision, sensitivity to light, pupil dilation, urinary retention, constipation, difficulty concintrating, short term memory loss, visual disturbances, hallucinations, confusion, erectile dysfunction, and delirium

FORMULATION and DOSAGE OF DIPHENHYDRAMINE 1) 25-, 50-mg tablet Adult: 25-50 mg q4-6h 2) 12.5 mg/5 mL syrup Age 6-12 yr: 12.5-25 mg q4-6h

Ethanolamines Carbinoxamine(Clistine) Doxylamine succinate Is used to treat Hay fever and is especially popular to children due its its mild taste After 21 reported deaths in children under 2, its now only marketed to children above 3 (FDA, June 2006) 2nd in effectiveness of anti-allergy activity only to Benadryl Potent anti-cholinergic effects

Ethanolamines Dimenhydrinate (Dramamine) Clemastine (Tavist) Dramamine is actually a combination of two drugs: diphenhydramine (Benadryl) and 8-chlorotheophillinate (similar to caffeine and is a mild CNS stimulator) Exhibits fewer side effects than most antihistamines Widely used as an antiprurtic (stops itching) Anti-emetic (anti nausea) Also causes strong sedation Readily crosses the BBB

3-Alkylamines Isomerism is an important factor in this class of drugs, which is due to the positioning and fit of the molecules in the H1- receptor binding site These drugs have fewer sedative and GI adverse effects, but a greater incidence of CNS stimulation These drugs lack the “spacer molecule” (which is usually a nitrogen or oxygen) between the two aromatic rings and at least one of the rings has nitrogen included in the aromatic system

Akylamines Chlorphenamine Brompheniramine (Dimetapp) Originally used to prevent allergic conditions Shown to have antidepressant properties and inhibit the reuptake of serotonin The first SSRI was made as a derivative of chlorphenamine Available over the counter Used to treat the common cold by relieving runny nose, itchy, watery eyes and sneezing

FORMULATION and DOSAGE OF CHLORPHENORAMIN 1) 2-, 4-, 8-, 12-mg tablet Adult: 4 mg tid, qid; 8-12 mg bid 2) 2 mg/5 mL syrup Age 6-11 yr: 2 mg q4-6h

Akylamines Triprolidine hydrochloride Pheniramine (Avil) Used to alleviate the symptoms associated with allergies Can be combined with other cold medicine to relieve “flu-like” symptoms Used most often to treat hay fever or urticaria (hives) Antihistamine component of Visine-A

4-Piperazines Cyclizine Structurally related to the ethylenediamines and the ethanolamines and thus produce significant anti-cholinergic effects Used most often to treat motion sickness, vertigo, nausea and vomiting Cyclizine Used to treat the symptoms associated with motion sickness, vertigo and post-op following administration of general anaesthesia and opiods Mechanism of inhibiting motion sickness is not well understood, but it may act on the labyrinthine apparatus and the chemoreceptor trigger zone (area of the brain which receives input and induces vomiting)

Piperazines Chlorcyclizine Hydroxyzine In addition to treating itches and irritations, its an anitemetic, a weak analgesic and an anxiolytic (treat anxiety) This drug is used to treat motion sickness

FORMULATION and DOSAGE OF HYDROXYZINE 1) 10-, 25-, 50-, 100-mg tablet Age ≥ 6 yr: 25-50 mg q6-8h or qhs 2) 10 mg/5 mL syrup Age < 6 yr: 25-50 mg qd

Piperazines Meclizine Cetirizine (Zyrtec) It is most commonly used to inhibit nausea and vomiting as well as vertigo, however it does cause drowsiness This drug treats indoor and outdoor allergies and is safe to use in children as young as 2

5-Tricyclics Promethazine (Phenegran) These drugs are structurally related to tricyclic antidepressants, which explains why they have cholinergic side effects Promethazine (Phenegran) This drug has extremely strong anticholinergic and sedative effects It was originally used as an antipsychotic, however now it is most commonly used as a sedative or antinausea drug (also severe morning sickness) and requires a prescription

