PHARMACOLOGY

Chapter 16/Lecture #9
Histamine and Antihistaminics
Dr. TAC Abella July 22, 2014
OBJECTIVES:
1. To discuss histamine, serotonin and ergot alkaloids
chemistry, pharmacokinetics and pharmacodynamics.
2. To identify drugs with action on histamine and serotonin
receptors.
3. To discuss its mode of action and clinical use.
4. To know associated drugs adverse effects and its
contraindications.
INTRODUCTION
Histamine, Serotonin (5-Hydroxytryptamine)
o
biologically active amines
o
function as neurotransmitters
o
found in non-neural tissues
o
have complex physiologic and pathologic effects
through multiple receptor subtypes
o
often released locally
o
constitute the autacoid drugs
HISTAMINE

o
o
o
o
o
o

similarities between effects of IV histamine and the

s/sx of anaphylactic shock and tissue injury
an important mediator of immediate allergic (urticaria)
and inflammatory reactions
modest role in anaphylaxis
gastric acid secretion
neurotransmitter and neuromodulator
possible role in immune functions and chemotaxis of
WBC

Chemistry & Pharmacokinetics

o
occurs in plants and animal tissues
o
a component of some venoms and stinging secretions
o
formed by decarboxylation of the amino acid Lhistidine by histidine decarboxylase
o
once formed, either stored or rapidly inactivated.
o
very little is excreted unchanged.
o
conversion to N -methylhistamine,
methylimidazoleacetic acid, and imidazoleacetic acid
(IAA)
* Histamine stored in vesicles by mast cells, basophils,
platelets
- tissues high histamine amt slow turn-over, longer to
replenish
takes weeks
o
bound in granules (vesicles) in mast cells (tissue) or
basophils (blood)
o
the histamine content of many tissues is directly
related to their mast cell content
o
Mast cells are especially rich at sites of potential
tissue injurynose, mouth, and feet; internal body

surfaces; and blood vessels, particularly at pressure

points and bifurcations
o
Bound form is biologically inactive
o
Enterochromaffin-like (ECL) cells of the fundus of
stomach, second important nonneuronal site of
histamine storage and release
1. release histamine (one of the primary gastric
acid secretagogues)
2. activate the acid-producing parietal cells of
the mucosa
o
Non-mast cell histamine is found in several tissues,
including the brain, where it functions as a
neurotransmitter
o
neuroendocrine control, cardiovascular regulation,
thermal and body weight regulation, and sleep and
arousal
*Histamine Pathway metabolized histamine is excreted in
urine the non-metabolized part will determine the amt of
histamine left in the body
Immunologic Release

o
o
o
o
o

most important pathophysiologic mechanism of mast

cell and basophil histamine release
Sensitized cells (IgE) degranulate when exposed to the
appropriate antigen
requires energy and calcium
release of histamine, ATP, and other mediators
immediate (type I) allergic reactions
ex. Hay fever and acute urticarial

Clavillas, Peralta, Perez CA, Ramones, Usman

PHARMACOLOGY
Chapter 16/Lecture #9
Histamine and Antihistaminics
Dr. TAC Abella July 22, 2014
b. basophils
without negative feedback:
a. lung mast cells
acts to limit the intensity of the allergic reaction in the
skin and blood.
local vasodilation and leakage of plasma containing
mediators of acute inflammation (complement, Creactive protein) and antibodies
chemotactic attraction for inflammatory cells such as:
- neutrophils
- eosinophils
- basophils
- monocytes
- lymphocytes
inhibits release of lysosome contents and several Tand B-lymphocyte functions (H2 or H4)
release of peptides from nerves in response to
inflammation (H3)
o
o

o
o

Chemical and Mechanical Release

1.

2.
3.

