Role of histamine & Antihistaminics

1. Histamine and
Antihistaminics
Dr. Divya Krishnan
KMCT Medical College

2. Autacoids
autos ( self) + akos ( healing substance) (Greek)
• Substances produced by a wide variety of cells that have intense
biological activity locally at the site of their synthesis & release.
• Also called “LOCAL HORMONES’’ – but differs from hormones
(?)
• Involved in physiological & pathological processes
Types
Amine Autacoids : Histamine , Serotonin (5HT)
Lipid derived : Prostaglandins, Leukotrienes, PAF

3. Histamine
“tissue amine” (histos – tissue)
• Present in animal tissues & plants (e.g. stinging nettle)
• Mediator of hypersensitivity & inflammation
Primary sites : mast cell granules in skin, intestinal & gastric
mucosa, lungs, liver, placenta
Other sites (non mast cell)
– Brain, epidermis, gastric mucosa
– Blood, body secretions, venoms & pathological fluids

4. Histamine – synthesis, storage and release
• Synthesized from amino acid histidine.
• +vely charged histamine stored inside mast cells granules along
with -vely charged acidic protein / heparin . Immune mediated
or non immune mediated release into blood occurs by
exocytosis.(Figure & Explanation of immune mediated release)
• Released histamine acts through histamine receptors to bring
about responses.
• Degraded in liver rapidly by oxidation & methylation.
Eliminated in urine

5. HA HA
HA
HA
HA
HA
Y Y Non-immune
Releasers
(opioids,
tubocurarine,
vancomycin etc)
IgE
ANTIGEN
PGs & LTs PROTEASES HISTAMINE OTHER MEDIATORS (PAF,TNF,ILs)
IgE - Antibody
Induced Release
(food, penicillin,
venoms, etc)
ACUTE INFLAMMATORY RESPONSE - IMMEDIATE
HYPERSENSITIVITY REACTION
Inhibitors of
Release
(Cromolyn,
Albuterol)
HA
Fc€RI
Prot + Hista
Or
Hep + Hist
Hist
Na+ or Ca++
t-pr-K
PIP2
IP3
Ca++

6. • In sensitized individual, IgE antibody produced in response to
antigens . It binds to Fc epsilon receptor I (FcεRI) on the
surface of mast cells.
• On challenge, the antigen bridges 2 IgE molecules resulting in
transmembrane activation of a tyrosine-protein kinase which
inturn activates phospholipaseC.
• Phospholipase C hydrolyses Phosphatidyl inositol
bisphosphate (PIP2) to (IP3) which triggers intracellular
release of Ca2+.
• The Ca2+ ions induce fusion of granule membrane with
plasma membrane of the mast cell resulting in exocytotic
release of granule contents.
• In the granule, positively charged histamine is held with
negatively charged protein and heparin. Cationic exchange
with extracellular Na+ (and Ca2+) sets histamine free.

7. Histamine Receptors-GPCRs
H1 H2 H3
(autoreceptor)
Selective
agonist
2-Methylhistamine Impromidine α-Methylhistamine
Selective
antagonis
t
Mepyramine
Chlorpheniramine
Cimetidine
Ranitidine
Thioperamide
Distributi
on
& action
• Smooth muscle : Contraction
• Blood vessels
Endothelium of small vessels :
NO and PGI2 release 
Vasodilatation
Vascular smooth muscle of large
vessels : vasoconstriction
Increased capillary permeability
• Afferent nerves : stimulation
• Ganglion cells : stimulation
• Adrenal medulla : CAs release
• Gastric glands : acid
secretion
• Blood vessels smooth
muscles : Vasodilatation
• Heart : +vechronotropy
& +ve inotropy
• Uterus : relaxation
• Brain – transmitter
• Brain : inhibition of
histamine release
• Lung, spleen, gastric
mucosa : inhibition of
histamine release
• Ileum : inhibition of
Ach release
• Cerebral vessels :
inhibition of NA release
vasodilatation

