Autacoids: (Histamine, Serotonin, Eicosanoids, Kinins)

Autacoids
(Histamine, Serotonin, Eicosanoids, Kinins)

Autacoids
• Endogenous substances with complex physiologic &
pathophysiologic functions that have potent nonautonomic
pharmacologic effects when administered as drugs.
Histamine
• Formed by the decarboxylation of L-Histidine
• Can be found in:
– Mast cells
– Basophils
– Enterochromaffin-like cells (ECL) of the fundus of
the stomach
Histamine
• Mechanisms of Release
– Immunologic
• Sensitization of mast cells  IgE attachment 
degranulation  release of Histamine & ATP
• Mediates Type I allergic reaction (eg. Urticaria)
– Chemical or Mechanical
• Displacement of histamine from binding sites
Histamine
Receptors Location Response
H1 Vascular SM Vasodilation
Extravascular SM (bronchial) Bronchoconstriction
Sensory Nerve Endings Itch and Pain
Capillary Endothelial Cells Contraction (Extravasation)
H2 Parietal Cells of the Basal Gastric Secretion (peak at
Stomach the height of deep sleep)
H3 Neurons Decrease release of transmitters
H4 Leukocytes in the bone Chemotaxis
marrow & circulating blood
Histamine
• Organ System Effects
– CNS
• Stimulant of sensory nerve endings (pain & itching)
• Appetite & satiety
• Decrease release of acetylcholine, amine & peptide
neurotransmitters
– Cardiovascular
• Decrease BP due to vasodilation on the arterioles
• Increase HR due to stimulatory actions on the heart & reflex
tachycardia
• Increase contractility & pacemaker rate
Histamine
– Bronchiolar SM
• Bronchoconstriction
– GIT
• Contraction of intestinal SM
– Secretory Tissues
• Stimulant of gastric acid secretion, pepsin & intrinsic factor
production
Histamine
– Triple Response of Lewis
• Itch & pain
• Endothelial contraction  swelling
• Vasodilation  redness
Histamine
• Clinical Uses (Obsolete use)
– Diagnostic Agent in Pulmo Challenge Test
• Provocative test
– Diagnostic Agent in Pheochromocytoma

• Gastic acid secretion
Histamine
• Pharmacologic Antagonists (H1)
Histamine
• Physiologic Antagonist – Epinephrine

Histamine
– Sedation
• First generation
• Ethanolamines – most sedating
• Used as sleep aids
– Antinausea / Antiemetic
• Prevention of motion sickness (Meclizine, Cyclizine)
• Doxylamine – used in the past as treatment for nausea &
vomiting in pregnancy
Histamine
– Antiparkinsonian Effects
• Suppressant effects for EPS (Diphenhydramine)
– Anticholinergic Effects
• Atropine-like effects (Ethanolamines, Ethylenediamine)
– Alpha Blocking Effects

• Causes orthostatic hypotension (Promethazine)
Histamine
– Serotonin Blocking Effects
• Cyproheptadine
– Local Anesthesia
• Diphenhydramine, Promethazine
• For patients allergic to LA
– Inhibition of Mast Cell Release

• Cetirizine
Histamine
– Inhibits basal gastric acid secretion
– Cimetidine, Ranitidine, Famotidine, Nizatidine
– Uses
• Alternative drugs in the mx of acid peptic disease and GERD
– ADRs
• Cimetidine
– Anti-androgenic effects in males (gynecomastia, infertility, sterility, loss of
libido, nipple tenderness)
– Galactorrhea in females
– Enzyme inhibitor
• Ranitidine
– Weak enzyme inhibitor but may have significant effects
Serotonin
• 5-Hydroxytryptamine (5-HT)
• 1st found in the intestinal mucosa  enteramine
• Enteramine & serotonin – metabolites of 5-
hydroxytryptamine
• Biosynthesis
– Hydroxylation then decarboxylation of L-tryptophan
– Rate limiting step: hydroxylation process
– Inhibited by: p-chlorophenylalanine (PCPA; fenclonine) & p-
chloroamphetamine
Serotonin
• Location
– Enterochromaffin cells in the intestine
– Platelets
– Stomach cells
– Brain
Serotonin
• Effects
– CNS
• Regulation of mood (sensational mood of well-being)
• BP and thermoregulation
• Nausea and Vomiting (CTZ)
• Appetite Suppression
• Temperature regulation
• Pain & itch
• Chemoreceptor Reflex or Bezold-Jarisch Reflex
(bradycardia & hypotension)
Serotonin
• Effects
– Respiratory System
• Release of Ach  bronchoconstriction
• Hyperventilation (chemoreceptor reflex)
– Cardiovascular
• Contraction of vascular SM
• Potent vasocontrictor (except for skeletal & heart
muscles)
• Platelet aggregation
Serotonin
• Effects
– GIT
• Increase tone & facilitates peristalsis
• Prokinetic agent
– Skeletal Muscles & Eye

