autacoids histamine and 5-ht 2008

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

Synthesized by decarboxylation of histidine

Important role in Allergic reactions Regulation of Gastric acidity

HN N

CH2CH2NH2

HistamineHistidine

HN N

CH2CH-NH2

COOH

L-histidine decarboxylase

Physiologic effects of Histamine

Effects of intradermal injection of histamine

Symptom Time frame

Red spot, few secs to 1 min

Flare slower

Wheal 1-2 minutes

“Triple response”:

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

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

Intravenous injection of a histamine liberator induces a dramatic response known as anaphylaxis:

Effects of Histamine poisoning

Injestion results in: severe nausea vomiting headache flushing sweating

Spoiled scombroid fish, such as mackerel or tuna contains a high content of histamine

Production and Metabolism of Histamine

Sites of production and storage of histamine

Mast cells

BasophilsHistamine stored in secretory granules – 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

Continuous release of histamine – rapid turnover

Enterochromaffin-like cells in the Gastric mucosa

Histaminergic neurons in the CNS

Regenerating or rapidly growing tissues

Histamine is metabolized by methylation and oxidation and secreted in the urine

HN N

CH2CH2NH2

Histamine

CH3N N

CH2CH2NH2

N-Methylhistamine

N-Methyltransferase

Monoamine Oxidase BN-Methylimidazole

Acetic Acid

CH3N N

CH2COOH

CH3N N

CH2CH2NH2

N-Methylhistamine

The level of N-Methylhistamine in the urine provides a reliablemeasure endogenous histamine production

What conditions might be reflected by high levels of N-Methylhistamine in the urine?

Why not just measure the level of histamine 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)

Mast cell

FcRI

IgE

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 responseOther 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 2-adrenoreceptor agonists H2 receptor agonists

(Histamine may down-modulate its own release,to limit the intensity of allergic reactionsespecially 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 asthmaWith regular use reduces airway hyperreactivityBut ineffective in the case of ongoing bronchoconstriction

Mechanism of action unclear but includes:inhibition of mast cell degranulationinhibition of leukocyte activationinhibition 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 muscleEndotheliumBrain

IP3, DAG

H2 Gastric MucosaCardiac muscleMast cellsBrain

cAMP

H3 Presynaptic in: Brain Myenteric plexus others

cAMP Ca2+

H4 EosinophilsNeutrophilsCD4 T cells

cAMP Ca2+

Pharmacology of histamine receptors

Very small changes the ligand structure can have a dramatic effect on receptor specificity:

2-methylhistamine

HN N

CH2CH2NH2

CH3

4(5)-methylhistamine

HN N

CH2CH2NH2CH3

(R)--methylhistamine

HN N

CH2CHNH2

CH3

CH3

H1 agonist

H1:H2

8:1

H2 agonist

H2:H1

170:1

H3 agonist

H3:H1

15:1

Histamine receptors and the effects they mediate in various peripheral organs

Receptor Physiologic Response Result

H1

Endothelium

Smooth muscle

Brain

Nerve Endings

-Vasodilation of small blood vessels(rapid response to low concentrations of histamine)

-Increased permeability of post-capillary venules

-Stimulation of sensory neuronal receptors

-contraction of smooth muscle of the ileum, bronchi, bronchioles and uterus

Redness, flushing,Hypotension

Edema, urticaria

Itching, pain, flare

Bronchoconstric-tion, especially in asthmatics

Histamine receptors and the effects they mediate in various organs


H2

Gastric mucosa

Cardiac muscle

Vascular smooth muscle

Mast cells

Brain

-Secretion of gastric acid

-Direct Cardiac stimulation

-Vasodilation (slower, prolonged response to high concentrations of histamine)

Contribute to peptic ulcer

less important than baroreceptor reflex

Hypotension

Histamine receptors and the effects they mediate in various organs


H3

Presynaptic

-Presynaptic inhibition of the release of neurotransmitters

unknown

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:

X-C-C-N

Ar1

Ar2

HN N

CH2CH2NH2

Histamine

H1 Antagonists

C CH2O N

H

CH2

CH3

CH3

Diphenhydramine

1st generation

N

N CO

OC2H5

Cl

Loratadine

2nd generation

First Generation H1 Antagonists(Diphenhydramine, Mepyramine)

Well absorbed from GI tract, generally effective for 4-6 hours, but may persist longer in skinHave many side effectsCross the blood brain barrier -> CNS effects, especially sedation, but sometimes excitationMany have activity as muscarinic antagonists-may explain their usefulness as antiemetics(dimenhydrinate, diphenhydramine, promethazine)-atropine-like side effectsSome drugs may have other side effects: -adrenoreceptor antagonists Serotonin blocking Local anesthesia

Drug allergy may develop

Many first generation H1 Antagonists have anti-muscarinic effects

C CH2O N

H

CH2

CH3

CH3

Diphenhydramine

1st generation

Muscarine

CH CH2

ONCH

CH3

CH3

CH3+

CH CH2HO

H3C

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

CHO NCH2CH2CH2CHOH

C(CH3) 3

Terfenadine

CHO N CH2CH2CH2CHOH

CCH3

CH3

COOH

Fexofenadine

Cyp3A4

KetoconazoleMacrolide antibiotics

Grapefruit juice

Therapeutic uses of H1 antagonists

Suppress many of the effects of histamine:edema and whealflare and itchallergic rhinitis, urticaria, conjunctivitis,

Not useful for: the common coldallergic bronchoconstriction asthmasystemic anaphylaxis

a. Antihistamine

b. Adrenaline

Adrenaline is a physiologic antagonist of histamine It acts on different receptors, so is not a true antagonistBut it has opposing physiologic effects:

1. Vasoconstriction and increased cardiac output => increased bp2. Bronchorelaxation

What is the best way to treat an anaphylactic response?

