1

State-of-the-Art-Review

Histamine: metabolism, physiology, andpathophysiology with applications inveterinarymedicineLisa J. Peters, DVM and Jan P. Kovacic, DVM, DACVECC

Abstract

Objective To review the human and veterinary literature on histamine physiology and pathophysiology andpotential applications for clinical use in veterinary critical care.

Data Sources Human and veterinary clinical studies, reviews, texts, and recent research in histaminereceptor and antagonist therapy.

Human Data Synthesis Recent progress in molecular biology has led to a more complete understanding ofthe enzymes involved in histamine metabolism and histamine receptor physiology. The past decade ofresearch has confirmed the role of histamine in the classical functions (contraction of smooth muscle, increase invascular permeability, and stimulation of gastric acid secretion) and has also elucidated newer ones that arenow under investigation. Data on the roles of histamine in angiogenesis, circadian rhythm, bone marrowregeneration, bacterial eradication, and cancer are emerging in the literature. Newer histamine antagonists arecurrently in drug trials and are expected to advance the clinical field in treatment of allergic, gastrointestinal,and cognitive disorders.

Veterinary Data Synthesis Veterinary histamine research is directed at identifying the effects of certainpharmacological agents on blood histamine concentrations and establishing the relevance in clinical diseasestates. Research demonstrates important species differences in regards to histamine receptor physiology andtissue response. Studies in the area of trauma, sepsis, anaphylaxis, allergy, and gastrointestinal disorders havedirect applications to clinical veterinary medicine.

Conclusions Histamine plays a key role in the morbidity and mortality associated with allergy, asthma,gastric ulcers, anaphylaxis, sepsis, hemorrhagic shock, anesthesia, surgery, cardiovascular disease, cancer,CNS disorders, and immune-mediated disease. Histamine antagonism has been in common use to block itsadverse effects. With recent advances in the understanding of histamine receptor physiology, pharmaceuticalagents targeting these receptors have increased the therapeutic options.

(J Vet Emerg Crit Care 2009; 19(4): 311328) doi: 10.1111/j.1476-4431.2009.00434.x

Keywords: amine, anaphylaxis, antagonists

Introduction

Histamine, (2-[4-imidazolyl]ethylamine), was discov-

ered in 1910 by Dale and Laidlaw, as an isolate from the

mold ergot. They identified that histamine not only

stimulated smooth muscle contraction but induced a

shock-like syndrome when injected into mammals.1,2

Further research in 1927 finally classified histamine as a

natural constituent of the body and mediator of ana-

phylactic reactions.3,4 To date, histamine has been

linked to at least 23 different physiological functions

and is one of the most extensively studied chemical

compounds with physiologic activity.5 Histamine is

known for its role in inflammation, gastric acid secre-

tion, and neurotransmission; however, new roles arebeing elucidated. Histamine research has led to the de-

velopment of drug therapies in both human and vet-

erinary medicine specifically targeted for allergies,

gastric ulcers, asthma, and anaphylaxis; however, there

are also implications for management of sepsis, hem-

orrhagic shock, anesthesia, surgery, cardiovascular dis-

ease, cancer, CNS disorders, and immune-mediated

disease.

Address correspondence and reprint requests toDr. Lisa J Peters, Department of Emergency and Critical Care, Fox ValleyAnimal Referral Center, 4706 New Horizons Blvd, Appleton, WI 54914,USA. Email: [email protected]

From the Department of Emergency and Critical Care, Fox Valley AnimalReferral Center, Appleton, WI 54914.

Journal of Veterinary Emergencyand Critical Care 19(4) 2009, pp 311328doi:10.1111/j.1476-4431.2009.00434.x

& Veterinary Emergency and Critical Care Society 2009 311

Histamine and Histamine Synthesis

Histamine is classified as a biogenic amine and is one ofthe smallest biomolecules with a molecular weight of

111Da. It consists of 17 atoms forming 3 components:

an imidazole ring, an amino group, and a connecting

ethylene chain.5 The formation of histamine in the body

occurs in 1 rate-limiting step. The amino acid L-histi-

dine, catalyzed by L-histidine decarboxylase (HDC),

undergoes exothermic decarboxylation, which releases

60120 kcal/mol.5 Histamine is synthesized by mastcells, basophils, platelets, histaminergic neurons, and

enterochromaffin cells, where it is stored intracellularly

in vesicles and released on stimulation.4 There are at

least 14 nonidentical molecular forms of histamine that

differ in electrical charge, conformation, proton bind-

ing, and electron distribution. These isoforms enable

histamine to take part in different biological reactions.5

The action of histamine can be terminated in 2 alterna-tive pathways. Histamine inactivation can occur either

by methylation of the imidazole ring by histamine-

N-methyltransferase or by oxidative deamination ofthe primary amino group with diamine oxidase4,6,7 (see

Figure 1).

Histamine Receptors

The diverse biological effects of histamine are mediated

through different histamine receptors. Histamine has

agonistic action on at least 4 receptors: H1, H2, H3, and

H4.8,9 Histamine receptor numbering refers to the chro-

nology of their discovery. All agonist receptors when

activated by histamine transmit the extracellular signal

via G-protein systems coupled to intracellular second

messengers. This coupling triggers a cascade of intra-cellular events that results in nuclear transcription

modification and manifestation of the biological event.8

Histamine receptors vary in expression, signaling, func-

tion, and histamine binding ability and therefore have

Figure 1: Summary of histamine synthesis and metabolism. Histamine is synthesized when L-histidine undergoes decarboxylation

with L-histidine decarboxylase (HDC) (1). Histamine can be metabolized by extracellular oxidative deamination of the primary amino

group by diamine oxidase (DAO) (2), or by intracellular methylation of the imidazole ring by histamine-N-methyltransferase

(HNMT) (3). DAO and HNMT can both be inhibited by their respective reaction products in a negative feedback loop (4).

N-methylhistamine is broken down further to N-methyl-imidazole acetaldehyde by MAO-B (5) or by DAO (6). (Adapted fromMaintz

L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr 2007; 85(5):11851196. Reprinted with permission.)

& Veterinary Emergency and Critical Care Society 2009, doi: 10.1111/j.1476-4431.2009.00434.x312

L.J. Peters & J.P. Kovacic

different potential therapeutic applications10 (see Table

1). Species variability exists with location and predom-

inance of receptor types.11,12

H1 histamine receptor

The H1 histamine receptor (H1R) activities include

smooth muscle contraction and interaction with theendothelium leading to vasodilatation and increased

vascular permeability. It is the main histamine receptor

subtype involved in acute inflammatory and allergic

disorders in humans and animals.13,14 H1Rs have been

identified on cells of the brain, airway smooth muscle,

skin, gastrointestinal tract, genitourinary tract, adrenal

medulla, immune system, heart, and the vascular en-

dothelium.1315 The primary mechanism of agonist-activated H1R-mediated responses occurs with the ac-

tivation of phospholipase C enzyme (PLC) by the Gqfamily of proteins. The activated PLC causes cleavage

of the membrane phosphatidyl inositol diphosphate,

which results in the formation of inositol triphosphate,

and 1,2-diacylglycerol. Inositol triphosphate triggers

the release of Ca21 from the cytoplasmic stores and also

increases the Ca21 influx from the extracellular space.This increased Ca21 leads to a number of biological

effects such as ileal and airway smooth muscle con-

traction, catecholamine release from the adrenal chro-

maffin cells, and vascular smooth muscle effects.8 H1R

activation also stimulates endothelial cells to convert

the amino acid L-arginine into nitric oxide (NO) to

cause potent vasodilation.16,17 In addition, multiple

secondary signaling pathways are triggered from theincreased intracellular Ca21 resulting in the production

of prostaglandin E2, prostacyclin, thromboxane A2,

cAMP, cyclic guanosine monophosphate, and nuclear

factor kb.8,14,18 These secondary-signaling pathways canlead to systemic vasodilatation, increased cell perme-