8. H4 Receptor
• Discovered in 2001.
• Selective H4 agonist - 4-Methyl histamine
• Sites where present - Eosinophils, mast cells, basophils,
intestines and brain.
• Function - Role in allergic inflammation.
Enhances chemotaxis of eosinophils,
basophils

9. Histamine - actions
1. Blood vessels
• Dilatation of small vessels ( arterioles, capillaries and venules)
(H1 mediated release of NO from vascular endothelium & H2
mediated vascular smooth muscle relaxation).
• Constriction of larger arteries and veins ( H1 mediated contraction
of vascular smooth muscles)
• Increased capillary permeability due to separation of endothelial
cells – exudation of plasma (H1 response).

10. What happens when histamine administered by SC/IV/ID
routes ????
On SC administration  flushing, heat, not much fall in BP
On Rapid IV injection  Fall in BP .
- Early short lasting BP fall due to H1 component & slow
persistent fall in BP due to H2 component .
- low doses of histamine produce short lasting BP fall due
to H1 only while high doses of histamine produce BP fall
due to H1 & H2. (Reversal of BP effect of high doses thus
requires both H1 & H2 antagonists)

11. On intradermal injection:-
TRIPLE RESPONSE OF LEWIS
(H1 mediated)
1. Red spot : Capillary dilatation
2. Flare : Redness in surrounding area due to arteriolar
dilatation mediated by axon reflex
3. Wheal : Due to exudation of fluid from capillaries &
venules.

12. 2. Heart
• No direct effect on insitu heart
• Positive chronotropic & inotropic effect on isolated heart of
guinea pig.(H2 mediated)
3. Visceral smooth muscles
• Bronchoconstriction (H1)
• intestinal contractions increased (colic) (H1)
• Human Uterus not much affected

13. 4. Glands
• Increases gastric secretion of acid & pepsin ( H2 )
5. Sensory Nerve endings
• stimulates sensory nerve endings & produces itching, pain
6. Autonomic ganglia and Adrenal Medulla
• Stimulated Adrenaline release –>secondary rise in BP
7. CNS
• Does not cross BBB – no CNS effects on IV

14. Histamine - Pathophysiological Roles
 Prominent role in Gastric acid Secretion
 Allergic Phenomena : Mediates immediate type of hypersensitivity
(Urticaria, angioedema, bronchoconstriction, anaphylactic reaction)
 Transmitter : Mediates itch & pain in sensory nerve endings
Maintains wakefulness , suppresses appetite, regulates body
temperature, thirst in brain.
 Inflammation: Mediates vasodilatation & chemotaxis.

15. Any clinical use of histamine??
Betahistine for Vertigo

16. ANTI-HISTAMINICS

17. Histamine H1-receptor antagonists
• Competitively antagonize actions of histamine at the H1
receptors.
• First antihistaminics introduced in 1930s
• More commonly employed now the second generation H1
antihistamines introduced after 1980.

18. Classification
• 1st
Generation (conventional antihistaminics)
– Highly sedative : Diphenhydramine, Dimenhydrate,
Promethazine , Hydroxyzine
– Moderately : Pheniramine, Cyproheptadine, Meclizine,
Buclizine , Cinnarizine
– Mild : Chlorpheniramine, Dexchlorpheniramine,
Cyclizine, Clemastine
• 2nd
Generation : Fexofenadine, Loratidine, Desloratidine,
Cetirizine, Levocetirizine,
Azelastine, Mizolastine,
Ebastine , Rupatidine

19. H1 Antihistaminics – Pharmacological
actions
Antagonism of Histamine
– Blocks histamine induced bronchoconstriction & contraction of
intestinal &other smooth muscles
– blocks triple response
– BP fall due to low dose of histamine antagonized, but needs
additional H2 blockers to counter fall in BP due to high
histamine doses.
– No effect on histamine induced gastric secretion

