Introduction to Autacoids:

Histamine and 5-HT

 Autacoids
Autacoids - locally acting mediators,
with important roles in mediating
 Inflammation, pain and allergies
 Smooth muscle tone and blood pressure
 GI functions
 Hemostasis
 Many others
Types of autacoids we will study:
 Amines: Histamine and 5-HT
 Vasoactive peptides: Angiotensin and Bradykinin
 Eicosanoids: Prostaglandins and Leukotrienes
 Structure and synthesis of Histamine

CH2CH-NH2 CH2CH2NH2
COOH
HN N HN N

Histidine Histamine
L-histidine decarboxylase
Synthesized by decarboxylation of histidine
Important role in
 Allergic reactions
 Regulation of Gastric acidity
Physiologic effects of Histamine
 Effects of intradermal injection of histamine

“Triple response”:

Symptom Time frame

Red spot, few secs to 1 min
Flare slower
Wheal 1-2 minutes
 Effects of intradermal injection of histamine

“Triple response”:

Symptom Time frame Cause

Red spot, few secs to 1 min vasodilation
Flare slower axon reflex =>vasodilation
Wheal 1-2 minutes increased permeability of
post-capillary venules

Often accompanied by itching

 The involvement of Histamine in
Local Inflammation

Local vasodilation and leakage of

inflammatory mediators into the tissue
Chemoattractant for some types of
inflammatory cells
May modulate release of inflammatory
peptides
Intravenous injection of a histamine liberator induces
a dramatic response known as anaphylaxis:

A burning, itching sensation,

especially in the palms of the hands, face scalp and ears
A feeling of intense warmth
Reddening of the skin (flushing)
Drop in blood pressure (hypotension)
Acceleration of heart (tachycardia)
Headache
After a few minutes, blood pressure recovers and hives
appear on the skin (wheals)
Colic, nausea and hypersecretion of gastric acid
Moderate bronchospasm
 Effects of Histamine poisoning

Spoiled scombroid fish, such as mackerel or tuna

contains a high content of histamine

Injestion results in:

severe nausea
vomiting
headache
flushing
sweating
Production and Metabolism of
Histamine
 Sites of production and storage of
histamine

Mast cells Histamine stored in secretory granules –

Basophils slow turnover

Mast cells are found in nearly all tissues of the body,

especially in tissues prone to injury:
nose, mouth, skin, feet, and exposed internal surfaces
(lungs and GI tract)
Basophils are found in the blood
 Sites of production and storage of
histamine

Enterochromaffin-like
cells in the Gastric mucosa
Histaminergic neurons Continuous release of
in the CNS histamine –
rapid turnover
Regenerating or
rapidly growing tissues
 Histamine is metabolized by methylation
and oxidation and secreted in the urine
CH2CH2NH2
HN N

Histamine CH2CH2NH2
N-M CH3N N
ethy
ltra
nsfe
rase N-Methylhistamine
CH2COOH
Mo
noami CH3N N
ne O
xida
s e BN-Methylimidazole
Acetic Acid
 CH2CH2NH2
CH3N N

N-Methylhistamine

The level of N-Methylhistamine in the urine provides a

reliable
measure endogenous histamine production

What conditions might be reflected by high levels of

N-Methylhistamine in the urine?
Control of Histamine Release
Histamine is released from mast cells
during an allergic response

Receptor-induced exocytosis triggered by:

-Antigen binding to cell-bound IgE
( immediate or type I hypersensitivity)

FcεRI

IgE
Mast cell
 What clinical conditions result from
type-1 hypersensitivity?

Hay fever
Initial phase of asthma
Urticaria
Anapylactic shock
Hypersensitivity responses to some drugs

Note: histamine mediates some, but not all of the immediate

hypersensitivity response
Other mediators released by mast cells including Platelet
activating factor (PAF) and leukotrienes contribute significantly
to allergic brochospasm
 Other stimuli that trigger release of
histamine from mast cells

Complement C3a or C5a

Passive release may be induced by some drugs,
usually organic bases:
-Morphine
-Tubocurarine
-Radiocontrast media, etc.
Tissue Injury or mechanical injury to mast cells
Heat or cold
Agents that inhibit the release of histamine
from mast cells

Agents that increase cAMP

 β 2-adrenoreceptor agonists
 H2 receptor agonists
(Histamine may down-modulate its own release,
to limit the intensity of allergic reactions
especially in mast cells in skin and basophils,
but not in lungs)

Mast cell “stabilizers”

