Respiratory System- Asthma,copd, Antihistamines By Maloney

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Respiratory System- Asthma,COPD, antihistamines by Maloney

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Respiratory System- Asthma,COPD, antihistamines by Maloney

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Asthma is a response of

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Th2. Allergy stuff.

Antigen activates Th2 cells, releasing cytokines, stimulating B cells and eosinophils.

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The antibody related to allergy is

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IgE. produced by B cells. An antigen will bind with IgE, which will bind with a mast cell, releasing histamine, leukotrienes and cytokines. this will cause chronic inflammation, bronchospasm and airway hyperresponsiveness. Eosinophils do the same thing.

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Do we use antihistamines in the treatment of asthma?

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nope.

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What are examples of Bronchodilators?

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-b2 agonists
-M blockers
-methylxanthines

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Which are the short acting B2 selective Agonists?

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-2 to 6 hours
-onset is quick
-inhalation

-metaproterenol
-albuterol
-levalbuterol
-pitbuterol

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Which are the long acting B2 selective Agonists?

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-up to 24 hrs

-Salmeterol (15 min onset)
-formoterol
-arformoterol

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What are the anticholinergics?

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-ipatropium bromide
(similar to atropine, 15 min onset)

-tiotropium bromide
(mainly for COPD, once a day dosing)

-inhalation
-not absorbed well b/c they're charged, so not many side effects

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What do M3 receptors do in the lungs? what about B2?

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when activated they bronchoconstrict the smooth muscle. this is innervated by parasympathetics.

b2 innervated by sympathetics. when epi is released, it'll bronchodilate the lungs.

*ipatropium bromide will block the muscarinic receptors (causing bronchodilation), and albuterol will activate B2s, causing bronchodilation.

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Which is a better bronchodilator? ipatropium bromide or albuterol?

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albuterol. it's a functional/physiological antagonist, antagonizing bronchoconstriction from any stimulus. whereas ip.bromide will antagonize bronchoconstriction from parasymp mediated bronchoconstriction.

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Side effects of B2 agonists?

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-tremor
-hypokalemia
-palpitations
-sinus tachy
-increased BP

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how do you get hypokalemia from b2 agonists?

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shifting of K into the cells when you use these drugs. So albuterol is actually a treatment for HYPERkalemia.

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What is the signaling pathway by which b2 receptor activation causes bronchodilation?

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All beta receptors are coupled to Gs, which causes an increase in cAMP, which phosphorylates proteins via PKA, causing smooth muscle relaxation and bronchodilation.

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What enzyme breaks down cAMP?

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phosphodiesterase 3.

phosphodiesterase 5 is for cGMP.

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What are the methylxanthines?

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-theophylline
-aminophylline

*good b/c they're cheap and oral
*caffeine is also a methylxanine, causing bronchodilation

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MoA of methylxanthines?

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-inhibits phosophodiesterase to increase cAMP concentrations.

-inhibits adenosine receptors.

*mostly works on the smooth muscle cells, but can also work on the white blood cells and prevent cAMP degradation, blocking adenosine receptors, leading to an anti-inflammatory response.

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Problems with methyxanthines?

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-narrow therapeutic index
-erratic bioavailability
-must monitor drug levels

*toxicity is dose-related

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Adverse effects of methyxanthines

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-irritating to gastric mucosa
--NV, epigastric pain, anorexia, cramps, not really diarrhea

-CNS stimulation: headache, irritable, nervous, insomnia, dizzy, seizures

-CV: palpatations, sinus tachy, arrhythmias, flushing, hypotension

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First line for acute asthma attack?

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short acting beta agonist.

-works quickly and well. good for asthma symptoms and exacerbations.

-prevent exercise induced bronchoconstriction

-use ipatropium bromide with a SABA in moderate/severe asthma exacerbations

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First line for long term therapy?

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inhaled corticosteroids.

LABA- adjunct to inhaled corticosteroids
-can be used before exercise to prevent EIB
--not recommended for use as monotherapy for long-term control of persistent asthma
-not for acute symptoms/exacerbations of asthma

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Hey, do you use theophylline for acute asthma attacks?

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no. no added benefit. it's used as an alternative (but not preferred) adjunctive therapy with inhaled corticosteroids for long-term control in moderate or persistent asthma.

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What are the anti-inflammatory drugs?

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-corticosteroids
-mast cell stabilizers
-leukotriene modifiers
-omalizumab

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What are the inhaled corticosteroids?

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-beclomethasone dipropionate
-fluticasone
-triamciolone
-flunisolide
-budesonide
-ciclesonide

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inhaled corticosteroids are for long or short therapy?

