Autacoids

Autacoids

Objective

At the
end of this lecture, student will be able to

• Explain autacoids

• Describe the pharmacology of histamine

• Discuss the pharmacology of antihistamine

Content

Autacoids

Histamine

                                Introduction

                                Synthesis

                                Release

                                Histamine
receptors

                                Pharmacological
action

                                Pathophysiological
role

                                Antihistamine

Autacoids

Autacoid:
derived from Greek: autos-self, akos-healing substance or remedy

These are
diverse substances produced by a wide variety of cells in the body, having
intense biological activity, but generally act locally at the site of synthesis
and release

Also
known as local hormones

Autacoids
are involved in a number of physiological and pathological processes

Even
serve as transmitters or modulators in the nervous system

Classification of autacoids:

1. Amine autacoids Histamine,
5-Hydroxytryptamine (Serotonin)

2. Lipid derived autacoids:
Prostaglandins, Leukotrienes, Platelet activating factor

3. Peptide autacoids: Plasma kinins (Bradykinin),
Cytokines (interleukins, INFo., GM-CSF etc)

Histamine

Synthesized
in 1907 & later isolated from mammalian tissue

Tissue
amine

Present
in animal tissues, certain plants, venoms

Manifestations
of certain allergic reactions

Mediator
of hypersensitivity, phenomena and tissue injury reactions

Play
important physiological roles

Present
mostly within storage granules of mast cells (Tissues rich in histamine are
skin, gastric and intestinal mucosa, lungs and placenta)

Non mast
cell histamine occurs in brain, epidermis, gastric mucosa and growing regions

Synthesis,
storage and destruction

Histamine
is imidazolylethylamine

Synthesized
from amino acid histidine

Degraded rapidly
by oxidation and methylation

IgE
antibody is produce and get bound to receptor-1 on the surface of mast cell

An binds
to Ab and forms An-Ab complexs

ca2+
induce Exocytosis for release of histamine

Histamine receptor

Pharmacological action of Histamine

Blood vessels:

Dilatation
of smaller blood vessels (arterioles, capillaries and venules)

• Vasodilatation is partly indirect mediated through EDRF

• Large arteries and veins are constricted mediated by H1
receptor

• ↑se capillary permeability due to separation of
endothelial cells which leads to exudation of plasme (H1 receptor)

       Intra dermal inj: Elicits triple
response

                Red
spot: due to intense capillary dilatation

                Wheal:
due to exudation of plasma

Flare: redness in surrounding area
due to arteriolar dilation

Heart (H1 receptor):

↑se  HR, FOC, +ve chronotropy and +ve inotropy

Smooth
muscle
(H1 receptor): Bronchoconstriction, uterus and
intestinal smooth muscle (abdominal cramps) constriction

• Glands (H2 receptor): ↑se gastric secretions

• Sensory nerve ending (H1 receptor): stimulated
cause itching, pain etc

• Adrenal medulla (H2 receptor): increase the
release of AD produce secondary hypertension

• CNS(H1 & H2 receptor): does not penetrate BBB & no
central effects are seen

Pathophysiological role of Histamine

Gastric secretions: ↑se HCl secretion
in stomach and cause ulcers (H2 receptor)

Allergicphenomena: Mediate by hypersensitivity reactions leads to urticaria, angioedema,
bronchoconstriction and anaphylactic shock

As transmitter: initiates the sensation of itch and pain at sensory nerve ending,  act as a transmitter in regulating body
temperature, CVS function, Thirst, Hormone release from anterior pituitary

Inflammation:
mediator of vasodilatation and other changes that occur during inflammation and
promotes adhesion of leukocytes to vascular endothelium

Uses of Histamine 

       Histamine has no therapeutic use.
Only for experimental use

       Contraindications:
in asthmatic and ulcer patients

Antihistamines or H1 antagonists 

       These drugs competitively antagonize
actions of histamine at the H1 receptors

       Classification
of antihistamines

                All
antihistamines have similar action, but differs in sedative property

  1. Highly
    sedative: Diphehydramine, Promethazine, Hydroxyzine

  2. Moderately
    sedative: Pheniramine, Cyproheptadine, Cinnarizine

  3. Mild
    Sedative: chlorpheniramine, Cyclizine, Dexchlorpheniramine

  4. Non
    sedative (Second generation antihistamines): Cetirizine, Loratadine,
    Levocetirizine 

Pharmacological action of H1 antagonists 

       Histamine antagonism:

Blocks:  histamine induced bronch, intestinal and
uterus contraction

                                Triple response-especially wheal,
flare and itch

                                Fall in BP

                                Release of Adr
from adrenal medulla

                                Constriction of
larger blood vessel

       Anti allergic action: Immediate
hypersensitivity (type I reactions) are suppressed

                Urticaria, itching and
angioedema are well controlled

                Anaphylactic fall in BP is only
partially prevented

       CNS: Older antihistamines produce
variable degree of CNS depression

                Sedative antihistamine causes
CNS depression

                Stimulant effects like
restlessness and insomnia

                Excitement and convulsions are
frequently seen at toxic doses

                Effective in preventing motion
sickness

                Controls vomiting of pregnancy

                Reduce tremor, rigidity of
parkinsonism

       Anticholinergic action: antagonize
muscarinic actions of Ach

       Local anaesthetics: it has membrane
stabilizing property

       BP: cause a fall in BP on i.v.
injection

       H1 antihistaminics are
well absorbed from oral and parenteral routes

       Metabolized in the liver

       Excreted in urine

       Widely distributed in the body and
enter brain

       Newer compounds penetrate brain
poorly

       Duration of action of most agents is
4 to 6 hours, except meclizine, loratadine, cetirizine and fexofenadine which
act for 12-24 hours or more

Side effects and toxicity of H1
antagonists 

       Sedation, diminished alertness and
concentration, light headedness, motor incoordination, fatigue and tendency to
fall asleep are the most common

       Impairment of psychomotor
performance

       Few individuals become restless,
nervous and are unable to sleep (Second generation compounds are largely free
of CNS effects)

       Dryness of mouth, alteration of
bowel movement, urinary hesitancy and blurring of vision due to anticholinergic
property

       Epigastric distress and headache are
also common

       Local application can cause contact
dermatitis

       Acute overdose produces central
excitation, tremors, hallucinations, muscular incordination, convulsions,
flushing, hypotension, fever and some other features of belladonna poisoning

       Death is due to respiratory and
cardiovascular failure

Advantages of second generation H1
antagonists 

       Higher H1 selectivity

       No anticholinergic side effects

       Absence of CNS depressant property

       Additional antiallergic mechanisms
apart from histamine blockade

       Inhibit late phase allergic reaction
by acting on leukotrienes or by anti platelet activating factor effect

       Advantage of not impairing
psychomotor performance

       No sleepiness, Do not potentiate
alcohol or benzodiazepines

Uses of H1 antagonists 

       Allergic disorders: Antihistaminics
do not suppress AG:AB reaction, but block the effects of released histamine-are
only palliative (allergies, e.g. itching, urticaria, seasonal hay fever,
allergic conjunctivitis and angioedema of lips, eyelids, etc)

       Pruritides

       Common cold, Cough

       Motion sickness, Vertigo

       Preanaesthetic medication

       Parkinsonism

       Acute muscle dystonia

       As sedative, hypnotic, anxiolytic

Summary

       Histamine is an amine autacoid

       Mediator of hypersensitivity ,
phenomena and tissue injury reactions

       Betahistine
is histamine receptor analogue

       Antihistamines competitively
antagonize actions of histamine at the H1 receptors

       Antihistamines are commonly used in
Allergic disorders