ANTI-HISTAMINE :
Histamine : an important mediators of immediate allergic & inflammatory reaction, has an
important role in gastric acid secretion & function as neurotransmitter or neuromodulators .
their receptor include H1(smooth muscle , endothelium & brain ) , H2(gastric mucosa , cardiac
muscles, mast cell & brain ) , H3(CNS as brain , neurons ,myenteric plexus ..etc ) .
anti-histamine
:
the effect of histamine release in body can be reverse via one of the following way :
1-phsiologic antagonist : especially epinephrine that its effect on smooth muscle opposite to
histamine , but act at deferent receptor this consider important in case of anaphylactic shock
where a large amount of histamine was release .
2-release inhibitors : reduce degradation of mast cell that result from immunologic trigger by
antigen IgE like in case of cromolyn & nedocromil that used in asthma .
3-receptor antagonist : as competitive inhibitor as in case\e of H2 receptor antagonist
Burimamide & selective H3 antagonist like Thioperamide & Clobenpropit .
Classification of H1 receptor antagonist
:
A-first generation include
1-ethanolamines likeCarbinoxamine,Dimenhydrinate,Diphenhydramine, Doxylamine .
2-ethylaminediamines like Pyrilamine , Tripelennamine .
3-piperazine derivatives like Meclizine , Cyclizine & Hydroxyzine .
4-Alkylamines like Brompheniramine &Chlorpheniramine .
5-Phenothiazine derivatives like Promethazine .
6-miscellneous like Cyproheptadine
B- second generation
:
1-piperidines like Fexofenadine .
2-miscellneous like Loratadine & Cetirizine .
first generation of more sedative & autonomic receptor blocking effect than second one .
second generation less completely distributed into CNS , so of less sedative effect . all rapidly
oral absorbed & peak blood conc. Achieve in 1-2 hours . widely distributed into the body & for
first generation into CNS . their effective duration of action 4-6 hours after single dose except
for meclizine & second generation 12-24 hours .
H1 receptor antagonist of effect not due to H1 receptor blocking (multi-systemic effects ) , this
is really due to or result from the similarity of general structure to the structure of the drug that
having these effects at M-receptor , alfa adrenoceptor , serotonin & local anesthetic receptor .
these effects include :
1-sedation which is a considerable effect of the first generation , useful as for sleep aids , &
unsuitable for day times this due to anti-muscarnic effect .
2-anti-nausea & anti-emetic effect of some benefit in treatment of motion sickness .
3-anti-parkinsonism effect as an anti-cholinergic effect .
4-anti-cholinergic effect .
5-adrenoceptive blocking action on alfa receptor like promethazine .
6-serotonin blocking effect .
7-local; anesthetic effect block Na+ channels as in promethazine & diphenhydramine consider
as more potent than procaine as local anesthetic agent .
8-other effects like cetirizine inhibit mast cell release of histamine by unknown mechanism
clinical uses :
1-allergic reaction as in case of following states allergic rhinitis , urticaria , atopic dermatitis ,
hay fever :
2-motion sickness & vestibular disturbance especially dihpenhydramine , promethazine &
piperazine in dose like that of allergy to treat or as prophylaxis of motion sickness , also used in
treatment of minier’s syndrome .
3-nausea & vomiting in pregnancy especially doxylamine .
toxicity of H1 antagonists :
1-commonest like sedation & anti-muscarnic effects which may get some therapeutic benefit .
2-less common like excitation & convulsion in children , postural hypotension , allergic
response especially after topical uses .
treatment of sever systemic over dose like that of atropine .
anti-histamine & their metabolite are cardiac toxicity may become or cause lethal ventricular
arrhythmia especially if take with one of the following agent ketoconazole , traconazole ,
macrolide antibiotic since all above agent increase anti-histamine conc. That cause blocking of
K
+
channel & I
kr
channel that cause a prolongation of action potential which may cause
arrhythmias
-Greapefruit juice inhibit CYP3A4 that cause increasing level of terfenadine to a significant
level .
combination of both H1 & H2 receptors antagonist more effective in preventing the action of
histamine than either agent alone .