ability, and modulation of circadian rhythm.15,19,20


The H2 receptor (H2R) is involved in the regulation ofthe right atrial and ventricular muscle of the heart, in-

hibition of basophil chemotaxis, various actions of im-

mune cells, secretion of gastric acid, and inhibition of

prostaglandin E2 stimulation of duodenal bicarbonate

secretion.20 The H2R exists on many cell types includ-

ing the brain, gastric mucosa, adipocytes, cardiac my-

ocytes, vascular smooth muscle, basophils, and

neutrophils.8,20 Agonist-activated H2R-mediated re-sponses occur when H2Rs couple to adenylyl cyclase

via the Gs protein pathway. This causes cAMP accu-

mulation that activates protein kinase A enzymes that

phosphorylate a wide variety of proteins involved in

regulatory processes.8 Activation of the H2Rs has also

been associated with increased intracellular Ca21 in

gastric parietal cells and some mammalian ventricular

myocytes.12,20 This is thought to occur through stimu-

lation of the PLC activity by a different G-related pro-

tein pathway. Effects such as stimulation of gastric acid

secretion, smooth muscle relaxation, inhibition of anti-

body synthesis and cytokine production, alterations in

gastrointestinal motility, and colonic secretion are a re-sult of agonist-activated H2Rs.4,20,21 It is now apparent

that H2Rs are involved in many biological actions and a

single receptor can activate several G-proteins and cre-

ate cross-talk within the cells. This makes H2Rs more

diverse and gives them a broader range of biological

actions.8,22,23


The H3 receptors (H3R) primary function is to influ-

ence neuronal histamine release and release of other

neurotransmitters such as acetylcholine, dopamine,

glutamate, norepinephrine, and serotonin mainly in

the central but also peripheral nervous system.8,24 The

H3R is widely distributed in the brain (hypothalamus,

frontal cortex, hippocampus, caudate nucleus), right

atrium, and gastric mucosa.13 In the 1980s, the agonist-activated H3R was identified as a presynaptic

inhibitory autoreceptor that inhibited the release and

synthesis of histamine.13 In the early 1990s, the H3R

was also found to be an inhibitory heteroreceptor on

nonhistaminergic neurons that inhibits the release of

the aforementioned neurotransmitters.25 Signal trans-

duction pathways of H3Rs involve coupling of Gi or Goproteins. This coupling results in inhibition of adeny-late cyclase activity, inhibition of depolarization-in-

duced Ca21 channels, inhibition of Na1/H1 exchanger,

and activation of mitogen-activated protein kinase.13,25

Although H3R expression in peripheral nerves is lim-

ited, these receptors inhibit sympathetic neurotrans-

mission in the right atrium and gastric acid secretion in

cats, dogs, and rabbits.13 The H3Rs play a crucial role in

appetite and weight regulation, attention, cognition,mood, and sleep in humans, dogs, cats, rats, and guinea

pigs.


The H4 receptor (H4R) is expressed primarily on cells

involved in inflammation and the immune response. It

effects chemotaxis as well as cytokine and chemokine

production of mast cells, eosinophils, dendritic cells,

and T cells.10 The H4R most closely resembles H3R inexpression pattern; however, where H3R is mostly re-

stricted to the CNS, the H4R receptor seems to be lim-

ited to hemopoietic cells such as mast cells, eosinophils,

basophils, and T cells. There is also recent evidence for

H4R expression in dendritic cells and peripheral nerves

in humans.26 The H4R is a Gi and Go protein-linked

& Veterinary Emergency and Critical Care Society 2009, doi: 10.1111/j.1476-4431.2009.00434.x 313

Histamine

Table1:Characteristicsandfunctionsofactivated

histaminereceptors.

Characteristic

H1Receptor

H2Receptor

H3Receptor

H4Receptor

G-p

rote

inG

qG

sG

ior

Go

Gior

Go

Intr

acellu

lar

sig

nals

activate

dP

hospholip

ase

CP

IP2/D

AG

syste

m

Ca

21

Media

tecG

MP

,cA

MP

,N

O

and

NF

kb

pro

duction

Adenyla

tecycla

se

cA

MP

Pro

tein

kin

ase

A

Ca

21

Inhib

itio

nofadenyla

tecycla

se

Inhib

itio

nof

cA

MP

Inhib

itio

nof

Na/H1

exchanger

Activation

of

MA

PK

Ca

21

Inhib

itio

nof

cA

MP

Recepto

rexpre

ssio

nW

idespre

ad,

inclu

din

gairw

ay

and

vascula

rsm

ooth

muscle

,

nerv

ecells

,endoth

elia

l,and

epithelia

lcells

Wid

espre

ad,

inclu

din

g

sm

ooth

muscle

,heart

,and

gastr

icm

ucosalcells

Centr

alnerv

ous

syste

m

main

lyin

clu

din

gbasal

ganglia

,hip

pocam

pus,

and

cort

ex

Periphera

lnerv

ous

syste

m

inclu

din

gairw

ays,

GI,

and

card

iovascula

r

Bone

marr

ow

,periphera

l

blo

od,

sple

en,

thym

us,

lung,

sm

all

inte

stine,

colo

n,

and

heart

.

Expre

ssio

nin

bra

in,

liver,

and

skele

talm

uscle

Centr

alnerv

ous

syste

mD

ecre

ased

perm

eabili

tyof

mic

rovessels

and

inhib

itio

nof

action

pote

ntials

Altera

tions

info

od

inta

ke,

em

otions,

and

mem

ory

Aff

ects

sle

ep/w

ake

cycle

Incre

ased

perm

eabili

tyof

mic

rovessels

Inhib

itio

nof

his

tam

ine,

acety

lcholin

e,

dopam

ine,

glu

tam

ate

,sero

tonin

,and

NE

Decre

ases

att

ention

and

incre

ase

impuls

iveness

Altera

tions

info

od

inta

ke,

em

otions

and

mem

ory

Aff

ects

sle

ep/w

ake

cycle

Neglig

ible

impact

Coro

nary

circula

tion

Vasoconstr

iction

Vasodila

tion

Vasodila

tion

thro

ugh

inhib

itio

n

of

NE

Neglig

ible

impact

Endocrine

syste

mC

ate

chola

min

ere

lease

by

adre

nalchro

maffi

ncells

Neglig

ible

impact

Impacts

the

adre

nerg

ic

response

by

inhib

itio

nof

neuro

transm

itte

rs

Neglig

ible

impact

Endoth

eliu

mV

asodila

tion,

via

NO

and

pro

sta

cyclin

pro

duction

Vasodila

tion

Vasodila

tion

thro

ugh

inhib

itio

n

of

NE

Neglig

ible

impact

Gastr

oin

testinal

tract

Sm

ooth

muscle

contr

action

Incre

ased

gastr

icacid

secre

tion

from

parieta

lcell

Altera

tions

inm

otilit

ydue

to

inhib

itio

nofN

E,acety

lcholin

e,

and

som

ato

sta

tin

May

pla

ya

role

in

gastr

opro

tection

from

ulc

ero

gens

Inflam

mato

ry

Imm

une

syste

mIn

cre

ased

chem

ota

xis

of

eosin

ophils

and

neutr

ophils

Enhanced

T-c

ell

response

Stim

ula

tion

of

IL-6

Blo

ckin

gof

hum

ora

lim

munity

and

IgE

pro

duction

Induction

of

cellu

lar

imm

unity

Decre

ased

eosin

ophil

and

neutr

ophil

chem

ota

xis

Decre

ased

T-c

ell

response

Suppre

ssio

nof

IL-6

Induction

ofhum

ora

lim

munity

Suppre

ssio

nof

cellu

lar

imm

unity

Involv

ed

incontr

olof

neuro

genic

inflam

mation

though

localneuro

nand

mast

cell

feedback

loops

Incre

ased

chem

ota

xis

of

eosin

ophils

and

mast

cells

Induction

and

modula

tion

of

Tcells

and

dendritic

cells

Decre

ased

pro

duction

of

IL-4

,

IL-6

,and

IL-1

7

Myocard

ium

Negative

inotr

opic

and

chro

notr

opic

eff

ects

Positiv

ein

otr

opic

and

chro

notr

opic

eff

ect

Inhib

itory

pre

synaptic

recepto

rsdecre

ase

NE

thro

ugh

inhib

itio

n

Neglig

ible

impact



receptor. This linkage induces calcium mobilization,

inhibits formation of cAMP, and stimulates phosphor-

ylation of MAP kinases.10,27 In both man and animals

H4Rs are modulators of inflammation, seen with colitis,

allergic airway disease pruritus, and some immune-

mediated disorders.26

Histamine Measurement

Sensitive tests for plasma histamine concentration in-

clude radio enzyme assay, high-performance liquid

chromatography, and radioimmunoassay.28 An enzyme

immunoassay has also been developed that has spec-

ificity and sensitivity similar to the radioimmunoas-

say29 and has been validated for measurement ofplasma histamine in animals.2932 Concentrations above

