Histamine

RVS Chaitanya Koppala

AUTOCOID

• Auto- self , akos –healing substance or remedy• Acts locally ( with in inflammatory cells) at the site of synthesis and

release• Also known as local hormones• Differ from the hormones in two way?• Acts as mediator in physiological and pathological processes, reaction to

injury and immunological insult)• Serve as transmitter or modulator in nervous system

AUTOCOID

Classification of autocoids

Amine autocoids: Histamine, 5-Hydroxytryptamine

Lipid derived autocoids: prostaglandins, leukotrienes, platelet

activation factor

Peptide autocoids: plasma kinins (bradykinins, kallidin),

Angiotensin

In addition Cytokines ( interleukins, TNFalpha, GM-CSF etc)

Several peptides Gastrin, somatostatin, vasoactive intestinal peptide

Histamine

• Histos: Tissue

N N

NH2

H

1

2

3

45

Histamine

•Present mostly in mast cells: skin, lungs, GIT Mucosa •Non mast cell histamine: Brain, Gastric Mucosa

Histamine is a biogenic amine present in many animal and plant tissues .

Histamine• Meaning tissue amine, present in animal tissues and in certain plants eg: stinging

nettle• Implicated as mediator in hypersentivity and tissue injury reactions• Present almost and stored in mast cell• Tissues rice in histamine are skin gastric mucosa and intestinal mucosa, lungs,

liver and placenta.• Non mast cell histamine occurs in brain , epidermis, gastric mucosa and growing

regions• Also presents in body secretions, venoms and pathological fluids

Synthesis, storage & metabolism of histamine

• Synthesized by decarboxylation of amino acid histidine

Pharmacological actions

• Blood vessels: – Dilates arterioles, capillaries, venules, • IV injection- decreased BP• Intradermal- Triple response

Stimulating H1, H2, H3 Receptors

Red spot (dilatation)

Wheal (exudation of fluids)

Flare(Reflex arteriolar dilatation)

Pharmacological actions (Contd)

• CVS: rate as well as force of contraction is increased (H2)• Visceral smooth muscles:

Bronchoconstriction, abdominal cramps, colic by intestinal contractions, uterus is contracted in animalsSmooth muscle is H1 response, sometimes H2 mediated relaxation is also seen

• Secretions:– Increased gastric secretion (H2) primarly of gastric but also pepsin mediated by

increase cAMP generation – Increased nasal secretions (H1)

Pharmacological actions (Contd)

• Sensory Nerve Endings: i.v/ Intracutaneosly occurs itching

Higher concentrations injected more deeply causes pain

• Autonomic ganglia and adrenal medulla: stimulated and release Adr-

causes secondary rise in BP

• CNS: Doesnot cross/ penetrate BBB- no central effects are seen on i.v

– Wakefulness, rise in BP, cardiac stimulation, behavioral arousal,

hypothermia, vomiting and ADH release on intra

Cerebroventricular Injection (H1/H2)

Pathophysiological Roles

• Gastric secretion(H2)• Allergic phenomena (H1)• As transmitter : regulate body temperature, CVS, thirst etc (H1)• Inflammation (p-selection adhesion of leukocytes)• Tissue growth and repair • Head ache

Therapeutic Uses• Betahistine • H1 Selective histamine analogue– To control vertigo in Meniere`s disease 8 mg tab ½ tablet QID

(probably by vasodilatation in inner ear)

Histamine releasers • stings and venom •Ag-Ab reaction •Drugs d-tubocurarine Morphine

Histamine releasers

• Variety of mechanical , chemical and immunological stimuli are capable of releasing histamine from mast cell

• Tissue damage: trauma, stings and venoms, proteolytic enzymes, phospholipase A

• Polymers like dextrans, polyvinyl pyrrolidone• Basic drugs: tubocurarine, morphine, atropine,

pentamidine, plymyxin B, vancomycin

Adverse effects of histamine release

• Itching, Urticaria • Flushing • Hypotension • Tachycardia • Bronchospasm • Angioedema• Wakefullness • Increased acidity (Gastric acid secretion)

Mechanism of Action of Histamine

Histamine

H1 Receptors H2 Receptors H3 Receptors (presynaptic auto

receptors)

↑ Ca2+

Smooth muscle contractionIncreased capillary permeability Vasodilation Sensory nerve endings pain & itching

↑ cAMP

↑ Gastric acid secretion Blood vessels: vasodilation Increased capillary permeability

↓ histamine release ↓secretion Vasodilation

↓ cAMP

Classification of H1 Antagonists

Mechanism of action

Competitive antagonism

Histamine General formula of H1 Blocker

Pharmacological actions • CNS depression: (More with first generation)– Sedation and drowsiness– Some have antiemetic and antiparkinsonian

effects • Antiallergic action• Anticholinergic actions (More with first

generation)– Dryness of mouth , Blurring of vision– Constipation – Urinary retention

