Histamine and Antihistamine ppt / Histamine and Antihistamine Classification PHARMACOLOGICAL ACTIONS / Histamine and Antihistamine pharmacology action
Histamine and Antihistamine
Qualitatively all H1 antihistaminics have similar actions, but there are quantitative differences, especially in the sedative property.
1. Antagonism of histamine :
The H1
antagonists effectively 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. Pretreatment with these drugs protects
animals from death due to i.v. injection of
large doses of histamine. Release of Adr from
adrenal medulla in response to histamine is
abolished. Constriction of larger blood vessel
by histamine is also antagonized. Action of
histamine on gastric secretion is singularly
not affected by these drugs. Cyproheptadine
had additional 5-HT2
receptor blocking activity (see p. 189).
2. Antiallergic action :
Many 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, though anaphylactic
bronchoconstriction in guinea pig is largely
prevented. This tissue and species dependence
of response probably reflects extent of involvement of histamine in the reaction. It is now
well established that leukotrienes (LTC4
, LTD4
)
and PAF are more important mediators for
human asthma.
3. CNS :
The older antihistamines produce variable degree of CNS depression. This appears to
depend on the compound’s ability to penetrate
the blood-brain barrier and its affinity for the
central (compared to peripheral) H1
receptors.
Individual susceptibility to different agents varies considerably. The same drug and dose may
incapacitate some subjects, while others may
remain alert. An overall grading of the sedative
property of H1
antihistaminics is presented in
Table 11.2. Some individuals also experience
stimulant effects like restlessness and insomnia.
Excitement and convulsions are frequently seen
at toxic doses. The second generation antihistaminics are practically nonsedating.
Certain (see below) 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.
Some older antihistamines, especially
cyproheptadine, have appetite stimulating effect.
Some H1
antihistamines are also effective
antitussives (see Ch. 16).
4. Anticholinergic action :
Many H1
blockers
in addition antagonize muscarinic actions of ACh.
The antimuscarinic action can be graded as:
If used concurrently with atropine or its substitutes, phenothiazines, tricyclic antidepressants or
disopyramide, the anticholinergic action adds up.
5. Local anaesthetic :
Some drugs like
pheniramine, promethazine, diphenhydramine
have strong while others have weak membrane
stabilizing property. However, they are not clinically suitable local anaesthetics because
they cause irritation when injected s.c.
Membrane stabilizing activity confers antiarrhythmic property to these compounds.
6. BP :
Most antihistaminics cause a fall in BP
on i.v. injection (direct smooth muscle relaxation
or α adrenergic blockade). Promethazine has
significant α blocking activity. However, this
is not evident on oral administration, though
postural hypotension can occur in susceptible
individuals.
PHARMACOKINETICS :
The conventional 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 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.
The H1
antihistaminics are mainly administered
orally, but few are available for i.m./i.v. use
as well.
SIDE EFFECTS AND TOXICITY :
Side effects of first generation H1
antihistaminics are frequent, but generally mild. Individuals show marked differences in susceptibility
to side effects with different drugs. Some
tolerance to side effects develops on repeated
use.
Sedation, diminished alertness and concentration, light headedness, motor incoordination,
fatigue and tendency to fall asleep are the most
common. Objective testing shows impairment
of psychomotor performance. Patients should
be cautioned not to operate motor vehicles or
machinery requiring constant attention. Alcohol
synergises in producing these effects as do other
CNS depressants. Few individuals, however,
become restless, nervous and are unable to sleep.
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 of
older antihistaminics.
Epigastric distress and headache may be felt.
Local application can cause contact dermatitis.
Some drugs like hydroxyzine, cyclizine and
fexofenadine are teratogenic in animals; but
there is no evidence of excess malformations
in humans. Caution is nevertheless to be
exercised in prescribing an antihistaminic during pregnancy.
Acute overdose produces central excitation,
tremors, hallucinations, muscular incordination,
convulsions, flushing, hypotension, fever and
some other features of belladonna poisoning.
Death is due to respiratory and cardiovascular
failure.
SECOND GENERATION ANTIHISTAMINICS :
The second generation antihistaminics (SGAs)
may be defined as 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 modifying release/ action of leukotrienes, platelet activating factor (PAF) and cytokines, etc.
As per an international consensus group of experts,
no compound developed so far merits labelling as ‘third
generation antihistaminic’.
These newer drugs have the advantage of
not impairing 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. 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: they 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.
The SGAs have poor antipruritic, antiemetic
and antitussive actions.
Fexofenadine :
It is the active metabolite
of terfenadine, the first nonsedating SGA that
was withdrawn because of several deaths due
to polymorphic ventricular tachycardia (Torsades de pointes) occurring with its higher
doses or when it was coadministered with CYP3A4 inhibitors (erythromycin, clarithromycin,
ketoconazole, itraconazole, etc.). This toxicity
is based on blockade of delayed rectifier K+
channels in the heart at higher concentrations.
