ANTIHISTAMINES

Tri Widyawati

Introduction
HISTAMINE: distributed throughout the periphery and in
a few select areas of the brain.
PERIPHERY:
A) mast cells in tissue
Which tissues have a high concentration of mast cells?
Bronchioles, skin, intestinal mucosa

B) basophils circulating
BRAIN:
The majority of cell bodies of histaminergic neurons are
located in the posterior basal hypothalamus and
RETICULAR FORMATION
What does this suggest?
Histamine is involved in cortical stimulation

 The most important stimulus for

HISTAMINE release is
ANTIGEN BRIDGING of IgE antibodies on the
surface of MAST cells & BASOPHILS

The following DRUGS also stimulate the

release of HISTAMINE:
A) neuromuscular blockers (degranulation
of mast cells)
B) morphine (releases histamine dilates a
and v decr preload and afterload)
C) VANCOMYCIN (red man syndrome, tx
methicillin resistant S. Aureus)
Characterized by:
flushing of upper body and facial area, hypotension,
tachycardia (baroreflex)

 What is the clinical significance of

drug induced HISTAMINE release?
Rx induced anaphylactiod reaction (not
IgE mediated)
Characterized by:
Burning, itching sensation in hands, face,
scalp, ears followed by a feeling of intense
warmth. Soon, these areas and the whole
trunk turn red.

BP FALLS reflex incr HR. Pt.

complains of headache.
HIVES appear accompanied by NAUSEA,
acid secretion, and BRONCHOSPASMS
(life threatening)

3 TYPES OF HISTAMINE
RECEPTORS:
H1:
Higher affinity for HISTAMINE than H2
Mediates rapid onset, but short lived
vasodilation.
Coupled to PHOSPHOLIPASE C
hydrolyzes membrane phospholipids
to form:
IP3, DAG

IP3:
Ca++ activated Ca++/calmodulindependent MYOSIN LIGHT CHAIN KINASE
& PHOSPHOLIPASE A2

 MLCK:
Phosphorylates myosin
Causes BRONCHOCONSTRICTION and
incr peristalsis
PLA2 produces NITRIC OXIDE &
PROSTACYCLIN (PGI2), both of which are
VASODILATORS

DAG:
Facilitates process by activating
PROTEIN KINASE C, which facilitates
Ca++ release from the SR

H2:
Mediates slow onset, but sustained
vasodilation.
Does not mediate bronchoconstriction.
Stimulates adenylyl cyclase incr in cAMP
which activates a cAMP-dependent
PROTEIN KINASE that:
1. phosphorylates and activates Ca++ pump,
that pumps Ca++ out of cell, into SR
2. phosphorylates and inactivates MLCK, which
prevents activation of myosin.

Stimulating H2 receptors also increases

gastric acid secretion.

H3:
Act as:
1) autoreceptors
2) heteroreceptors (NE, serotonin,
dopamine)
Blocking H3 with an antihistamine
might alter the release of other
neurotransmitters.
No Rx works on H3 yet.

PHYSIOLOGICAL EFFECTS OF
HISTAMINE
1. ALLERGIC RESPONSE:
Cross-linking by antigen of IgE
antibodies on the surface of mast cells
and basophils leads to exocytosis of
HISTAMINE-containing granules.

2. VASODILATION
3. INCREASED CAPILLARY
PERMEABILITY
HISTAMINE causes endothelial cells to
contract and separate exposing the
basement membrane which is freely

4. TRIPLE RESPONSE (flare and wheal)

A) localized RED SPOT few seconds
immediate vasodilation H1
B) BRIGHT FLARE 1 cm around red spot
develops slowly H2
C) WHEAL couple minutes edema
(leakage thru basement membrane)

5. (+) INOTROPIC/CHRONOTROPIC
EFFECTS
DIRECT effect: H2 incr automaticity
INDIRECT effect: baroreflex tachycardia
HIGH LEVELS, as might occur during
anaphylaxis, can cause ARRYTHMIAS