Tricyclics Cyproheptadine Ketotifen (Zaditor) This drug both an antihistamine and an antiserotonergic agent It is a 5-HT2 receptor antagonist and also blocks calcium channels Used to treat hay fever and also to stimulate appetite in people with anorexia This drug is available in two forms: an ophthalmic form used to treat allergic conjunctivitis or itchy red eyes and an oral form used to prevent asthma attacks It has several adverse side effects including drowsiness, weight gain, dry mouth, irritability and increased nosebleeds

FORMULATION and DOSAGE OF CYPROHEPTADINE 1) 4-mg tablet Adult: 4 mg tid, qid 2) 2 mg/5 mL syrup Age 7-14 yr: 4 mg bid, tid Age 2-6 yr: 2 mg bid, tid

Tricyclics Alimemazine (Vallergan) Azatadine (Optimine or Trinalin) This drug is used to treat itchiness and hives that results from allergies Since it causes drowsiness, it is useful for rashes that itch worse at night time It is also used to sedate young children before operations This drug is used to treat symptoms of allergies and the common cold such as sneezing, runny nose, itchy watery eyes, itching, hives and rashes

Tricyclics The tricyclic antidepressant most commonly used in dermatology is doxepin. Oral doxepin has been used successfully in the treatment of refractory chronic idiopathic urticaria, physical urticaria, and pruritus associated with systemic conditions. Topical preparations are also available. topical doxepin cream reduced pruritus in patients with atopic dermatitis and lichen simplex chronicus. Sedation is the most common adverse effect with both the oral form and the topical form, which is absorbed percutaneously. Oral doxepin has been classified by the FDA as a pregnancy category C drug; topical doxepin is classified as a pregnancy category B drug.

Second generation H1-receptor antagonists These are the newer drugs and they are much more selective for the peripheral H1-receptors involved in allergies as opposed to the H1-receptors in the CNS. These agents are chemically derived from the first generation agents, for example Cetrizine is a metabolite of Hydroxyzine. These agents bind non competitivelly to the H1-receptors, they are not easily displased by histamen, dissociated slowely and have a longer duration of action than the first. Therefore, these drugs provide the same relief with many fewer adverse side effects. They are however Electrostatic charge, bulkier and less lipophilic than the first generation drugs, therefore they do not cross the BBB as readily.

Second generation H1-receptor antagonists Loratadine (Claritin) Terfenadine (Seldane) It was formerly used to treat allergic conditions In the 1990’s it was removed from the market due to the increased risk of cardiac arrythmias It is the only drug of its class available over the counter It has long lasting effects and does not cause drowsiness because it does not cross the BBB

FORMULATION and DOSAGE OF LORATADINE LORATADINE: 1) 10-mg tablet Age ≥ 6 yr: 10 mg qd 2) 5 mg/mL suspension Age 2-9 yr: 5 mg qd

Second generation H1-receptor antagonists Acrivastine (Semprex-D) Astemizole (Hismantol) This drug has a long duration of action It suppresses the formation of edema and puritus It doesn’t cross the BBB It has been taken off the market in most countries because of adverse interactions with erythromycin and grapefruit juice This drug relieves itchy rashes and hives It is non-sedating because it does not cross the BBB

Second generation H1-receptor antagonists Azelastine (Astelin or Optivar) Levocabastine (Livostin) Olopatadine (Patanol) It is a mast cell stablilizer Available as a nasal spray (Astelin) or eye drops for pink eye (Optivar) Both of these drugs are used as eye drops to treat allergic conjunctivitis

Third generation H1-receptor antagonists These drugs are derived from second generation antihistamines They are either the active enantiomer or metabolite of the second generation drug designed to have increased efficacy and fewer side effects. Levocetirizine (Zyzal) This drug is the active enantiomer of cetirizine and is believed to be more effective and have fewer adverse side effects. Also it is not metabolized and is likely to be safer than other drugs due to a lack of possible drug interactions (Tillement). It does not cross the BBB and does not cause significant drowsiness It has been shown to reduce asthma attacks by 70% in children

Third generation H1-receptor antagonists Deslortadine (Clarinex) Fexofenadine (Allegra) It was developed as an alternative to Terfenadine Fexofenadine was proven to be more effective and safe It is the active metabolite of Lortadine Even though it is thought to be more effective, there is no concrete evidence to prove this

