Autacoids (Local Hormones) - Histamine

Autacoids (Local Hormones) Definition:

Autacoids (Local Hormones)

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Autacoids (Local Hormones)

·       The word “autacoids” come from the Greek "Autos" (self) and "Acos" (remedy), so autacoids basically can be defined as the chemical substances produced within the body to help in the remedy of local injuries”.

·       Autacoids can be defined as “Active Substance in the Body”

·       Autacoids can have many different biological actions including modulation of the activity of smooth muscles, glands, nerves, platelets and other tissues.

·       Local hormones: These hormones are secreted into the interstitial fluid and they act locally in two ways:

1)    Paracrine Hormones: Act on the neighboring cells

2)    Autocrine Hormones: Act on the cells from which they were secreted.

Local hormones: Not released or stored in glands, not circulated in blood, are formed at the site of action & produce localized action.

Autacoids Classification:

Decarboxylated amino acids:

ü  Histamine

ü  Serotonin

Polypeptides:

Ø  Angiotensin

Ø  Plasmakinin

Ø  Vasopressin

Ø  Atrial Natriuretic Peptide (ANP)

Ø  Vasoactive Intestinal Polypeptide (VIP)

Ø  Substance P

Eicosanoids:

·       Prostaglandins

·      Leukotrienes 

Decarboxylated Amino Acids:

Biosynthesis:

Histamine is formed by decarboxylation of the amino acid

L-histidine, a reaction catalyzed by histidine decarboxylase enzyme.

Storage:

- Once formed, histamine is either stored or rapidly inactivated.

- Histamine is found in:

·       Tissues:

o   It is found in most tissues but is present in high conc. Þ

In the lungs, skin and fundus of the stomach (Enterochromaffin Like; ECL cells).

·       Cells:

o   It is found largely in mast cells and basophils.

·       Neurons:

o   Histaminergic neurons in the brain.

·       Release

A) Immunologic Release:

§  Hypersensitivity reaction (Type I) (immediate hypersensitivity):

§  Antigen (allergen) react with antibody (IgE) on the mast cell → this reaction increases release of histamine from mast cells.

B) Chemical and Mechanical Release:

Morphine and Tubocurarine can displace histamine from its bound form within cells. This type of release is not associated with mast cell injury or degranulation. 

Histamine Receptor Subtypes

Histamine exerts its biological actions by combining with specific cellular receptors located on the surface membrane.

Subtype	G-protein	Main Location	Main Function
H1	Gq	-          Smooth muscle -          Endothelium -          Brain	-          Spasmogenic effect on smooth muscle. -          Vasodilatation. -          Skin itching
H2	GS	-          Gastric Mucosa -          Cardiac muscle -          Mast cells -          Brain	-          Increase Gastric HCl secretion. -          Cardiac stimulation.
H3	Gi	-          Presynaptic autoreceptors	-          Decrease neurotransmitter release.
H4	Gi	-          Neutrophils -          Eosinophils	-          Plays a role in chemotaxis.

Pharmacological Action

• Histamine exerts powerful effects on smooth and cardiac muscle, on certain endothelial and nerve cells, on the secretory cells of the stomach, and on inflammatory cells.

• Histamine is powerful stimulant of sensory nerve endings, especially those mediating pain and itching.

- This effect mediated by H₁ receptor and it is an important component of the urticarial response to insects. 

• Direct vasodilatation (H₁) → rapid ↑ NO production:

-          Decrease in systolic and diastolic blood pressure.

-          Flushing, sense of warmth and headache.

-          Increase capillary permeability → Edema formation.

- Increase heart rate: (Due to)

1) Direct stimulatory action on the heart (H2).

2) Reflex tachycardia (VD).

• “Triple Response of Lewis”

- Intradermal histamine injection → cause:

1) Red spot (extending few millimetres around the site of injection):

→ Caused by direct dilatation of small vessels.

2) Flare (extend about lcm):

→ Caused by axon reflex.

3) Edema (Wheal) formulation:

→ Caused by increase capillary permeability.

• Bronchoconstriction (H₁):

- This effect causes death in histamine toxicity.

- Patients with asthma are very sensitive to histamine.

- Small dose of inhaled histamine have been used in diagnosis of bronchial hyperreactivity in patients with suspected asthma or cystic fibrosis.

• Intestinal smooth muscle contraction (H₁):

- Histamine generally has insignificant effects on the smooth muscle of the eye and genitourinary tract.