 6. HISTAMINE SHOCK: massive

vasodilation decr BP
7. INCREASED GASTRIC ACID
SECRETION: H2
8. PAIN & ITCHING:
Stimulating H1 receptors in the dermis

PAIN

Stimulating H1 receptors in the

epidermis
ITCHING

H1 ANTAGONISTS
1ST GENERATION:
Penetrate CNS, highly sedating
Most also have considerable
ANTICHOLINERGIC activity which can
provide an ANTIEMETIC EFFECT
(particularly against motion sickness)
As a group, mainly used for type I
hypersensitivity reactions (various
rashes and ALLERGIC RHINITIS)

1. DIPHENHYDRAMINE (Benadryl)
For topical, oral, IV, or deep IM use
TYPE I IgE mediated hypersensitivity
reactions
MOTION SICKNESS (anticholinergic
activity)
NIGHTTIME SLEEP AID
ANTITUSSIVE mech unkn
Topically for itch
CAUTION:
repeated topical use has resulted in
allergic reactions

2. DOXYLAMINE (Unisom Nighttime

Sleep Aid)
OTC
Rx 1 & 2 are the
MOST SEDATING

3. DIMENHYDRINATE (Dramamine)
Available OTC for N, V, dizziness,
vertigo.
Very sedating (contains
diphenhydramine)

4. MECLIZINE (Antivert)
Motion sickness
Long acting, 12-24 hours
5. CYCLIZINE (Marezine)
Motion sickness
6. HYDROXYZINE (Atarax)
Motion sickness
PRURITIS
PRE-OP & POST-OP SEDATION
ANTIANXIETY

7. PROMETHAZINE (Phenergan)
Also blocks alpha 1 receptors side
effects
USES:
TYPE I hypersensitivities ex.
Allergic rhinitis

SEDATIVE, either pre op, post op, or

obstetric sedation
ANTI-ANXIETY to relieve apprehension
pre or post op and facilitate sleep
ANTIEMETIC a phenothiazine w/ good
antiemetic activity pre op to prevent N, V
associated w/ general anesthetics

 MECH OF ANTIEMETIC EFFECT:

Blocking DA D2

MOTION SICKNESS
CAUTION:
Might LOWER SEIZURE THRESHOLD

8. TRIPELENNAMINE (PBZ =
pyribenzamine)
Highly sedating
9. CLEMASTINE (Tavist)
Long acting, 12-24 h
10. CHLORPHENIRAMINE (ChlorTrimeton)

11. DEXCHLORPHENIRAMINE (Polaramine)

12. CYPROHEPTADINE (Periactin)
Has been known to cause weight gain and
to block 5-HT2 receptors.
Some claim it is the best one to tx ITCHING
13. BROMPHENIRAMINE (Dimetapp)
Available only with other ingredients:
Pseudoephedrine, APAP, dextromethorphan

14. AZATADINE (Optimine)

15. AZELASTINE (Astelin)
16. PHENINDAMINE (Nolahist)

 SIDE EFFECTS (all)

SEDATION use w/ caution w/ other
sedating Rx, such as
Hypnotics, Opioids, EtOH

CAUTION IF NARROW ANGLE

GLAUCOMA WHY?
b/c of anticholinergic activity relaxes
ciliary mm narrow angle impedes
flow of aqueous humor incr pressure

What are other common

anticholinergic side effects:
Blurred vision, dry mouth, constipation

 CNS stimulation can

Restless, unable to sleep, hallucinations,
ataxia
Antihistamines have been known to
cause CONVULSIONS IN CHILDREN
CAUTION with other Rxs with a high
degree of anticholinergic activity

2ND GENERATION H1 ANTAGONISTS:

Poorly penetrate the CNS
Thus LITTLE OR NO SEDATION

LITTLE OR NO ANTICHOLINERGIC OR
ANTIEMETIC EFFECTS
1. FEXOFENADINE (Allegra)
2. CETIRIZINE (Zyrtec)
Active metabolite of hydroxyzine
Slightly sedating
Long acting, 12-24 h

3. LORATADINE (Claritin)
Reported to stimulate appetite wt
gain
4. DESLORATADINE (Clarinex)
Isomer of loratadine
REMEMBER: BETA AGONISTS,
CROMOLYN, AND NEDOCROMIL ALL
HAVE ANTIHISTAMINIC ACTIVITY BY
BLOCKING DEGRANULATION OF MAST
CELLS!

