Overview of Discussion- H1 -antagonists Classification of H1 -antagonists Pharmacological actions Pharmacokinetics Adverse effects Second generation antihistaminics Therapeutic uses

1. H1 - Antagonists
Mr. Vishal Balakrushna Jadhav
Assistant professor (Pharmacology)
School of Pharmaceutical Sciences (SOPS), Sandip University, Nashik
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2. Overview of Discussion
H1 -antagonists
Classification of H1 -antagonists
Pharmacological actions
Pharmacokinetics
Adverse effects
Second generation antihistaminics
Therapeutic uses
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3. H1 -antagonists
 Conventional antihistaminics competitively antagonize actions of
histamine at the H1 receptors and also have inverse agonistic
potency.
 Clinically used agents are less sedating/ non-sedating second
generation H1 antihistamines.
 Have diverse chemical structures, but majority have a substituted
ethylamine side chain.
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4. Classification of H1 -antagonists
 Includes first- and second generation drugs (as shown in figure).
 The older first-generation drugs are still widely used because they are
effective and inexpensive. They penetrate the CNS and cause sedation, tend to
interact with other receptors, producing a variety of unwanted adverse effects.
 In contrast, the newer second-generation agents are specific for peripheral
H1 receptors, polar in nature (presence of carboxyl groups, for example,
cetirizine), do not penetrate the blood–brain barrier, causing less CNS
depression (sedation) than the first generation drugs.
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5. Fig. Classification of H1 –antagonists 5

6. Pharmacological actions
Actions are qualitatively similar, but quantitative different, especially in
concern with the sedative property.
1. Antagonism of histamine
2. Antiallergic action
3. Central nervous system (CNS)
4. Anticholinergic action
5. Local anaesthetic
6. Blood pressure (BP)
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7. 1. Antagonism of histamine- H1 –antagonists-
 Blocks histamine induced bronchoconstriction, contraction of intestinal and
other smooth muscle and triple response- especially wheal, flare and itch.
 Blocks fall in BP produced by low doses of histamine, but additional H2
antagonists are required for complete blockade of that caused by higher doses.
Pretreatment with these drugs protects animals from death due to i.v. injection
of large doses of histamine.
 Inhibits the release of adrenaline (Adr) from adrenal medulla in response to
histamine.
 Antagonize constriction of larger blood vessel by histamine .
 Action of histamine on gastric secretion is singularly not affected by these
drugs (H2 blockers may required).
 Cyproheptadine had additional 5-HT2 receptor blocking activity.
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8. 2. Antiallergic action- H1 –antagonists-
 Suppress manifestations of immediate hypersensitivity (type I reactions) →
urticaria, itching and angioedema are well controlled.
 Prevent partially anaphylactic fall in BP.
 Human asthma is practically unaffected, though anaphylactic
bronchoconstriction in guinea pig is largely prevented → this tissue and species
dependence response probably reflects extent of involvement of histamine. It is
now well established that leukotrienes (C4 and D4) and PAF are more
important mediators for human asthma.
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9. 3. Central nervous system (CNS)
 Because of penetration across blood-brain barrier and affinity for the central
(compared to peripheral) H1 receptors, older first generation
antihistaminics produces variable degree of CNS depression (sedation).
Intersubject variation may develop to CNS effect → same drug and dose may
sedate some subjects, while others may remain alert.
 According to sedative potential, agents are classified as-
a) Highly sedative (e.g. Diphenhydramine, Dimenhydrinate, Promethazine,
Hydroxyzine), b) Moderately sedative (e.g. Pheniramine, Cyproheptadine,
Meclozine, Cinnarizine), and c) Mild sedative (e.g. Chlorpheniramine,
Dexchlorpheniramine, Triprolidine, Clemastine). Some individuals also
experience CNS stimulant effects like restlessness and insomnia.
Excitement and convulsions are frequently seen at toxic doses.
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10.  The second generation antihistaminics are practically non-sedating.
 Promethazine, diphenhydramine, dimenhydrinate and meclozine are effective in
preventing motion sickness. It is not clear whether this is due to antagonism
of histamine in the brain or reflects antimuscarinic property of these drugs.
 Promethazine also controls vomiting of pregnancy and other causes.
 Promethazine and few other antihistaminics reduce tremor, rigidity and
sialorrhoea of parkinsonism because of anticholinergic and sedative
properties.
 Cyproheptadine, have appetite stimulating effect.
 Some H1 antihistamines are also effective antitussives.
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11. 4. Anticholinergic action
Many H1 blockers in addition antagonize muscarinic actions of ACh. The
anticholinergic action can be graded as:
Concurrent administration with atropine or its substitutes, phenothiazines,
tricyclic antidepressants or disopyramide → additive anticholinergic
action.
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12. 5. Local anaesthetic
Pheniramine, promethazine and diphenhydramine have strong while others have
weak membrane stabilizing property. However, they are not used
clinically as local anaesthetic because they cause irritation when injected s.c.
Membrane stabilizing activity confers antiarrhythmic property to these
compounds.
6. Blood pressure (BP)
Promethazine cause direct smooth muscle relaxation or α- adrenergic
blockade → fall in BP on i.v. injection. However, this is not evident on oral
administration.
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13.  The conventional first generation H1 antihistaminics are well absorbed
from oral and parenteral routes, metabolized in the liver and excreted in
urine. They are widely distributed in the body and enter brain.
 The newer second generation compounds penetrate brain poorly
accounting for their low/absent sedating action.
 Duration of action of most agents is 4–6 hours, except meclozine,
chlorpheniramine, mesolastine, loratadine, cetirizine and fexofenadine which
act for 12–24 hours or more.
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Pharmacokinetics