 Cromolyn Sodium
 Nedocromil Sodium
 Nedocromil Sodium/Cromolyn Sodium

Inhibits antigen-induced bronchospasm and mast cell

degranulation
Used prophylactically to treat mild to moderate asthma
With regular use reduces airway hyperreactivity
But ineffective in the case of ongoing bronchoconstriction
Mechanism of action unclear but includes:
inhibition of mast cell degranulation
inhibition of leukocyte activation
inhibition of chemokine-induced recruitment of neutrophils,
eosinophils, and monocytes
Delivered by inhalation several times daily (since only 1% of
oral dose is absorbed)
drug excreted with half life of 45-100 min
Histamine Receptors and
Antagonists
 Four types of histamine receptors
All are G-protein coupled
Receptor Distribution Signaling Mechanism
H1 Smooth muscle IP3, DAG ↑
Endothelium
Brain
H2 Gastric Mucosa cAMP ↑
Cardiac muscle
Mast cells
Brain
H3 Presynaptic in: cAMP ↓ Ca2+↓
Brain
Myenteric plexus
others
H4 Eosinophils cAMP ↓ Ca2+↓
Neutrophils
CD4 T cells
 Pharmacology of histamine receptors

Very small changes the ligand structure can have a

dramatic effect on receptor specificity:

CH2CH2NH2 CH3 CH2CH2NH2 CH2CHNH2

HN N HN N HN N CH3

CH3
2-methylhistamine 4(5)-methylhistamine (R)-α-methylhistamine

H1 agonist H2 agonist H3 agonist

H1:H2 H2:H1 H3:H1
8:1 170:1 15:1
 Histamine receptors and the effects they mediate
in various peripheral organs

Receptor Physiologic Response Result

H1 -Vasodilation of small blood vessels Redness, flushing,
Endothelium (rapid response to low Hypotension
Smooth concentrations of histamine)
muscle
-Increased permeability of post- Edema, urticaria
Brain capillary venules
Nerve -Stimulation of sensory neuronal Itching, pain, flare
Endings receptors
-contraction of smooth muscle of Bronchoconstric-
the ileum, bronchi, bronchioles tion, especially in
and uterus asthmatics
 Histamine receptors and the effects they mediate
in various organs

Receptor Physiologic Response Result

H2 -Secretion of gastric acid Contribute to peptic
Gastric ulcer
mucosa
-Direct Cardiac stimulation less important than
Cardiac
baroreceptor reflex
muscle
Vascular -Vasodilation Hypotension
smooth (slower, prolonged response to
muscle high concentrations of histamine)
Mast cells

Brain
 Histamine receptors and the effects they mediate
in various organs

Receptor Physiologic Response Result

H3 -Presynaptic inhibition of the unknown
Presynaptic release of neurotransmitters
 Many drugs familiar from everyday life are
histamine antagonists:

First generation H1 antagonists:

Diphenhydramine (Benadryl)
Dimenhydrinate (Dramamine, Travamine)
Second generation (nonsedating) H1 antagonists:
Loratadine (Clarintin, Lorastin)
Fexofenadine (Allegra, Telfast)
H2 antagonists:
Cimetidine (Tagamet, Cimi)
Ranitidine (Zantac, Zanidex)
Famotidine (Pepcid, Gastro)
 H1 receptor antagonists

Reversible, competitive inhibitors of the general

structure: Ar1
X-C-C-N
Ar2

CH2CH2NH2

HN N

Histamine
 H1 Antagonists

CH3

C O CH2 CH2 N 1st generation

H CH3
Diphenhydramine

Cl

O
N C 2nd generation
OC2H5
N

Loratadine
 First Generation H1 Antagonists
(Diphenhydramine, Mepyramine)

Well absorbed from GI tract, generally effective for 4-6

hours, but may persist longer in skin
Have many side effects
Cross the blood brain barrier
-> CNS effects, especially sedation, but sometimes excitation
Many have activity as muscarinic antagonists
-may explain their usefulness as antiemetics
(dimenhydrinate, diphenhydramine, promethazine)
-atropine-like side effects
Some drugs may have other side effects:
 α-adrenoreceptor antagonists
 Serotonin blocking
 Local anesthesia
Drug allergy may develop
Many first generation H1 Antagonists have
anti-muscarinic effects

CH3

C O CH2 CH2 N 1st generation

H CH3
Diphenhydramine

CH3
HO CH CH2
+
H3C CH CH CH2 N CH3
O
CH3
Muscarine
 Second Generation H1 Antagonists
(Cetirizine, Loratadine Fexofenadine)