Amines: morphine and tubocurarine can displace

histamine from its bound form within cells
does not require energy
not associated with mast cell injury or
degranulation
Loss of granules from the mast cell
Compound 48/80
experimental drug

selectively releases histamine from tissue

mast cells by an exocytotic degranulation

process
requires energy and calcium
PHARMACODYNAMICS

Structure of Histamine Receptors

o
Seven membrane spanning regions
o
Coupled with G proteins

o
o

H1 receptor ~ muscarinic receptor parasympathetic

H2 receptor ~ 5-HT1 receptor same serotonin effect

o
H3 receptor ~ H4 receptor (40% homology)
** Study this table!

*Histamine is useless without receptors

- H1, H2, H3, H4 are not similar in appearance so
effects are specialized
Mechanism of Action
o

has negative feedback control mechanism mediated

by H2
receptors thus modulate its own release

with negative feedback:

a. mast cells skin

o
o

Histamine exerts its biologic actions by combining

with specific cellular receptors on the surface
membrane
It has four different histamine receptors: H1 H4

Clavillas, Peralta, Perez CA, Ramones, Usman

PHARMACOLOGY
Chapter 16/Lecture #9
Histamine and Antihistaminics
Dr. TAC Abella July 22, 2014

all four receptors belong to the large superfamily

of receptors GPCR

all four has constitutive activity: a molecule may

be an agonist at one histamine receptor and an
antagonist or inverse agonist at another

and an

Ex. clobenpropit - an agonist at H 4 receptors

antagonist or inverse agonist at H 3 receptors

In the brain:
H1, H2- postsynaptic
H3- presynaptic
H1 receptors
present in endothelium, smooth muscle cells,
and nerve endings
H2 receptors
gastric mucosa, cardiac muscle cells, and
some immune cells
H 4 receptors
leukocytes in the bone marrow and
circulating blood

Activation of Receptors
o
H1 activation - present in endothelium, smooth
muscle cells, and nerve endings
o
Inc phosphoinotisol hydrolysis
o
Inc intracellular calcium muscle
contraction
o
Inc IP3
o
H2 activation gastric mucosa, cardiac muscle cells,
and some immune cells,
o
increases intracellular cyclic adenosine
monophosphate (cAMP) via Gs
o
H3 activation
o
Decrease transmitter release
* Increases appetite obesity
o
H4 activation - leukocytes in the bone marrow and
circulating blood
o
Chemotaxis on eosinophils and mast cells
Tissue and Organ System Effects of Histamine
o
Histamine exerts powerful effects on smooth and
cardiac muscle, on certain endothelial and
nerve cells, on the secretory cells of the
stomach, and on inflammatory cells.
Nervous System
o
Powerful stimulant of sensory nerve endings (H3,H1)

Pain

Itching

Roles in appetite and satiety

antipsychotic drugs that block these

receptors weight gain
o
Important component of the urticarial response and
reactions to insect and nettle stings (H1)
o
Modulates respiratory neurons signaling inspiration
and expiration in mice(H1)
o
Modulates release of several neurotransmitters (H3)

Acetylcholine

Amine

Peptide
Cardiovascular System
o
systolic and diastolic BP
Direct vasodilator action on arterioles and
precapillary sphincters

Flushing

Warmth

headache
HR
Stimulatory action on heart
Reflex tachycardia 2 to BP
* decrease blood volume, increase rounds of
circulation to compensate
o Vasodilation (small doses)- H1
release of nitric oxide from endothelium
BP reflex tachycardia
Can be antagonized by H1-receptor
antagonists alone
o Vasodilation (higher doses)- H2
cAMP
direct cardiac stimulation
*Anaphylactic rxns give epinephrine (physiologic antagonist)
not antihistamine
o
Edema- H1
Action of amine on H1 receptors in the
vessels of the microcirculation (esp
postcapillary vessels)
Separation of the endothelial cells

Due to contraction of actin and

myosin

Results in increased peermeability

Transudation of fluid and molecules

as large as small proteins into the
perivascular tissue

Urticaria (hives)
o
Direct Cardiac Effects
Increased contractility (H2)
Increased pacemaker rate (H2)
Decrease contractility in atrial smooth muscle
(H1)
*H1 located in AV node, result decrease transmission
arrythmia
*H2 SV node increase firing
o
Some of the cardiovascular signs and symptoms of
anaphylaxis are due to released histamine.
o