FORMULATION and DOSAGE OF DESLORATADINEN and FEXOFENDINE A-DESLORATADINE: 1) 2.5-, 5-mg tablet Age ≥ 12 yr: 5 mg qd 2) 5 mg/mL syrup Age 6-12 yr: 2.5 mg qd Age 1-6 yr: 1.25 mg qd Age 6-12 mo: 1 mg qd B- Fexofenadine: 1) 30-, 60-, 120-, 180-mg tablet Age ≥ 12 yr: 60 mg qd, bid; 120-180 mg qd Renal impairment Age 6-12 yr: 30 mg qd, bid

H2-receptor antagonists 1-Cimetidine [Tagamet] 2-Ranitdine [Zantac] 3-Famotidine [Pepcid] 4-Nizatidine [Axid]

Mechanism of Action Similar to their H1-binding counterparts, H2 antihistamines are inverse agonists that bind H2 receptors located throughout the body, including epithelial and endothelial cells. More recently, there is evidence that H2 receptors are expressed on mast cells and dermal dendritic cells as well. Through binding of these receptors. H2 antihistamines may mediate cutaneous vascular permeability, local release of inflammatory mediators and cellular recruitment, and antigen presentation, but these pathways remain poorly understood, and their clinical significance is unknown. Displaces histamine from the H2 receptors, a G- protein coupled receptor, because histamine activates cAMP, H2 blockers leads to a decrease in cAMP and a concomitant decrease in Ca ion.

H2-receptor antagonist Pharmacological Effects 1-Competitive antagonsts at the H2 receptors. 2-Inhibits secretory function of gastric mucosa. 3-Few other effects than those on gastric secretion. 4-Reduce gastric acid volume & concentration of pepsin.

Dermatologic Indications for Treatment with H2 Antihistamines. Acute allergic reactions. Chronic urticaria. Urticaria pigmentosa and systemic mastocytosis. Pruritus associated with other conditions.

Most Common Side Effects 1- Diarrhea 2-Dizziness 3-Somnolenece 4-Headache 5-Rash 6-Constipation 7-Vomiting 8-Arthralgia Gynecomastia

Special Patient Populations 1-CHILDREN The H2 antihistamines, ranitidine and famotidine have pharmacokinetics that have been relatively well. studied in children, and these drugs have acceptable safety profiles with appropriate dosing. Cimetidine and nizatidine are not recommended for children. One adverse effect unique to children is an uncommon but drug class-wide risk of necrotizing enterocolitis in neonates. 2-ELDERLY Older patients may require downward adjustment of dosage to accommodate decreased creatinine clearance, as well as careful review of medication lists. Elderly patients also appear more susceptible to CNS disturbances such as confusion and dizziness. 3-PREGNANT WOMEN The H2 antihistamines are classified as FDA pregnancy category B drugs. Cimetidine, ranitidine, famotidine, and nizatidine are all excreted in breast milk; potential effects on the nursing infant have not been studied.

Drug Interactions of H2-receptor antagonist Through inhibition of the CYP system, cimetidine increases the serum levels of numerous drugs, including some of the most common medications used in the care of the medical patient.Of note, cimetidine increases levels of warfarin and may cause dangerous increases in prothrombin time and risk of bleeding. Cimetidine also interacts with many cardiac drugs—several β blockers, calcium channel blockers, amiodarone, antiarrhythmic agents, among others. Other common drugs with which cimetidine interacts are phenytoin, several benzodiazepines, metformin, sulfonylureas, and selective serotonin reuptake inhibitors. Although ranitidine interacts with other medications less frequently than does cimetidine, significant interactions with fentanyl, metoprolol, midazolam, nifedipine, theophylline, and warfarin have been observed. Ranitidine may decrease the absorption of diazepam and reduce its plasma concentration by 25 percent. Famotidine and nizatidine are associated with fewer drug interactions.

H3-receptor antagonists Believe to act as feedback inhibitors in a wide variety of organ system in the CNS, agonists cause sedation GI:-agonists dowen regulate histamine. Thereby decreasing gastrin. Lung:-agoninsts have a bronchodilater effect. Mechanism of Action= G-protein coupled receptor, decrease of intracellular Calcium.

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