Well absorbed
Fewer side effects
Do not cross the blood brain barrier - nonsedating
No antimuscarinic activity - no atropine-like effects
Older drugs (Astemizole, Terfenadine) sometimes
induced fatal arrhythmia, and were withdrawn
from the market
The newer drugs (Loratadine, Fexofenadine) do not
have this side effect.
 Fexofenadine is the safer, active metabolite
of Terfenadine

Ketoconazole
OH
C(CH3) 3
Macrolide antibiotics
HO C N CH2CH2CH2CH
Grapefruit juice
Terfenadine

Cyp3A4

OH CH3
HO C N CH2CH2CH2CH C COOH
CH3
Fexofenadine
 Therapeutic uses of H1 antagonists

Suppress many of the effects of histamine:

edema and wheal
flare and itch
allergic rhinitis, urticaria, conjunctivitis,

Not useful for:

the common cold
allergic bronchoconstriction
asthma
systemic anaphylaxis
 What is the best way to treat an anaphylactic response?

a. Antihistamine

b. Adrenaline

Adrenaline is a physiologic antagonist of histamine

It acts on different receptors, so is not a true antagonist
But it has opposing physiologic effects:

1. Vasoconstriction and increased cardiac output => increased bp

2. Bronchorelaxation
Regulation of gastric acid secretion: the
basis for therapy of peptic ulcer disease
 Regulation of gastric acid secretion

Acid secreted by parietal cells in the lining of the

stomach
Regulated by multiple factors:
neuronal (Ach, Vagal nerve)
paracrine (histamine)
endocrine (gastrin)
Prostaglandins play a protective role
-promote secretion of mucus and bicarbonate
-inhibit acid secretion by parietal cells
-enhance mucosal blood flow
 Diseases Associated with Excessive
Gastric Acid

Gastroesophageal reflux disease

Peptic ulcers of the stomach and duodenum
(Generally results from Heliobacter pylori infection)
Ulcers secondary to NSAID use
Ulcers due to Zollinger-Ellison syndrome
(a tumor of gastrin-secreting cells, or gastrinoma)
Regulation of gastric acid secretion: the
basis for therapy of peptic ulcer disease
 Structure and relative potency
of H2 receptor antagonists

Relative potency
1 Cimetidine

4-10x Ranitidine

20-50x Famotidine

4-10x Nizatidine
H2 Receptor Antagonists
 H2 Receptor Antagonists

Competitive inhibitors at H2 receptors

Reduce acid secretion by 60-70% for about 10 hours
Basal secretion of gastric acid reduced more than stimulated
secretion
 >90% of nocturnal acid secretion (basal)
 60-70% of daytime acid secretion (meal stimulated)

Drug and its metabolites are excreted by kidney by glomerular

filtration and renal tubular secretion
=>important to reduce dose in patients with renal insufficiency
Generally few side effects, though Cimetidine is more
problamatic than others, since it inhibits cytochrome P450
(potential for drug interactions)
 H2 Antagonists, therapeutic uses

First line treatment for frequent GERD, that does not

respond to lifestyle changes,
Treatment of persistent heartburn requires twice daily
dosage.
No longer recommended for treatment of peptic ulcers,
PPIs are preferable
May heal NSAID-induced ulcers, if NSAID use is
discontinued
If NSAID use is continued, PPI is required to prevent
recurrence
Activation of proton pump inhibitors at acid pH
and covalent modification of the proton pump
 Omeprazole: mechanism of action

Pro-drug is converted to the active compound at acid pH

Delivered in enteric coated pill so it may pass through acid
environment of stomach unharmed
Pills dissolve in small intestine and drug is rapidly absorbed
into the blood stream
Great specificity attained since the prodrug is inactive, and
only the portion of the drug that accumulates in the acid
canaliculi of the parietal cells is activated
Once activated it binds covalently to the extracellular domain
of the proton pump, thereby irreversibly inactivating the
pump
 Characteristics of Omeprazole
(brand name- Prilosec):

Plasma half life of 1-2 hours,

but duration of action is 24-48 hours
Once a day dosage takes 3-4 days to reach steady state
level of inhibition
Acid required to activate drug
=> Drug should be taken on an empty stomach,
one hour before a meal, so peak serum concentration
coincides with peak acid production
=> Co-administration of H2 antagonist will decrease
efficacy
 Characteristics of Omeprazole
(brand name- Prilosec):