20. Antiallergic action
• Manifestations of immediate Type 1 hypersensitivity reactions
suppressed (Itching, urticaria, angioedema of lips &eyelids)
• However, their action is slow. Adrenaline is the life-saving
drug in laryngeal angioedema & anaphylactic shock .
Antihistaminics have only adjuvant role.
• Not useful in bronchial asthma – 1) mediators other than
histamine involved 2) concentration at the site may not be
sufficient
• Not effective in humoral and cell mediated allergies (since
histamine is not the mediator)

21. Anticholinergic
• 1st
gen antihistaminics have anticholinergic properties in
varying degrees (Promethazine, Pheniramine have higher
anticholinergic activity)
• SGAs have no/minimal anticholinergic action.

22. CNS
• 1st
generation antihistamines produce variable degree of CNS
depression ( depending on the drug’s ability to penetrate BBB ,
its affinity for the central (compared to peripheral) H1 receptors.
). Individual Variation among subjects. Some individuals
experience stimulant effects like restlessness and insomnia.
• 2nd generation antihistaminics are nonsedating.
• Some 1st
gen antihistaminics prevent motion sickness &morning
sickness (unknown mechanism)
• Some 1st
gen antihistaminics reduce tremor, rigidity &
sialorrhoea of parkinsonism due to their anticholinergic &
sedative properties.
• Some 1st
gen antihistaminics have appetite stimulating effect.

23. Local anaesthetic
Some have membrane stabilizing effects (eg: pheniramine) , but
not used as LA as it causes irritation.
BP
Fall in BP with IV injection (all) but not with Oral

24. Adverse drug reaction
1ST
Gen antihistaminics have mild ADRs.(SGA minimal ADRs)
 Sedation (Paradoxical Excitation in children), diminished
alertness, loss of concentration, dizziness, motor
incordination, tendency to fall asleep – commonest –SAY NO
TO MOTOR VEHICLE DRIVING AND MACHINERY OPERATION
 contact dermatitis on topical use
 Peripheral antimuscarinic effects (Dryness of mouth, blurred
Vision, constipation, urinary retention)
(Acute overdose: CNS excitation, tremor ,hallucinations –
resemble Atropine poisoning - death due to respiratory
failure and CVS failure)

25. 2nd
Generation antihistaminics
- Introduced after 1980s
– Higher affinity for H1 receptors:
– no anticholinergic side effects
– Absence of CNS depressant property
– Additional antiallergic mechanisms e.g. LT and PAF
inhibition
• Advantages over 1st
generation antihistaminic
- They have a much lower incidence of adverse effects
than the first generation agents
- No psychomotor impairment – driving etc. can be
allowed
- No subjective effect
- No sleepiness

26. Individual Antihistaminics (2nd
generation)
Terfenadine,
• First SGA
• Banned due to risk of fatal polymorphic ventricular tachycardia
(Torsades de pointes) with higher doses or when co-administered
with CYP3A4 inhibitors like erythromycin, ketoconazole etc.
Astemizole
• SGA banned for the same reason as above.
Fexofenadine
• Active metabolite of Terfenadine
• Doesn’t prolong QT interval.
• Minimally metabolized, no interaction with CYP3A4 inhibitors.
• However, avoided in patients with long QT, bradycardia or
hypokalemia.

27. Loratidine
• Fast acting
• Long acting ( metabolized by CYP3A4 to an active metabolite
having a t1/2 of 17hrs).
Desloratidine
• Metabolite of Loratidine
• Effective at half the dose.

28. Cetirizine (commonly used SGA)
• Metabolite of hydroxyzine
• Marked affinity for peripheral H1 receptors;
• Penetrates brain poorly, but mild sedation experienced by many
recipients.
• Not metabolized; No arrhythmogenic risk when given with CYP
inhibitors.
• Additional antiallergic mechanisms like inhibition of release of
cytotoxic mediators from platelets & eosinophil chemotaxis.
• High & longer lasting concentration in skin( once daily dosing despite
elimination t½ of 7–10 hr.)
• Uses: Upper respiratory allergies, pollinosis, urticaria ,atopic
dermatitis, seasonal asthma. Dose : 10mg orally at bedtime.
Levocetirizine : active R(–) enantiomer of cetirizine. Effective at half the
dose & produces less sedation and other side effects.

