By Dr.Kinde

1. Medicine
autacoids

2.  Histamine and serotonin (5-hydroxytryptamine) are
biologically active amines that function as
neurotransmitters and are found in non-neural tissues,
 have complex physiologic and pathologic effects
through multiple receptor subtypes, and are often
released locally.
 Together with endogenous peptides prostaglandins
and leukotrienes and cytokines - called autacoids or
local hormones

3. HISTAMINE
 important mediator of immediate allergic and
inflammatory reactions, although it plays only a
modest role in anaphylaxis.
 plays an important role in gastric acid secretion and
 functions as a neurotransmitter and neuromodulator.
 plays a role in chemotaxis of white blood cells.

4. BASIC PHARMACOLOGY OF HISTAMINE
 Histamine :occurs in plants as well as in animal
tissues
- a component of some venoms and stinging secretions.
 formed by decarboxylation of the amino acid l-
histidine, a reaction catalyzed in mammalian tissues by
the enzyme histidine decarboxylase.
 histamine is either stored or rapidly inactivated.
 Very little histamine is excreted unchanged.
 The major metabolic pathways involve conversion to N-
methylhistamine, methylimidazoleacetic acid, and
imidazoleacetic acid (IAA).

5.  Most tissue histamine is sequestered and bound in granules
(vesicles) in mast cells or basophils; the histamine content of
many tissues is directly related to their mast cell content.
 especially rich at sites of potential tissue injury—nose,
mouth, and feet; internal body surfaces; and blood vessels,
particularly at pressure points and bifurcations.
 The bound form of histamine is biologically inactive
 Non-mast cell histamine is found in several tissues, including
the brain, where it functions as a neurotransmitter
 A second important nonneuronal site of histamine storage
and release is the enterochromaffin-like (ECL) cells of the
fundus of the stomach.

6. Storage & Release of Histamine
 in mast cells
 can be released through several mechanisms.
-IMMUNOLOGIC RELEASE
-if sensitized by IgE antibodies attached to their surface
membranes, degranulate explosively when exposed to the
appropriate antigen
-requires energy and calcium.
- is a mediator in immediate (type I) allergic reactions, such as hay
fever and acute urticaria
IgG- or IgM-mediated immune reactions that activate the
complement cascade also release histamine from mast cells and
basophils
-CHEMICAL AND MECHANICAL RELEASE
-morphine and tubocurarine, can displace histamine from its bound
form within cells

7. An Allergic Reaction
 Early phase reaction:
occurs within minutes of
exposure to an allergen
and lasts for 30-90
minutes
 Late phase reaction:
begins 4-8 hours later
and can last for several
days, often leading to
chronic inflammatory
disease

8. MECHANISM OF ACTION
 exerts its biologic actions by combining with specific cellular receptors on
surface membrane.
 The four different histamine receptors - H1–H4
 H1 and H2 receptors are distributed widely in the periphery and in the CNS
and their activation by histamine can exert local or widespread effects
 histamine causes itching and stimulates secretion from nasal mucosa.
 It contracts many smooth muscles, such as those of the bronchi and gut, but
markedly
relaxes others, including those in small blood vessels.
 Histamine also is a potent stimulus of gastric acid secretion.
 less-prominent effects include formation of edema and stimulation of
sensory nerve endings.
 Bronchoconstriction and contraction of the gut are mediated by H1
receptors.
 In the CNS, H1 activation inhibits appetite and increases wakefulness.
 Gastric secretion results from the activation of H 2 receptors.
 Some responses, such as vascular dilation, are mediated by both H1and H2
receptor stimulation.

9.  The H3 receptors are expressed mainly in the
CNS, especially in the basal ganglia,
hippocampus, and cortex
 Presynaptic H3 receptors function as
autoreceptors on histaminergic neurons, inhibiting
histamine release and modulating the release of
other neurotransmitters.
 H3 receptors are also found postsynaptically,
especially in the basal ganglia, but their function
is still being unraveled H3 agonists promote
sleep, and H3 antagonists promote wakefulness.

10.  The H4 receptors primarily are found in
eosinophils, dendritic cells, mast cells,
monocytes, basophils, and T cells but have also
been detected in the GI tract, dermal fibroblasts,
CNS, and primary sensory afferent neurons
 Activation of H4 receptors has been associated
with induction of cellular shape change,
chemotaxis, secretion
of cytokines, and upregulation of adhesion
molecules, suggesting that H 4 antagonists may
be useful inhibitors of allergic and inflammatory
responses

13. Actions of histamine
13

14. Toxicity & Contraindications
 Adverse effects of
histamine release- are
dose-related.
 Flushing, hypotension,
tachycardia, headache,
wheals,bronchoconstrictio
n, and gastrointestinal
upset are noted.
 observed afterthe
ingestion of spoiled fish ,
and
histamine produced by
bacterial action in the
flesh if improperly stored
 Histamine should not be
given to patients with
asthma (except as part of
a carefully monitored
test of pulmonary
function) or to patients
with active ulcer disease
or gastrointestinal
bleeding

15. HISTAMINE ANTAGONISTS
 Physiologic antagonists, especially epinephrine,
have smooth muscle actions opposite to those of
histamine, but they act at different receptors.
 important clinically because injection of
epinephrine can be lifesaving in systemic
anaphylaxis and in other conditions in which
massive release of histamine—and other
mediators—occurs.