Astemizole is another SGA banned for the
same reason. Fexofenadine has a low propensity
to block delayed rectifier K+ channels, does
not prolong QTc interval. Since it is minimally metabolized, no interaction with CYP3A4
inhibitors have been reported. It is largely free
of arrhythmogenic potential, but some cases
of ventricular arrhythmia in patients with preexisting long QT interval have been reported.
Thus, it is not entirely safe in patients with
long QT, bradycardia or hypokalemia.
Fexofenadine penetrates blood-brain barrier
poorly; produces minimal sedation or impairment of psychomotor performance. It is free of
atropinic side effects. oral absorption is rapid.
It is mainly excreted unchanged in urine and
bile, has plasma t½ 11–16 hours and duration
of action 24 hours.
Dose: For allergic rhinitis 120 mg OD; for urticaria and other
skin allergies 180 mg OD.
Loratadine :
Another long-acting selective
peripheral H1
antagonist which lacks CNS
depressant effects and is fast acting. It is
partly 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. No interaction
with macrolides or antifungals has been noted.
Good efficacy has been reported in urticaria
and atopic dermatitis.
Desloratadine :
It is the major active
metabolite of loratadine effective at half the
dose. Noninterference with psychomotor performance and cardiac safety are documented.
Cetirizine :
It is a metabolite of hydroxyzine
with marked affinity for peripheral H1
receptors; penetrates brain poorly, but mild sedation
and subjective somnolence is experienced by
many recipients. It is not metabolized; does
not prolong cardiac action potential or produce
arrhythmias when given with erythromycin/
ketoconazole.
Cetirizine in addition inhibits release of
histamine and of cytotoxic mediators from
platelets as well as eosinophil chemotaxis during
the secondary phase of the allergic response.
Thus, it may benefit allergic disorders by other
actions as well. It attains high and longer lasting
concentration in skin, which may be responsible
for superior efficacy in urticaria/atopic dermatitis, as well as for once daily dosing despite
elimination t½ of 7–10 hr. It is indicated in
upper respiratory allergies, pollinosis, urticaria
and atopic dermatitis; also used as adjuvant
in seasonal asthma.
Levocetirizine :
is the active R(–) enantiomer
of cetirizine. It is effective at half the dose
and appears to produce less sedation and other
side effects.
Azelastine :
This newer H1
blocker has good
topical activity; in addition it inhibits histamine
release and inflammatory reaction triggered by LTs
and PAF. After intranasal application it has been
shown to down regulate intracellular adhesion
molecule-1 (ICAM-1) expression on nasal mucosa.
Its t½ is 24 hr, but action lasts longer due to
active metabolite. Its metabolism is inhibited by
CYP 3A4 inhibitors. Given by nasal spray for
seasonal and perennial allergic rhinitis it provides This newer H1
blocker has good
topical activity; in addition it inhibits histamine
release and inflammatory reaction triggered by LTs
and PAF. After intranasal application it has been
shown to down regulate intracellular adhesion
molecule-1 (ICAM-1) expression on nasal mucosa.
Its t½ is 24 hr, but action lasts longer due to
active metabolite. Its metabolism is inhibited by
CYP 3A4 inhibitors. Given by nasal spray for
seasonal and perennial allergic rhinitis it provides.
Mizolastine :
This nonsedating antihistaminic
is effective in allergic rhinitis and urticaria by
single daily dosing despite a t½ of 8–10 hr
and no active metabolite.
Ebastine :
Another newer SGA that rapidly
gets converted to the active metabolite carbastine having a t½ of 10–16 hr. It is nonsedating
and active in nasal and skin allergies. Animal
studies have found it to prolong Q-Tc interval which makes it liable to arrhythmogenic
potential and CYP3A4 interaction, but actual
reports are still few.
Rupatadine :
This recently introduced antihistaminic has additional PAF antagonistic property,
and is indicated in allergic rhinitis.
USES :
The uses of H1
antihistaminics are based on
their ability to block certain effects of histamine
released endogeneously, as well as on their
sedative and anticholinergic properties.
1. Allergic disorders :
Antihistaminics do
not suppress AG: AB reaction, but block the
effects of released histamine—are only palliative. They effectively control certain immediate
type of allergies, such as itching, urticaria,
seasonal hay fever, allergic conjunctivitis and
angioedema of lips, eyelids, etc. However,
their action is slow, therefore Adr alone is
life-saving in laryngeal angioedema, while
intravenously administered antihistaminic may
have adjuvant value. Similarly, they cannot be
relied upon in anaphylactic shock and have
a secondary place to Adr. Benefits are less
marked in perennial vasomotor rhinitis, atopic
dermatitis and chronic urticarias; combination with an H2
antagonist succeeds in some
cases of chronic urticaria not responding to
H1
antagonist alone.
The antihistaminics are ineffective in bronchial
asthma: reasons may be—
- Leukotrienes (LTC4 , D4 ) and PAF are more important mediators in humans than histamine.
- Concentration of antihistamines attained at the site may not be sufficient to block high concentration of histamine released locally in the bronchi.
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