Bronchiolar Smooth Muscle

o
Bronchoconstriction (H1)
o
Dangerous to patients with asthma

Hyperactive neural response

100 to 1000 times more sensitive

(both to histamine and metacholine)
o
Inhaled histamine used for diagnosis of
bronchial hypersensitivity in patients with
suspected asthma or cystic fibrosis

Methacholine provocation test more

commonly used
*Histamine same rxn as that of asthma
Gastrointestinal tract smooth muscle
o
Contraction of intestinal smooth muscle
o
Large doses of histamine may cause diarrhea (H1)
Other organ systems:
Histamine is insignificant in the ff:
o
Smooth muscle of the eyes
o
Genitourinary tract
o
Uterus affected pregnant women suffering
anaphylactic
reactions may abort as a result of histamine-induced
contractions
Secretory tissue
o
Stomach
powerful stimulant of gastric acid secretion
(H2)
Clavillas, Peralta, Perez CA, Ramones, Usman

PHARMACOLOGY
Chapter 16/Lecture #9
Histamine and Antihistaminics
Dr. TAC Abella July 22, 2014
activation of H2 receptors on gastric
parietal cells

increased adenylyl cyclase activity,

cAMP concentration and intracellular
Ca+ concentration
gastric pepsin and intrinsic factor
production (H2)
o
Small and Large Intestines
Stimulates glandular secretions
H 3 -selective histamine agonists inhibit acid secretion
stimulated by food or pentagastrin

Metabolic Effects
o
Absence of H3 receptors in knockout mice
increased food intake
decreased energy expenditure
Obesity
insulin resistance
increased blood levels of leptin
increased blood levels of insulin
Not yet proven in humans but intensive research is
underway to determine whether H 3 agonists are useful
in the treatment of obesity
The Triple Response
o
Intradermal injection of histamine shows ff
characteristics:
Red spot

dilation of small vessels

Edema

wheal
Flare

caused by an axon reflex

o
Involves three separate cell types:
1. smooth muscle in the microcirculation red spot
2. capillary or venular endothelium, flare
3. sensory nerve endings after effect
o
Similar local effects may be produced by

injecting histamine liberators (compound

48/80, morphine, etc) intradermally
applying appropriate antigens to the skin of a
sensitized person
o
Can be prevented by adequate doses of an H1receptorblocking agent
o
H2 and H3 receptors may also be involved

Clinical Use: Histamine

o Aerosolized form used as a provocative test of
bronchial hyperreactivity
o
no other current clinical applications

Other Effects
Histamine: local stimulation of peripheral pain nerve
endings via H 3 and H 1 receptors and play a role in
nociception in the central nervous system

Physiologic Antagonists
o
Epinephrine: smooth muscle actions opposite to
those of histamine
o
act at different receptors
o
i.e. epinephrine injection lifesaving in systemic
Anaphylaxis
Release inhibitors
o
reduce the degranulation of mast cells (antigen-IgE
interaction)
o
i.e. Cromolyn and nedocromil (tx: Asthma)
o
Beta 2 -adrenoceptor agonists also capable of
reducing
histamine release

Burimamide
o
an early candidate for H2 -blocking action,
and newer analogs
o
no effect on H1 , H2 , or H3 receptors
o
significant analgesic action in rodents via
CNS
o
analgesia comparable to opioids
o
no tolerance, respiratory depression,
constipation

Histamine: Toxicity
o
dose related
o
flushing
o
hypotension
o
tachycardia
o
headache
o
wheals
o
bronchoconstriction
o
gastrointestinal upset
o
symptoms similar to scombroid fish poisoning
histamine produced by bacterial action in the flesh of
the fish
o
should NOT be given to patients with asthma, active
ulcer disease or gastrointestinal bleeding
HISTAMINE ANTAGONISTS

