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
- Highly
sedative: Diphehydramine, Promethazine, Hydroxyzine - Moderately
sedative: Pheniramine, Cyproheptadine, Cinnarizine - Mild
Sedative: chlorpheniramine, Cyclizine, Dexchlorpheniramine - 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