H2 ANTAGONISTS
INHIBIT GASTRIC ACID SECRETION by
parietal cells
Used in treating duodenal & gastric
ulcers
1. CIMETIDINE (Tagamet)
Oral & IV/IM
Tagamet HB (histamine blocker) is
available OTC
2. RANITIDINE (Zantac)
Oral & IV/IM

3. FAMOTIDINE (Pepcid)
Pepcid AC (acid controller) is OTC
IV by prescription only
PEPCID COMPLETE (OTC)
famotidine + calcium carbonate +
magnesium hydroxide
4. NIZATIDINE (Axid)
Oral only

 SIDE EFFECTS:
Vary in potency, but
THERAPEUTICALLY EQUAL
Generally safe
Standard SE:
HEADACHE, DIARRHEA, CONSTIPATION,
DROWSINESS

CNS effects RARE why?

Too hydrophilic possibly more CNS
effects in ELDERLY

 CIMETIDINE is the worst regarding S-E, and

then only in HIGH DOSES. It binds to
cytochrome P450 SIGNIFICANT
INHIBITION OF RX METABOLISM
SIDE EFFECTS OF CIMETIDINE:
1. INCREASED ESTRADIOL (E2) LEVELS in
men mech:
Failure to hydroxylate

2. INCREASES PROLACTIN

GYNECOMASTIA (high doses)

High doses of cimetidine (up to 14 gms/d) and
other H2 blockers are used to tx ZOLLINGERELLISON SYNDROME (ZES) vs. 2-3 gms/d of
cimetidine for most other indications

ZES: a non beta cell TUMOR (gastroma of the

PANCREATIC ISLETS that causes secretion of sufficient
amount of GASTRIN to stimulate ACID secretion to
LIFE THREATENING LEVELS

3. INHIBITS CONVERSION OF
TESTOSTERONE TO
DIHYDROTESTOSTERONE (DHT), the
active form of testosterone in the
testes
Mech: Inhibiting 5 alpha reductase

4. INHIBITS BINDING OF DHT to

receptor
IMPOTENCE & DECREASED LIBIDO

**PROBLEM FOR ALL H2 BLOCKERS:

THE CHANGE IN ACIDITY MIGHT
ALTER THE ABSORPTION OF DRUGS

 (remember, the H2 antagonists

inhibit gastric acid secretions,
therefore the pH increases)
What happens to weakly acidic Rxs?
Since the pH is increased, the ionization
of the Rx will incr, and the absorbability
of the Rx will decrease

What happens to weakly basic Rxs?

The Rx stays non-ionized, therefore the
absorption increases

FDA CLASSIFICATION OF OTC

PRODUCTS
CATEGORY I
Ingredients safe & effective for
advertised use

CATEGORY II
Ingredients are not safe & effective, or
they have unacceptable indications

CATEGORY III
Insufficient data to classify

NASAL DECONGESTANTS
MECH:
Alpha 1 constriction

1. PHENYLEPHRINE (Neo-Synephrine)
This Rx is also given IV for SHOCK or for
SUPRAVENTRICULAR TACHYCARDIA
WHY IS IT USED FOR SVT?
Vasoconstriction incr BP baroreflex

It is also used as an ophthalmic MYDRIATIC

WHAT IS A MYDRIATIC?
Dilates

BY WHAT MECH DOES IT CAUSE MYDRIASIS?