• Powerful stimulant of gastric acid secretion (H₂)

• 
  

1) Runny nose and watery eyes (due to hyper-secretion from glandular tissue).

2) Sneezing (due to histamine-associated sensory neural stimulation).

3) Nasal congestion (due to vascular congestion associated with vasodilation and increased capillary permeability).

• Histamine neurons in the brain increase wakefulness and prevent sleep, block H₁ receptor in the brain cause sedation.

- Hypothalamus H₁ receptors in the brain are crucial for the regulation of the diurnal rhythm of food intake and the regulation of obesity.

Histamine Antagonists

1)    Physiological Antagonist of Histamine:

Adrenaline having opposite effect to histamine on H1 receptor, cause bronchodilatation (β2) and vasoconstriction (α1).

2)    Mast Cell Stabilizers (Inhibitors of histamine release).

→ Decrease histamine release from mast cell → used as prophylactics in asthma.

A)   Cromolyn (or Cromoglycate), Nedocromil and Ketotifen.

B)   β2-adrenoceptor agonists e.g. Salbutamol.

C)   Methylxanthines e.g. Theophylline. 

3)    Histaminase Enzyme (Diamine Oxidase): → Responsible for histamine metabolism.

4)    Histamine Receptors Blockers:

A: H1-receptor blockers.

B: H2-receptor blockers.

C: H3-receptor blockers.

D: H4-receptor blockers.

A: H1-receptor Antagonists 

Ø  The term antihistamine refers primarily to the classic H1-receptor blockers.

Ø The new classification of H1-receptor blockers, first-, second- and Third-generation.

First Generation (Sedating Antihistamines)

ü  The older first-generation drugs are still widely used because they are effective and inexpensive.

ü  Most of these drugs penetrate the CNS (lipophilic) and cause sedation.

ü  Short duration of action (4 to 6 hours).

ü  Some of these drugs have another action in addition of H1-blockers e.g. Anticholinergic, Antiemetic, Antiserotonin and local anesthetic effects.

 

Chlorpheniramine (Anallerge®)	Brompheniramine (VaZol®)		Hydroxyzine (Atarax®)	Triprolidine (Actifed®)		Dimethindene (Fenistil®)
Clemastine (Tavegyl®)		Pheniramine (Avil®)			Mequitazine (Primalan®)

First Generation (Sedating Antihistamines)

§  Chlorpheniramine [klor-fen-IR-a-meen] (Anallerge^®), Triprolidine [try-PRO-lih-deen] (Actifed®); slight sedation, common component of cold medications.

§  Hydroxyzine [hye-DROX-ee-zeen] (Atarax®); marked sedation.

§  Brompheniramine [BROM-fen-IR-a-meen] (VaZol®), Dimethindene [dye-mese-NE-deen] (Fenistil®), Clemastine [CLEM-as-teen] (Tavegyl®), Pheniramine [fen-AIR-uh-meen] (Avil®) and Mequitazine [mek-yo-TAZ-een] (Primalan®); slight sedation.

Diphenhydramine (Dramenex®)	Cyclizine (Emetrex®)	Doxylamine (Donormyl®)
Dimenhydrinate (Dramamine®)	Meclizine (Navidoxine®)	Promethazine (Phenergan®)

First Generation

Ø  Diphenhydramine [dye-fen-HYE-dra-meen] Dimenhydrinate [dye-men-HYE-dri-nate], Cyclizine [SYE-kli-zeen], Meclizine [MEK-lizeen], Doxylamine [dox-IL-a-meen] and Promethazine [proe-METH-a-zeen] are the most effective agents for prevention of the symptoms of motion sickness and vertigo (prevent nausea and vomiting). The antiemetic action; due to blocking central H1 and M1 muscarinic receptors.

Ø  Diphenhydramine (Dramenex^®), Dimenhydrinate (Dramamine^®) and Promethazine (Phenergan^®); marked sedation.

Ø  Cyclizine (Emetrex^®) and Meclizine (Navidoxine^®); slight sedation.

Ø  Doxylamine (Donormyl^®); strong sedation, used in the treatment of insomnia.

Cyproheptadine (Triactin^®)

Cyproheptadine

Cyproheptadine [SYE-proe-HEP-ta-deen] also acts as a serotonin antagonist on the appetite center and is sometimes used off-label as an appetite stimulant.

Second Generation (Non-sedating Antihistamines)

-          The newer second-generation drugs are expensive.

-          They were made polar mainly by adding carboxyl group; don't pass the BBB, causing less CNS sedation.

