DEENT Exam 4 Material

most of the time, we are going to use ____________ to treat allergies

second generation antihistamines

we will use ______________ for treating the cough from rhinorrhea

first generation antihistamines

so in general, we treat systemic allergies with

second generation antihistamines

antihistamines are specifically

H1 inverse agonists

the ______________ can cause a cough

rhinorrhea post-nasal drip

what is rhinorrhea?

runny nose

post nasal drip: sometimes the mucus from your nose comes out the front and you blow it out. Other times, it is running down the back of your throat (yuck) and THAT will often trigger a cough reflux

ok

how are we gonna treat that cough?

first generation antihistamines (H1 inverse agonists)

and then antihistamines are also used for __________ reasons

miscellaneous reasons

miscellaneous:

first generation antihistamines (H1 inverse agonists) but for these miscellaneous conditions, we are taking advantage of side effects caused by these medications with may be H1 inverse agonism or their interaction with other receptors

ok

Where is histamine located?

-basophils and mast cells

-CNS

-ECL (enterochromaffin like cells) in stomach

_________ carry histamine in granules throughout the body (through the blood)

basophils

so thanks to the basophils, you have histamines being carried throughout your bloodstream

ok

and then Mast cells are located in

almost all tissues

mast cells will fight pathogens, and they also have the granules holding the histamine

ok

is histamine produced in your CNS?

yes, histamine is produced in the CNS

Histamine in your CNS acts like a _________ instead of an autocoid

neurotransmitter

whenever histamine is released from neuronal cells, it has effects controlling your ____________ systems

endocrine system, your cardiovascular system, your thermal regulation, your body weight, and your sleep-wake cycle

action of histamine in the CNS:

-neuroendocrine control

-cardiovascular regulation

-thermal and body weight regulation

-sleep and arousal

whenever histamine is secreted by the ECL cells in the stomach, that activates

acid production

most of the time, we get histamine released when we have been exposed to something that we are allergic to, and then our body has been __________, your body will make those IgE antibodies

sensitized

so then the second time you are exposed to that antigen, that antigen will bind to the ______ expressed on the surface of your mast cells

IgE

and once the antigen binds to that IgE that is expressed on the surface of your mast cells, that will trigger

the release of those granules that contain histamine and inflammatory cytokines

slide: histamine is released from storage granules as a result of the interaction of antigen with IgE antibodies on the mast cell surface

ok

Histamine plays a central role in ___________ and _________

immediate hypersensitivity and allergic response

so the most common way that histamine gets released is due to an antigen. but there are nonantigen-mediated histamine release from your

basophils and macrophages

Some _________ directly cause histamine release from mast cells

compounds

some compounds directly cause histamine release from mast cells

-do they require prior sensitization?

nope

what compounds and agents cause the release of histamine?

-thermal or mechanical stress of sufficient intensity

-basic drugs and chemicals such as

-morphine

-codeine

-dturbocuraine

-guanethidine succinylcholine

-vancomycin

now that there is a release of histamine, no matter why, it will be in your circulation. What are the different receptors and where are they located?

H1, H2, H3, and H4

H1: smooth muscle, endothelium, brain

H2: gastric mucosa, cardiac muscle, mast cells, brain

H3: presynaptic autoreceptors and heteroreceptors: brain, myenteric plexus, and other neurons

H4: eosinophils, neutrophils, mast cells, CD4 T cells

what is postreceptor mechanism for H1?

G1 increase IP3, DAG

what is the postreceptor mechanism for H2?

Gs, increase cAMP

H2 is what deals with GERD

ok

what is the postreceptor mechanism for H3?

Gi, decrease cAMP

what is the postreceptor mechanism for H4?

Gi, decrease in cAMP

when histamine finds your H1 receptor, what will occur?