16.  Release inhibitors: Cromolyn and nedocromil
Beta2-adrenoceptor agonist
 receptor antagonists
 H2-receptor antagonist burimamide
 H1 antagonists

17.  The H1 antagonists are conveniently divided into
first-generation and second-generation agents.
 the relatively strong sedative effects of most of the
first-generation drugs
 The first-generation agents are also more likely to
block autonomic receptors.
 The relatively less sedating characteristic of the
second-generation H1 blockers - less complete
distribution into the central nervous system.

20.  Sedation
 Antinausia /antiemetic- doxylamine
 Antiparkinsons - diphenhydramine
 Anticholinoceptor - ethanolamide
 Adrenoceptor blocking- phenothiazine sub group
promethazine -orthostatic hypotension
 Serotonin blocking - cyproheptadine
 Local anesthetic - dyphenhydramine

21. CLINICAL PHARMACOLOGY OF H1-RECEPTOR ANTAGONISTS
 Clinical Uses
Allergic Reactions
 allergicrhinitis (hay fever), the H1 antagonists are
second-line drugs after glucocorticoids administered
by nasal spray.
 In urticaria, in which histamine is the primary
mediator, the H1 antagonists arethe drugs of choice
and are often quite effective if given before exposure.
 in bronchial asthma, which involves several
mediators, the H1 antagonists are largely ineffective.

22. Motion Sickness And Vestibular Disturbances
 Scopolamine and certain first-generation H1
antagonists are the most effective agents available
 The antihistaminic drugs with the greatest
effectiveness in this application are
diphenhydramine and promethazine.
 The piperazines (cyclizine and meclizine) also have
significant activity and are less sedating than
diphenhydramine in most patients.

23. Nausea And Vomiting Of Pregnancy
 The piperazine derivatives were withdrawn from
such use when it was demonstrated that they
have teratogenic effects in rodents.
 Doxylamine, an ethanolamine H1 antagonist, was
promoted for this application as a component of
Bendectin, a prescription medication that also
contained pyridoxine.

24.  Common Cold-inhibits Rhinorrhoea
 Extrapyramidal Symptoms
 Preanesthetic Medication

25. Drug Interactions
 Lethal ventricular arrhythmias occurred in several
patients taking either of the early second-
generation agents, terfenadine or astemizole, in
combination with ketoconazole, itraconazole, or
macrolide antibiotics such as erythromycin-
CYP3A4
 mechanism - blockade of the HERG (IKr)
potassium channels in the heart that contribute to
repolarization of the action potential
 prolongation and a change in shape of the action
potential, and these changes lead to arrhythmias.

26. H2-RECEPTOR ANTAGONISTS
 peptic ulcer disease and related gastrointestinal
complaints
 cimetidine, ranitidine,famotidine, and nizatidine.
 These drugs are less potent than PPIs but still
suppress 24-hour gastric acid secretion by about
70%.
 Suppression of basal and nocturnal acid
secretion is about 70%

27. GERD

28.  H3-selective ligands may be of value in sleep
disorders, obesity, and cognitive and psychiatric
disorders.
 Tiprolisant, an inverse H3-receptor agonist, has
been shown to reduce sleep cycles in mutant
mice and in humans with narcolepsy.
 H4 blockers have potential in chronic inflammatory
conditions such as asthma, in which eosinophils
and mast cells play a prominent role.

29. PHARMACOKINETICS
Second generation antihistamines:
 Relatively rapid onset
 Elimination Half-Lives:
 Loratadine-up to 28 hours
 Fexofenadine-14 hours
 Cetirizine-8 hours
 Children metabolize Cetirizine faster, but rates are similar for the others

30. ADVERSE REACTIONS
AND SIDE EFFECTS
First Generation Drugs:
 Anticholinergic CNS interactions
 Gastrointestinal reactions
 Common side effects: sedation, dizziness, tinnitus, blurred
vision, euphoria, lack of coordination, anxiety, insomnia,
tremor, nausea and vomiting, constipation, diarrhea, dry
mouth, and dry cough
Second Generation Drugs:
 Common side effects: drowsiness, fatigue, headache,
nausea and dry mouth
Side effects are far less common in Second
Generation drugs