1 ng/mL are considered elevated in human beings33

and concentrations 42 ng/mL are often correlatedwith cardiovascular changes.34,35 Similarly, normal

values in dogs and cats have been reported to be

o1 ng/mL.31,32

Histamine Physiology and Pathophysiology

Histamine and the immune system

Mast cells and basophils are the major sources of his-

tamine in normal tissue. Each cell can contain as much

as 38pg of histamine per cell, comprising up to 70% of

the weight of each cell.9,36 Mast cells and basophils

synthesize and store histamine in granules and release

these and other mediators following immunological

and nonimmunological challenge.36 Immunological ac-tivation and subsequent release of histamine and other

inflammatory mediators, occurs when the immuno-

globulin E receptor on the cell surface of mast cells and

basophils is crosslinked to antigen or antibody. Non-

immunological activation occurs with cytotoxic and

noncytotoxic stimulation. Cytotoxic stimulation re-

leases intracellular contents through plasma membrane

rupture and noncytotoxic stimulation induces mediatorrelease while allowing the plasma membrane to remain

intact. Compounds such as cytokines, neuropeptides,

anaphylatoxins, growth factors, and free radicals all

have the ability to induce nonimmunological activation

of mast cells and basophils.9,36,37 Other histamine-

producing cells with immune function include mono-

cytes, lymphocytes, fibroblasts, ovarian cells, and

murine bone marrow-derived macrophages. These cellsdiffer in that they contain far less histamine per cell and

unlike mast cells and basophils, do not store histamine

in specific granules but secrete it after stimulation trig-

gers synthesis and immediate release.36 Monocytes and

lymphocytes contain 0.05 pg histamine per cell and

fibroblasts, ovarian cells and murine macrophagesRespirato

rysyste

mB

ronchospasm

Incre

ased

cough

and

wate

ry

nasaldis

charg

evia

stim

ula

tion

of

airw

ay

vagal

aff

ere

nt

nerv

e

Rhin

itis

Bro

nchodila

tion

Incre

ased

mucous

pro

duction

inairw

ays

Decre

ases

bro

nchoconstr

ictio

n

Pro

inflam

mato

ry

Skin

Incre

ased

pru

ritu

sN

eglig

ible

impact

Antiin

flam

mato

ryat

nerv

e

cells

Incre

ased

pru

ritu

s

Vascula

rsm

ooth

muscle

Vasodila

tion

Incre

ased

vascula

r

perm

eabili

ty

Vasodila

tion

Incre

ased

vascula

r

perm

eabili

ty

Vasodila

tion

thro

ugh

inhib

itio

n

of

NE

Neglig

ible

impact

Most

rele

vant

clin

icalre

sponse

Anaphyla

xis

and

acute

inflam

mato

ryand

alle

rgic

dis

ord

ers

Gastr

icacid

secre

tion

and

contr

actile

activity

of

the

heart

Neuro

transm

issio

nin

the

centr

alnerv

ous

syste

ms

and

eff

ects

on

cognitio

n,

sle

ep,

mem

ory

,and

appetite

Chro

nic

inflam

mato

ryand

alle

rgic

dis

ease

CN

S,

centr

al

nerv

ous

syste

m;

PIP

2,

phosphatidyl

inositol

dip

hospahte

;D

AG

,1,2

-dia

cylg

lycero

l;cA

MP

,cyclic

adenosin

em

onophosphate

;cG

MP

,cyclic

guanosin

em

onophosphate

;IL

,in

terleukin

;G

I,

gastr

oin

testinal;

NE

,nore

pin

ephrine;

NO

,nitric

oxid

e;

MA

PK

,m

itogen-a

ctivate

dpro

tein

kin

ase;

NFkb

,nucle

ar

facto

rkappa

beta

.


Histamine

contain 0.008 pg histamine per cell.38 Monocytes have

been shown to express the immunoglobulin E receptor

but this is variable and found mainly in patients with

chronic atopy.36,39 Even though these cells are minor

sources of histamine, they play a significant role in the

immune system by modulating the cytokine profile and

functions of antigen-presenting cells.36,40 Mast cells,basophils, monocytes, and lymphocytes can themselves

be modulated by histamine as they express H1, H2,

and H4 receptors. This has led to varying and

sometimes counteracting effects of histamine on a

particular cell depending on the concentration of his-

tamine and the specific histamine receptors that are

activated.9

Other immune activities of histamine include theability to influence the expression and activity of sev-

eral cytokines and the complement cascade. Con-

versely, cytokines have also been shown to influence

histamine actions directly. Three principal regulators in

the inflammatory and acute phase response (tumor ne-

crosis factor-a, interleukin-1, and interleukin-6) all in-teract with histamine and influence the synthesis and

release of one another.9,41 Likewise, the complementcascade, which provides a major defense against patho-

gens and plays an important role in inflammation and

regulation of the immune system, has been shown to

stimulate the release of histamine.42 The anaphylatoxic

complement peptides C3a, C4a, and C5a, have the ca-

pability to release histamine from mast cells and baso-

phils. In addition, histamine has also been shown to

stimulate complement production in humans and someanimal species.42,43

Histamine and the cardiovascular system

Histamine and its receptors are present in all parts of

the circulatory system. Histamine directly regulates

heart function, peripheral vascular resistance, volume

of circulating blood, and indirectly influences nervous

and humoral cardiovascular regulation. Histamine isalso present in the CNS influencing cardiovascular con-

trol and in neuronal and nonneuronal peripheral struc-

tures associated with cardiovascular regulation (eg,

autonomic ganglia and the adrenal medulla).44,45 De-

spite numerous studies in humans and animals, the

cardiac, vascular, and coronary actions of histamine are

still obscure; yet histamine and its antagonists appear

to be clinically relevant.46 In humans, dogs, pigs, andlaboratory animals, the pathogenesis of coronary vaso-

spasm, arrhythmogenesis, myocardial ischemia, ath-

erosclerosis, and cardiac anaphylaxis have been linked

to histamine and it has been demonstrated that some

histamine antagonists exacerbate dysrhythmias and

atrioventricular (AV) conduction disturbances.44,47,48

Histamine is stored within mast cells in cardiac tissue

and endocardial cells. Mast cells are found in close

proximity to blood vessels making them easily acces-

sible to physical factors (hypoxia) and biological factors

(certain drugs) that cause degranulation.44,45 In the

heart, histamine causes both negative chronotropy via

H1R and positive chronotropy via H2R. More specifi-cally, activation of H1R causes a decrease in sinus rate,

atrial contractility, AV conduction, ventricular auto-

maticity, and ventricular contractility, whereas H2R

stimulation causes an increase in these same parame-

ters.44 H3R stimulation also impacts the cardiovascular

system; however, this is restricted to presynaptic post-

ganglionic sympathetic fibers. There is species variabil-

ity in the location and predominance of histaminereceptors in the heart. For example, in canine hearts