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

Acid secreted by parietal cells in the lining of the stomachRegulated 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

Regulation of gastric acid secretion

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

Cimetidine

Nizatidine

Famotidine

Ranitidine

1

4-10x

20-50x

4-10x

Relative potency

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 inhibitionAcid 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 productionPreferred 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

Functions both as neurotransmitter and as local hormone

“Involved in everything, but responsible for nothing”

5-HT = 5-Hydroxytryptamine = Serotonin

CH2 NH2CH2OH

NH

5-hydroxytryptamine

Powerful vasoconstrictor substance found in the serum, after blood has clotted

Functions Regulated by 5-HT

In PeripheryPeristalsis

Vomiting



Vomiting

Platelet aggregation, haemostasis

Microvascular control



Vomiting

Platelet aggregation, haemostasis

Microvascular control

Sensitization of nociceptors (pain, itch)

Inflammatory mediator


In Periphery In CNSPeristalsis Control of appetite

Vomiting Sleep

Platelet aggregation, haemostasis Mood

Microvascular control Hallucinations

Sensitization of nociceptors (pain, itch)

Stereotyped behavior

Inflammatory mediator Pain perception

Vomiting

Temperature regulation

Regulation of blood pressure

interspersed in mucosa of stomach and small intestine90% of 5-HT in body

in localized regions of the CNS - Raphe nuclei of the brain stem

in the Enteric Nervous System

don’t synthesize 5-HT but accumulate it from the plasma as they pass through the intestinal circulation

Distribution of 5-HT in body

Enterochromaffin cells

Neurons

Platelets

Plants, venoms and stings

Sites of synthesis an reuptake of 5-HT

Synthesis ReuptakeEnterochromaffin cells +Platelets +Neurons + +

5-HT Synthsized from tryptophan by a pathway analogous to catecholamine synthesis

NH

CH2CH

COOH

NH2

TryptophanOH

NH

CH2CH

COOH

NH2

5-hydroxytryptophanCH2 NH2CH2

OH

NH

5-hydroxytryptamine

Tryptophan

hydroxylase L-aromatic acid

decarboxylase

5-HT is degraded by oxidative deamination -analogous to Noradrenaline metabolism

CH2 NH2CH2OH

NH

5-hydroxytryptamine

CH2CHOOH

NH

CH2COOHOH

NH

5-hydroxyindoleacetic acid(5-HIAA)

MonoamineOxidase

Aldehyde

dehydrogenase

CH2COOHOH

NH

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?

Carcinoid syndrome

Malignant tumor of enterochromafin cells, arising in the small intestine and metastasizing to the liverTumor may secrete mediators such as 5-HTSymptoms include flushing, diarrhoea bronchoconstrictions, and hypotension, and sometimes stenosis of heart valves.

Treated with 5-HT2A antagonists

5-HT Receptors -a complex picture

1A

7

6

54

3

2C

2B2A

1D1B

??????!

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 STUDIESIn 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.

Cardio-vascular system

Mixture of vasoconstriction of large peripheral blood vessels via 5-HT2A

-via direct effect on vascular smooth muscle 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

Physiologic effects of 5-HT

Opposing effects of 5-HT on vasculature

1. Initial decrease in heart rate, cardiac output and blood pressure, due to the chemoreceptor response (5-HT3 receptors on nerve endings)

2. Increase in blood pressure due to vasoconstriction

3. Decrease in blood pressure due to vasodilation in skeletal muscle

Triphasic response follows injection 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



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


CNS Excitation

Inhibition

Presynaptic inhibition of neurotransmitter release Sleep/Wake Cycle

Aggression and ImpulsivityAnxiety and DepressionCognitionSensory PerceptionMotor ActivityTemperature RegulationNociceptionAppetiteSexual BehaviorHormone Secretion

Today known to be involved in many disorders including:carcinoid syndromemood disorders (depression, mania, anxiety)digestive disorders (irritable bowel syndrome and acid reflux disorder)vascular disordersmigraine

5-HT = 5-Hydroxytryptamine = Serotonin

CH2 NH2CH2OH

NH

5-hydroxytryptamine

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 defectsMigraine

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:

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) agonistlow 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 receptorsadrenoreceptorsdopamine receptorstimulate smooth muscleno clear structure/function relationship

Some of the ergot alkaloids have been isolated and are clinically useful

Structure of ergot alkaloids

ErgotamineAntagonist/partial agonist at -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 weekmay cause uterine contraction => contraindicated in pregnancy

Methysergide

Weak agonist at -adrenergic and dopamine receptors and antagonist/partial agonist at 5-HT2 receptors

Used for prophylaxis of migrainebut ineffective in the treatment of an impending or active migraine

Lacks cumulative vasospastic toxicity seen with ergotamine

Chronic use may induce retroperitoneal fibroplasiaand subendocardial fibrosis=> must go off the drug periodically

Side effects: nausea, vomiting and diarrhea

autacoids histamine and 5-ht 2008

Documents