Contracts dilator m

It is sometimes added to local anesthetics

why
Decr circulation, therefore keeps anesthetic

2. EPHEDRINE (Pretz-D)
Mixed alpha/beta agonist
Available OTC as nasal spray & jelly
Used as a DECONGESTANT & a
BRONCHODILATOR
IS ITS DECONGESTANT EFFECT
ALPHA OR BETA MEDIATED?
Alpha 1

IS ITS BRONCHODILATORY EFFECT

ALPHA OR BETA MEDIATED?
Beta 2

3. PSEUDOEPHEDRINE (Sudafed)
Stereoisomer of ephedrine
Tablets, oral, liquid, pediatric drops
4. DESOXYEPHEDRINE (Vicks Inhaler)
5. NAPHAZOLINE (Privine)
Nasal drops & spray
Ocular decongestant = Naphcon
6. OXYMETAZOLINE (Afrin)
Drops & spray
Ocular decongestant = Ocuclear
This Rx is an exception in that is is an alpha 2
agonist
Hypotenstion & pounding HR are possible side
effects explain:
Stim alpha 2 in brain decr sympathetic decr BP
baroreflex

7. PROPYLHEXEDRINE (Benzedrex)
Inhaler
Subject to abuse
It has amphetamine-like effects
Chronic abuse ventricular failure,
pulmonary HTN, & sudden death!
8. TETRAHYDROZOLINE (Tyzine)
Drops & spray
Ocular decongestant = Visine
Moisturizer
9. XYLOMETAZOLINE (Otrivine)
Drops & spray

 Thankyou

Antihistamine
s

Mechanisms
Mechanisms of
of type
type II allergic
allergic reaction
reaction
in
in the
the nose
nose

Allergic conditions
Subsequent
Subsequent
allergen
allergen exposure
exposure
triggers
triggers the
the release
release
of
of various
various
inflammatory
inflammatory
mediators
mediators from
from
sensitized
sensitized mast
mast
cells
cells
e.g.
e.g. histamine
histamine and
and
others
others
this
this degranulation
degranulation
reaction
reaction is
is the
the
result
result of
of the
the
interaction
interaction between
between
the
the allergen
allergen and
and the
the

Histamine
released
released from
from mast
mast cells
cells and
and basophils
basophils in
in
allergic
allergic conditions
conditions
produces
produces effects
effects by
by acting
acting on
on H
H11 -- or
or H
H22 -receptors
receptors on
on target
target organs
organs
stimulates
stimulates blood
blood vessels
vessels resulting
resulting in
in
dilation
dilation and
and increased
increased capillary
capillary
permeability
tissue
permeability which
which leads
leads to
to
tissue
edema
edema (e.g.
(e.g. urticaria)
urticaria) ----- H
H11

Histamine
causes
causes contraction
contraction of
of smooth
smooth
muscles
muscles in
in bronchial
bronchial tract
tract
(e.g.
(e.g. asthma)
asthma) ----- H
H11

stimulates
stimulates sensory
sensory nerve
nerve endings
endings in
in
the
the nose,
nose, resulting
resulting in
in itching,
itching,
sneezing,
sneezing, and
and nasal
nasal secretion
secretion
(e.g.
(e.g. allergic
allergic rhinitis)
rhinitis) --- H
H11

also
also stimulates
stimulates secretion
secretion of
of exocrine
exocrine
glands
(e.g.
glands
(e.g. gastric
gastric acid)
acid) --- H
H22

Histamine

Histamine
Histamine receptor
receptor antagonists
antagonists
displace
displace
histamine
histamine
competitivel
competitivel
yy from
from its
its
receptor
receptor
H
H11 -receptor
-receptor
antagonists
antagonists
affect
affect
various
various
inflammator
inflammator
yy and
and
allergic
allergic
mechanisms
mechanisms
H
H22 -receptor
-receptor
antagonists
antagonists

Antihistamines
Antihistamines (H
(H11 -receptor
-receptor antagonists)
antagonists)
prevent
prevent histamine-mediated
histamine-mediated effects
effects at
at
the
the H
H11 -receptor
-receptor site
site
effective
effective in
in reducing
reducing allergic
allergic reactions
reactions
e.g.
e.g. allergic
allergic rhinitis,
rhinitis, urticaria,
urticaria, atopic
atopic
dermatitis
dermatitis

more
more effective
effective when
when taken
taken
prophylactically
prophylactically
three
three generations
generations of
of antihistamines
antihistamines

