Autacoids and their Pharmacological

Modulators
Kumuti Jacob – Lecturer
Department of Clinical Medicine
Year II semester I
Learning outcome

• By the end of this topic, you should be able to:

1. Define autacoids
2. Classify autacoids
3. Discuss the pharmacology of autacoids
4. Discuss the pharmacology of antihistamines
5. Apply the autacoids agents in treatment of patients
6. Apply the antihistamines in treatment of patients
 I. Introduction
A. Definitions

• Autacoids are chemical mediators that are synthesized and function

in a localized tissue or area and participate in physiologic or

pathophysiologic responses to injury.

• They act only locally and therefore also termed “local hormone.”

Autacoids normally do not function as the classical blood-borne

hormones.

• Typically, autacoids are short-lived and rapidly degraded.

• Autacoid modulators interfere with the synthesis, inhibit the

B. Physiologic function
1. Autacoids modulate blood flow in specific tissues.
2. Some autacoids modulate secretory processes, for
example, histamine on gastric acid formation.
3. Autacoids modulate smooth muscle function.
4. Autacoids play a key role in allergy, inflammation,
smooth muscle function, pain, and certain types of drug
reactions (Anaphylaxis).
Classification

• The autacoids can be divided into three categories based on

their chemical structure.
1. Biogenic amines: Histamine, serotonin (5-
hydroxytryptamine)
2. Polypeptides: Bradykinin, angiotensin

3. Lipid-derived autacoids

a. Eicosanoids. Prostaglandins, leukotrienes,

thromboxane
b. Platelet activating factor
BIOGENIC AMINES (AMINE-DERIVED AUTACOIDS)

A. Histamine

Biosynthesis.

• Dietary histidine is decarboxylated by l-histidine decarboxylase to

form histamine

Metabolism.

• Two pathways are involved in the degradation of histamine.

• The major degradation pathway (>50% histamine degradation)

involves conversion of histamine to an inactive metabolite 1-
methylhistamine by imidazole-N-methyltransferase.

• The minor pathway (25% histamine degradation) involves

breakdown of histamine by diamine oxidase (histaminase) to form
Distribution and storage sites.
• Histamine is widely distributed in tissues and its concentration
and rate of synthesis varies greatly from tissue to tissue.
a. The primary tissue sites storing histamine are
the lungs, skin, mucosal layer of the stomach and basophils.
1. Food and vagal stimulation can release histamine from
the stomach mucosal enterochromaffin-like (ECL) cells.
The released histamine then initiates gastric acid
secretion
2. Allergic responses in the skin and lungs are due in part to
histamine release from mast cells.
b. Mast cells are the primary cells that store histamine where it exists in

a complex with heparin sulfate and chondroitin sulfate E in storage

granules. The rate of histamine synthesis and turnover in mast cells is

low.

c. Histamine is also found in CNS where it may act as a

neurotransmitter.

d. Many venoms and insect stings contain histamine, as well as other

biologically active substances.

e. Histamine is found in the digesta where it is formed in large part by

bacterial action. This histamine normally does not reach the systemic

circulation since it is metabolized by enzymes in the gut wall and liver.

Release

a. Immune release.
• When sensitized mast cells or basophils are coupled to IgE
antibodies and then exposed to the proper antigen, the mast cell
degranulates, thereby releasing histamine and other autacoids.
• This is also referred to type I IgE-mediated hypersensitivity
reaction.

b. Drug-induced release.
• Drugs, usually strong bases (morphine, polymyxin, tubocurarine,
codeine, lidocaine, penicillin), and/or their vehicles are capable of
releasing histamine but this release does not involve degranulation
or mast cell injury.
 • These drugs displace or compete with histamine for the
binding sites with heparin.
c. Plant and animal stings
• Are capable of releasing histamine, which is an important
component of the physiologic reaction (erythema, pain,
itch) to these stings.
d. Physical injury
• Such as heat, cold, or trauma can disrupt the mast cells
thereby releasing histamine.
Histamine Receptor pharmacology

• Four classes of receptors (H1, H2, H3, and H4) mediate the action
of histamine.

a. H1-receptors are coupled to Gq protein–phospholipase C and

mediate the following effects:
i. Contraction of smooth muscle and neuronal actions are
due to increases in [Ca2+]i and activation of protein kinase
C.
ii. Relaxation of vascular smooth muscle involves Ca2+-
induced formation of nitric oxide (NO).
iii. H1-receptors mediate contraction of:

• Bronchiolar and intestinal smooth muscle,

• Vasodilatation of small arteries and veins,
• Increased capillary permeability
• Pruritus.
b. H2-receptors are coupled to Gs protein-adenylyl cyclase

• Stimulation of Gs-coupled H2 receptors activate adenylyl

cyclase and increase tissue cAMP levels.
• This is the mechanism by which vascular smooth muscle
relaxes, and gastric acid secretion is stimulated.