-mediates pain and itchiness (stinging pain)

-contraction of the bronchi, gut, uterus, and iris

-relaxation of small blood vessels causing vasodilation (red looking eyes)

-contraction of endothelial cells causing edema (puffy eyes, stuffy nose, congestion in your lungs)

-increases AA release and prostaglandin synthesis (a lot of prostaglandins are inflammatory)

-increases the amount and viscosity of mucus from goblet cells

-stimulates the cough reflex

so an allergic response can have all of this happening

ok

when histamine finds the H3 receptor, what happens?

-will make you more awake (wakefulness)

and then histamine finds the H4 receptors, what happens?

-increases eosinophil chemotaxis (will increase production of eosinophils and contribute to the symptoms of an allergic response with inflammation)

all of these effects of histamine binding to its receptors contribute to ______________

allergic rhinitis, allergic conjunctivitis, and "hay fever"

We are going to use an __________ at the H1 receptor (the MOA of H1 antihistamines)

inverse agonist

our antihistamines are gonna bind and stabilize the ________ state of the histamine receptor

inactive

the histamine receptors are always going back and forth the active and inactive form (so we kind of say that they are always constitutively on)

ok

when we use an inverse agonist, we are gonna make that receptor more

inactive

inverse agonists are not a true antagonist because there is some opportunity for those receptors to still be active in the presence of our antihistamines, but you are switching that balance of their action to the inactive side

ok

what are the two main MOA of antihistamines?

-H1 inverse agonists (reduce constitutive activity of receptor and compete with histamine binding to the receptor)

-Mast cell stabilization

mast cell stabilization: you are preventing those cells from degranulating

ok

mast cell stabilization: reduces release of mast cell mediators during an

allergic response

Mast cell stabilization:

anti-inflammatory properties, reducing cytokine secretion, decreased adhesion molecule expression, and inhibition of eosinophil infiltration

ok

mast cell stabilization:

both H1 receptor dependent and independent

ok

mast cell stabilization:

Mechanisms still

unclear

mast cell stabilization:

may be more effective in the _______ treatment of allergic conjunctivitis or allergic rhinitis

topical

our first generation antihistamines have mast cell stabilization, but our second generation antihistamines they don't have so much mast cell stabilization characteristics

ok

our topical antihistamines for treating rhinitis, those medications that have mast cell stabilizing capabilities

ok

the diff between first and second antihistamines:

first gen have _____ sedative effects while second generation have ______ sedating effects

more, less

second generation are less sedating because of

reduced distribution into CNS

so we are now recommending more second generation meds than our first generation to treat allergies

ok

the diff between first and second antihistamines:

First generation are ______ likely to block autonomic receptors while second generation are _______ likely to block autonomic receptors

more, less

so first generation antihistamines are finding more autonomic receptors and that leads to more side effects that are not desirable

ok

and the second gen are more clean and just inverse agonizing the H1 receptor. They don't seem to be finding autonomic receptors

ok

Second generation: some metabolized by ________, so we need to watch for DIs (both drug drug interactions and food drug interactions)

CYP3A4

Pharmacodynamics of first generation antihistamines:

-some inhibit mast cell release of histamine

-sedation

-antinausea and antiemetic action

-antiparkinsonism effects

-antimuscuranic actions

-adrenoreceptor blocking actions

-serotonin blocking actions

-local anesthesia

antinausea and antiemetic action: H1 in the CNS, use these meds before you get on the boat and you feel bad.

ok

antiparkinsonism effects: EPS symptoms (antihistamines can help with shakiness)

ok

antimuscarinic actions: ANTI-DUMBBELSS

ok

serotonin-blocking actions: these will also help with

nausea

in the CNS

first generation antihistamines will target what receptors?

-muscarinic receptors

-alpha adrenoreceptors

-serotonin receptor

-H1 receptor

what side effects are seen with first generation antihistamines?