H1Rs predominate; in human hearts H2Rs are more

numerous. Cats and rats have fewer histamine recep-

tors in the heart.11

In the systemic and coronary vasculature, increased

histamine concentration causes dilatation of arterioles

and an increase in capillary permeability that leads to a

decrease in systolic and diastolic pressure. These vas-cular effects are related to the number of available

receptors and are dose and time dependent.44 H1R-

mediated effects after high-dose histamine injection

cause an early decrease in arterial pressure, whereas

H2R activation causes sustained hypotension.46 Gener-

ally, the H1R vasorelaxation mediated by NO and pros-

tacyclin (PGI2) from the endothelial cell predominates

in the systemic circulation. There is variability in dif-ferent circulatory beds and in different species.44

Histamine plays a role in the regulation of coronary

blood flow. Clinical studies in humans confirm that

histamine-induced coronary dilation with subsequent

increase in coronary blood flow is dependent on vas-

cular diameter and the concentration of histamine.46

More specifically, in proximal portions of the coronary

arteries that have a thicker intima, vasoconstrictionmediated by H1Rs on smooth muscle cells dominates

over the vasodilatory action of smooth muscle H2Rs

with high doses of histamine. Conversely, in distal seg-

ments of the coronary arteries the main action is vaso-

dilatation resulting from direct activation of smooth

muscle H2Rs.49,50 A similar pattern has been demon-

strated in dogs.51 In pigs and cattle, histamine-induced

vasoconstriction predominates in most segments of iso-lated coronary arteries via H1Rs on smooth muscle

cells.49

Histamine affects the function of the cardiovascular

system not only directly but indirectly through the

central histaminergic neurons. The cell bodies of all

histamine containing neurons in the CNS are localized

to the posterior hypothalamus. H1R, H2R, and H3Rs



have been identified as mediators of histamine in the

CNS that indirectly impact the cardiovascular sys-

tem.44,45 Histaminergic neurons send ascending and

descending fibers to major loci in the brain that con-

tribute to autonomic regulation of the cardiovascular

system. Pressor systems are mediated through H1R ac-

tivation and in humans, dogs, cats, and rats thesepressor systems have been found to be dose-related to

histamine. Increased concentrations of histamine stim-

ulate the central histaminergic system, which in turn

stimulate the sympathetic nervous system and causes

secretion of vasopressin. There is also a release of cat-

echolamines and activation of the renin-angiotensin-

aldosterone system. Catecholamines, vasopressin, and

angiotensin II are potent vasoconstrictors that increasearterial pressure.44,45 In cats, it has been shown that a

decrease in arterial blood pressure can trigger the re-

lease of histamine from the hypothalamus that in turn

stimulates the central histaminergic system to increase

mean arterial pressure.52

Although pressor responses appear to be mediated

through H1R stimulation, it appears that H2Rs mediate

the effects of central histamine on heart rate.53,45 Heart-rate response, in contrast to pressor effects, is different

between awake and anesthetized animals and appears

to be species dependent.45,54 Injection of histamine cen-

trally in anesthetized rats results in tachycardia but in

conscious rats results in bradycardia.45 In contrast, his-

tamine via central venous injection has little effect on

heart rate in conscious cats and produces a variable

response in goats.45,55 Stimulation of H3Rs also occursin the CNS that results in inhibition of norepinephrine

release and leads to vasodilatation and modulation of

feedback control mechanisms.44

Histamine antagonists have been evaluated in rela-

tion to the cardiovascular system. In dogs, the H2R

blockers famotidine and cimetidine improve myocar-

dial metabolism and protect against ischemia and re-

perfusion injury.56 H2R blockade in humans withchronic heart failure using famotidine showed that

cardiac symptoms and ventricular remodeling im-

proved.57 Other studies in humans have demonstrated

that many H1R and H2R antagonists at higher dosages

can lead to AV conduction disturbances.44 The H2R

antagonists cimetidine and ranitidine administered in

high dosages can cause sinus or cardiac arrest, AV

blockade of all degrees, and atrial fibrillation. In con-trast, famotidine did not cause any significant ECG

changes.58 H1R antagonists in higher dosages have also

been associated with dysrhythmias and AV conduction

disturbances in humans.46

Histamine has direct and indirect effects on cardiac

function, peripheral vascular resistance, and circulating

blood volume. The beneficial use of histamine antago-

nists in relation to cardiovascular disease remains

equivocal and future studies are needed in this area.

Histamine and the respiratory system

Mast cell degranulation and subsequent histamine re-

lease in the respiratory system causes airway smooth

muscle contraction, vasodilation, mucous secretion,

and mucosal edema formation. Most of the clinically

important effects of histamine on the respiratory system

are H1R mediated although H2R and H4R are also in-

volved. Because of these effects, histamine plays animportant role in allergic rhinoconjunctivitis, bronchial

anaphylaxis, and asthma.

Histamine and asthma: Asthma is a chronic inflam-

matory disease of the airways and is often accompaniedby acute bronchospasm. Histamine was the first medi-

ator implicated in the pathogenesis of asthma, and his-

tamine-induced bronchial smooth muscle contraction is

the primary mechanism of acute bronchospasm.59 In

the acute phase response of asthma in humans, IgE-

mediated activation of mast cells and basophils releases

histamine and other proinflammatory mediators (sero-

tonin and chemotactic factors) resulting in an increasedconcentration of these factors in the plasma and an in-

crease in airway resistance.60 In addition, these medi-

ators rapidly cause vasodilation, an increase in vascular

permeability, an inflammatory cell influx, and smooth

muscle contraction.

Pulmonary mechanics and their relation to histamine

have been studied in many other species and it is clear

that histamine-induced bronchial smooth muscle con-traction and acute bronchospasm are common.6168

The pathogenesis of asthma is complex and all symp-

tomatology cannot be accounted for by a single hista-

mine-dependent mechanism. This explains the

disappointing results when histamine antagonists are

used as sole therapy for asthma in humans and cats.59,69

In humans, numerous studies have reviewed the use of

antihistamines in asthma and H1R antagonists havebeen shown to protect against the early bronchocon-

strictor response to an allergen but do not completely

inhibit it. In chronic asthmatic human patients, the ef-

fects of H1R antagonists are weak.59 Another study

evaluating the newer H1R antagonists cetirizine and

terfenadine found that these were more potent inhib-

itors of histamine-induced bronchospasm but still were

not effective as a sole agent in the treatment ofasthma.70 H2R antagonists appear to have no consis-

tent effect on bronchial tone or histamine-induced

bronchoconstriction.59 Similarly in cats, histamine an-

tagonists may be useful in the treatment of bronchial

asthma; however, a recent study evaluating the use

of the H1R antagonist cetirizine in experimentally


Histamine

induced asthma concluded there was no significant

decrease in airway inflammation. It was, therefore, not

recommended as the sole treatment for cats with bron-

chial asthma.69,71 The pathophysiology and treatment

of feline bronchial asthma must consider histamine and

other mediators.71,72

In horses, both neutrophilic inflammation andbronchospasm are features of chronic obstructive pul-

monary disease (COPD), as well as signs of chronic

lower airway disease in humans and cats. Histamine,

serotonin, and leukotrienes are involved in the exacer-

bation of COPD and histamine in particular has been

shown to increase the tension in the equine small air-

way.73 The pathophysiology of COPD involves many

inflammatory mediators. This explains the low efficacyof histamine antagonists with their single therapeutic

action in contrast to the glucocorticoids that blunt most

of the inflammatory process.74

Histamine and anaphylaxis: Histamine is the major

mediator of anaphylaxis and has been measured in

plasma within 1 minute after triggering of an anaphy-

lactic event.59 Anaphylaxis is an immediate and poten-tially fatal systemic reaction most commonly caused by

IgE-mediated degranulation of mast cells and baso-

phils. Leukotrienes also contribute and their release

causes increased vascular permeability and vasodila-

tion. Hypovolemia results from plasma leakage into the

interstitial space with acute loss of effective circulating

volume.