Pharmacological Actions

• Local anesthetic• BP: smooth muscle relaxation/ alpha

adrenergic blocade• Antimotion sickness effect: Dimenhydrinate,

Promethazine• Antiemetic: Promethazine • Antiparkinsonism: Diphenhydramine,

orphenadrine, promethazine(IV) • Antivertigo: cinnarizine

Preparations & dosage (Daily)Drug Dose

1. Diphenhydramine 25-50 mg oral 2. Dimenhydrinate 25-50 mg oral 3. Promethazine 25-50 mg oral/injection 4. Chlorpheniramine 2-4 mg oral5. Pheniramine 25- 50 mg oral/im 6. Cinnarizine 25-150 mg oral 7. Cyprohepatidine 4 mg oral

Therapeutic uses

1. Allergic rhinitis & common cold 2. Allergic dermatitis, itching, urticaria 3. Wasp stings/ bite: pain and itching decreases 4. Mild blood transfusion reactions 5. Allergic conjunctivitis 6. Motion sickness: dimenhydrinate, promethazine 7. Morning sickness: promethazine

8. Vertigo: cinnarizine 9. Chronic urticaria10. Appetite stimulant: cyprohepatidine 11.Drug induced parkinsonism: Diphenhydramine,

Therapeutic uses (Contd..)

Adverse effects

• Sedation • Anticholinergic effects• Dermatitis on local use • Cyclizine, meclizine : teratogenicity

Second generation H1 Blockers(Non Sedative:Less anticholinergic property)

• Fexofenadine• Astemizole • Loratidine • Cetrizine • Levocetrizine• Azelastine • Terfenadine

Uses: • Allergic rhinitis • Allergic Dermatitis• Allergic conjunctivitis • Urticaria • Common cold

Advantages of second generation antihistaminics

• They have no anticholinergic side effects• Do not cross blood brain barrier (BBB), hence

cause minimal or no drowsiness and sedation • Do not impair Psychomotor performance

Serotonin

RVS Chaitanya Koppala

SEROTONIN

• Named after the vasoconstrictor substances which appeared in serum when blood clotted

• Smooth muscle contracting substance present in enterchromaffin cell of GIT

• About 95% of 5-HT receptors concentrated in Intestine remaining in platelets and brain

• Wasp and scorpion sting also contains serotonin• Widely distributed in invertebrates and plants (banana , pear, pineapple,

tomato, stinging)

SYNTHESIS, STORAGE AND DESTRUCTION

• 5-HT is ß-aminoethyl-5-hydroxyindole. • It is synthesized from the amino acid tryptophan and

degraded primarily by MAO and to a small extent by a dehydrogenase

SEROTONERGIC (5-HT) RECEPTORS

• Gaddum and Picarelli (1957) classified 5-HT receptors into musculotropic (D type)

and neurotropic (M type).

• Four families of 5-HT receptors (5-HT1, 5HT2, 5-HT3, 5-HT4-7) comprising of 14

receptor subtypes have so far been recognized.

• All 5-HT receptors (except 5-HT3) are G protein coupled receptors

• which function through decreasing (5-HT1) or increasing (5-HT4, 5-HT6, 5-HT7)

cAMP production or by generating IP3/ DAG (5-HT2) as second messengers.

• The 5-HT3 expresses large number of 5-HT2C receptors

Receptor 5-HT1 5-HT2 5-HT3 5-HT4 5-HT5 5-HT6 5-HT7

Subtypes A/B/D/E/F 2A/B/C 3A/B 5A/B

Signaling pathway

cAMP↓ IP3-DAG Ion channel cAMP↑ cAMP↓ cAMP↑ cAMP↑

Location Brain stem, raphe nucleaus, nerve ending

vascular visceral smooth muscle, platelets and cerebralNeurones.

Somatic autonomic,myenteric plexus, Area postrema nucleus tractus solitarious

mucosa, plexuses and smooth muscle of theGut, brain, hippocampus, colliculi

mucosa, plexuses and smooth muscle of theGut, brain, hippocampus, colliculi

mucosa, plexuses and smooth muscle of theGut, brain, hippocampus, colliculi

mucosa, plexuses and smooth muscle of theGut, brain, hippocampus, colliculi

Agonist Buspirone, sumatriptin

Alpha-methyl 5-HT

Alpha-methyl 5-HT

Cisapride, renzapride

----- Clozapine Clozapine

Antagonist Pindolol Ketenserin Odansetron ---- ----- ----

Receptor 5-HT1 5-HT2 5-HT3 5-HT4 5-HT5 5-HT6 5-HT7

Actions Antimigraine platelets, aggregation, bronchial contriction

Antiemetic, gut wall and brain

Intestinal secretions and peristalsis

Cloned receptors of 5HT4

Cloned receptors of 5HT4

Cloned receptors of 5HT4

Roles Constricts cranial blood vessels and inhibits release of inflammatory neuropeptides inthem; sumatriptan (antimigraine) acts through these receptors

vascular and visceral smooth muscle contraction, platelet aggregation, neuronal activationin brain

depolarizes neurones by gating cation channels; elicits reflex effectsof 5-HT—emesis, gut peristalsis, bradycardia, transient hypotension, apnoea, pain, itch

Mediate intestinal secretion, augmentation of peristalsis

unknown Unknown unknown

Drugs acting

Sumatriptan (antimigraine)

Ketanserin Odansetron Renzapride Unknown Unknown Unknown

Pharmacological action of serotonin

1. CVS Arteries are constricted (by direct action on vascular smooth muscle) as well as dilated (through EDRF release) by 5-HT, depending on the vascular bed and the basal tone BP: a triphasic response is classically seen on i.v. injection of 5-HT in animals.

