Antihistamines

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Antihistamines By Dr. Saad Raheem
Abed
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Antihistamines
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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.

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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.

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Histamine Storage and Release

• Histamine Stored in complex with
• Heparin
• Chondroitin sulphate
• Eosinophilic Chemotactic Factor
• Nnutrophilic Chemotactic Factor
• Proteases

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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 .

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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

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

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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)

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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)

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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.
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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.
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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.

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• 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

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Classes of First generation H1 receptor
antagonist antihistamines

• Ethylenediamines
• Ethanolamines
• Alkylamines
• Piperazines
• Tricyclics
• Piperadines

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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

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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, a-adrenergic, and serotonin
  receptors and cardiac ion channels

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1-Ethylenediamines

• These were the first group of clinically
  effective H1-antihistamines

Mepyramine (Pyrilamine)
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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, its 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)

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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

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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

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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

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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

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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

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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

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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

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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

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)

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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

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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 lt 6 yr 25-50 mg qd

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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

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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

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Tricyclics

• Cyproheptadine

• Ketotifen (Zaditor)

• 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

• 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

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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

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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

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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.

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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.

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Second generation H1-receptor antagonists

• Loratadine (Claritin)

• Terfenadine (Seldane)

• It was formerly used to treat allergic conditions
• In the 1990s 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

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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

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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 doesnt 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

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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

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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

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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

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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

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H2-receptor antagonists

• 1-Cimetidine Tagamet
• 2-Ranitdine Zantac
• 3-Famotidine Pepcid
• 4-Nizatidine Axid

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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.

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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.

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Dermatologic Indications for Treatment with H2
Antihistamines.

• Acute allergic reactions.
• Chronic urticaria.
• Urticaria pigmentosa and systemic mastocytosis.
• Pruritus associated with other conditions.

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Most Common Side Effects

• 1- Diarrhea
• 2-Dizziness
• 3-Somnolenece
• 4-Headache
• 5-Rash
• 6-Constipation
• 7-Vomiting
• 8-Arthralgia
• Gynecomastia

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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.

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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 drugsseveral ß 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.

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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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