Antihistamines
Antihistamines
Drug
DrugTrade
Trade Name
Name
Atarax
Atarax25mg
25mg
Benadryl
Benadryl 25mg
25mg
Clarityne
Clarityne 10mg
10mg
Periactin
Periactin 4mg
4mg

Drug
DrugGeneric
GenericName
Name

Drug
DrugRemarks
Remarks

Hydroxyzine
Hydroxyzine HCl
HCl 25mg
25mg
Diphenhydramine
Diphenhydramine HCl
HCl 25mg
25mg
Loratadine
Loratadine 10mg
10mg
Cyproheptadine
Cyproheptadine HCl
HCl 4mg
4mg

Periactin
Periactin 2mg/5ml
2mg/5ml

Cyproheptadine
Cyproheptadine HCl
HCl 2mg
2mg

Phenergan
Phenergan 10mg
10mg
Phenergan
Phenergan 25mg
25mg

Promethazine
PromethazineHCl
HCl 10mg
10mg
Promethazine
PromethazineHCl
HCl 25mg
25mg

Phenergan
Phenergan Syrup
Syrup 5mg/5ml
5mg/5ml

50%
50% co-payment
co-payment

Promethazine
PromethazineHCl
HCl 5mg/5ml
5mg/5ml

Antihistamines
Antihistamines
Drug
Drug
DrugTrade
TradeName
Name
Drug Generic
GenericName
Name Drug
Drug Remarks
Remarks
Piriton
Chlorpheniramine
Piriton 4mg
4mg
ChlorpheniramineMaleate
Maleate4mg
4mg
Piriton
Piriton Syrup
Syrup4mg/5ml
4mg/5ml Chlorpheniramine
ChlorpheniramineMaleate
Maleate4mg/5ml
4mg/5ml
Polaramine
Dextro-Chlorpheniramine
Polaramine2mg
2mg
Dextro-ChlorpheniramineMaleate
Maleate2mg
2mg
Polaramine
Polaramine6mg
6mg SR
SR Dextro-Chlorpheniramine
Dextro-ChlorpheniramineMaleate
Maleate6mg
6mg
Polaramine
PolaramineSyrup
Syrup 2mg/5ml
2mg/5ml Dextro-Chlorpheniramine
Dextro-ChlorpheniramineMaleate
Maleate2mg/5ml
2mg/5ml
Semprex
Acrivastine
50%
Semprex8mg
8mg
Acrivastine8mg
8mg
50%co-payment
co-payment
Telfast
Fexofenadine
Telfast 120mg
120mg
FexofenadineHCl
HCl120mg
120mg 50%
50%co-payment
co-payment
Telfast
Fexofenadine
Telfast 180mg
180mg
FexofenadineHCl
HCl180mg
180mg 50%
50%co-payment
co-payment
Zyrtec
Cetirizine
Zyrtec10mg
10mg
CetirizineHCl
HCl10mg
10mg 50%
50%co-payment
co-payment

Antihistamines

Drug Trade Name

Drug Generic Name Drug Remarks
Piriton 4mg
Chlorpheniramine Maleate 4mg
Piriton Syrup 4mg/5ml Chlorpheniramine Maleate 4mg/5ml
Polaramine 2mg Dextro-Chlorpheniramine Maleate 2mg
Polaramine 6mg SR Dextro-Chlorpheniramine Maleate 6mg
Polaramine Syrup 2mg/5ml Dextro-Chlorpheniramine Maleate 2mg/5ml
Semprex 8mg
Acrivastine 8mg
50% co-payment
Telfast 120mg
Fexofenadine HCl 120mg 50% co-payment
Telfast 180mg
Fexofenadine HCl 180mg 50% co-payment
Zyrtec 10mg
Cetirizine HCl 10mg 50% co-payment

