Autacoid (II) 2008

Hsiao G

Serotonin & HistamineBiosynthesisPharmacological EffectsAction MechanismsAdverse Effects

“Noxious pustule in the ear of grain” Assyrian Tablet, 600 B.C.

Vomiting, diarrhea, burning sensation, limbs gangrenous and rotted off, hallucination and manic excitement

Serotonin

5-Hydroxytryptamine (5-HT), serotonin (Page, 1976)

1. endogenous monoamine

2. central neurotransmitter

3. local (autacoid) action in various tissues

Occurrence and distribution

Mammalian: (1) about 90% of serotonin produced by

enterochromaffin cells in intestine (Erspamer, 1930s)

(2) 8% in platelet (uptake system, transporter)

(3) 2% in CNS (serotonergic neurons, rostral raphe nuclei), pineal gland, hypothalamus

SerotoninSerotonin

GIGI

PsychoPsycho..

CVCV

Haemo. & Thromb.Haemo. & Thromb.

(Carcinoid tumor)

Biosynthesis and metabolism

1. Serotonin is synthesized in neuron and enterochromaffin cells by hydroxylation and decarboxylation of the amino acid tryptophan. (melatonin)

2. 5-hydroxyindoleacetic acid (5-HIAA) is major serotonin metabolite.

5-HT4

+-CNS-

-GI-Prokinetic

(fast)

-CNS-

Serotonin (5-HT) MAO

Hybrid-like, multiple actions

Pharmacological effects

Cardiovascular system

1. Vasoconstraction (5-HT2A R.), arteriolar dilation (5-HT1 R.), peripheral adrenergic neurotransmission

2. Triphasic change in blood pressure

(1) a transient decrease (reflex stimulation of chemoreceptors within the coronary arteries) (Bezold- Jarisch reflex) (2) a period of hypertension that lasts several minutes (direct constraction of blood vessels of splanchnic and renal vascular beds) (3) a prolonged period of lowered pressure (vasodilation

of vessels in specific vascular beds) (ex. Skeletsl muscle)

3. heart: positive inotropic and chronotropic effect (5-HT1)

Platelet

1. 5-HT2A produces a weak platelet aggregation, but with adhesive factor (collagen)→5-HT can amplify the platelet aggregation reaction and speed clot formation

  GI tract

1. direct stimulation of intestinal muscle

2. indirect stimulation through excitation of ganalion cells within the intestinal wall→diarrhea and abdominal pain

3. Cisapride (5-HT4 receptor agonist)→propulsive motor activity of stomach and small, large intestine→treatment of motility disorder

Airway

bronchial smooth muscle cell constriction

CNS

1. stimulate afferent nerve ending, ganalion cells → pain perception, behavior, body temperature

2.synaptic transmission→antidepressant drugs

3. 5-HT1 receptors on adrenergic nerve terminal→NE release

4. 5-HT3 receptor located on sensory neuron mediate a depolarizing response→pain and itching

Mechanism of action

 

 

 

 

 

Receptor mechanism Response agonist antagonist

5-HT1A -AC Presynaptic autoreceptor which inhibt neurotransmitter release in doral raphe, hippocampus and cerebral cortex.Postsynaptic receptors at several sites including hippocampus

Ergotamine Buspirone

5-HT1C PI turnover Central neuronal depolarizing -- MianserinKetanserine

5-HT1D - AC Vasoconstriction in some cranial vascular beds, e.g. carotid artery, pial and dural vessels.Inhibitory presynaptic autoreceptors (which reduce 5-HT release)

Sumatriptan  

5-HT2 PI turnover Platelet aggregation, vasoconstriction, bronchoconstriction, poatsynaptic receptors mediate central and peripheral neuronal depolarization

-- MethysergidePizotifenmianserin

5-HT3 Ion channel Central and peripheral neuronal depolarization, vomiting via sensory nerve terminals of the vagus

-- ondansetron

ketanserin

Migraine (headache attack)

1. Premonitory aura: flashing lights, throbbing unilateral headache, photophobia, hemianopia, vomiting, polyurea, etc.

2. Prodromal phase: vasoconstriction

Headache phase: vasodilation (1950)

Inflammatory mediators: substance P & calcitonin gene-related peptide (1990)

Tx: ergot alkaloids or sumatriptan

5-HT agonists and antagonists

Ergot alkaloids (Ergotamine, dihydroergotamine, bromociptine, ergonovine, methylergonovine,

methysergide )

(1) from Secale cornutum (ergot), the sclerotium of fungus (Claviceps purpurea) parasitizing rye

(2) contain lysergic acid

(3) partial 5-HT, dopaminergic and -adrenergic receptor agonists (St Anthony’s fire)

(4) uterus and vascular smooth contraction

(5) prevent migraine headache

CNS

Methysergide

1. a congener of methylergonovine and LSD

2. vasoconstrictor and inhibit 5-HT2 receptor and - adrnergic block

3. prevent migraine headache, but not effective in treatment of established migraine

4. rebound headaches may occur when the drug is withdraw

5. side effect: nausea, dizziness, insomnia, behavioral changes

 

Cyproheptadine

1. H1, 5-HT2A receptor antagonist

2. used to relieve itiching of skin, intestinal hypermotility of carcinoid syndrom

3. side effect: antihistamine-like effect

Ketanserin

1.(selective) 5-HT2 antagonist

2. Vasodilation (1-antagonist), antihypertension 

Fluoxetine

1. second-line antidepressant (atypical) 2. Block 5-HT reuptake in serotonergic neuron 

Buspirone

1. anxiolytic drug 2. A partial central 5-HT1A agonist 

Ondansetron

1. chemotherapy-induced emesis/vomiting 2. Block 5-HT3 receptor 3. 5-HT → 5-HT3 receptor (chemoreceptor trizzer zone)

→ vomting center → vomting

,H4

Histamine

1. Histamine is synthesized, stores, and releases primarilyby mast cells (lung> skins> GI mucosa)

2. immediate hypersensitivity allergic responses

3. bronchoconstriction

4. intestinal peristalsis

5. dilatation and increased permeability of small blood vessels(edema)

Mechanism of histamine

H1 receptor: phosphoinositol-phospholipase C (PI-PLC)→↑Ca2+, DAG

H2 receptor: activate adenylyl cyclase→↑cAMP

H3 receptor: inhibit adenylyl cyclase→↓cAMP

H1 antagonists Pharmacology properties

1. Antiallergic action (perennial allergic rhinitis, conjunctivitis, itching)

2. Sediation (drug pass BBB and inhibit central H1)

3. Antimotion sickness (antimuscarinic action)

4. Antiemetic action (inhibit dopamine D2)

5. Antiparkinsonism (antimuscarinic action)

6. Local anesthetic action (inhibit sodium channel in excitable membrane)

Side effects

Cimetidine:

1. renal and hepatic damage (high dose)

2. dizzine, confusion (elderly pt), leukopenia, rashes or myalgias

3. interfere with metabolism of the druginhibit hepatic cytochrome p 450 (warfarin, phenytoin, benzodiazepine, propranolol metabolism)

4. antiandrogenic actionbinding to testosterone receptor in man (gynecomastia, tenderness, impotence)

5. Other new drugs did not interfere with metabolism of the drug and antiandrogenic action