-          Long duration of action (12 to 24 hours).

-          More selective for H1 receptors (no anticholinergic, no antiemetic and no antiserotonin activity).

Cetirizine (Zyrtec®)	Loratadine (Claritin®)		Acrivastine (Semprex®)
Ebastine (Kestine®)		Mizolastine (Zolim®)

Second Generation (Non-sedating Antihistamines)

ü Cetirizine [seh-TEER-ih-zeen] (Zyrtec^®) is a partially sedating second-generation agent.

ü  Loratadine [lor-AT-a-deen] (Claritin^®), Acrivastine [ACK-rih-VASS-teen] (Semprex^®), Ebastine [E-BASS-teen] (Kestine^®), Mizolastine [Meezo-LASS-teen] (Zolim^®); show the least sedation.

Ketotifen (Zaditen®)	Alcaftadine (Lastacaft®)	Bepotastine (Talion®)
Emedastine (Emadine®)	Azelastine (Azelast®)	Olopatadine (Patanol®)

[Ophthalmic Antihistamines]

[Ophthalmic Antihistamines]

·       Ketotifen [kee-toe-TYE-fen], Alcaftadine [al-KAF-ta-deen], Bepotastine [bep-oh-TAS-teen], Emedastine [em-e-DAS-teen], Azelastine [a-ZEL-uh-steen] and Olopatadine [oh-loe-PAT-adeen]; ophthalmic formulations and used for the treatment of allergic conjunctivitis.

·        Azelastine (Azelast^®) and Olopatadine (Patanol^®) → have intranasal formulations, Ketotifen (Zaditen^®)

·       → also have oral formulations.

·       Azelastine (Azelast^®) and Ketotifen (Zaditen^®); have mast cell stabilizing effects in addition to their H1-blocking effects.

Third Generation (Non-sedating Antihistamines)

-          Third-generation are the active enantiomer (Levocetirizine) or metabolite derivatives (Desloratadine & Fexofenadine) of second-generation drugs intended to have increased efficacy with fewer adverse drug reactions.

-          They are more expensive than second-generation.

-          Don't pass the BBB, causing no or less CNS sedation than second-generation.

-          Long duration of action (24 hours).

-          Pure selective for H1-receptors.

Levocetirizine (Allear®)

Desloratadine (Aerius®)

Fexofenadine (Telfast®)

Third Generation (Non-sedating Antihistamines)

-          Levocetirizine [lee-voe-seh-TEER-ih-zeen] (Allear®) is the active enantiomer of Cetirizine, and cause partially sedation.

-          Desloratadine (Aerius®) [des-lor-AH-tah-deen], Fexofenadine (Telfast®) [fex-oh-FEN-a-deen], are the least antihistamines sedation.

-          Desloratadine (Aerius®) is an active metabolite of Loratadine.

-          Fexofenadine (Telfast®) is an active metabolite of Terfenadine.

§     Terfenadine (Prodrug) is metabolized to Fexofenadine (Active drug), liver microsomal enzyme inhibitors (e.g. Erythromycin) inhibit this metabolism, lead to ↑ concentration of Terfenadine in the blood → Block K⁺ channels in the heart → cardiac arrhythmia (QT interval prolongation). (No cardiotoxicity with fexofenadine).

Pharmacodynamics

1)    Sedation:

a.     A common effect of first-generation antihistaminic is sedation, but the intensity of this effect varies among chemical structure and lipophilicity. This effect makes them useful as "sleep aid”.

b.     At very high toxic dose, marked stimulation, agitation and even convulsions may produce coma.

c.     Second-generation have little or no sedation or stimulant action.

2)    Antinausea and antiemetic actions:

a.     Several first-generation antihistaminic have significant activity in prevention motion sickness.

b.     The antiemetic effects are not fully understood, but its central block H1 and M1 receptors properties are partially responsible and it may affect the medullary chemoreceptor trigger zone (CTZ).

3)    Antiparkinsonism effects:

a.     Some of first-generation antihistaminic especially Diphenhydramine, have significant acute suppressant effects on the extrapyramidal symptoms associated with certain antipsychotic drugs (it given parenterally).

4)    Anticholinoceptor actions:

a.     Many first-generation antihistaminic have especially Diphenhydramine, Clemastine, Dimenhydrinate and Doxylamine have significant atropine-like effects (dry mouth, urinary retention and blurred vision).