Decrease both basal and meal-stimulated acid production

Preferred treatment for
 healing peptic ulcers
 GERD with complications (esophageal erosions, Barrett’s esophagus,
etc.)
 NSAID-induced ulcer if NSAID must be continued
 Gastrinoma, if cannot be surgically removed
Side effects:
-hypergastrinemeia (risk of hyperplasia of enterochromaffin-
like cells?)
-reduced absorption of vitamin B12
-increased risk of enteric infections
5-HT
 5-HT = 5-Hydroxytryptamine = Serotonin

HO
CH2 CH2NH2

Powerful vasoconstrictor substance N

found in the serum, after blood has H
clotted 5-hydroxytryptamine

Functions both as neurotransmitter and as local hormone

“Involved in everything, but responsible for nothing”

 Functions Regulated by 5-HT

In Periphery
Peristalsis
Vomiting
 Functions Regulated by 5-HT

In Periphery
Peristalsis
Vomiting
Platelet aggregation, haemostasis

Microvascular control
 Functions Regulated by 5-HT

In Periphery
Peristalsis
Vomiting
Platelet aggregation, haemostasis

Microvascular control
Sensitization of nociceptors (pain,
itch)
Inflammatory mediator
 Functions Regulated by 5-HT

In Periphery In CNS
Peristalsis Control of appetite
Vomiting Sleep
Platelet aggregation, haemostasis Mood

Microvascular control Hallucinations

Sensitization of nociceptors (pain, Stereotyped behavior
itch)
Inflammatory mediator Pain perception
Vomiting
Temperature regulation
Regulation of blood pressure
 Distribution of 5-HT in body

Enterochromaffin cells  interspersed in mucosa of stomach

and small intestine
90% of 5-HT in body

Neurons  in localized regions of the CNS -

Raphe nuclei of the brain stem
 in the Enteric Nervous System

Platelets  don’t synthesize 5-HT but accumulate

it from the plasma as they pass
through the intestinal circulation

Plants, venoms and stings

 Sites of synthesis an reuptake of 5-HT

Synthesis Reuptake
Enterochromaffin cells
+
Platelets
+
Neurons
+ +
 5-HT Synthsized from tryptophan by a pathway
analogous to catecholamine synthesis

COOH Tr
hy ypto
CH2CH dr ph
ox
NH2 yla an
N se
H L-
ar
Tryptophan COOH de om
ca ati
rb
ox c aci
HO
CH2CH
yla d
N
NH2 se
H
5-hydroxytryptophan HO
CH2 CH2NH2

N
H
5-hydroxytryptamine
 5-HT is degraded by oxidative deamination -
analogous to Noradrenaline metabolism
M
on
HO
CH2 CH2NH2 Ox oam
ida ine
N
se
H
5-hydroxytryptamine de Alde
hy
HO dr hyde
CH2 CHO og
en
ase
N
H
HO
CH2 COOH

N
H
5-hydroxyindoleacetic acid
(5-HIAA)
The level of 5-HIAA in urine is an indicator of
the rate of 5-HT production in body

What disease is characterized by a high level of

5HIAA in the urine?
HO
CH2 COOH

N
H
5-hydroxyindoleacetic acid
(5-HIAA)
Carcinoid syndrome
Malignant tumor of enterochromafin cells,
arising in the small intestine and
metastasizing to the liver
Tumor may secrete mediators such as 5-HT
Symptoms include flushing, diarrhoea
bronchoconstrictions, and hypotension, and
sometimes stenosis of heart valves.
Treated with 5-HT2A antagonists
 5-HT Receptors -a complex picture

1D ??????!
1B
1A
6 2C

5
4

2B
2A
7 3
5-HT Receptors
5-HT Receptors
More 5-HT Receptors
Still more 5-HT Receptors
 Roles of 5-HT in GI tract

GI tract Increased gastrointestinal motility and

contraction
-via direct excitation of smooth muscle (5-HT2)
-via indirect activation of enteric neurons
(5-HT3 and 5-HT4)

