1. Antihistamines work by blocking the action of histamine at H1 receptor sites. They are classified as first or second generation depending on their sedative effects.
2. H1 receptor antagonists are used to treat allergic reactions, motion sickness, and nausea. Their toxicities include excitation, convulsions in children, and postural hypotension.
3. H2 receptor antagonists reduce acid secretion through competitive inhibition of parietal cells. They are used to treat gastroesophageal reflux disease, peptic ulcer disease, and stress-related gastritis. Their adverse effects are generally mild.
3. Storage
Basophil & Mast
Cells sites of potential tissue injury—nose,
mouth, and feet; internal body surfaces
and blood vessels, particularly at
pressure points and bifurcations
Non mast cells including
brain Function as neurotransmitter
Enterochromaffin-like (ECL) cells of
the fundus of the stomach
6. Pharmacokinetics of H1 Receptor Antagonists
Based on Sedative Effect
First Generation Antagonists Second Generation Antagonists
• Stable Amines
• Administered orally
• Distributed widely throughout the body
• Readily enters CNS (First generation)
• Metabolized in the liver(First generation),CYP34A System ( Second
Generation) and subject to important interactions
• Effective Duration of 4-6 hours ( Exception- Meclizine 12-24 hours)
• Less lipid soluble newer agents
• Many active metabolites are active as drugs ( Ex:
Cetrizine,Fexofenadine,Desloratidine)
7. Pharmacodynamics of H1 Receptor Antagonists
Similar general structure as muscarinic cholinoceptor, α
adrenoceptor, serotonin and local anesthetics receptor sites
Also has some additional actions
due to structural similarity
Blocks action of Histamin
Fig: Actions of H1 Receptor Antagonists
1. Sedation
• Common effect of first generation H1 Antagonists
• Useful as “Sleep Aids” and unsuitable for daytime use
• Children occasionally manifest excitation at ordinary dosages(adults rarely).
• Marked agitation, stimulation and convulsions may precede coma at very high
toxic dose level
• Second generation H1 antagonists have little or no sedative or stimulant
actions
2. Antinausea & antimetic actions
• Significant activity in preventing motion sickness
• Less effective against episode of motion sickness already present
3. Antiparkinsonism Effect
• Significant acute suppressant effects on the extrapyramidal symptoms
associated with certain antipsychotic drugs.
8. Pharmacodynamics of H1 Receptor Antagonists
Similar general structure as muscarinic cholinoceptor, α
adrenoceptor, serotonin and local anaesthetic receptor sites
Also has some additional actions
due to structural similarity
Blocks action of Histamin
Fig: Actions of H1 Receptor Antagonists
4. Anticholinoceptor Actions
• Significant atropine like effects on peripheral muscarinic receptors
• May be responsible for some of the benefits of nonallergic rhinorrhoea
• May also cause urinary retention and blurred vision
5. Adrenoceptor blocking actions
• May cause orthostatic hypotension in susceptible individuals
6. Serotonin Blocking Action
• Strong blocking action at serotonin receptors by some first generation H1
receptor antagonists
7. Local Anaesthetic Action
• Potent local anaesthetics
• Blocks sodium and potassium ion channels
• Used to produce local anaesthesia in patients who are allergic to conventional
local anaesthetic drugs
9. Clinical Use of H1 Receptor Antagonists
Most extensively used due to sedative effects
Prevalence of allergic reaction and relative safety
contributes to heavy use and over the counter drugs
Used in allergic reactions, motion sickness and vestibular
disturbances, nausea and vomiting of pregnancy
Allergic Reaction
• Second line drugs in Hay Fever
• Quite effective if given before exposure
in Urticaria
• Largely ineffective in Bronchial Asthma
• Used in Angioedema
• Diphenhydramine used in Atopic
Dermatitis for sedative side effects which
reduces awareness of itching
• The second generation H1 antagonists
are mainly used for allergic rhinitis and
chronic urticaria
Motion Sickness
• Scopolamine, Diphenhydramine and
Promethazine are most effective
• Scopolamine and H1 antagonists when
combined with ephedrine and
amphetamine are more effective
• Dimenhydrinate and piperazines also
contribute in preventing motion sickness
• Dosage is the same as allergic disorders
Nausea and Vomiting
• Piperazine derivatives were withdrawn
due to teratogenic effect in rodents
• Doxylamine was promoted as a
component of Bendictin. Later
withdrawn due to possible teratogenic
effect
• Studies disclosed Bendictin ingestion do
not contribute to increase in the
incidence of birth defects
10. Toxicity of H1 Receptor Antagonists
Toxicity
• Drugs used for sedation and antimuscarinic action
constitute the most undesired actions
• Excitation, convulsion in children, postural hypotension
and allergic reactions are less uncommon side effects
• Drug allergy is relatively common after tropical use of
H1 antagonists
• Overdosage of astemizole terfenadine may induce
cardiac arrhythmias. Same effect may be caused at
normal dosage by interaction with enzyme inhibitors
Convulsion
Excitation
Toxicity
Postural
Hypotension
Allergy
Cardiac
Arrhythmias
Fig: Toxicity of H1 Receptor Antagonists
11. Pharmacokinetics of H2 Receptor Antagonists
• Four H2 antagonists are in clinical use: Cimetidine, Ranitidine,
Famotidine, Nizatidine
• Rapidly absorbed from the Intestine
• Cleared by a combination of hepatic metabolism, glomerular
filtration, renal tubular secretion
• Serum half lives range from 1.1 to 4 hours
• Dose reduction is required in patients with moderate to severe
renal insufficiency
12. Pharmacodynamics of H2 Receptor Antagonists
2 mechanisms
Direct
stimulation
of parietal
cells
Release of
histamin
from ECL
cells
• Exhibits competitive inhibition at parietal cells
• Some are inverse agonists
• Highly Selective
• Do not effect H3 or H4 receptors
• Suppress basal and meal stimulated acid secretion
• Reduction of acid secretion is stimulated by gastrin and
cholinomimetic agents through 2 mechanisms
Fig: H2 Receptor Mechanism of reducing acid secretion
13. Clinical Use of H2 Receptor Antagonists
Gastroesophageal Reflux Disease
• Taken prophylactically before meal to
reduce heartburn
• Are not short lived (6-10 hours)
compared with antacids (1-2 hours)
• Affords healing in less than 50% of
patients with erosive esophagitis.
Peptic Ulcer Disease
• Nocturnal acid suppression affords
effective ulcer healing in most patients
with uncomplicated gastric and duodenal
ulcers
• May be given daily at bedtime in half of
the usual ulcer therapeutic dose to
prevent ulcer recurrence for the minority
of patients in whom H pylori cannot be
successfully eradicated
Nonuclear Dyspepsia
• Used as over the counter drugs
• Used as prescription agents for
treatment of intermittent dyspepsia not
caused by peptic ulcer
Prevention of Bleeding from Stress related gastritis
• Preferable over proton pump inhibitors for patients
without a nasoenteric tube or with significant ileus
due to proven efficacy and lower cost
• Because of consistent, sustained intragastric pH,
continuous infusions of H2 antagonists are
generally preferred to bolus infusions
14. Adverse Effects of H2 Receptor Antagonists
• Adverse effects occur in less than 3% of patients
• Intravenous administration may increase risk in
critically ill patients
• Mental status changes include confusions,
hallucinations, agitation
• Long term or high dose may cause gynecomastia in men
and galactorrhoea in women
• No harmful effects on fetus
• May affect nursing infants if secreted into breast milk
Fig: Adverse effects of H2 Receptor Antagonists