Histamine Receptor Antagonists

o
Burimamide (H2) for peptic ulcer disease
o
H3 and H4 antagonists not yet available for clinical
use
o
Potent and partially selective experimental H3receptor antagonists

thioperamide

clobenpropit
Clavillas, Peralta, Perez CA, Ramones, Usman

PHARMACOLOGY
Chapter 16/Lecture #9
Histamine and Antihistaminics
Dr. TAC Abella July 22, 2014
A. H1-RECEPTOR ANTAGONISTS
- Compounds that competitively block histamine or as
inverse
agonists at H 1 receptors used in the treatment of
allergic
conditions

3.

Antiparkinsonism- (i.e. Diphenhydramine) - have

significant acute suppressant effects on the
extrapyramidal symptoms associated with certain
antipsychotic drugs

4.

Anticholinoceptor actions (ethanolamine,

ethylenediamine) - atropine-like effects on
peripheral muscarinic receptors; benefits reported for
nonallergic rhinorrhea but may also cause urinary
retention and blurred vision

5.

Adrenoceptor-blocking actions (phenothiazine

i.e promethazine)- Alpha-receptor blocking effects
may cause orthostatic hypotension in susceptible
individuals

6.

Serotonin-blocking action (i.e. cyproheptadine)

7.

Local anesthesia (i.e. diphenhydramine,

promethazine) - more potent than procaine as local
anesthetics used to produce local anesthesia in
patients allergic to conventional local anesthetic drugs

8.

Other actions

inhibit histamine and other inflammatory

mediators (i.e. cetirizine)

inhibit P-glycoprotein transporters in cancer

cells, gut epith, and brain capillaries (i.e.
terfenadine, acrivastine)

-Marketed in combination formulations such as cold

pills and sleep aids

Chemistry & Pharmacokinetics

o
First-generation lipophilic, can cross BBB &
placental barrier; similar to muscarinic brain:
causes sedative effect
o
Strong sedative effects
o
more likely to block autonomic receptors
o
Second-generation
o
Less sedating
o
less complete distribution into the central
nervous system
General Characteristics of H1 Blockers:
o
rapidly absorbed after oral administration
o
peak blood concentrations occurring in 12 hours
o
widely distributed throughout the body
o
first-generation drugs enter the CNS readily
o
metabolized by liver microsomal systems
o
second-generation agents metabolized by the
CYP3A4 system
o
important drug-drug interactions
(ketaconazole)
o
effective duration of action of 46 hour in single dose
o
Exceptions: meclizine, 2nd gen agents (12
24 hours)
* peak in 1-2 hrs, consider possible sedative effect to Pt.
Active metabolites:
o
Hydroxyzine= cetirizine
o
Terfenadine = fexofenadine
o
Loratadine = desloratadine

CLINICAL PHARMACOLOGY OF H1 -RECEPTOR

ANTAGONISTS
Clinical Uses:
o
Allergic Reactions
o
Motion Sickness and Vestibular Disturbances
o
Nausea and Vomiting of Pregnancy
Clinical Uses: Allergic Reactions
o
H1 antihistaminic agents
o
Often first-line drugs
o
2nd line in hay fever (alkylamines, 2nd gen)
o
Drug of choice in urticaria
o
Ineffective in bronchial asthma
o
atopic dermatitis (i.e.Diphenhydramine)

PHARMACODYNAMICS

both neutral H 1 antagonists and inverse H 1 agonists:

block the actions of histamine by reversible competitive
binding to the H 1 receptor
negligible potency at the H 2 receptor and little at the H3
receptor

histamine-induced contraction of bronchiolar or

gastrointestinal smooth muscle can be completely
blocked by H1 blocker, but the effects on gastric
acid secretion and the heart are unmodified
similarity in general structure to drugs with effects on
different receptor sites result in numerous actions:
1.