5)    Adrenoceptor-blocking actions:

a.     α1-adrenoreceptor blocking effects can be demonstrated for many first-generation antihistaminic especially Promethazine, this action may cause orthostatic hypotension.

6)    Serotonin-blocking action:

a.     Strong blocking effects at serotonin receptors have been demonstrated for some first-generation antihistaminic especially Cyproheptadine, it is used off-label as an appetite stimulant.

7)    Local anesthesia:

a.     Several first-generation antihistaminic are potent local anesthetics especially Diphenhydramine and Promethazine they block Na+ channels in excitable membranes.

Therapeutic Uses

1)    Allergic Reactions: Antihistaminic agents are the first drugs used to prevent or treat symptoms of allergic reaction.

a.     Allergic rhinitis (hay fever):

                                      i.     Antihistaminic agents are second line drugs after glucocorticoids administrated by nasal spray.

b.     Urticaria:

                                      i.     Antihistaminic agents are first line (given before exposure).

                                    ii.     Second-generation antihistaminic more preferred in chronic urticaria.

c.     Atopic dermatitis:

                                      i.     First-generation antihistaminic such as Diphenhydramine used mostly due to sedative effects (↓ itching awareness).

d.     Bronchial asthma and angioedema:

                                      i.     Antihistaminic agents are largely ineffective alone in bronchial asthma and angioedema, because in asthma and angioedema → increased release of histamine and other mediators, antihistaminic agents block only histamine action.

2)    Motion Sickness and Vestibular Disturbance:

                                      i.     Scopolamine and certain first-generation antihistaminic especially Diphenhydramine and Promethazine are the most effective agents available for prevention of motion sickness.

                                    ii.     Cyclizine and Meclizine also have significant activity in prevention of motion sickness and are less sedation than Diphenhydramine.

3)    Nausea and Vomiting of Pregnancy (NVP):

                                      i.     Meclizine, Cyclizine and Doxylamine are combined with Vitamin-B6 to control nausea and vomiting during pregnancy.

4)    Somnifacient (Hypnotic):

                                      i.     First-generation antihistaminic may be used as sleep aid in insomnia especially Doxylamine and Diphenhydramine (Strong sedative).

Contra indications

First-generation antihistaminic is contraindicated in the treatment of individuals working in jobs in which wakefulness is critical such as drivers and worker in dangerous machines.

Toxicity

Systemic Acute Toxicity with first-generation antihistaminic is relatively common, especially in young children, including hallucinations, excitement, ataxia, and convulsions. So, (Emetrex® Ampoule) is NOT recommended in CHILDREN younger than 6 years to prevent vomiting (serotonin antagonists such as Ondansetron is safer).

Drug Interactions

§     First generation antihistamines interact;

·       With anxiolytic and hypnotic drugs e.g. Benzodiazepines (BDZs) → increase sedative effect (Additive effect).

·       With MAO inhibitors → increase anticholinergic effects.

·       With cholinesterase inhibitors used in Alzheimer's disease (Donepezil, Rivastigmine and galantamine) → decrease cholinergic effects.

§     Second generation Terfenadine interact;

·       With Liver microsomal enzyme inhibitors (e.g. Erythromycin and Ketoconazole) inhibit metabolism of Terfenadine, lead to increase concentration of Terfenadine in the blood → Block K⁺ channels in the heart → cardiac arrhythmia (QT interval prolongation).

B: H2-receptor Antagonists

The H2 receptor antagonists (H2RA) are a class of drugs used to block the action of histamine on parietal cells (specifically the histamine H2 receptors) in the stomach, decreasing the production of acid by these cells.

Cimetidine (Tagamet®)	Ranitidine (Zantac®)
Nizatidine (Ulcfree®)	Famotidine (Antodine®)

H2-receptor Antagonists

§  Cimetidine [sye-ME-ti-deen] (Tagamet®), Ranitidine [ra-NI-ti-deen] (Zantac®), Famotidine [fa-MOE-tideen] (Antodine®), and Nizatidine [nye-ZA-ti-deen] (Ulcfree®) reduces the secretion of gastric acid by blocking H2 receptors.

§  Cimetidine (Tagamet®) is largely replaced by other H2 receptor blocker due to side effects.

Pharmacokinetics:

§  All four agents are rapidly absorbed from the intestine.

§  Cimetidine, Ranitidine and Famotidine → first-pass hepatic metabolism (bioavailability = approximately 50%), Nizatidine has little first-pass hepatic metabolism.

§  Half-life of four agents approximately 1.1 to 4 hours, duration of action depends on the dose given.