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loooooong. even for the rest of the pt's life.

systemic steroids are for acute severe exacerbations or chronic severe asthma

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MoA of inhaled corticosteroids?

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anti-inflammatory effect. it's the cornerstone of asthma therapy.

-upregulates b2 receptors; potentiates beta adrenergic agents by enhancing cAMP production and up regulating receptor level.

-no direct effect on muscle tension (ie not bronchodilators)

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What are the clinical effects of inhaled corticosteroids?

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*great for asthma
-reduce symptoms
-prevent exacerbations
-improve peak expiratory fow

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Clinical use of inhaled corticosteroids in asthma?

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-long term control of asthma
--most potent and consistently effective long term control of asthma

-NOT for ACUTE asthma attacks

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Goods and bads of inhaled corticosteroids?

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good:
-higher local drug concentration than an equivalent dose of systemic corticosteroid (goes straight to the lungs)
-minimize systemic effects

bad:
-unpleasant taste
-can cause oral candidiasis (thrush) from suppressed mouth immune system
-dysphonia (hoarse voice)
-reflex cough and bronchospasm

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What are ways to reduce/prevent adverse effects?

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-spacers/valved holding chambers (prevent big particles from depositing in the mouth)
-rinse and spit after inhalation
-use short acting b2 agonist before inhalation to prevent bronchospasm

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What are oral systemic corticosteroids good for? name 3.

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-acute severe exacerbations or chronic severe asthma.
-used for long-term-control ONLY in the most severe and difficult to control asthma cases.
-only use for several days, then taper off after controlled.

-prednisone
-prednisolone
-methylprednisolone

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Name the Mast Cell Stabilizers

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-cromolyn
-nedocromil

*prevent degranulation and hence the release of mediators from mast cells
**anti-inflammatory effect (not as good as steroids)

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Would cromolyn reverse acute bronchospasm?

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if all the mast cells are degranulated during an asthma attack, doing something to agranulate will not work.

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Clinical use of mast cell stabilizers in asthma

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-via inhalation
-alternative (not preferred) agent for LONG term mild persistent asthma
-preventative tx before exercise or unavoidable exposure to known allergens
-maximal tx response often occurs within 2 weeks

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Side effects of mast cell stabilizers?

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not many. rather non-toxic.
cough, irritation, transient bronchospasm

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What is the ultimate precursor of leukotrienes?

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arachidonic acid.

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what does LTB4 do? how about the LTC4, LTD4, LTE4?

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LTB4: activates its receptor on a lot of white blood cells, which causes chemotaxis (bring the WBC into the area)

others: their receptors are on smooth muscle cells and WBC which will cause bronchoconstriction, migration of eosinophils, edema, secretion of viscous mucous

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How can you prevent/modify the action of leukotrienes?

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-block the receptor
-inhibitor leukotriene production

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What is the 5-lipoxygenase inhibitor?

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Zileuton. it's the leukotriene modifier than inhibits leukotriene production.

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What are the leukotriene modifiers that block the receptor?

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Montelukast
Zafirlukast

*CytLT1 antagonists

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Clinical use of leukotriene modifiers

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-oral (not for acute)
-alternative for mild persistent
-adjunct with inhaled corticosteroids
-aspirin-sensitive asthmatics more responsive

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Why would montelukast reduce bronchoconstriction form aspirin induced asthma?

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not sure. ask someone.

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Adverse things for leukotriene modifiers

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Churg-Strauss Syndrome
-vasculitis

Elevated liver enzymes

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What does omalizumab do?

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anti-IgE therapy

*recombinant humanized monoclonal antibody to IgE. So it binds to the IgE, preventing the IgE from binding to the mast cell, preventing allergen induced activation of mast cells and basophils. (no release of histamine, leukotrienes, cytokines)

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Clinical use for omalizumab?

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-subq injection every 2-4 wks
-approx. serum elimination halflife of 26 days
-second line therapy in pts with refractory asthma, after all attempts have been made to optimize use of traditional therapies.

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Adverse of omalizumab?

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anaphylaxis.

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So which are the quick relief drugs for asthma?

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Bronchodilators:
-inhaled short acting b2 agonists
-anticholinergics

Anti-inflammatory:
systemic corticosteroids

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which are the long term control drugs?

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Anti-inflammatory:
-inhaled corticosteroids
-leukotriene modifiers
inhibitors of mast cell degranulation
-omalizumab

Bronchodilator:
-inhaled LABA
-methylxanthines

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Which white blood cells contribute to the inflammation that goes along with COPD?

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neutrophils. this is different from asthma (mast cell, eosinophils, B cell induced inflammation)

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Which drugs are beneficial for COPD?