DRUDS USED IN TREATMENT OF ASTHME :-
A- Cromolyn & Nedocromil
:-
cromolyn sodium is Di-Na-cromoglycate & nedocromil
both are of values when taken as prophylaxis to inhibit antigen & exercise inducing asthma , &
in asthma due to aspirin or of occupational origin . in the chronic asthma they reduce over all
bronchial reactivity , they are of no role in bronchial spasm . both drugs poorly absorbed via
GIT , so only available as inhaler or aerosolized solution . their mode of action include [ an
alternation in function of delayed chloride channels in the cell membrane causing an inhibition
of cellular activation , by this action on airway they suppress cough , on mast cell they inhibit of
early response to antigen , on esosinophil they inhibit inflammatory reaction to antigen . to exert
their effect used short period prior to exercise . less potent & of predictable effect than inhaled
corticosteroid .cromolyn solution also used in treatment of allergic rhino-conjunctivitis as nasal
or eye drops . their adverse effects (throat irritation , mouth dryness , cough , chest tightness ,
wheezing can be reduce by inhale B-adrenergic agent before it these the most common side
effects , while rare side effects are reversible dermatitis , myositis , gastro-enteritis ,
anaphylaxis ) .it consider as 1-alternative to inhaled corticosteroid in patient with a symptoms
occur in attach more that twice a week , or wakened him from sleep .2-for patient of seasonal
attach .
B-Methyl-xanthenes drug :- which include 1-natural type [ theophylline , theobromide &
caffeine ]which found in [tea, coca & coffee] respectively .2- synthetic type like
aminophylline(theophylline- ethylene-di-amine complex)& dyohylline analog synthetic
theophylline of less potent & short acting than theophylline . mechanism of action of this group
include (1-inhibit phosphodiesterase enzyme causing increase of intra-cellular concentration of
cAMP that lead to smooth muscles relaxation & cardiac stimulation . / 2-inhibition of cell
surface receptors of adenosine (adenosine cause smooth muscle contraction & provoke release
of histamine via mast cells ) . / 3- it has an anti-inflammatory effects . / 4-inhibit antigen induce
histamine release . )
Theophylline of more smooth muscle relaxation than caffeine which in turn of more CNS
effect . these drugs of CNS effects(in mild dose cause nervousness , insomnia& on large dose
cause tremor & convulsion ) , CVS effects( arrhythmias. Increase COP ,& sinus tachycardia ,
relax vascular smooth muscle except of cerebral one contract it , increase pulse rate & blood
pressure this may be due to catecholamine release ) , GIT effects( stimulate both secretion of
gastric & digestive enzyme ) , GUT effects(weak diuretic) , smooth muscle relaxation ,
skeletal muscle effects causing strength contraction .
Clinical use of xanthenes in case of acute attach of asthma in dose of 3-4 mg/kg every 6 hours .
C-Sympathomemtic drugs :- their mode of action include 1- smooth muscle relaxation .2-
inhibit release of some broncho- constrictor substance via mast cells degradation . 3-inhibit
micro-vascular leakage to decrease edema . 4-increase muco- cilliary transport by increase
cilliary activity & change the composition of mucous .
---- drugs included like epinephrine , ephedrine , isoproterenol , numbers of B2 selective agents
like albuterol (salbutamol) , terbutaluine , metaproterenol , pirbuterol , bitolterol , salmeterol &
formoterol .
epinephrine :- it is effective of rapid acting bronchodilators on S.C injection in dose 0.4 ml of
1:1000 solution , or as inhaler . non-selective stimulate both B1B2 so may cause arrhythmia &
worse angina .
ephedrine :- of long duration , orally active , of more CNS effect but less potent .
isoproterenol : potent bronchodilators , on inhalation improve dilatation after 5 min. it is of 60-
90 min. duration of action .
B2 selective drugs most widely used drug in treatment of asthma , they are active orally ,
parenterally & as inhaler or nebulizer . they are of long duration of action . they are selective
for B2 . as inhaler improve dilatation after 30 min. & persist for 3-4 hours .
Albuterol , metaproterenol & terbutaline used as tablet as 1 tablet 2-3 times a day .
Trebutaline only available as injection for S.C route so use in emergency treatment of asthma .
Salmeterol & formoterol a newer selective B2 agents of long duration of action 12 hours &
more potent .
D-anti-muscarnic antagonist :- this group effective in 1- patient with sever airway obstruction .
2- patient of significant effect in chronic obstruction pulmonary disease . 3- useful for patient
intolerant to B receptors agonist .
-Their mode of action include block contraction of airway smooth muscle by blocking Ach.
release from efferent vagus nerve ending & decrease mucous secretion .
