Antihistamines

Where do you find histamine?

present in every cell

What are autacoids?

local hormones, short acting endogenous mediators usually acting as part of an inflammatory response, act like ligand

What are the different autacoids?

bradykinin, eicosanoids - prostaglandins, thromboxanes and leukotrienes, histamine, kallidin, platelet activating factor and serotonin

When is histamine released?

during inflammatory processes

Where is histamine produced?

synthized, stored and released by professional histamine cells:
mast cells - found in skin, GI and respirtary tract - inflammatory cells
basophils - found in the blood - inflammatory cells - transport to other organs
some neurons - in the CNS and PNS (act as neurotransmitter)
also produced by cancer cells
de novo synthisis by neutrophils, T cells, dendritic cells, monocytes and platelets

What is histamine?

endogenous substance, biological pleiotropic effects are mediated by 4 subtypes of histamine receptor

What are the histamine target cells?

epithelium, muscle, neuron, epicelial cell, immune cells

What are the effects of histamine on target cells?

acid secretion, mucosal protection, fluid transport, neurotransmission, visceral sensitivity, motility, inflammation, allergy, tumour growth

How is histamine synthisised, released and metabolised?

synthesized by decarboxylation from an amino acid precursor histidine, stored in granules in certain cells, released in reponse to certain stimuli, in the presence of histamine methyltransferase, the histamine is futher metabolised into monoamine oxidase (the largest one) and others, eliminated by oxidative deamination and/or transmethylation

What do each of the histamine receptors do?

H1 - allergy
H2 - acid reflux
H3 - CNS + PNS - causes excessive daytime sleepiness
H4 - inflammation and itch - CNS, PNS and immune cells - no drugs on market

What kind of receptors are histamine receptors?

G-coupled receptors
H1 - Gq coupled to phospholipase C
H2 - Gs coupled to Adenylyl cyclase - increase cAMP
H3 - Gi/o coupled to Adenylyl cyclase, also to K⁻ channels and reduce Ca influx, inhibit presynaptic neutrotransmitter release
H4 - availible data consistent with coupling to Gi/o in mast cells as well as eosinophils, that can trigger calcium mobilization and mast cell chemotaxis

What are some examples of drugs that work on each of the histamine receptors?

H1 - loratidine and cetirizine
H2 - cimetidine, famotidine
H3 - pitolisant, irabisant
H4 - no drugs on market

What do H1 receptors do?

found in smooth muscle, endothelium and CNS, causes bronchoconstriction, vasodilation, seporation of endothelial cells, pain and itching, allergic rhinitis, motion sickness

What do H2 receptors do?

found in gastric parietal cell, vascular smooth muscle cells, basophils, causes - regulates gastric acid secreation, vasodilation, inhibition of IgE-dependent degrandulation

What do H3 receptors do?

found in CNS cells, and some in PNS, causes presynaptic, feedback inhibition of histamine synthisis and release, also control release of DA, GABA, Ach, 5-HT, and NE, regulates some CNS conditions

What do H4 receptors do?

highly expressed in bone marrow and white blood cells, they mediate mast cell chemotaxis

What is the triple reponse of Lewis (in the skin)?

cutaneous response,
firm stroking of the skin produces an initial red line (few mm) - in seconds - direct vasodlation effect, H1 receptor mediated
followed by a flare around that line (1cm beyond site) - axonal reflexes, indirect vasodilation, and itching, H1 receptor mediated
finally a wheal (1-2 mins) - same area as original spot, edema due to increased capillary permeability, H1 receptor mediated
histamine is released from mast cells or locally, can activate neurons to send signals to CNS

What are the histamine effects on the heart?

H2 receptors and cAMP circulation - increases force of contration of atrial and ventricular muscle by promoting influx of Ca²⁺, speeds up heart rate by hastenng diastolic depolarisation in the sinoatrial node,
H1 receptors - acts directly to slow atrioventicular conduction, to increase automatically and in high doses epecially to elicit arrhythmias
if histamine given i.v., direct cardiac effects of histamine are overshadowed by baroreceptor reflexes elicited by the reduced blood pressure

What are the effects of histamine on the lungs?

H1 - bronchoconstriction, increased mucus viscosity
- stimulation of vagal sensory nerve endings, cough
H2 - slight brochodilation, increased mucus secreation

What are the other cardiac effects of histamine?

H1 and H2 - decreased peripheral vascular resistance - flushing, headaches
H1 - increased vascular permeability, especially post capillaries, local edema
H2 - tachycardia direct and relex

What are the nervous system effects of histamine?