-sedation

-paradoxical excitement in children

-other nervous system effects

-anticholinergic effects (antiDUMBBELSS)

-cardiovascular effects

Sedation: the sedative effect may be a result of inverse agonism at the _____ H1 receptors

central

first generation antihistamines: readily cross the BBB and occupy 50 to 90% of the H1 receptors in the brain

ok

first generation antihistamines:

Paradoxical excitement in children:

restlnessness, tremors, euphoria, delirium, and seizures

the paradoxical excitement in children is not very predictable, so we don't know what kids have it and which ones do not.

ok

first generation antihistamines:

Other nervous system effects:

-disturbed coordination

-decreased cognition

-increased appetite

-abuse potential

-peripheral sodium channel blockage

____________ and _________: associated with euphoria, hallucinations, and "getting high"

diphenhydramine and dimenhydrinate

the peripheral sodium channel blockade: this contributes to what effect of these first generation antihistamines?

topical anesthetic

anti-dumbbelss:

-dryness of the mouth, nose, and throat

-urinary retention and impotence

-blurred vision, loss of accommodation and mydriasis

-thickening of bronchial secretion, wheezing, and nasal stuffiness

-decreased GI motility and constipation

-tachycardia and chest tightness

Cardiovascular effects of first generation antihistamines?

once again, look at anti-dumbbelss

-tachycardia

-prolongation of QT interval

-hypotension or orthostatic hypotension can occur as a result of the alpha adrenoreceptor blockade

another odd first generation antihistamines is if we use them topically:

sensitivity reactions to antihistamines

sometimes, especially when used topically, some people can end up with an IgE mediated type 1 allergic response to the use of topical antihistamine

ok

so sensitivity reactions occurs most commonly with

topically applied antihistamines

the _______________ are the most common chemical type to cause the reaction

ethylenediamine derivatives (structured antihistamines)

the antihistamines act as ______ to cause IgE mediated type I reactions or T-cell medaited type IV reactions

haptens

second generation antihistamines: they often have ________ sedation

no or low sedation

second generation antihistamines: often have no or low sedation (don't cross the BBB)

special note: _________ food-drug drug interaction

fexofenadine

fexofenadine has has food-drug drug interaction with

orange, apple, or grapefruit juice

orange, apple, and grapefruit juice will ______ the serum levels of fexofenadine by 40%

decrease

the juices will reduce the ___________ activity, therefore decreasing oral bioavailability (decreases gut absorption) of fexofenadine

OATP (organic anion transporting polypeptide)

you should separate the use of fexofenadine and these juices by ________

2 hours

apparently you have to know the link information this time. You need to know which ones have a high relative sedative effects, and which ones have a high relative anticholinergic effects

ok

which antihistamines have relative high sedative effects?

-Carbinoxamine maleate

-diphenhydramine hydrochloride

-promethazine hydrochloride

-clemastine fumarate (moderate)

which antihistamines have relative high anticholinergic effects?

-carbinoxamine maleate

-clemastine fumarate

-diphenhydramine HCl

-promethazine hydrochloride

-brompheniramine maleate (moderate)

-chlorpheniramine maleate (moderate)

-dexchlorpheniramine maleate (moderate)

and then cetirizine and levocetirizine both have low to moderate sedative effects even though they are second generation antihistamines

ok

what is our nasal mast cell stabilizer product?

cromolyn sodium

cromolyn sodium is also known as nasalcrom

ok

cromolyn sodium is used for treating

allergic rhinitis

the reason we use cromolyn sodium is that this medication is

stabilizing the mast cells (won't allow them to release histamine)

so cromolyn sodium won't work well if the patient's mast cells have already released that histamine

ok

nasal mast cell stabilizers:

pharmacologic effect: prevents release of inflammatory and constricting mediators like histamine, leukotrienes, cytokines, and degradative enzymes from activated mast cells.

-prevents the allergic event rather than alleviating symptoms

ok

we use corticosteroids for

allergic rhinitis

we use corticosteroids in allergic conditions like

rhinitis, conjunctivitis, and type I hypersensitivity responses to decrease inflammation