• H2-receptor primarily mediates gastric acid secretion and

vasodilatation.
i. Agonists include 4-methylhistamine and dimaprit.

ii. H2-Antihistamines include: cimetidine, ranitidine,

famotidine, and nizatidine.
c. H3-receptors are coupled to Gi/o protein.

• Inhibition of the release of histamine and other

neurotransmitters involves inhibition of cAMP synthesis,
opening of K+ channels to increase K+ efflux, and closure of
Ca2+ channels to block Ca2+ entry into the nerve.

• H3-receptors are located presynaptically on neurons and

inhibit neurotransmitter release.
d. H4-receptors are coupled to Gi/o protein and activate
phospholipase C.
• These receptors are selectively expressed in mast cells,
basophils, and eosinophils.

• Activation of H4-receptors mediates histamine-induced

mast cell chemotaxis and leukotriene B4 production via

activation of phospholipase C.

• Thus, H4-receptors may play a role in early events of

inflammation, edema, and thermal hyperalgesia.
6. Physiologic and pathologic roles

a. Gastric acid secretion.

• Histamine is the most important regulator of gastric
acid secretion and it stimulates secretion via
H2 receptors

b. Allergic reactions and anaphylactic shock.

• The binding of antigenic substances to IgE molecules on
mast cells causes the release of histamine.
• Other biologically active substances such as
prostaglandin D2 and leukotrines (LTC4 and LTD4) are
also released.
c. Inflammation.
• Histamine may be involved in the vasodilatation observed
in the inflammatory process.
d. Neurotransmission.
• Histamine is a neurotransmitter in various brain areas and
is involved in activating sensory nerves resulting in pain
and itch sensations.
e. Microcirculation.
• Histamine relaxes arterioles and increases capillary
permeability.
7. Pharmacologic effects
a. Cardiovascular system
• Histamine dilates arterioles, capillaries, and venules,
increases cardiac contractility and heart rate by activating
both H1– and H2-receptors.

• There is a decrease in peripheral resistance (vasodilatation),

resulting in hypotension.
• The stimulation of cardiac activity involves a direct action and
reflex activation of the sympathetic nervous system, which is
activated by the low blood pressure.
• There is an increase in capillary permeability brought about
by contracting the endothelial cells, which exposes the
basement membrane.
• Fluid and protein pass across the basement membrane to
produce edema.
b. Respiratory system.

• Respiratory smooth muscle is contracted in most species via H1-

receptors.
• There is also stimulation of glandular secretion and
prostaglandin formation.
• Asthmatics are generally more sensitive to histamine.

c. Glandular tissue.
• Histamine can stimulate glandular tissues to increase secretion.
• A most important action of histamine is its ability to increase
gastric acid and pepsin secretion from the gastric mucosa via H2-
receptors.
d. Intradermal tissue.
• Intradermal injection of histamine produces a triple response
(of Lewis).
• Insect and plant stings mimic many of these responses.
• A reddening at the site of injection is due to dilation of the
small arterioles.
• Dilation of arterioles extends beyond injection site (Flare).
• The flare involves an axon reflex since cutting the cholinergic
nerves abolishes the reflex.
• Swelling (Wheal) occurs at the injection site due to separation
of the endothelial cells and edema caused by the increased
capillary permeability, which is due to H1-receptor-mediated
contraction of endothelial cells.
• The intradermal injection of histamine causes pain and itching
by stimulation of H1-receptors on sensory nerve endings.
Therapeutic uses of histamine agonists

a. a. Histamine phosphate can be used for diagnostic purposes

for testing of gastric acid secretion and pheochromocytoma.

However, its profound side effects limit its use.

b. b. Betazole is an analog of histamine, which is an H2-receptor

agonist.