H3 -stimulation of nerve endings - pain

What are the GI effects of histamine?

increased mucus production
H1 - GI motility
H2 - increased gastric acid and pepsin secretion

What are some pathophysiological actions of histamine?

cellular mediator of immediate hypersensitivity reaction and acute inflammatory response, anaphylaxis, seasonal allergies, duodenal ulcers, systemic mastocytosis, gastrinoma (zollinger-ellison syndrome)

What compound can promote histamine release?

morphine can cause degredation of mast cells and therefore release of histamine which can cause lots of itchy skin - particularly occurs in pallative care
vancomycin causes red neck syndrome - associated with degregation of muscles in skin and release of histamine
experimentally - induce histamine response by administrating histamine, also have compound 48/80 that causes muscle degregation
Hives - always associated with histamine, interaction between antibody and antigen

What causes anaphylaxis?

Histamine-induced reactions range from mild allergic symptoms to anaphylatic shock, it is a type 1 allergic response (immediate hypersensitivity reaction), mediated by IgE antibodies, IgE binds to receptors on mast cells and basophils, Fab portion of antibody binds antigen and causes release of: histamine, leukotienes, prostaglandins, etc. in different quanities

What are the symptoms of anaphylatic shock?

decreased blood pressure, decreased cardiac output, bronconstriction and increased pulmonary secreations, pruritis - itching

What is the treatment for anaphylaxis?

epinephrine - not initially antihistamines - epinephrine is a physiological antagonist of antihistamine not a pharmcological antagonist. alpha 1 - vasoconstction, beta 1 - increased HR, beta 2 - bronchodilation

What are the three mechanistically different approaches to minimize histamine reactions?

physiological antagonism - adrenalin
inhibit release of histamine - e.g. cromolyn - mast cell stabilisers
pharmacological antagonism - antihistamines

What are the adverse effects of first generation H1 antihistamines?

sedation, drowsiness, headache, nausea and vomitting, cough, anti-muscarinic effects: constipation, diarrhea, dry mouth, blurred vision, urinary retention

What are first gen antihistamines used for?

adjunctive in anaphylaxis (alongside other drugs) and other cases where histamine release can occur, antiallergy, seditive/sleep aid, antiemetic, antitussive

What are the properties of first generation H1 antihistamines?

lipid soluble - CNS penertration and effects, placental and BBB easy transfer, well absorbed, metabolised in liver, half life about 5-6 hours

What are the adverse effects of second generation H1 antihistamines?

agents have much lower incidence of adverse effects than the first gen agents, terfenadine and astemizole were removed from market due to effects on cardiac K⁺ channels - prolong QT interval (potential fatal arrythmia)

What are the pharmocokentics of second gen H1 antihistamines?

well absorbed, excreated mainly unmetabolised form, primarily excreated in the urine, they induce Cyt P450 liver enzymes

Why are second gen H1 antihistamines better than first gen?

they avoid drowsiness of first-gen, and major adverse reaction of injected corticosteroids

What are the properties of second gen H1 antihistamines?

lipid soluble structure with a highly ionised functional group - less CNS penertration - more selective for peripheral H1 antagonism, less useful in CNS indications, well absorbed, metabolised in liver, half life 5-6 hours

What is the H3 -receptor antagonist?

pitolisant, enhances activity of brain histaminergic neurons, designed to promote wakefulness and so reduce excessive daytime sleepiness, whilst also resulting in segnificant reduction in cataplexy, helps reduce the symptoms of idiopathic hypersomnia, H3 receptors are present in the pre-synaptic neurone, histamine once released will go back and bind to the H3 receptor (its own presynaptic neuron)

Where are the H1 and H2 receptors on neurones?

on the post-synaptic neurone

Where will histamine released from the presynaptic neurone bind to?

own presynaptic receptor - H3, postsynaptic receptors - H1 and H2, also act on H3-heteroreceptor on non-histaminergic neuron, causes selective inhibition of neurotransmitter uptake, so causes increased activity, why H3 antagonism is used for excessive daytime drowsiness and narcalepsy

What is allergic rhinitis?

symptomatic disorder of the nose resultng from an IgE-mediated immunological reaction following exposure to an allergen

What are the major symptoms of allergic rhinitis?

rhinorrhea, nasal itching - histamine in nose, congestion/obstruction - inflammation, sneezing - inflammation and allergen

How is allergic rhinitis reversible?

spontaneously - removal of allergen, with treament when allergen is unavailible

How is allergic rhinitis caused?

exposure to allergen (person may have genetic sensitivity),
chemotaxis - trans-endothelial migration of eosinophils, mast cells precursors, macrophages, langerhans cells, lymphocytyes
- activation and prolongation of chemocytes, IgE synthesis and cross-linking wth allergen to trigger hypersensitivity, release of histamine, trypase, prostaglandins and leukotrienes
allergen causes irritation to nerve endings so causes sensory nerve activation causes sneezing, nasal itch and vasodilation, plasma exudation and mucus cell production - increased pentration of vascular so more fluid, causes up-regulation of adhesion molecules causing a blockage

What are the two classification systems - what is classed in these symptoms?