Sedation - common effect of first - generation H 1

antagonists make them useful as sleep aids

2.

Antinausea and antiemetic- (i.e. Doxylamine) first generation

H 1 antagonists have activity in preventing motion
sickness

Second-generation H1 antagonists
o
allergic rhinitis
o
chronic urticaria

Motion
o
o
o
o

Sickness and Vestibular Disturbances

Scopolamine, diphenhydramine, promethazine
Dimenhydrinate
piperazines (cyclizine and meclizine)
scopolamine and the H 1 antagonists are more
effective in preventing motion sickness when
combined with ephedrine or amphetamine.

Nausea and Vomiting of Pregnancy

o
Piperazine derivatives
o
teratogenic effects in rodents
o
Doxylamine
Clavillas, Peralta, Perez CA, Ramones, Usman

PHARMACOLOGY
Chapter 16/Lecture #9
Histamine and Antihistaminics
Dr. TAC Abella July 22, 2014
o
o

Ethanolamine H 1 antagonist
controversy

Toxicity
Sedation
antimuscarinic action
excitation and convulsions in children
postural hypotension
allergic responses
atropine overdosage
cardiac arrhythmias
astemizole or terfenadine
Drug Interactions
o
Lethal ventricular arrhythmias
o
early second-generation agents, terfenadine or
astemizole,
o
in combination with ketoconazole, itraconazole, or
macrolide, erythromycin, grapefruit

inhibit CYP3A4 inc blood conc

o
blockade of the HERG (IKr) potassium channels in
the heart

Prolongation and a change in shape of

the action potential
o
Significant sedation
o
Cause central nervous system depression
o
o
o
o
o
o
o

Clavillas, Peralta, Perez CA, Ramones, Usman

PHARMACOLOGY
Chapter 16/Lecture #9
Histamine and Antihistaminics
Dr. TAC Abella July 22, 2014
o

H 4 blockers
potential in chronic inflammatory conditions
in which eosinophils and mast cells play a
prominent role
pruritus, asthma, allergic rhinitis, and pain
conditions

COMMON RESPIRATORY OVER-THE-COUNTER AGENTS

B. H 2 -RECEPTOR ANTAGONISTS
o
drugs that blocked gastric acid secretion
o
no H 1 agonist or antagonist effects
o
very low toxicity
o
peptic ulcer disease
C. H 3 - & H 4 -RECEPTOR ANTAGONISTS
o
homology between the H 3 and H 4 receptors
o
no selective H 3 or H 4 ligands are presently available
for general clinical use
o
H 3 -selective ligands
sleep disorders, narcolepsy, obesity, and
cognitive and psychiatric disorders
Tiprolisant
Clavillas, Peralta, Perez CA, Ramones, Usman

PHARMACOLOGY
Chapter 16/Lecture #9
Histamine and Antihistaminics
Dr. TAC Abella July 22, 2014
MCQs:
1.

2.

3.

4.

5.

What is the Triple Response?

a. redspot, edema, flare
b. redspot, hypotension, edema
c. edema, hypertension, tachycardia
d. flare, redspot, hypotension
Releases histamine and activate the acidproducing parietal cells of the mucosa
a. Histamine releasing cell
b. ECL
c. Alpha cell
d. Beta cell
Amines that candisplace histamine from its bound
form within cells
a. morphine, tubocurarine
b. hexacurarine, morphine
c. tubocurarine, hexacurarine
d. morphine, dopamine
24 year old Patrick Angas, goes to your clinic
complaining of difficulty of breathing, after history
taking you found out that he was a male sex
worker and had been escorting older women for
money for almost 10 years and he has a history of
asthma. What receptor would have caused the
patients difficulty of breathing?
a. H1
b. H2
c. H3
d. H4
What H1 receptor agonist generation would you
give to a patient who works with heavy
machinery?
a. 1st generation
b. 2nd generation
c. 3rd generation
d. Generation X

ABAAB

Clavillas, Peralta, Perez CA, Ramones, Usman