The document provides a comprehensive overview of antihistamines, detailing their definition, mechanisms of action, and various classes. It discusses the clinical uses, side effects, and contraindications of antihistamines, emphasizing the differences between first-generation and second-generation antihistamines. Special populations, drug interactions, and key examples of specific antihistamines are also covered.

1. AntihistaminesAntihistamines
ByBy
Dr. Saad Raheem AbedDr. Saad Raheem Abed
2016

2. AntihistaminesAntihistamines

3. 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.

4. 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.

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

6. 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 .

7. 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

8. 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,a
ngioedema
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
Unknown In addition to
benefiting allergic
conditions, research
in the h4 receptor
may lead to the
treatment of
autoimmune
diseases.
(rheumatoid arthritis
and IBS)

9. 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

10. 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)

11. 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)

12. 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.

13. 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.

14. 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.

15. 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

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

17. 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

18. 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

19. 1-Ethylenediamines
 These were the first group of clinically
effective H1-antihistamines
Mepyramine (Pyrilamine)

20. 2-Ethanolamines
 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)

21. 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

22. Ethanolamines
Carbinoxamine(Clistine) Doxylamine succinate
•2nd in effectiveness of anti-allergy
activity only to Benadryl
•Potent anti-cholinergic effects
•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)

23. Ethanolamines
Clemastine (Tavist) Dimenhydrinate
(Dramamine)
•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

24. 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

25. 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

26. 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

27. 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

28. 4-Piperazines
 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
•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)
Cyclizine

29. 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

30. 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

31. 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

32. 5-Tricyclics
 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

33. 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

34. 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

35. 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

36. 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.

37. 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.

38. Second generation H1-receptor
antagonists
Loratadine (Claritin)
Terfenadine
(Seldane)
•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
•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

39. 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

40. 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

41. Second generation H1-receptor
antagonists
Azelastine
(Astelin or Optivar)
Levocabastine
(Livostin)
•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
Olopatadine
(Patanol)

42. 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

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

44. 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

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

46. 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.

47. 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.

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

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

50. 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

51. 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

52. 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.

53. Thank you
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