Atropine : prototype of this group (induce bronchial dilatation at dose lower than that induce
increasing heart rates ) , can be use as inhaler (atropine sulfate aerosol) it equal to the B2
selective agents in effectiveness , but their uses limited due to their systemic adverse effects but
on developing quaternary ammonium derivatives of atropine as (ipratropium bromide ) due to
the fact that it is of poorly absorption & not enter CNS may be use in large doses , in acute
sever attach of asthma it may combine with albuterol nebulizer . Tiotropium of 24 hours
duration of action .
E-corticosteroid :use in case of frequent attachs of asthma or persistence of airflow
obstruction , corticosteroid should be started , orally as 30 mg a day prednisolone for three
weeks once improvement achieve reduce the dose then start inhaler corticosteroid .if the
symptoms are inadequately control by standard dose of corticosteroid we may need long acting
B –receptors agonist which is more effective than doubling corticosteroid doses during a period
then on improvement we should change to short acting B receptors agonist & inhaler
corticosteroid .
they act by 1- their broad anti-inflammatory efficacy by inhibit production of inflammatory
cytokines . 2- directly not relax smooth muscle of airway but indirectly reduce bronchial
reactivity , increase airway caliber & reduce frequency of asthma exacerbation . in treatment w
start with 30-60 mg of prednisolone per a day or methylprednisoline 1 mg/kg every 6 hours as
injection /day , to be reduce gradually within 7days . by introduction of lipid soluble
corticosteroid like [ beclomethasone , triamicinolone , flunisolide , fluticasonide ,
budesonide & mometasone ] mike a possibility to prepare corticosteroid as inhaler to decrease
their systemic effects. an especial problem to be occur on inhaled corticosteroid as 1-
oropharyngeal candidiasis ( can prevent by using gargle water ) . 2- hoarseness .
F-Leukotriene pathway inhibitors : arachidonic acid converted into leokotriene(LT) via
catalyze of 5-lipoxygenas ae (synthesis by a variety of inflammatory cell like eosinophile,
macrophage , mast cell , basophile ) , such a LT (c4) that cause 1-broncho-constrictors . 2-
increase bronchial reactivity . 3- mucosal edema . 4-mucus hyper-secretion .
Inhibition of LT pathway can achieve either via 1- inhibition of 5-lipoxygenas which obtain by
Zileuton (in dose of 600 mg four times a day not used more due to their high frequency &
liver toxicity ) or by 2- inhibition of binding of LT to their target organ ( LT antagonist like
Zafirlukast in dose of 20 mg twice a day & Montelukast in dose 10mg once daily ) .
LT inhibitors less potent than corticosteroid , also can be taken orally .use as prophylactic agent.
G-Other drugs used in treatment of asthma like
1- Anti-IgE monoclonal antibodies(omalizumab) it is a newer approach in treatment of
asthma , by collection of monoclonal antibodies raised in mice against IgE antibodies itself ,
this will inhibit binding of IgE to surface of mast cell , then this antibodies genetically
humanized by replacing all small portion of amino acid with that found in human , used for a
period of 10 weeks , to lower IgE to a level to be undetectable to reduce both early & late
response bronchospasm to antigens . on repeated IV injection or SC it lead to 1-derease
severity of asthma . 2- decrease requirement of corticosteroid .may cause site
reaction,sinusitis,headache.
2-calcium channels blockers (nifedipne & verapamil ) these agents of no effect on the
baseline airway diameter , but they inhibit significant airway narrow induce by a variety of
stimuli . both agent if use as inhaler will inhibit broncho-contraction significantly that induce by
exercise , hyperventilation , histamine inhalation , & antigen . they are less effective than
albuterol .
3-Nitric oxide donors : it is a lypophillic drug can be inhaled as a gaseous , in acute attach of
asthma , it will cause a dilatation of pulmonary blood vessels & airway smooth muscles .
4-Potassium channels openers (cromakalim) : it is of vaso-dilators effects due to a- alfa
adrenoceptor blockage & b- direct hyper polarization of smooth muscles cells by activation of
potassium channels including airway smooth muscles .
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bronchodilators in case of mild attach of asthma inhaler of B receptors agonist enough , if he
need more frequent inhaled more than twice per week or in case of nocturnal attach additional
of inhaled corticosteroid or cromolyn or orally treated with LT receptor antagonist . if
symptoms still & poorly control reverse treatment by theophylline . if no response check plasma
level of theophylline to not be more than normal level (10-20 mg/L) .
treatment of acute attach of asthma ;treatment start by oxygen therapy , frequent of continuously
administrate albuterol , systenmic treatment with prednisolone or methyl-prednisolone (0.5
mg/kg every 6 hours ) , intubations & mechanical ventilation of the patient if need to save the
life .