§  Dose reduction is required in moderate to severe renal dysfunction and severe hepatic impairment. 

Drug	Relative potency	Usual dose	Parenteral form
Cimetidine	1	400 mg twice or 800 mg at bedtime	50 mg
Ranitidine	4-10	150 mg twice or 300 mg at bedtime	50 mg
Nizatidine	4-10	150 mg twice or 300 mg at bedtime	Not available
Famotidine	20-50	20 mg twice or 40 mg at bedtime	20 mg

Mechanism of action

Ø  Histamine released from enterochromaffin-like (ECL) cells in the fundus of the stomach by gastrin or vagal parasympathetic stimulation (acetylcholine).

Ø  H2 receptor antagonists block the actions of histamine at parietal cell H2 receptors and suppress basal and meal stimulated acid secretion.

Ø  H2 receptor antagonists inhibit 60-70% of total 24 hours acid secretion.

Therapeutic Uses

1)    Peptic Ulcer Disease (PUD):

a.     All four agents are equally effective in promoting the healing of duodenal and gastric ulcers.

b.     Proton pump inhibitors (PPIs; see GIT chapter) have largely replaced H2-antagonists in the treatment of acute peptic ulcer (NSAID-induced ulcers and ulcer caused by H.pylori), because these agents heal and prevent recurrence.

c.     H2-antagonists used in Zollinger-Ellison Syndrome (ZES), ZES is a gastrin-secreting tumor of the pancreas that stimulates the acid secreting cells of the stomach, cause mucosal ulceration.

2)    Gastroesophageal Reflux Disease (GERD):

a.     Is a chronic symptom which stomach acid coming up from the stomach into the esophagus → Heartburn.

b.     H2-antagonists act by stopping acid secretion. Therefore, they may not relieve symptoms for at least 45 minutes.

c.     Antacids more quickly and efficiently neutralize stomach acid, but their action is only temporary.

d.     PPIs are now used preferred in the treatment of GERD.

3)    Non-ulcer Dyspepsia:

a.     Commonly used for dyspepsia not caused by peptic ulcer.

4)    Acute Stress Ulcers:

a.     Given as an IV infusion to prevent and manage acute stress ulcers.

b.     PPIs are favor for this indication.

Side Effects

Ø  H2-antagonists are extremely safe drugs. Side effects occur in less than 3% of patients include diarrhea, headache and fatigue.

Ø  Cimetidine (Tagamet®) inhibits binding of dihydrotestosterone to androgen receptors (Anti-androgenic effect) and ↑ serum prolactin long term use may cause:

o   Impotence in male (Anti-androgenic effect).

o   Gynecomastia in male (Increase prolactin).

o   Galactorrhea and amenorrhea in female (Increase prolactin).

Ø  Rapid IV infusion of H2-antagonists may rarely cause bradycardia and hypotension by blocking cardiac H2-receptors.

Ø  H2-antagonists in pregnancy → FDA category B.

Drug Interactions

-          Cimetidine (Tagamet®) inhibits several cytochrome P450 isoenzymes (is an LME inhibitor) and can interfere with the metabolism of many other drugs, such as Warfarin and Phenytoin.

-          All of H2-antagonists except Famotidine (Antodine®) inhibit gastric first pass metabolism of Ethanol especially in women resulting in increased bioavailability of ethanol → increase blood ethanol level.

-          H2-antagonists compete with Creatinine and certain drugs (e.g. Procainamide) for renal tubular secretion.

C: H3- & H4 receptor Antagonists

Although no selective H3 or H4 ligands are presently available for general clinical uses.

Betahistine (Betaserc®)

Betahistine (Betaserc®)

Betahistine [bay-ta-HISS-teen] is an anti-vertigo drug used in balance disorders or relieve vertigo symptoms associated with Meniere’s disease [men-YEERS].

Mechanism OF Action

·       Betahistine has a very strong affinity as an antagonist for histamine H3 receptors and a weak affinity as an agonist for histamine H1-receptors.

·       Betahistine seems to dilate the blood vessels within the inner ear which can relieve pressure from excess fluid and act on the smooth muscle. 

Meniere’s disease

Ø  Is a disorder of the inner ear that causes spontaneous episodes of vertigo, fluctuating hearing loss, ringing in the ear (tinnitus) and affects only one ear.

 

N.B: Tiprolisant is a selective H3-receptor inverse agonist/antagonist; it is currently in clinical trials for schizophrenia and Parkinson's disease.

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