The histaminergic system and antihistamines

histamine is particularly present in

fermented food/drink

what are autocoids

local hormones - short acting endogenous mediators

what cells contain histamine

mast cells and basophils

( and some neurons )

target cells for histamine

epithelium, muscle, neuron, ECL cell, immune cell

effects of histamine

- acid secretion

- mucosal protection

- fluid transport

- neurotransmission

- visceral sensitivity

- motility

- inflammation

- allergy

- tumour growth

histamine is synthesised from

decarboxylation from the aa precursor histidine

histamine is stored in

granules

histamine is released in response to

certain stimuli (Ca dependent exocytosis)

histamine eliminated by

oxidative deamination

how many histamine receptors are there

4 receptors

H1, H2, H3, H4

H1 receptors

histamine receptors responsible for allergic symptoms

H2 receptors

Located in stomach

Stimulation results in secretion of hydrochloric acid

H3 receptors

are involved in central nervous system functioning and feedback control of histamine synthesis and release.

H4 receptors

located in peripheral WBCs and mast cells, are also involved in immune responses

H1 act on

smooth muscle, endothelium, CNS

H2 act on

gastric parietal cells, vascular smooth muscle cells, basophils

H3 act on

CNS cells and some peripheral NS

H4 act on

highly expressed in wbc and bone marrow

H1 causes

bronchoconstriction, vasodilation, separation of endothelial cells, pain and itching, allergic rhinitis, motion sickness

H2 causes

regulation og gastric acid secretion, vasodilation, inhibition of IgE-dependent degranulation

H3 causes

inhibition of histamine synthesis and release, control release of DA,GABA, ACh,5-HT and NE

H4 causes

mediation of mast cell chemotaxis

histamine receptors are all

G-protein coupled receptors

H1

Gq couple to PLC

H2

Gs coupled to AC: increase cAMP

H3

Gi/o couple to AC, also to K- channels and reduce Ca influx

H4

available data consistent with Gi/o

triple response of Lewis

Redness, Flare, Weal

1. Scratch/redness

red line; vasodilation release of H in that part

2. Flare

(1cm beyond site): axonal reflexes, indirect vasodilation, and

itching, H1 receptor mediated;

3. Wheal

oedemaue to increased

capillary permeability, H1 receptor mediated.

Injected ID: red spot

in seconds, direct vasodilation effect, H1

Injected ID: flare

1cm beyond site;

axonal reflexes, indirect vasodilation and itching, H1

Injected ID: wheal

1-2 min;

same area as og spot,

oedema due

histamine effects what in the heart

- contractility

- electrical events

- AV conduction

Effect on cardiac contractility

increase the force of contraction in A and V by promoting Ca2+ influx

Effect on electrical events (HR)

speeds HR by hastening SA node depolarisation

effects on AV conduction

slows conduction, high doses elicit arrhythmias;

involves H1 but H2 responsible for effects

effects on lungs

H1:

H2:

H3:

1: bronchoconstriction, increased mucus viscosity

2: slight bronchodilation, increased mucus secretion

3: stimulation of vagal sensory nerve endings = cough

effects of histamine

- decreased peropheral vascular resistance (flushing, headache) H1/2

- increased vascular permeability H1

- stimulation of nerve endings (pain) H3

- tachycardia H2

- increased mucus production H1/2

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

pathophysiological actions of histamine

- hypersensitivity reaction

- anaphylaxis

- seasonal allergies

- duodenal ulcers

- systemic mastocytosis

- gastrinoma

histamine release can be promoted by many compounds

therapeutic: morphine causes itch or vancomycin causes red neck syndrome (by mast cell degredation)

experimental: compound 48/80

cause of hives is

rarely determined

anaphylaxis

Life threatening allergic reaction

anaphylaxis is a

type 1 allergic response - immediate hypersensitivity reaction

anaphylaxis is mediated by

IgE antibodies

IgE binds to

receptors on mast cells and basophils

Fab portion of antibody binds and causes release of

histamine, leukotrienes, prostaglandins etc

anaphylaxis effects

- decreased bp

- decreased cardiac output

- bronchoconstriction and increased pulmonary secretions

- pruritis (itching)

anaphylaxis treatment

epinephrine/adrenaline via epipen usually

why treat with epinephrine/adrenaline

physiological antagonist of histamine

three mechanistically different approaches to mimimise histamine reactions

- physiological eg adrenaline

- inhibit the release eg cromolyn

- pharmacological eg antihistamines

histamine related drugs

- mast cell stabilisers

- H1RA

- H2RA

- H3RA

mast cell stabiliser example

cromolyn

H1RA example

1st and 2nd gen

H2RA example

cimetidine, ranitidine

H3RA example

pitolisant

uses of first gen H1 antihistamines

- antiallergy

- sedative/sleep aid

- antiemetic in motion sickness

- antitussive (cough)

properties of 1st gen H1 antihistamines

- lipid soluble -> CNS penetration and BBB crossing

- well absorbed

- metabolised by liver

- t1/2 5-6hrs

adverse reactions to 1st gen H1 antihistamines

- sedation, drowsiness

- headache

- cough

- constipation or diarrhoea

- dry mouth

- urinary retention

properties of 2nd gen (non-drowsy) H1 antihistamines

- lipid soluble -> less CNS penetration therefore less CNS effect/side effect

- well absorbed

- metabolised in liver

- t1/2 5-6hrs

2nd gen H1 antihistamines adverse effects

- lower incidence than 1st gen

- some removed due to effects on cardiac K+ channels -> prolong QT interval (terfenadine and astemizole)

2nd gen H1 antihistamines pharmacokinetics

- well absorbed and excreted mainly unmetabolised form

- primarily excreted in urine

- induce CYP450s

H3RA- pitolisant

- enhances activity of brain histaminergic neurons

- promote wakefulness and reduce excessive daytime sleepiness

- reduce symptoms of idiopathic hypersomnia

if it crosses BBB

cause sleepiness

H3 present as autoreceptor

responds to endogenous substance cell releases itself