29. Azelastine
• SGA with topical action – also inhibitor of inflammatory response
mediated by LT and PAF
• Down regulation of Intracellular adhesion molecule-1 (ICAM-1)
expression on nasal mucosa – Intranasal application
• Used intranasal in seasonal and perennial rhinitis
Mizolastine:
• Effective in rhinitis and urticaria (no active metabolite)
Ebastine:
• Newer SGA – converts to carbastine
• Used in nasal and skin allergies
• Arrhythmogenic potential
Rupatadine
• Additional PAF antagonistic property, indicated in allergic
rhinitis.

30. Therapeutic uses
1. Allergic reactions
– Itching, urticaria, seasonal hay fever, allergic conjunctivitis,
angioedema of lips-eyelids etc.
– Adjuvant to adrenaline in Anaphylactic shock & laryngeal
angioedema.
2. Other conditions involving histamine e.g. insect bite , ivy
poisoning, blood/saline infusion induced rigor.
3. Pruritides : Many conventional antihistamines have antipruritic
action independent of H1 antagonism. E.g. chlorpheniramine,
diphenhydramine .

31. 4. Common cold : Produce symptomatic relief by anticholinergic
(reduce rhinorrhoea) and sedative actions. E.g. chlorpheniramine,
Pheniramine.
SGAs less effective in this respect.
5. Motion sickness : Promethazine, diphenhydramine, meclozine
can be taken 1 hour before starting journey.
6. Morning sickness, drug induced and postoperative vomiting,
radiation sickness. E.g. Promethazine
7. Vertigo : They inhibit vestibular sensory nuclei in the inner ear,
suppresses postrotatory labyrinthine reflexes by reducing influx
of Ca2+ from endolymph into the vestibular sensory cells. E.g.
Cinnarizine

32. 8. As appetite stimulant : Cyproheptadine used in
anorectic/convalescent patients for improving appetite.(Off
label use). Such use in underweight children inappropriate
since its CNS depressant action can affect learning.
9. Preanaesthetic medication : e.g. Promethazine used for its
anticholinergic & sedative properties.
10. Cough : Symptomatic relief by sedative and anticholinergic
property. E.g. chlorpheniramine, promethazine
11. Parkinsonism : Mild symptomatic relief in early case due to
anticholinergic & sedative property. E.g. Promethazine

33. 12. Acute drug induced muscle dystonias : Relieved by
promethazine due to central anticholinergic action.
11.As sedative, hypnotic, anxiolytic : Antihistamines with CNS
depressant action (e.g Promethazine) have been used as
sedative and to induce sleep, esp. in children.
However, promethazine has produced fatal respiratory
depression in young children. It is not indicated in children 2
years or less. For promoting sleep, antihistaminics are not as
dependable as Benzodiazepines.
NOTE : SGA indications are: (i) Allergic rhinitis and conjunctivitis,
hay fever, pollinosi (ii) Urticaria, dermographism, atopic eczema.
(iii) Acute allergic reactions to drugs and foods.
They have poor antipruritic, antiemetic and antitussive actions

34. H2-receptor antagonists
Cimetidine, Ranitidine, Famotidine and
Roxatidine …….
….. Will be discussed – in “Drugs for Peptic
Ulcer”

35. Important questions
• Histamine receptors – locations and actions
• Classification of antihistaminics – 1st
generation and
2nd
generation
• 1st
generation Vs 2nd
generation
• 2nd
generation antihistaminics
• Uses of antihistaminics
• Cetirizine
• Drugs for vertigo

36. Thank you