Antihistamines Flashcards by Elliot Mui

Distribution of mast cells

high numbers in skin, nose, mouth, lungs, intestinal mucosa

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storage granules of mast cells

histamine is complexed with sulfated-polysaccharides, heparin sulfate, chondroitin sulfate, and proteases

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what are some non-mast cells with histamine

nerve terminals in some areas of the brain (neurotransmitter)

fundus of the stomach - specialized cells store histamine for stimulation of acid secretion

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Causes of histamine release from mast cells and basophils

Antigen mediated-binding of antigen (allergens) to antibodies bound to cell surface (IgE)

Non-antigen mediated - thermal or mechanical stress, cytotoxic agents - venoms, various drugs (e.g. high dose morphine)

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what other inflammatory agents are released from mast cells after antigen mediated binding to allergens?

Aside from histamie, kinins, serotonin, leukotrienes, prostaglandins

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number of different types of histamine receptors

mechanism of downstream activation

four histamine receptor subtypes

all are G-protein coupled

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Distribution of H1 receptor

throughout CV, respiratory systems, GI smooth muscle

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H1 receptor is linked to what sort of GPCR downstream activity in smooth muscle

linked to phosphoinositol pathway, contracts GI smooth muscle

H1+histamine->Gq->PLC->IP3+DAG->ups Ca2+->ups Ca2+-calmodulin->phospho MLC

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H1 receptor in vascular endothelial cells

Hist+H1->ups NO release->NO diffuses to vascular smooth muscle->ups cGMP->drops Ca2+

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How is H1 receptor linked to stimulation of sensory nerves

Hist+H1 (in cutaneous or nasal mucosal nerve endings) -> sneezing and itching

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Distribution of H2 receptor

CV system, GI smooth muscle, stomach

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function of H2 receptor

linked to relaxation of vascular smooth muscle and gastric secretion

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Downstream activation of H2 Rs

Histamine+H2-> Gs->ups adenylate cyclase->ups cAMP

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H1 and H2 colocalization

H1 in vascular endothelium -> ups NO, ups contraction of endothelial cells

H2 in vascular muscle -> relaxation

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H3 distribution

mainly in CNS

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histamine’s use in the CNS

auto-receptor in neurons that use histamine as a neurotransmitter

linked to inhibition of NT release

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downstream mechanism of H3 R activation

histamine+H3-> downs Ca2+ influx through voltage-gated channels

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H4 distribution

mast cells, basophils, and eosinophils

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function of H4 R

linked to histamine-induced chemotaxis

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possible future for H4 R drugs

promising target for future antiinflammatory drugs

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histamine’s affects on cardiovascular system

heart-moderate increase in HR & contraction force (H2 increases in SA conduction; reflex tachy)
Vasodilation - (H1 in endothelium; H2 in smooth muscles)

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histamine’s affects on respiratory

H1 mediated constriction of bronchial smooth muscle

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histamine’s affect on acid release on the stomach

H2 mediated release from parietal cells in stomach

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histamine’s role in anaphylaxis

hypotension and loss of fluid to the interstitial space, drops effective blood volume; swelling

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histamine's effects are (increased/decreased) when both H1 and H2 Rs are targeted

histamine blockage increases when both H1 and H2 are blocked

Triple response

1. Red spot at point of injection (immediate) 2. Red flare radiating ~1cm from injection site (~10s) 3. Wheal (raised welt)@ site of injection (1-2min)

skin pathologies caused by histamine

urticaria-hives, rash, edematous welts dermatographia-redness/welt w/mechanical stim flushing(erythema)-redness due to vasodilation

how many different H1 R antagonists are there

23-24 different compounds | 120 products including combos

antihistamines

H1 antagonists | DO NOT bind H2 Rs

acid blockers

H2 antagonists | DO NOT bind H1 Rs

Mechanism of action of H1 R antagonists

competitive inhibition

First generation antihistamines

alkylamines, ethanolamines, ethylenediamines, phenothiazines, piperadines, piperazines

eg of alkylamine

brompheniramine

eg of piperadine

cyrpoheptadine

eg of ethanolamine

diphenhydramine

eg of phenothiazine

promethazine

eg of piperazine

hydroxyzine

eg of ethylanolamine

pyrilamine

uniform characteristic of all H1 R antagonists

all lack amidazole group in H1

side effects of H1 R antagonists

sedative effects CNS stim @ high doses paradoxical excitation in kids at normal dose

most sedative H1 R antagonists

ethanolamines & phenothiazines e.g. diphenyhydramine, promethazine sedatives of others vary

are 2nd gen antihistamines sedative

limited to no CNS affects

do peripheral antihistamines have sedatvive effects

no relationship (2nd gen antihistamines are not sedative)

OTC sedatives commonly contain

diphenhydramine eg Sominex & Nytol contain diphenhydramine

reason for 1st gen antihistamines being sedative

accumulate in CNS -> drowsiness

how selective are 1st gen H1 R antagonists

not very selective

what types of autonomic effects do H1 R antagonists have

anti-cholinergic effects - lipid solubility -> ups CNS penetration - imparts anti-motion sickness/vertigo effect & anti-emetic effect - NOT SEEN with clinical doses of 2nd gen drugs

which 1st gen H1 R antagonists have local anesthetic effect

pyrilamine & promethazine, especially

which 1st gen H1 R antagonists have anti-serotonin effects

cyproheptadine & azatadine

which 1st gen H1 R antagonists have weak alpha-adrenergic antagonism

phenothiazines

general side effects of 1st gen H1 R antagonists aside from sedation

headaches & hypotension

2nd gen H1 R antagonists

``` loratadine (claritin) desloratidine (clarinex) fexofenadine (allegra) cetirizine (zyrtec) levocetirizine (xyzal) ```

sedative effects of 2nd gen H1 R antagonists

little or no sedation

reason for little/no sedation of 2nd gen H1 R antags

decreased lipid solubility | Efflux from CNS by P-glycoprotein transporter

compare extra activities between 1st gen and 2nd gen H1 R antags

2nd gen do not have anti-emetic, anti-muscarinic, ant-motion sickness 1st gen does

origin of the 2nd gen H1 R antags

active metabolites of 1st gen, metabolites are not sedative eg Terfenidine -> Fexofenadine hydroxyzine->cetirizine

cell processes that 2nd gen H1 R antags may also block

LTC4 neutrophil migration eosinophil infiltration

topical H1 R antags

Olopatadine (eye drops/nasal spray) azelastine (eye drops/nasal spray) Ketotifen (eye drops)

when are topical H1 R antags used

indicated for tx of seasonal allergic rhinitis +/- conjunctivitis

what is another use for Ketotifen (H1 R topical antag)

chronic asthma prevention in Europe

H1 R antags are used in adjunct with epinephrine to treat

anaphylaxis

1st gen H1 R antags' sedative effects may interact with

alcohol, anxiolytis, antipsychotics

1st gen drugs & (des)loratidine are contraindicated in

urinary retention, narrow angle glaucoma,

promethazine (a phenothiazine) is structured similarly to ______ and can cause what sxs

promazine (antipsychotic drug) can cause extrapyramidal effects - dystonia - akathisia (agitation) - Parkinsonian rigidity

mechanism for H1 R antag CNS depression

1. gains entry to CNS 2. H1 R in thalamic relay cells have depolarized membrane potential, low freq. action potentials -> Wakefullness 3. H1 antags block Rs-> hyperpolarization-> bursts of APs-> SLEEP

noted effect of sedation from H1 R antags

tolerance to sedation can occur over time