Histamine in anaphylaxis acts through H1, H2, andH3 receptors.75 H1R activation results in rhinitis,

pruritus, bronchoconstriction, coronary vasoconstric-

tion, cardiac depression, and stimulates production of

NO to eventually cause vasodilation. H2R activation

stimulates gastric acid secretion, and produces coro-

nary and systemic vasodilation, increased heart rate,

and ventricular contractility. H3R activation inhibits

norepinephrine release that blocks neural adrenergicstimulation and accentuates the degree of shock

observed.75,76

Previously there was a distinction made between

anaphylaxis and anaphylactoid reactions (nonIgE-me-

diated reactions); however, the term anaphylactoid is

no longer recommended.77

Anaphylactic reactions are now classified as:

1. Immunologic IgE mediated caused by insectbites, food, or medications such as b-lactam anti-biotics.

2. Immunologic non-IgE mediated caused by im-mune aggregates, complement activation, coagu-

lation activation, and autoimmune mechanisms.

3. Non-immunologic caused by exercise, cold, andcertain medications such as opioids and some

chemotherapeutic agents.78

Universal clinical criteria for classifying anaphylaxis

have recently been defined in humans77 but complete

universal criteria have not been established for other

species. Case reports suggest that there is variability inclinical presentation of anaphylaxis in veterinary spe-

cies such as dogs, cats, and horses.79,80,74

Recognition of anaphylaxis in both humans and

animals can be difficult due to the wide variability

of clinical signs and response to therapy. The use of

plasma histamine levels to support the diagnosis

of anaphylaxis is problematic in part because the

appearance and disappearance of histamine in thecirculation can vary, making the time of sampling an

important factor.78 Evaluation of histamine blood lev-

els in animals is not practical or clinically useful

due to this same variability. Rapid diagnosis and

therapy for a potentially life-threatening anaphylactic

event must therefore be based on history and clinical

signs.

In dogs, initial clinical signs of anaphylaxis are pre-dominately hepatic in origin with hepatic vein con-

gestion and portal hypertension leading to vomiting

and diarrhea. This may progress to the respiratory

system with hypovolemic shock and death if not

recognized rapidly. In cats, respiratory tract signs

predominate with dyspnea resulting from laryngeal

and pharyngeal edema and bronchoconstriction.

Dermal and ocular manifestations can occur in bothspecies.76

Animal models of anaphylaxis have been established

in mice, dogs, and pigs and have led to refinement in

the treatment of anaphylaxis in humans.78 Treatment

strategies in both humans and animals include epi-

nephrine, oxygen, IV fluids, and ancillary medications

such as inhaled b-agonists, H1R antagonists such asdiphenhydramine, H2R antagonists such as ranitidineand cimetidine, glucocorticoids, and vasopressors if

needed.76,78 Some pretreatment models evaluated in

the dog have been disappointing with regards to car-

diovascular function during an anaphylactic event.

Pretreatment with an H1R antagonist such as chlor-

pheniramine maleate or an H2R antagonist such as

ranitidine did not prevent cardiovascular collapse in a

canine anaphylactic shock model. Pretreatment in thecanine with the H3R antagonist thioperamide maleate

did increase heart rate and improve left ventricular

systolic function.81 Although histamine antagonists

alone are not highly beneficial for treating the cardio-

vascular collapse of anaphylaxis, the H1 and H2 block-

ers frequently benefit dogs and cats in reducing

pruritus and gastric acid secretion.76



Histamine and pruritus

Pruritus or itch is defined as an unpleasant cutaneous

sensation leading to the desire to scratch. Pruritus

serves as a physiological self-protective mechanism to

help defend the skin against harmful external agents

and pruritus is a major symptom of skin diseases and

various systemic disease.82 Histamine has long beenknown to be a mediator of itch particularly in diseases

such as atopic dermatitis and idiopathic chronic urti-

caria. In addition, autoimmune, neurological, meta-

bolic, and psychological factors without an obvious

histaminergic component also contribute to pruritus.9

The neurological pathways causing itch are dedi-

cated itch-sensing C-fibers in the periphery, and hista-

mine-specific neurons projecting into the brain.9,82

Dorsal root ganglion neurons have been shown to ex-

press H1Rs. Similar expression of H4Rs has not been

found on these neurons but their existence in peripheral

neurons is reported.26 Pruritogenic mediators released

into the periphery can directly activate the C-fibers,

which indirectly release pruritic mediators from other

cells. Other endogenous mediators of pruritus in addi-

tion to histamine include proteases, neurokinins,cytokines, cannabinoids, and opioids.83 A major source

of these mediators are mast cells that accumulate in

pruritic disease.84

Histamine antagonists are effective in pruritic states

such as acute and chronic urticaria that result in mast

cell degranulation. Therapeutic antipruritic benefits

with H1R antagonists such as diphenhydramine are

proven in these conditions, especially acute situationsassociated with hives and insect stings.85,86 The effec-

tiveness of histamine antagonists in atopic dermatitis,

however, is variable.86,87 In general, the conclusion of a

large retrospective review in humans showed H1R an-

tagonists are mostly ineffective in the treatment of

atopic dermatitis-associated pruritus with only modest

benefits derived from the sedative properties of the first

generation compounds.88 In dogs, treatment of atopicdermatitis and response to histamine antagonists are

unpredictable; however, the H1R antagonist cetirizine

in 1 study showed improvement in 18% of dogs.89 H2R

antagonists are ineffective for pruritus.90 Recent studies

in mice91 have raised the possibility that the H4R may

be an additional receptor contributing to histamine-

mediated pruritus.9 Future studies in the area of

pruritus are focusing on therapeutics that result incombined H1R and H4R antagonism.9

Histamine and the gastrointestinal system

Histamine is a potent stimulator of gastric acid secre-

tion. Sources of histamine in the GI tract are entero-

chromaffin-like cells (ECL), mast cells, and neuronal

fibers. ECL cells are under both humoral and neuronal

regulation and are stimulated by inflammation in the

gastric mucosa. Multiple regulatory substances such as

gastrin, cholecystokinin, vasoactive intestinal peptide,

endothelin, and norepinephrine also mobilize hista-

mine from ECL cells. Mast cells in the GI mucosa are

involved in IgE-mediated hypersensitivity and in anti-

parasitic reactions and play a role in gastric acid secre-tion, especially in species that have fewer ECL cells

such as dogs, cats, and humans.21 The release of his-

tamine from ECL cells and mast cells is an important

step in the development of peptic ulcers.92

The histamine receptors H1, H2, and H3 have been

found in gastric mucosa and histamine interaction with

these receptors is partially dependent on which isoform

is produced. For example, the histamine from ECL cellsacts on H2Rs of the parietal cell, whereas mast cell his-

tamine works on H1 and H2 receptors.21 The delicate

balance in the activity between ECL cells and mast cells

is needed in order to maintain mucosal integrity.

H2R antagonists are widely accepted and used in the

treatment of gastric acid-related disease in both humans

and animals.92 In humans, peptic ulcers associated with

Helicobacter pylori are exacerbated by increased gastrichistamine and acid secretion93 and suppression of his-

tamine with H2 antagonists is pivotal in the therapy of

this disease.94 Multiple studies in dogs and horses eval-

uating the effects of gastric acid suppression with H2R

antagonists have been performed9599 and conclude that

although different H2R antagonists have different de-

grees of gastric acid suppression, they are effective

agents either alone or in combination with proton pumpinhibitors in the therapy of gastric ulcer disease.