14.  First-generation H1-receptor blockers have a low specificity,
interacting not only with histamine receptors but also with muscarinic
cholinergic receptors, α-adrenergic receptors, and serotonin receptors.
Nature of the side effects varies with the structure of the drug and extent
of interaction with these receptors.
 Some side effects may be undesirable, and others may be of therapeutic
value. Furthermore, the incidence and severity of adverse reactions for a
given drug varies between individual subjects.
 Interaction of H1-receptor blockers with abovementioned receptors and
possible side effects is shown below-
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Adverse effects

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Figure- Some adverse effects observed with antihistamines

17. Second generation antihistaminics
Ideal properties of second generation H1- blockers-
 Absence of CNS depressant property (less/ no sedative potency).
 Higher H1 selectivity → no anticholinergic side effects.
 Additional antiallergic mechanisms apart from histamine blockade → some
also inhibit late phase allergic reaction by acting on leukotrienes or by
antiplatelet activating factor effect.
 No impairment of psychomotor performance (driving etc. need not be
contraindicated), produce no subjective effects, no sleepiness, do not
potentiate alcohol or benzodiazepines.
 Some patients do complain of sedation, but incidence is similar to that with
placebo.
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18. Second generation H1- blockers have a narrow spectrum of therapeutic
use and are indicated for the treatment of-
 Allergic rhinitis and conjunctivitis, hay fever, pollinosis→ control sneezing,
runny but not blocked nose, and red, watering, itchy eyes,
 Urticaria, dermographism, atopic eczema, and
 Acute allergic reactions to drugs and foods.
They have poor antipruritic, antiemetic and antitussive actions.
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19. Therapeutic uses
The uses of H1 antihistaminics are based on their ability to block certain effects of
histamine released endogeneously, as well as on sedative and
anticholinergic properties. The indications are-
1. Allergic disorders 9. Cough
2. Other conditions 10. Acute muscle dystonia
3. Pruritides 11. As sedative, hypnotic, anxiolytic
4. Common cold
5. Motion sickness
6. Vertigo
7. Preanaesthetic medication
8. Parkinsonism
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20. 1. Allergic disorders
 Do not suppress AG: AB reaction, but block the effects of released histamine-
are only palliative.
 Effectively control certain immediate type of allergies, e.g. itching, urticaria,
seasonal hay fever, allergic conjunctivitis and angioedema of lips, eyelids, etc.
 IV antihistaminic may have adjuvant value in laryngeal angioedema, and have
a secondary place to Adr in anaphylactic shock .
 Benefits are less marked in perennial vasomotor rhinitis, atopic dermatitis
and chronic urticarias→ combination with an H2 antagonist may required.
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21.  The antihistaminics are ineffective in bronchial asthma: reasons may be—
(i) Leukotrienes (C4, D4) and PAF are more important mediators than
histamine, and (ii) Concentration of antihistamines attained at the site may
not be sufficient to block high concentration of histamine released locally in
the bronchi.
 Cetirizine have adjuvant role in seasonal asthma.
 Ineffective in other types of humoral and cell mediated allergies because
histamine is not involved.
 Suppress urticaria and swellings in serum sickness.
 Type I hypersensitivity reactions to drugs (except asthma and anaphylaxis)
are suppressed. Some skin rashes also respond.
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22. 2. Other conditions involving histamine
 Block symptoms produced by histamine liberators; afford symptomatic relief
in insect bite and ivy poisoning.
 Suppressed abnormal dermographism.
 Have prophylactic value in blood/saline infusion induced rigor.
3. Pruritides
 Antipruritic action independent of H1 antagonism.
 Older antihistaminics chlorpheniramine, diphenhydramine, cyproheptadine
remain the first choice drugs for idiopathic pruritus.
4. Common cold
 Afford symptomatic relief by anticholinergic (reduce rhinorrhoea) and
sedative actions. Newer nonsedating antihistamines are less effective.
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23. 5. Motion sickness
 Promethazine, diphenhydramine, dimenhydrinate and meclozine have
prophylactic value in milder types of motion sickness; should be taken one
hour before starting journey.
 Promethazine can also be used in morning sickness, drug induced and
postoperative vomiting, radiation sickness.
6. Vertigo
 Cinnarizine is the H1 antihistamine having additional anticholinergic, anti-5-
HT, sedative and vasodilator properties which has been widely used in
vertigo. It modulates Ca2+ fluxes and reduces vasoconstrictor action of many
endogenous mediators.
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24.  Cinnarizine inhibits vestibular sensory nuclei in the inner ear, suppresses
postrotatory labyrinthine reflexes, possibly by reducing stimulated influx of
Ca2+ from endolymph into the vestibular sensory cells. Beneficial effects have
been reported in Meniere’s disease and other types of vertigo.
 Side effects are sedation and mild g.i. upset.
 Dimenhydrinate is another effective antivertigo antihistaminic.
7. Preanaesthetic medication
Promethazine has been used for its anticholinergic and sedative properties.
8. Parkinsonism
Because of anticholinergic and sedative property, promethazine and some
others afford mild symptomatic relief in early cases.
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25. 9. Cough
Chlorpheniramine, diphenhydramine and promethazine are constituents of
many popular cough remedies. They have no selective cough suppressant
action, but may afford symptomatic relief by sedative and anticholinergic
property.
10. Acute muscle dystonia
Because 0f central anticholinergic action, parenteral promethazine,
diphenhydramine or hydroxyzine relieve acute muscle dystonia caused by
antidopaminergic- antipsychotic drugs.
11. As sedative, hypnotic, anxiolytic
Antihistamines with CNS depressant action have been used as sedative and to
induce sleep, especially in children. Anxiety associated with autonomic
manifestations is treated by hydroxyzine. 25

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