• Unknown physiologic role
• Note: Serotonin Syndrome (contraction 
hyperthermia)
Serotonin
Receptors Location Response

5 HT 1A Pre-synapse Inhibits further 5HT release
5 HT 1D Peripheral BV Vasoconstriction
5 HT 2A Smooth Muscles Bronchoconstriction
(Vascular SM; Uterine SM) Vasodilation
Diarrhea
5 HT 3 Brain Emesis
(area postrema / CTZ)
5 HT 4 Periphery, GIT Peristalsis, increase motility
Serotonin
Serotonin Agonists
• 5-HT 1A Partial Agonist
– Buspirone - Anxiolytic
• 5-HT 1D Agonist
– Triptans (Sumatriptan, Naratriptan, Zolmitriptan)
• Management of Acute Migraine HA
• ADRs: exacerbation of HTN, precipitates chest pain,
angina pectoris in CAD px
Serotonin Agonists
• 5-HT 2C Agonist
– Dexfenfluramine – appetite suppressant
• 5-HT 4 Full Agonist

– Cisapride – for GERD & motility disorders but toxic
• 5-HT 4 Partial Agonist

– Tegaserod – for irritable bowel syndrome with
constipation
Serotonin Antagonists
• 5-HT 2 Antagonists
– Cyproheptadine
• For the treatment of the smooth muscle manifestations of Carcinoid
syndrome & cold-induced urticaria
• Also have H1 blocking effect
– Ketanserin
• For hypertension & Carcinoid syndrome
• Also blocks Alpha1 receptors
– Ritanserin
• Alters bleeding time & reduce thromboxane formation
Serotonin Antagonists
• 5-HT 3 Antagonists
– Ondansetron (& other –setrons)
• Prevention of nauseas & vomiting associated with
cancer chemotherapy
Ergot Alkaloids
• Produced by Claviceps purpurea
• Affects Alpha, Dopamine, & serotonin receptors
• Ergotism – Poisoning
– Formerly known as St. Anthony’s Fire (vasospastic
ischemia)
– Dementia with florid hallucinations
– Prolonged vasospasm  gangrene
– Stimulation of uterine smooth muscle  abortion
Ergot Alkaloids
• Effects & Drugs
– CNS
• Hallucinogenic (eg. LSD)  5HT 2 stimulation
• EPS muscular control & prolactin suppression (eg. Bromocriptne,
cabergoline, pergolide)  dopamine activation
• Senility & Alzheimer’s dementia (dihydroergotoxine)
– Vascular Smooth Muscles

• Vasoconstriction & vasospasm, used in the dx of variant angina (eg.
Ergotamine)  partial agonist at alpha receptors
• Antimigraine (eg. Ergotamine, ergonovine, methysergide)  partial
agonist at 5HT 2 receptors
Ergot Alkaloids
• Effects & Drugs
– Uterine SM
• Small doses  rhythmic contraction & relaxation of the
uterus
• Higher doses  contraction
• Eg. ergonovine
Ergot Alkaloids
• Toxic Effects
– GI disturbances (diarrhea, nausea, vomiting,
bowel infarction)
– Prolonged vasospasm (ergonovine, ergotamine) 
gangrene  amputation
• Tx: NTG, nitroprusside
– Hydronephrosis, cardiac murmur caused by long-
term methysergide therapy
Continuation: Eicosanoids
*This is the start of the Midterm

Coverage
*Prelim Exam on Fri 

Autacoids: (Histamine, Serotonin, Eicosanoids, Kinins)

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Autacoids

(Histamine, Serotonin, Eicosanoids, Kinins)

– Diagnostic Agent in Pheochromocytoma

• Physiologic Antagonist – Epinephrine

– Alpha Blocking Effects

– Inhibition of Mast Cell Release

– Skeletal Muscles & Eye

Receptors Location Response

• 5-HT 4 Full Agonist

• 5-HT 4 Partial Agonist

– Vascular Smooth Muscles

*This is the start of the Midterm

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