Vomiting Stimulates vomiting

-via 5-HT3 receptors in GI tract on vagal nerve
(5HT released in mucosa upon irritation by
chemotherapy, radiation therapy, distention, etc)
-via 5-HT3 receptors in the chemoreceptor trigger
zone and vomiting center of brain
 Ondansetron
5-HT3 antagonist
Used to prevent:
-chemotherapy-induced nausea and emesis
-radiotherapy-induced nausea and emesis
-postoperative nausea and emesis
Not known whether it acts centrally or
peripherally, but serotonin is released from
enterochromaffin cells upon chemotherapy
 5-HT4 Agonists and their use in
gastrointestinal disorders
5-HT4 agonists promote GI motility - stimulate
coordinated peristaltic activity
Tegaserod – Newer and more specific 5-HT4 agonist.
Used to treat irritable bowel syndrome with
constipation (abdominal pain, swelling and
constipation)
Found effective in women only
CLINICAL STUDIES
In three multicenter,double-blind,placebo-controlled
studies, 2,470 women (mean age 43 years [range 17-
89 years]; 86%Caucasian, 10%Afri can American)
with at least a 3-month history of IBS symptoms prior
to the study baseline period that included abdominal
pain, bloating and constipation received either
Zelnorm™ (tegaserod maleate) 6 mg b.i.d.or placebo.
In all patients, constipation was characterized by at
least two of the following three symptoms each
occurring >25% of the time over a 3-month period:
<3 bowel movements/week, hard or lumpy stools, or
straining with a bowel movement. Study design
consisted of a 4-week placebo-free baseline period
followed by a 12-week double-blind treatment period.
Study 1 and 2 evaluated a fixed dose regimen of
tegaserod 6 mg b.i.d. while Study 3 utilized a dose-
titration design. Each week of the 4-week placebo-
free baseline period and the 12-week double-blind
treatment period, patients were asked the question,
“Please consider how you felt this past week in regard
to your IBS, in particular your overall well-being, and
symptoms of abdominal discomfort, pain and altered
bowel habit. Compared to the way you usually felt
before entering the study ,how would you rate y our
relief of symptoms during the past week?” The
response variable consisted of the following 5
categories: completely relieved, considerably
relieved, somewhat relieved, unchanged, or worse.
Patients were classified as responders within a month
if the y were considerably or completely relieved for a
t least two of the four weeks, or if they were at least
somewhat relieved for each of the four weeks.
 Physiologic effects of 5-HT
Cardio- Mixture of vasoconstriction
of large peripheral blood vessels via 5-HT2A
vascular
-via direct effect on vascular smooth muscle
system of cranial blood vessels via 5-HT1
and vasodilation
in skeletal muscle and heart
-via indirect effect on vascular endothelium
=> production of NO
-via inhibition of NA release from sympathetic nerve terminals
Reflex Bradycardia (Chemoreceptor reflex)
-via 5-HT3 on chemoreceptor nerve endings,
triggering vagal output to the heart=>bradycardia
Venoconstriction
leading to increased capilary filling and flushing
 Opposing effects of 5-HT on vasculature

Triphasic response follows injection of 5-HT:

Initial decrease in heart rate, cardiac output and

blood pressure, due to the chemoreceptor response
(5-HT3 receptors on nerve endings)

Increase in blood pressure due to vasoconstriction

Decrease in blood pressure due to vasodilation in

skeletal muscle
 Physiologic effects of 5-HT

Platelets Platelet aggregation,

In the case of blood clotting there is release of
5T by the aggregating platelets
=> vasodilation if endothelium is intact
=> vasoconstriction if endothelium is damaged
Platelet released 5-HT may promote
thrombus or hemostasis
 Physiologic effects of 5-HT

Nerve Endings Stimulates nociceptive nerve endings (5HT3)

Inhibits transmitter release from peripheral

adrenergic neurons
Stimulates autonomic chemoreceptor reflex in
heart and lungs (bradycardia and hypotension)
Stimulates vomiting
via 5-HT3 receptors in GI tract on vagal nerve
via vomiting center of brain
 Physiologic effects of 5-HT

CNS Excitation
Inhibition
Presynaptic inhibition of neurotransmitter release
Sleep/Wake Cycle
Aggression and Impulsivity
Anxiety and Depression
Cognition
Sensory Perception
Motor Activity
Temperature Regulation
Nociception
Appetite
Sexual Behavior
Hormone Secretion
 5-HT = 5-Hydroxytryptamine = Serotonin

HO
CH2 CH2NH2

N
H
5-hydroxytryptamine
Today known to be involved in many disorders including:
carcinoid syndrome
mood disorders (depression, mania, anxiety)
digestive disorders
(irritable bowel syndrome and acid reflux disorder)
vascular disorders
migraine
 The complex (poorly understood, but convincing)
role of 5-HT in many diseases