2.Vascular smooth muscle: potent stimulator of g.i.t., both by direct action as well as through enteric plexuses. Peristalsis is increased and diarrhoea can occur

3. Glands 5-HT inhibits gastric secretion: (both acid and pepsin), but increases mucus, It thus has ulcer protective property. Effect on other glandular secretions is not significant.

Pharmacological action of serotonin

4. Nerve endings and adrenal medulla Afferent nerve endings are activated causing

tingling and pricking sensation, as well as pain.

5. Respiration A brief stimulation of respiration (mostly reflex from bronchial

afferents) and hyperventilation are the usual response

6. Platelets By acting on 5-HT2A receptors 5-HT causes changes in shape of platelets,

but is a weak aggregator.

7. CNS Injected i.v. 5-HT does not produce central effects

Direct injection in the brain Produces sleepiness, changes in body temperature and a

variety of behavioural effects

Pathophysiological roles

• Neurotransmitter (sleep, temperature regulation, thought, cognitive function, behaviour and mood, appetite, vomiting and pain perception)

• Precursor of melatonin(regulate the biological clock and maintain circadian rhythm)

• Neuroendocrine function (anterior pituitary hormones are probably regulated by serotonergic mechanism)

• Nausea and vomiting (evoked by cytotoxic drugs or radiotherapy is mediated by release of 5-HT)

Pathophysiological roles Migraine:5-HT is said to initiate the vasoconstrictor phase of migraineHaemostasis (5-HT accelerates platelet aggregation and clot formationAngina (5-HT released from platelets has been implicated in causing

coronary spasm and variant angina)Hypertension (Increased responsiveness to 5-HT as well as its reduced

uptake and clearance by platelets has been demonstrated in hypertensive Patients)

Intestinal motility (5-HT containing neurones may regulate peristalsis and local reflexes in the gut)

Carcinoid syndrome (Bowel hypermotility and bronchoconstriction in carcinoid is due to 5-HT)

Drugs affecting serotonin system

• Drugs Action/activity5-HT precursor Increase level of serotonin (tryptophan)Synthesis inhibitor P-chloropheniramine –reduce 5-HT levelUptake inhibitor TCA- antidepressant/antianxietyStorage inhibitor Reserpine – anorectic propertyDegradation inhibitor NON-MAO/ SELECTIVE MAO antidepressant

Neural degeneration 5-6-dihydoxy tryptamine5-HT receptor agonist Azapirones, sumatriptin, cisapride5-HT receptor antagonist Cyproheptadine, methysergide, ketanserin

Serotonin antagonist

S.NO Drug Activity Adverse effect1 Methysergide (5-HT2 and 5HT1) Migraine prophylazxis, Abdominal, intestinal,

endocarial fibrosis

2 Ketanserin (5HT2) Antihypertensive, vasoconstriction, bronchoconstriction

Vasospastic

3 Clozapine (5HT blocker) Efficient cases in schizophrenia

4 Risperidone (5-HT2A-D2) Ameloriative negative symptoms

Extrapyramidal symptoms

5 Odansetron (5-HT3) Nausea and vomiting Anticancer and radiotherapy

6 Ergotamine (5-HT1 /2) (agonist) Vascular, visceral constractions, potent emetic

Damage to capillary endothelium

MigraineMigraine is a mysterious disorder characterized by pulsating headache, usually restricted to one side,lasting 4–48 hoursAssociated with nausea, vomiting, sensitivity to light and sound, flashes of light, vertigo, loose motions and other symptoms. Two major types are—• migraine with aura (classical migraine) in which headache is

preceded by visual or other neurological symptoms• migraine without aura (common migraine).

Pathogenesis

• Pulsatile dilatation of certain large cranial vessels is the immediate cause of pain.

• Initial vasoconstriction or shunting of blood through carotid arteriovenous anastomoses

produces cerebral ischaemia and starts the attack.

• Inflammation of the affected blood vessel wall which is amplified by retrograde transmission in

the afferent nerves and release of mediators like 5-HT, neurokinin, substance P, calcitonin gene

related peptide (CGRP), nitric oxide, etc.

Specific antimigraine drugs

• Ergotamine (partial agonism of 5HT1 receptor vasoconstriction)• Dihydroergotamine (DHE)• Selective 5HT1 (agonist)– Sumatriptans (5HT1 only and only)–Rizatriptan

Prophylaxis of migraine• Beta adrenergic blockers (propranolol)• Calcium channel blockers• Tricyclic antidepressants• Anticonvulsants