The relationship of disease progression and plasma

histamine levels was also evaluated in dogs with mast

cell tumors.31 Hyperhistaminemia is regarded as the

main contributing factor to gastroduodenal ulceration

and perforation in these patients.100 In 1 study, 83% of

dogs that died of progressive mast cell tumors had

gastroduodenal ulceration on postmortem examina-tion.101 This same study noted that the plasma hista-

mine concentrations in dogs whose clinical signs

responded to the H2 blocker cimetidine were not sig-

nificantly different from those dogs without gastroin-

testinal signs, whereas plasma histamine concentration

in dogs that did not respond to H2 blockers were 18

158 times higher than healthy control dogs. This study

concluded that dogs with mast cell disease that do notdemonstrate a clinical response to H2 blockers may

have marked hyperhistaminemia and may need more

intensive therapy to block the effects of histamine.31

Histamine and sepsis

Sepsis is often associated with progressive hypotension,

vascular leak, and myocardial dysfunction all of which


Histamine

can contribute to multiple organ failure and death.

Histamine may be a part of the pathogenesis of sep-

sis.102 Elevated plasma histamine has been documented

in the post-endotoxin period in rats,103 rabbits,104

dogs,79,105 primates,106 cats,107 and humans.108 One of

the most recent studies in rabbits found that after in-

jection of lipopolysaccharides (LPS), there was not onlyan immediate rise in plasma histamine concentration

but a sustained increase in plasma histamine when

measured at 30 minutes and 6 hours. The proposed

mechanism of this immediate increase in histamine was

thought to be due to degranulation of mast cells and

basophils.102 The mechanism of the sustained increase

in histamine may be related to an increase in HDC ex-

pression.102,109 A large prospective controlled study ofseptic humans demonstrated that an increase in hista-

mine concentration was statistically related to death.108

Histamine appears to contribute to the early cardio-

vascular changes in sepsis by H1R mediator activation

that opposes the effects of catecholamines. In later

stages of sepsis in humans, histamine appears to act via

H2R activation with strong vasodilatory and positive

inotropic effects.108 H3Rs have also been implicated insepsis,110 and in the dog the resulting inhibition of

norepinephrine release leads to a decrease in the

adrenergic response.111

Many studies in humans, rabbits, rats, and dogs have

examined whether treatment with histamine receptor

antagonists are beneficial for septic patients and these

results are varied.102 Early studies demonstrated that

administration of the H1R antagonist diphenhydra-mine had no effect on portal pressure or systemic

arterial vasodilation produced by endotoxin in anes-

thetized dogs.112 Later studies in septic dogs showed

that administration of diphenhydramine did prevent a

fall in systemic arterial pressure, left ventricular pres-

sure, and cardiac output.113 Chlorpheniramine (H1R

antagonist) given either before or after Escherichia coliinfusion prevented severe hypotonia and improvedurinary output in dogs.114 In a study of endotoxic shock

in pigs, only pretreatment with the H1R antagonist

dimethindene was effective in preventing a decrease in

cardiac output and deterioration of the microcircula-

tion.115 H2R and H3R antagonists have also demon-

strated variable results in septic models. In rabbits,

administered LPS, the H2R antagonist ranitidine pre-

vented the sustained tachycardia seen in the earlyphases after LPS injection.104 In septic dogs, H3R block-

ade with thioperamide maleate and clobenpropit 4

hours after E. coli infusion was associated with an im-provement in left ventricular contractility.110 Although

histamine appears to be a mediator in sepsis, its impact

on hemodynamic alterations and its response to ther-

apeutic antagonism are highly variable in septic

patients. This is most likely the result of sepsis being

a culmination of complex interactions between multiple

mediators, the infecting organism, and the host re-

sponse. With evidence from experimental studies that

some patients respond to histamine receptor antago-

nism even after clinical signs develop, histamine recep-

tor antagonists may be considered in the managementof sepsis.

Histamine during hemorrhagic shock and trauma

Traumatic and nontraumatic causes of massive hemor-

rhage can be a significant cause of mortality in

veterinary patients. Hemorrhagic shock leads to hemo-

dynamic decompensation caused by inadequate organ

perfusion. This decreased perfusion leads to inadequate

cellular oxygen delivery and increased build-up ofmetabolic products that alter the cells structure and

lead to cell death. The mortality rate is variable in dogs

with nontraumatic hemoabdomen116 and with trau-

matic hemoabdomen mortality is reported as high as

27%.117 Indicators for inadequate organ perfusion in

hemorrhagic shock include the increase in metabolic

products such as lactate and histamine.118,119 Systemic

lactate levels are generally accepted for determinationof shock severity in humans and veterinary patients in

the clinical and experimental setting.118,120 Research

evaluating histamine changes during hemorrhagic

shock demonstrate that histamine is also a good marker

for insufficient organ perfusion in hemorrhagic

shock118,119 and increased blood levels have been

demonstrated in rats, pigs, dogs, cats, and hu-

mans.55,119,121123 In dogs, both systemic and local tis-sue histamine levels were increased significantly

during hemorrhagic shock.121 Likewise in pig hemor-

rhagic shock models, systemic histamine levels were

elevated but local tissue histamine levels were not.119 In

regards to trauma, plasma histamine levels have been

measured in human polytrauma patients (3 or more

body regions involved) on days 1, 5, and 14 after the

trauma and were shown to be elevated. Those patientswith plasma histamine levels above the normal range

(1 ng/mL) on days 1 and 5 died.123 This and similar

studies of polytrauma victims demonstrate mortality in

patients with high histamine levels is more frequent

than in polytrauma patients with low histamine

levels.123125

Blood products are frequently used in the clinical

setting for management of hemorrhagic shock and inhuman and veterinary medicine. The use of blood

products has been shown to increase histamine levels in

humans.126 Studies evaluating prophylactic pretreat-

ment of patients with diphenhydramine (H1R

antagonist) did not significantly lower the risk of non-

hemolytic transfusion reactions.127 In dogs and cats



pretreatment with antihistamines to reduce the risk of

transfusion reactions remains controversial.128

The use of histamine antagonists has been studied

extensively in circulatory shock models over the past

few decades. Early studies on the use of antihistamines

in circulatory shock in rats showed that pretreatment

with H1R antagonists resulted in significantly highermean arterial blood pressures. However, this same

study concluded that pretreatment with an H2R antag-

onist increased mortality in circulatory shock leading to

the conclusion that H2R antagonism may be detrimen-

tal.129 Later studies in dogs treated with promethazine

had increased mean arterial pressures and enhanced

survival when this H1R antagonist was given 1 hour

before hemorrhage and 30 minutes after hemorrhage.130

In rats, selected H1 and H2 antagonists were adminis-

tered in hemorrhagic shock and none of the antagonists

affected the time of onset or the rate of decompensation

of the patient.131 Most recent studies have evaluated the

effects of histamine antagonists in hemorrhagic shock

and although most of the experimental evidence con-

cludes the histaminergic system influences cardiovas-

cular regulation in hemorrhagic shock, this influence iscomplex. The benefit of histamine antagonism for treat-

ment of hemorrhagic shock has not been proven.132134

Histamine and anesthesia/surgery

Many drugs and interventions used with anesthesia

and surgery are associated with histamine release

and hypotension.135 Drug-induced histamine release

was first identified following curare administration in

dogs.3,136 Other agents that induce histamine release indogs and humans include colloids, neuromuscular

blocking agents, injectable anesthetics, and some opio-

ids.34,137140 Histamine levels increase in dogs given

morphine and this correlates with dose and rate of IV

injection.141,142 Morphine given to conscious healthy

dogs by continuous rate infusion causes a variable

release of histamine with minimal cardiovascular ef-

fects.140 Butorphanol, fentanyl, sufentanil, and oxymor-phone do not induce histamine release in humans or

dogs.143145 In cats, morphine-induced vasodilatory re-

sponses appear to be mediated in part by histamine

receptor pathways.146 Fentanyl and sufentanil both

produce dose-dependent vasodepressor responses in

the feline vascular bed.146148 Anaphylactic reactions

occur in cats given the ophthalmic ointments ba-

citracin1neomycin1polymyxin and although plasmahistamine levels have not been evaluated in these pa-