First Generation
e.g. chlorpheniramine, diphenhydramine,
promethazine
short duration of action, require
multiple dosing
penetrate blood-brain barrier, have
potential to cause sedation and CNS
impairment
most agents possess weak
anticholinergic
side-effects : dry mouth, urinary
retention, blurred vision

1 generation antihistamines
st

chlorpheniramine
(Piriton )

promethazine (Phenergan )

diphenhydramine
(Benadryl )

First-generation antihistamines
Therapeutic uses :
symptomatic treatment of allergic
conditions
e.g. chlorpheniramine and others

preanesthetic medication
e.g. promethazine

temporary sleep disorders

e.g. diphenhydramine, promethazine

First-generation antihistamines
Therapeutic uses

anti-motion sickness prophylaxis

e.g. diphenhydramine

nausea and vomiting prevention during

pregnancy
e.g. cyclizine

in cough preparations
e.g. diphenhydramine, chlorpheniramine

in cream and lotion to relieve itching in skin

conditions

Second-generation antihistamines
(non-sedating antihistamines)
e.g. terfenadine, loratadine
limited sedation as their penetration
into CNS is poor
longer duration of action require less
frequent dosing
no or little anticholinergic side effects
loratadi
ne

Terfenadine

(Seldane

first non-sedating antihistamine

on the market
bioactivated by cytochrome P450 3A4
to form fexofenadine
rare, but serious, cardiac toxicity in
patients taking drugs or foods which
inhibit its metabolism (e.g. macrolide
antibiotics, azole antifungal agents,
grapefruit juice)

taken off the market in 1998

Astemizole
(Hismanal )
second non-sedating antihistamine on the
market
slower onset of action, serum half-life ~ 10
days
bioactivated by cytochrome P450 3A4 to
form norastemizole
drug interactions problem, overdosage may
induce cardiac arrhythmias
taken off the market in 1999

Loratadine

(Clarityn

fast acting and long duration ( >

24 hr)
requires metabolic bioactivation
to desloratadine
lack of association
cardiac toxicity

with

Cetirizine

(Zyrtec

active metabolite of
hydroxyzine, a sedating
antihistamine
long duration of action
side effects are mild or
moderate including
drowsiness, fatigue and dry
mouth
recently approved for the
treatment of allergic rhinitis

Third-generation antihistamines
developed from the active
metabolites of 1st and 2nd
generation antihistamines
e.g. fexofenadine from terfenadine
norastemizole from astemizole
desloratadine from loratadine
levocetirizine from hydroxyzine

better pharmacokinetics
lack of the side effects associated
with 1st and 2nd generation
antihistamines

Fexofenadine
carboxylate
derivative of
terfenadine
lower risk of
arrhythmia

(Telfast

Desloratadine

(NeoClarityn

orally active metabolite of loratadine

rapidly absorbed, bioavailability not
affected by food or grapefruit juice
does not cross blood-brain barrier
does not cause sedation and impair
CNS performance
not significantly metabolized by
cytochrome P450 3A4, half-life ~ 27
hr
does not cause arrhythmias

Desloratadine

(NeoClarityn

Effects on HERG channel

inhibition

Overdose of terfenadine results an inhibition of a delayed

ventricular potassium repolarization current, Ikr (seen as

Desloratadine

(NeoClarityn

Intervention points in allergic cascade

Desloratadine

(NeoClarityn

Norastemizole

(Soltara

a highly selective peripheral H1receptor antagonist, more potent

than loratadine
inhibits the expression of cell
adhesion molecules, the generation
and release of inflammatory
mediators and cytokines
effectively controls both nasal and
non-nasal symptoms of seasonal
allergic rhinitis
also effective in the treatment of

Norastemizole

(Soltara

major metabolite of astemizole

long duration of action
selective H1- antagonist, 13-16 times more
potent than astemizole
Levocetirizine (Xyzal

the levo-isomer is more potent, with lesser

sedation potential
further studies underway

DECARBETHOXY LORATADINE
(Desloratadine)

loratadine

Loratadine and
desloratadine