Antihistaminics
H1 ANTAGONISTS (Conventional antihistaminics)
-Competitively antagonize actions of histamine at the H1 receptors.
- H1 antagonists are also inverse agonists.
Now , commonly employed are the lesssedating/nonsedating second generation H1 antihistamines added after 1980.
PHARMACOLOGICAL ACTIONS
All H1 antihistaminics have similar actions qualitatively, but there are quantitative differences, especially in the sedative property.
1. Antagonism of histamine
>>block histamine induced bronchoconstriction, contraction of intestinal and other smooth muscle and triple response—especially wheal, flare and itch.
>>Fall in BP produced by low doses of histamine is blocked, but additional H2 antagonists are required for complete blockade of that caused by higher doses. Constriction of larger blood vessel by histamine is also antagonized.
>> Action of histamine on gastric secretion is singularly not affected by these drugs.
2. Antiallergic action
>>Manifestations of immediate hypersensitivity (type I reactions) are suppressed. Urticaria, itching and angioedema are well controlled.
>>Anaphylactic fall in BP is only partially prevented.
>>Asthma in man is practically unaffected ,it is now well established that leukotrienes (C4 and D4) and PAF are more important mediators for human asthma.
3. CNS
>> Older antihistamines produce variable degree of CNS depression which depend on the compound’s ability to penetrate the blood-brain barrier and its affinity for the central (compared to peripheral) H1 receptors. I
The second generation antihistaminics are practically nonsedating. Certain H1 antihistamines 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. Anticholinergic and sedative properties underlie the benefit.
4. Anticholinergic action
Most of the H1 blockers in addition antagonize muscarinic actions of ACh.
5. Local anaesthetic
Pheniramine, promethazine, 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.6. BP
>> fall in BP on i.v. injection (direct smooth muscle relaxation or a adrenergic blockade as in promethazine). However, this is not evident on oral administration.PHARMACOKINETICS
>> 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 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.
SIDE EFFECTS AND TOXICITY
>>Sedation, diminished alertness and concentration, light headedness, motor incoordination, fatigue and tendency to fall asleep are the most common.
>>impairment of psychomotor performance,patients should be cautioned not to operate motor vehicles or machinery requiring constant attention.
Second generation compounds are largely free of CNS effects.
>>Regular use of conventional antihistamines is not advisable in children, because the CNS depressant property may interfere with learning and academic tasks.
>>Dryness of mouth, alteration of bowel movement, urinary hesitancy and blurring of vision can be ascribed to anticholinergic property.
>> Epigastric distress and headache may be felt. Local application can cause contact dermatitis
SECOND GENERATION ANTIHISTAMINICS
The second generation antihistaminics (SGAs) are those H1 receptor blockers marketed after 1980 which have one or more of the following properties:
• Absence of CNS depressant property.
• Higher H1 selectivitiy: 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.
However, they have a narrow spectrum of therapeutic usefulness which is limited by the extent of involvement of histamine (acting through H1 receptors) in the disease state.
Their principal indications are:
(i) Allergic rhinitis and conjunctivitis, hay fever, pollinosis—control sneezing, runny but not blocked nose, and red, watering, itchy eyes.
(ii) Urticaria, dermographism, atopic eczema.
(iii) Acute allergic reactions to drugs and foods.
Fexofenadine
- active metabolite of terfenadine
-the first nonsedating SGA that was withdrawn because of several deaths due to polymorphic ventricular tachycarida (Torsades de pointes) occurring with its higher doses or when it was coadministered with CYP3A4 inhibitors (erythromycin, clarithromycin, ketoconazole, itraconazole, etc.).
Loratadine
-long-acting selective peripheral H1 antagonist which lacks CNS depressant effects and is fast acting.
- metabolized by CYP3A4 to an active metabolite with a longer t½ of 17 hr, but has not produced cardiac arrhythmia in overdose, though seizures are reported.
Desloratadine
- major active metabolite of loratadine effective at half the dose. Noninterference with psychomotor performance and cardiac safety are documented.
Cetirizine
- Metabolite of hydroxyzine with marked affinity for peripheral H1 receptors. It attains high and longer lasting concentration in skin, which may be responsible for superior efficacy in urticaria/atopic dermatitis.
Levocetirizine
>>active R(–) enantiomer of cetirizine. It is effective at half the dose and appears to produce less sedation and other side effects.
Azelastine
>> newer H1 blocker has good topical activity; in addition it inhibits histamine release and inflammatory reaction triggered by LTs and PAF.
Given by nasal spray for seasonal and perennial allergic rhinitis it provides quick symptomatic relief lasting 12 hr.
Stinging in the nose and altered taste perception are the local side effects. Some somnolence has been reported on nasal application and a tendency to weight gain noted after oral use.
Mizolastine
>> nonsedating antihistaminic is effective in allergic rhinitis and urticaria by single daily dosing.
Ebastine
>>newer SGA that rapidly gets converted to the active metabolite carbastine .
It is nonsedating and active in nasal and skin allergies.
Rupatadine
>> recently introduced antihistaminic has additional PAF antagonistic property,
and is indicated in allergic rhinitis.
USES
are based on their ability to block certain effects of histamine released endogeneously, as well as on sedative and anticholinergic properties.
1. Allergic disorders
>>Do not
suppress AG: AB reaction, but block the effects
of released histamine—are only palliative. They
effectively control certain immediate type of
allergies, e.g. itching, urticaria, seasonal hay fever,
allergic conjunctivitis and angioedema of lips,
eyelids, etc.
2. Other conditions involving histamine :
Antihistaminics block symptoms produced by
histamine liberators; afford symptomatic relief in
insect bite and ivy poisoning.
3. Pruritides
Many conventional antihistamines
have antipruritic action independent of H1
antagonism
4. Common cold
>>Afford
symptomatic relief by anticholinergic (reduce
rhinorrhoea) and sedative actions. The newer
nonsedating antihistamines are less effective in
this respect.
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.
7. Preanaesthetic medication
Promethazine
has been used for its anticholinergic and sedative
properties.
8. Cough
Antihistaminics like 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.
9. Parkinsonism
Promethazine and some others
afford mild symptomatic relief in early cases—
based on anticholinergic and sedative property.
10.Acute muscle dystonia
Caused by antidopaminergic-antipsychotic drugs is promptly
relieved by parenteral promethazine, diphenhydramine or hydroxyzine. This is again based on
central anticholinergic action of the drugs.
11.As sedative, hypnotic, anxiolytic
Antihistamines with CNS depressant action have been used
as sedative and to induce sleep, especially in
children.
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