tients, its use for ocular lubrication during anesthesia

may have been a factor in anesthetic deaths of young

cats during routine surgery.80

Histamine release can impact the preoperative, op-

erative, and postoperative periods.135 In the preopera-

tive period in humans scheduled for surgery several

conditions are associated with increased histamine lev-

els. These include polytrauma,124,125 septic shock,102,108

duodenal ulcer, and stress-induced lesions with upper

gastrointestinal bleeding.21,149 Histamine release in

the operative periods appears to be greatest during

celiotomies particularly with the manipulation andbreakdown of adhesions.150 Major abdominal or tho-

racic procedures such as cholecystectomy, lung lobec-

tomy, and anterior resection of the colon increased

plasma histamine significantly (41 ng/mL) in 32%of patients.126 Studies in both humans and dogs eval-

uating histamine release with laparoscopic versus

conventional surgery have had variable results.135 Car-

diovascular surgery including cross clamping of theaorta is associated with significant histamine release

and related symptoms.151,152 In humans the incident of

histamine release and arrhythmias during anesthesia

and surgery is reduced in individuals receiving both

H1 and H2 prophylaxis at standard dosages.153 Hista-

mine release in the postoperative period has also been

demonstrated. In a study of postoperative human pa-

tients, there was a positive effect of H1 and H2 receptorantagonist prophylaxis versus placebo on the compli-

cation rate (infection and wound healing).154

Clinicians should recognize that anesthetic and ther-

apeutic agents have the potential to induce histamine

release with subsequent clinical signs of rash, broncho-

spasm, and cardiovascular collapse. Some of these ad-

verse reactions can be prevented by being aware of

previous reactions, decreasing the speed of drug ad-ministration, and utilizing both H1 and H2 antagonists

in the perioperative period of higher risk individuals.

High-risk patients include those with previous hyper-

sensitivity reactions and those undergoing procedures

with higher risk of histamine release.34,124

Histamine antagonists

The term antihistamine is reserved for drugs that blockH1Rs only; the more general term for pharmaceutical

agents that block histamine receptors is histamine an-

tagonist. Histamine antagonists bind but do not activate

histamine receptors, thereby blocking the actions of

histamine or histamine agonists by competitive inhi-

bition.

H1R antagonists are used primarily in the treatment

of allergic disorders in humans and animals. Dogs haverelatively few adverse effects to H1R antagonists when

used at appropriate dosages; however, effective clinical

response in allergic disorder management is variable.

In contrast, cats are relatively sensitive to H1R antag-

onists and appear to have more adverse effects than

dogs.85 H1R antagonists are divided into first, second,


Histamine

Table2:Histamineantagonists

andclinical

use

inveterinarymed

icine.

Antagonist(Trade

name)

Histamine

receptor

Dose(m

g/kg)

Use/indications

Precautions

Veterinary

approval

Am

itripty

line

hydro

chlo

ride

(Ela

vil)

H1

th

isis

prim

arily

an

antidepre

ssantw

ith

secondary

H1

anta

gonis

m

Dog:

12,

PO

,q

12

h

Cat:

n510

mg/c

at,

PO

,q

24

h

Incre

ases

sero

tonin

and

nore

pin

ephrine

levels

,acts

as

atr

icyclic

behavio

ralm

odifi

er

Used

as

adju

nctive

thera

py

for

pru

ritu

s

Prim

ary

use

isfo

rbehavio

ral

dis

ord

ers

and

incats

as

an

adju

nctive

treatm

ent

for

low

er

urinary

tract

dis

ease

Adv

erse

effects

Sedation

and

anticholin

erg

ic

pro

pert

ies

such

as

constipation,

urinary

rete

ntion,

and

hypers

aliv

ation

Con

traind

ications

Hypers

ensitiv

epatients

,

seiz

ure

dis

ord

ers

,gla

ucom

a,

card

iac

failu

re,

bla

dder

neck

obstr

uction

None

Cetirizin

ehydro

chlo

ride

(Zyrt

ec)

H1

second

genera

tion

Dog:

0.5

1.0

,P

O,

q

1224

h

Cat:

n1.0

5.0

mg/c

at,

q24

h

Tre

atm

ent

of

urt

icaria

and

pru

ritu

s

May

be

usefu

lin

chro

nic

ato

pic

derm

atitis

indogs

Less

sedating

then

firs

t

genera

tion

com

pounds

Adv

erse

effects

Vom

itin

gand

hypers

aliv

ation

are

rare

sid

eeff

ects

,m

ild

sedation

Con

traind

ications

Patients

hypers

ensitiv

eto

hydro

xyzin

e

None

Chlo

rpheniram

ine

male

ate

(Chlo

r-T

rim

eto

n)

H1

firs

tgenera

tion

Dog:

0.2

0.4

,P

O,

q

812

h

Cat:

n24

mg/c

at,

PO

,

q1224

h

Tre

atm

ent

of

pru

ritis

most

com

monly

used

for

cats

Adv

erse

effects

Anticholin

erg

icactivity

in

additio

nto

antihis

tam

inic

eff

ects

-can

lead

tosedation

Con

traind

ications

Hypers

ensitiv

epatients

,

gla

ucom

a,

card

iac

failu

re,

bla

dder

neck

obstr

uction

Not

as

asin

gle

entity

but

appro

ved

inoth

er

com

bin

ation

pro

ducts

Cim

etidin

e(T

agam

et)

H2

Dog:510,P

O,IM

,IV

,

q6

h

Cat:

510,

PO

,

q68

h

Reduces

gastr

icacid

outp

ut

and

has

been

used

totr

eat

hypers

ecre

tory

conditio

ns

associa

ted

with

gastr

inom

as

and

masto

cyto

sis

Adv

erse

effects

Rare

but

inclu

de

confu

sio

n,

transie

nt

card

iac

arr

hyth

mia

s

ifadm

inis

tere

dto

rapid

IV

Inhib

its

the

mic

rosom

al

enzym

es

inth

eliv

er

whic

h

may

late

rm

eta

bolis

mof

oth

er

medic

ations

Con

traind

ications

Hypers

ensitiv

epatients

,

geriatr

icpatients

or

those

with

hepatic

or

renalin

suffi

cie

ncy

None

Cle

mastine

fum

ara

te(T

avis

t)H

1

firs

tgenera

tion

Dog:

0.0

51.5

,P

O,

q

12

h

Cat:

n0.3

40.6

8m

g/

cat,

PO

,q

12

h

Ora

lantihis

tam

ine

with

gre

ate

ranticholin

erg

ic

pro

pert

ies

Adv

erse

effects

Dogs:

sedation,

para

doxic

al

hypera

ctivity

and

dry

ness

of

mucous

mem

bra

nes;

Cats

:

dia

rrhea

None



Con

traind

ications

Hypers

ensitiv

epatients

gla

ucom

a,

card

iac

failu

re,

bla

dder

neck

obstr

uction

Cypro

hepta

din

ehydro

chlo

ride

(Periactin)

H1

firs

tgenera

tion

Dog:

0.3

2,

PO

,q

8

12

h

Cat:

n2

mg/c

at,

PO

,q

12

h

Antipru

ritic,

and

antihis

tam

inic

indogs

and

cats

Appetite

stim

ula

nt

incats

thro

ugh

sero

tonin

anta

gonis

m

Adv

erse

Effe

cts

Sedation

but

cats

may

have

a

para

doxic

alhypere

xcitabili

ty

Con

traind

ications

Hypers

ensitiv

epatients

None

Dip

henhydra

min

e(B

enadry

lH

1

firs

tgenera

tion

Dog:

14,

PO

,IM

,

q8

h

Cat:

n24

mg/c

at,

PO

,

IM,

q12

h

Tre

atm

ent

of

pru

ritis

associa

ted

with

alle

rgic

response,

pre

vention

of

motion

sic

kness,

and

has

antiem

etic

pro

pert

ies

Adv

erse

effects

Anticholin

erg

icactivity

in

additio

nto

antihis

tam

inic

eff

ects

-can

lead

tosedation

Con

traind

ications

Hypers

ensitiv

epatients

,

gla

ucom

a,

card

iac

failu

re,

bla

dder

neck

obstr

uction

No

syste

mic

pro

ducts

.A

sham

poo,

topic

alspra

yand

topic

al

liquid

are

availa

ble

Fam

otidin

e(P

epcid

ac)