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albuterol, iproatropium bromide, prednisone, theophylline, fluticasone.

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Corticosteroids are not beneficial for COPD. Why?

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Asthma involves mast cells, eosinophils and B cells. Corticosteroids are good at knocking these down. On the other hand, COPD involves neutrophils and corticosteroids don't work good for this inflammation.

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Which of that previous list are bronchodilators?

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albuterol, ipatropium bromide, theophylline.

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What do you use for acute exacerbations of COPD?

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short acting beta 2 agonists. if prompt response doesn't occur, then add anticholinergic

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What do you use for management of stable COPD?

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bronchodilators. combination therapy based on whichever works well with that patient.

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What are the main cells that contain histamine?

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mast cells and basophils. the highest concentration of histamine-containing mast cells and basophils are on the skin, GI and lungs

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H1 histamine receptor is coupled to...

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Gq. These H1 receptors are on smooth muscle, vascular endothelium, sensory neurons,

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Since hisatmine is coupled with Gq, what is that going to do to calcium?

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Gq raises calcium, so there will be more muscle contraction. so when histamine activates the H1 receptor (coupled with Gq), you get smooth muscle contraction.

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Are H1 receptor blockers effective in preventing/treating bronchoconstriction in patients with asthma?

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no.

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How is histamine release related to vasodilation?

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histamine binds to H1, activates Gq in endothelial cell, produces nitric oxide, diffuses to vascular smooth muscle cell and you get vasodilation/relaxation of arterioles and post capillary venules.

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how do you increase vascular permeability?

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endothelial cells of post capillary venule has H1 receptors. these cells will contract with histamine, creating space between the cells, allowing fluid and protein to leak out. this can cause edema.

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What effect does histamine have on BP?

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decrease it. bc of the vasodilation courtesy of nitric oxide.

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When histamine binds to nerve endings, what do you get?

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itching and pain.

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How do these actions of histamine contribute to the problems that people have with allergies?

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histamine in the nasal mucosa, you get more vasodilation means more blood there, so you have increased vascular permeability and fluid leaking out into the tissue, hence you get nasal congestion, allergic rhinitis.

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Histamine and skin. What causes red spots, wheals, and flares?

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Red spot from NO induced vasodilation.

Wheal from vessel leakage

Flare from axon reflex-> peripheral vasodilation

-wheal and flare-> acute urticaria

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Which are the 1st generation H1 antagonists (antihistamines)?

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-diphenhydramine
-meclizine

sedation,
antiemetic effect (cross BBB),
antimuscarinic effect

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Which are the 2nd generation H1 antagonists (antihistamines)?

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-fexofenadine
-loratadine

low antisedative,
no anti emetic,
more selective for H1 (low muscarinic side effects)

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MoA of Antihistamines?

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blocking the H1 receptors will block edema formation, block h1 induced vasodilation and block flare and itching.

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Will h1 blockers treat hypotension and bronchoconstriction associated with anaphylaxis?

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no. take epinephrine. if you have anaphylaxis, antihistamines will help, but they will not do much for hypotension, and do a little for bronchoconstriction.

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what ELSE is antihistamines good for?

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-in the hypothalamus, there are h1 receptors. this is the part associated with wakefulness. if you block h1, you will get tired/sedated (cns depression for sedation)

-vestibular apparatus (vomit center) has H1 to prevent motion sickness.

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Clinical use for 1st and 2nd generation antihistamines

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-allergic rhinitis and conjunctivitis
-urticaria (wheal and flare)
-angioedema (supportive to epi; less porous blood vessels)

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clinical use of diphenhydramine

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topical for temporary relief of pruritis and pain. (minor burns, suburn, cuts, scrapes)

-all 1st gen antihistamines can be used as a sleep aid
-motion sickness
-common cold (antimuscarinic activity)

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Side effects

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sedation, dizziness, fatigue (CNS stuff); mainly with 1st generations

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What are atropine-like adverse effects of antihistamines?

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dry mouth, blurred vision, dry eyes, urinary retention/hesitancy. mainly with 1st gen.

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WIth the first generation and the antimuscarinic effects, what can you get?

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acute poisoning. its similar to atropine poisoning.

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What else could you use if you have seasonal rhinitis instead of antihistamine?

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cromolyn (inhibit mast cell release of histamine; prophylactic use)

alpha agonist (pseudoephedrine and phenylephrine)

Intranasal corticosteroids (improve itching, rhinorrhea, congestion, but not conjunctivitis)

Leukotriene modifiers (esp montelukast; mast cells contain leukotrienes)