Betazole has a 10-fold selectivity for stimulation of gastric

acid production over vasodilation.

Pentagastrin is also used for this purpose.

Antihistamines

• Therapeutically useful antihistamine drugs are H1-

antihistamines and H2-antihistamines.

• At present there are no clinically useful H3 or H4-

antihistamines.

• H1-antihistamines were the first type of antihistaminic drugs

discovered and are sometimes referred to as the classical
antihistaminics.
Mechanism of action.

• Traditionally, it was thought that H1-antihistamines act as

competitive antagonists of histamine receptors.
• However, recently it has been demonstrated that most, if not all,
of H1-antihistamines act as inverse agonists rather than the
receptor antagonists.

Classification of H1–antihistamines.

• Histamine can be broadly classified into two groups based on

usage:

i. First-generation H1-antihistamines .

ii. Second generation H1-antihistamines.

• Most frequently used first-generation H1-antihistamines

are diphenhydramine, dimenhydrinate, hydroxyzyline,

chlorpheniramine, meclizine, promethazine, and cyproheptadine.

• These drugs are unionized drugs at physiological pH and easily

cross the blood–brain barrier (BBB).

• Therefore, they produce CNS side effects, in particular, sedation.

• Commonly used second-generation drugs are loratadine

(Claritin®), cetirizine (Zyrtec®), and fexofenadine (Allegra®).

• This class of drugs is ionized at physiological pH and is difficult to

cross BBB.
c. Pharmacologic effects of H1-antihistamines

1. Relaxation of contracted bronchiolar smooth muscle.

2. Relaxation of contracted intestinal smooth muscle.
3. Inhibition of histamine-induced vasodilation and increased
capillary permeability and thereby blocking formation of edema
and wheals.
4. Inhibition of itch sensation by prevention of stimulation of
sensory nerves. Many H1-antihistamines have a potent local
anesthetic action that may contribute to their inhibition of
itching and pain.
d. Other pharmacologic effects of H1-antihistamines

1. Sedation is a common effect of first-generation H1 -

antihistamines but sedation does not correlate with their
potency for inhibiting H1-receptors.

Sedation may be a desirable/undesirable effect and can

be expected to be additive to other CNS depressants.

2. Antimuscarinic effects are prominent for some H1-

antihistamines. e.g.
diphenhydramine and promethazine, which decrease
secretions and relax smooth muscles.
3. Antimotion sickness (antiemetic) effects.
• This effect is due to the inhibition of histaminergic signals
from the vestibular nucleus to the vomiting center in the
medulla.

• All H1-antihistamine have this effect, but some of them

(diphenhydramine, dimenhydrinate, and meclizine) have
more potent antimotion sickness effect than others in the
group.
Pharmacokinetics

– All H1-antihistamines

• Are effectively absorbed following oral administration

(1–3 hours).
• Are well distributed and are bound by plasma proteins
(≥60%).
• Are metabolized by cytochrome P450 enzymes, and
these metabolites further undergo conjugation.
• The first-generation antihistamines are excreted
primarily by the kidneys as metabolites.
• The second-generation antihistamines that cause least
or no sedation are excreted more into feces when
compared with the first-generation drugs: cetirizine
(70% in urine, 30% in feces); loratadine (40% in urine,
40% in feces as metabolites).
Therapeutic uses.

• H1-antihistamines are administered orally, parenterally, or

topically for the following conditions.
1. Treatment of patients with allergic conditions and to
reduce or ameliorate the effects due to histamine.
Conditions benefited from H1-antihistamines include:

1. Urticaria and pruritus

2. Allergic reactions to drugs
3. Anaphylaxis
2. Prevention of motion sickness.
Diphenhydramine, dimenhydrinate, and meclizine are
more effective in preventing motion sickness than other
H1 antihistamines.

3. Sedation induction.
Promethazine and diphenhydramine are the most potent
for inducing sedation.
Adverse effects

1. CNS depression (lethargy, somnolence, ataxia) are the most

common but they may diminish with time.

2. Antimuscarinic effects (dry mouth, urinary retention) occur with

many H1-antihistaqmines. They should be used with caution in

patients with angle closure glaucoma.

3. Some individuals could develop allergy to the use of H1-

antihsitamines.

4. Drug tolerance. The decrease in efficacy and sedation (also

called subsensitivity) can develop during the use of H1-