•Some pathologic conditions may be treated with drugs that

influence 5-HT levels or 5-HT function
For Example:
Depression
-TCA (tricyclic antidepressants)
-SSRI (selective serotonin reuptake inhibitors)
(fluoxetine = prozac)
-MAOI (monoamine oxidase inhibitors)
Obesity
(fenfluramine, dexfenfluramine) (inhibitors of 5-HT reuptake)
Induce weight loss but can cause pulmonary hypertension and
heart valve defects
Migraine
 Buspirone
5-HT1A partial agonist
Anti-anxiety drug
Anxiolytic, but not sedative
Effects take days or weeks to develop
- not effective for panic attacks
 Migraine - a poorly understood disorder

Affects 10-15% of population

Symptoms: Aura, followed by severe throbbing headache,

starting unilaterally, often with photophobia, nausea, vomiting,
prostration, and lasting for several hours

Or Migraine without aura (more common):

episodic attacks of headache lasting 4-72 hrs
with at least two of the following (unilateral pain, throbbing,
aggravation on movement, moderate to severe intensity)
and one of the following (nausea, vomiting, photophobia,
phonophobia)
 Migraine - a poorly understood disorder

Pathophysiology not well understood and hotly contested:

Cause may be vascular, neural, inflammatory, or associated
with platelet function

Strong evidence implicates 5-HT:

-sharp increase in urinary excretion of 5-HIAA during the
attack with concomitant fall in blood concentration of 5-HT
-migraines may be precipitated by agents like reserpine and
fenfluramine that release 5-HT from intracellular storage sites
-many effective drugs are 5-HT agonists or antagonists
 Sumatriptan- an effective
antimigraine drug

5-HT1D (and 5-HT1B) agonist

low or no affinity for other receptor subtypes

The clinical effect of triptans correlates with their affinity

for 5-HT1D and 5-HT1B

Causes constriction of intracranial blood vessels

Used to treat acute attacks of migraine

but not useful for prophylaxis

Reduces the nausea and vomiting associated with migraine

 Sumatriptan- an effective
antimigraine drug

For fast onset, can give subcutaneously (12 min) or as a nasal

spray (15 min) rather than orally (1-2 hrs)
Short acting (half life of 2 hours)
metabolized by MAO
Side effects:
-rare but serious cardiac events, especially in patients at risk
for coronary artery disease (causative relationship not clear)
Tendency to cause chest pain due to coronary artery spasm

Contraindicated in patients with cardiovascular disease

or uncontrolled hypertension
or in patients who are taking MAO inhibitors
How does Sumatriptan work? - some hypotheses:

Clinical efficacy may be due to constriction of

carotid arteriovenous anastomoses
According to one theory, migraine is associated with
abnormal dilation of these anastomoses, located mainly
in the cranial skin and ears, which may “shunt” as
much as 80% of the carotid arterial blood flow, leading
to cerebral ischemia and hypoxia
May activate presynaptic 5-HT1D and 5-HT1B receptors,
blocking the release of proinflammatory neural
peptides in the perivascular space
 Ergot Alkaloids (Ergotamine, Methysergide)

Natural substances derived from the fungus Claviceps

purpurea, which infects damp grains, esp. rye.

Complex tetracyclic alkaloids based on lysergic acid

Symptoms of Ergot poisoning (St. Anthony’s fire)

-mental disturbances, hallucinations
-intensely painful peripheral vasoconstriction, which may
result in gangrene
-uterine contraction, which may lead to abortion
 Ergot Alkaloids (Ergotamine, Methysergide)

Act on:
5-HT receptors
adrenoreceptors
dopamine receptor
stimulate smooth muscle
no clear structure/function relationship
Some of the ergot alkaloids have been isolated and are
clinically useful
Structure of ergot alkaloids
 Ergotamine
Antagonist/partial agonist at α-adrenergic receptors and
partial agonist at 5-HT1D receptors
– also stimulates smooth muscle
Effective if given early during a migraine attack
Often combined with caffeine, to increase absorption when
given orally
Side effects:
When taken repeatedly, induces long lasting and cumulative
vasoconstriction, which may result in gangrene
=> patient must be well informed as to maxium dose
per attack and per week
may cause uterine contraction => contraindicated in
 Methysergide
Weak agonist at α-adrenergic and dopamine receptors
and antagonist/partial agonist at 5-HT2 receptors
Used for prophylaxis of migraine
but ineffective in the treatment of an impending or
active migraine
Lacks cumulative vasospastic toxicity seen with
ergotamine
Chronic use may induce retroperitoneal fibroplasia
and subendocardial fibrosis
=> must go off the drug periodically
Side effects: nausea, vomiting and diarrhea