H2

Dog:

0.5

1,

PO

,S

C,

IM,

IV,

q1224

h

Cat:

0.5

,P

O,

SC

,IM

,

IV,

q1224

h

see

advers

eeff

ects

about

IVuse

incats

Reduces

gastr

icacid

pro

duction

and

usefu

lfo

rth

e

treatm

ent

and

pre

vention

of

gastr

icand

duodenal

ulc

ers

,

esophagitis

,and

duodenal

gastr

icre

flux

and

esophageal

reflux

Adv

erse

effects

Bra

dycard

iaif

adm

inis

tere

d

rapid

lyIV

Dry

mouth

,headache

Intr

avascula

rhem

oly

sis

has

been

report

ed

when

giv

en

IV

tocats

Con

traind

ications

Hypers

ensitiv

epatients

,or

patients

with

impaired

hepatic

or

renalfu

nction

Possib

lenegative

inotr

opic

eff

ects

None

Fexofe

nadin

e(A

llegra

)H

1

second

genera

tion

Dog:

12,

PO

,q

12

24

h

Cat:n10

mg/c

at,

q12

h

Tre

atm

ent

of

urt

icaria

and

pru

ritu

s

Less

sedating

then

firs

t

genera

tion

com

pounds

Adv

erse

effects

Vom

itin

gand

hypers

aliv

ation

are

rare

sid

eeff

ects

,le

ss

likely

sedation

Con

traind

ications

Hypers

ensitiv

epatients

Possib

lybre

eds

with

MD

R-1

muta

tion,

itra

conazole

can

incre

ase

concentr

ations

None

Hydro

xyzin

ehydro

chlo

ride

(Ata

rax)

H1

firs

tgenera

tion

Dog:

2.2

,P

O,

q8

h

Cat:

12,P

O,q

812

h

or

n510

mg/c

at,

PO

,q

812

h

Antihis

tam

inic

,antipru

ritic

and

sedation

inato

pic

patients

Adv

erse

effects

Dogs:

rare

lytr

em

ors

,

seiz

ure

s;

Cats

:poly

dip

sia

,

depre

ssio

nand

behavio

ral

changes

Con

traind

ications

Hypers

ensitiv

epatients

gla

ucom

a,

card

iac

failu

re,

bla

dder

neck

obstr

uction

None


Histamine

Lora

tidin

e(C

laritin)

H1

second

genera

tion

Dog:

0.2

50.5

,P

O,

q

24

h

Cat:

0.5

,P

O,

q24

h

Tre

atm

ent

of

urt

icaria

and

pru

ritu

s

Less

sedating

then

firs

t

genera

tion

com

pounds

Adv

erse

effects

Vom

itin

gand

hypers

aliv

ation

are

rare

sid

eeff

ects

,le

ss

likely

sedation

Con

traind

ications

Hypers

ensitiv

epatients

Mecliz

ine

hydro

chlo

ride

(Bonin

e)

H1

firs

tgenera

tion

Dog:n12.5

25

mg/

dog,

PO

,q

24

h

Cat:

n6.2

5m

g/5

kg,

PO

,q

24

h

Antihis

tam

ine

with

sedative

and

antiem

etic

eff

ects

used

for

motion

sic

kness

Adv

erse

effects

Sedation

Con

traind

ications

Hypers

ensitiv

epatients

None

Mirta

zapin

e(R

em

ero

n)

H1

th

isis

prim

arily

an

antidepre

ssantw

ith

secondary

H1

anta

gonis

m

Dog:n0.6

mg/k

g/d

,P

O

tonot

exceed

30

mg/d

Cat:n3.7

5m

g/c

at,

PO

,

q72

h

Sero

tonin

anta

gonis

tand

tetr

acyclic

antidepre

ssant

Used

as

an

appetite

stim

ula

nt

and

antiem

etic

indogs

and

cats

.

Can

be

used

with

oth

er

antiem

etics

Adv

erse

effects

Sedation

Con

traind

ications

Hypers

ensitiv

epatients

Use

with

caution

inpatients

with

hypote

nsio

n,

or

pre

-

exis

ting

hem

ato

logic

al

dis

ease

None

Ranitid

ine

hydro

chlo

ride

(Zanta

c)

H2

Dog:

0.5

2,

PO

,IV

,

IM,

q812

h

Cat:

12,

PO

,

q812

h

Reduces

gastr

icacid

outp

ut

and

has

pro

kin

etic

activity

by

inhib

itin

gacety

lcholin

este

rase

Longer

dura

tion

of

action

and

few

er

dru

gin

tera

ctions

then

cim

etidin

e

Adv

erse

effects

Rare

but

inclu

de

confu

sio

n,

transie

nt

card

iac

arr

hyth

mia

s

ifadm

inis

tere

dto

rapid

IV

Pain

at

inje

ction

site

with

IM

adm

inis

tration

Con

traind

ications

Hypers

ensitiv

epatients

,

geriatr

icpatients

or

those

with

hepatic

or

renalin

suffi

cie

ncy

None

Thio

pera

mid

em

ale

ate

H3

None

Incre

ase

wakefu

lness

incats

and

rat

researc

hm

odels

Decre

ases

appetite

and

food

consum

ption

None.

Used

only

inre

searc

h

sett

ings

and

curr

ently

underg

oin

gclin

icaltr

ials

nU

nle

ss

specifi

ed

oth

erw

ise.

Table2:Continued

.

Antagonist(Trade

name)

Histamine

receptor

Dose(m

g/kg)

Use/indications

Precautions

Veterinary

approval



and third generation antagonists. First generation com-

pounds commonly used in veterinary medicine include

diphenhydramine, chlorpheniramine, cyproheptadine,

and hydroxizine. These cross the blood brain barrier

and are more sedating. There are increased adverse ef-

fects such as sedation and vomiting with first genera-

tion compounds. Second generation compounds suchas loratidine are less fat soluble and have minimal CNS

adverse effects. The second generation compounds

have not shown greater efficacy over the first genera-

tion compounds in dogs and cats with allergic disor-

ders.85 Third generation compounds are not currently

in use in veterinary medicine.9

H2R antagonists such as famotidine and ranitidine

are widely used to treat peptic ulcers, and gastrointes-tinal bleeding in dogs and cats.95 In humans, H2R an-

tagonists are used not only for gastroesophageal reflux

disease and healing gastric, duodenal, and esophageal

ulcers but also in the prevention of gastrointestinal

ulcers in critically ill patients.155

H3R antagonists may be useful in treating metabolic

disorders in dogs and cats and, in humans, sleep and

wakefulness disorders, attention disorders, obesity andAlzheimers disease.

H4R antagonists have been shown to be useful in

animal models of inflammatory bowel disease and co-

litis, asthma, other allergic airway disease, pruritus,

and autoimmune disease. Currently, H3R and H4R an-

tagonists are limited to research models and clinical

trials. There is an ongoing study exploring the combi-

nation of peripherally acting H4R antagonists and acentrally acting H1R antagonists to treat both acute and

chronic pruritus that may prove to be useful in veter-

inary patients156 (see Table 2).

Summary

Histamine plays a key role in the morbidity and mor-

tality associated with allergy, asthma, gastric ulcers,

anaphylaxis, sepsis, hemorrhagic shock, anesthesia,

surgery, cardiovascular disease, cancer, CNS disorders,

and immune-mediated disease. Histamine antagonism

has been in common use to block its adverse effects in

clinical veterinary and human medicine. With recent

advances in the understanding of histamine receptorphysiology, pharmaceutical agents targeting these

receptors have increased therapeutic options.

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