type - infectious, drug induced e.g. asprin - allergic symptoms made worse, occupational - exposure to allergens, hormonal - puberty, pregnancy, menstral cycle, idiopathic - seasonal and perennial
time - persistant - majority of days a week or >28 days at a time - may need steroids, intermittent - <4 days per week or less than 28 days at a time

What are you looking at when diagonosing allergic rhinitis? (SOCRATES)

Age (Licenced medications), sex (female = higher risk), assessment: site - nose, sinuses, throat, ears; Onset - time of year?; Character - persistant or intermittent; relieving factors - avoiding/removing allergen, associated symptoms - conjuctivitis, cough, wheeze, sore throat; timing - worse in day or night; exacebating features; severity - disterbing sleep, activities of daily living

What history are you looking at with allergic rhinitis?

medication histroy - medication for atopic diseases (chronic and uncontrolled, diabetes instead, autoimmune trigger) , inhalers, or creams - other allergic conditions
social history - live, work or socialise around allergens
family history - strong link
previous medical history - atopic diseases - athsma, eczma
conjunctivitis

What are some diagnostic tests for allergic rhinitis?

rhinoscopy - avoid it
allergy test - identify allergen - high levels of IgE
cytology of nasal secreations - rare - immune cells into nose for immune candidates
CT scan - if there is a blockage for other reasons

What symptoms will you find on examination of a patient with allergic rhinitis?

red or irritated nose - trauma from using tissues, blocked nose - breath sounds and sound of voice, clear mucus present, nasal endothelial tissue may be ‘boggy’ - wet and inflammed, sinuses may be tender - fluid filling sinuses, eyes may appear red, conjessted and watery

What are the differential diagnosis of allergic rhinitis?

polyps (soft tissues that block nose), tumours, deviated septum, foreign bodies, granulomatosis - autoimmune blood vessel disorder with similar symptoms

What are the three types of pharmcotherapy for allergic rhinitis?

mast cell stabilisers - reduce immune activation, mast cell activation and histamine production
steroids
antihistamines - antinflammatory

What is sodium cromoglicate?

stablised mast cells - decreases histamine release from mast cells and decreases release of other inflammatory agents, normally given as eye drops, can be OTC, 1 drop in each eye morning and night, formulation seeps into nasal cavity, suggested that it is useful in prophylaxis of histamine release but may not antagonise histamine once it has been released - should be used prior to symptoms

What are the side effects/issues with sodium cromoglicate?

very few side effects - headache, rash, sensitivity to eye drops (prescribe in this case other drugs), don’t use with contact lenses as has preservitives that binds to contact lenses and turns them yellow, wait 15 mins before using contact lenses

What is Beclomethasone?

corticosteroid - more effective for nasal symptoms than antihistamines, equally effective for associated conjunctivitis, aqueous nasal spray for topical effect, suggests most effective prior to symptom development, 2 sprays each morning and night, blow nose before to clear mucus - make sure drug binds to nasal mucosa, only to be used for 3 months in a row as can cause rebound congestion, helpful for seasonal allergies, also helps with conjuctivitis

What are the drugs that are first gen H1 receptor antagonists?

diphenhydramine, chlorphenamine, promethazine, hydroxyzine, and cyclizine

What are the second gen H1 receptor antagonist drugs?

loratidine and cetririzine

What are the other uses of first gen H1 receptor antagonists?

sedating - cholorphenamine, promethazine and diphenhydramine, useful if patient’s allergy symptoms are disterbing sleep, insomnia preporations have diphenhydramine in them
Antiemetic - promethazine, cyclizine, and hydroxysine, not normally OTC
Vertigo - meclizine, prescription only

What are the symptoms of a H1 antihistamine overdose?

fever, excitement (temporary), pupillary dilatation, hallucinations - high amounts only, convulsions - high amounts only

What are the interaction for H1 antihistamines?

drugs causing sedative effects e.g. opoids and alcohol, drugs with anti-muscarinic effect e.g. tricyclics
azoles - increase exposure to antihistamines, QT prolongation (arrhythmia risk), ketoconazole and loratidine (most likely)
second gen still have these but less so

What second gen H1 antihistamine formulations are availible?

tablets, capsules and suspentions of: certirizine, fexofenadine, loratidine and desloratadine
nasal spray: azelastine
some people won’t use eye drops or nasal spray
children and the elderly will want suspensions

What are the general properties of second gen H1 antagonists?

lipid soluble structure with a highly ionised functional group, less CNS penertration as more selective for peripheral H1 antgonism, well absobed, metabolised in liver, half life 5-6hrs

What is loratidine?

most commonly used non-sedating anti-histamines (GSL and P med), once a day dosing, >6 years 10mg, 5mg 2-5 years, questionable safety in pregnancy and breastfeeding

What is ceririzine?

Metabolite of hydroxyzine, mast cell stabiliser and anti-muscarinic, typical doses: 10mg OD >6 years, 5mg BD if feel drowsy, 2.5 mg OD 23months - 6 year, OTC, licenced in children over 2