Histamine & H1-Antagonists

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H1 Receptor Antagonists (Antihistimines / Antihistaminics)

Autacoids (Local Hormones) : 

Autacoids (Local Hormones) Derived from Greek ‘autos’ = self and ‘akos’ = remedy. Autacoids include: Histamine, Serotonin, Prostaglandins, Leukotrienes and Thromboxanes, Angiotensin, Kinins , Substance P , Vasoactive intestinal peptide (VIP). Many Autacoids & their receptor antagonists have been synthesized & used extensively in therapeutics

Histamine : 

Histamine Synthesized in 1907 , later isolated from human tissues. In humans Histamine is an important mediator of Type-I allergic & inflammatory reactions It has important role in gastric acid secretion. Histamine also occurs in plants ,animals , it is a component of some venoms & insect sting secretion. It occurs in all tissues but unevenly– high amounts in LUNG , SKIN & GIT. It is found in high concentrations in mast cells or basophils

Synthesis and storage and release of histamine : 

Synthesis and storage and release of histamine Mechanism of Synthesis: histamine is synthesized by decarboxylation of the amino acid histidine by the action of the enzyme histidine decarboxylase. Once formed, histamine is stored at the site of synthesis.

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Site of synthesis and storage: Histamine is synthesized and stored in the following sites: 1- Neurons in the brain 2- Enterochromaffin cells in the gastric mucosa 3- Mast cells & Basophils with Heparin in granules as inactive complex , if not stored it is rapidly inactivated by amine oxidase enzyme.

Sources of histamine release in the body : 

Sources of histamine release in the body 1- Mast cells Mast cells are of two types: 1- connective tissue mast cells (especially around blood vessels and in the skin) 2- mucosal mast cells (lungs, digestive tract, mouth, conjunctiva and nose) Release of histamine from mast cells 1- Immune mediated 2- Non immune mediated (chemical and mechanical release) They synthesize and store histamine in granules

Release of histamine from mast cells (1) : 

Release of histamine from mast cells (1) Immune mediated release = hypersensitivity reactions 2 stages: 1- First exposure to an antigen (inhalation,ingestion) results in the formation of antibodies (type IgE) specific for that antigen. These antibodies are fixed on mast cells 2- Subsequent exposure to the same antigen (may occur after a variable period, days,months) Results in binding of the antigen to its specific IgE on mast cells and cross linking of IGE receptors. This results in release of histamine

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Non-immune mediated release = Chemical and mechanical release Certain drugs such as morphine and tubocurarine, can displace histamine from mast cells. This type of release does not require prior exposure.

2- Non mast cell sources of histamine in the body : 

2- Non mast cell sources of histamine in the body 1- Brain: (functions as neurotransmitter) 2- Enterochromaffin cells (EC) in the stomach (function: stimulates HCL secretion by parietal cells of the stomach)

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Termination of Histamine Action Cellular uptake Metabolism by histamine N-methyltransferase and histaminase enzymes in the liver. Very little amount is excreted

Symptoms associated with histamine release from mast cells : 

Symptoms associated with histamine release from mast cells Mild cutaneous release Moderate release Severe release (anaphylactic) erythema, urticaria, and/or itching skin reactions, tachycardia, moderate hypotension, mild respiratory distress severe hypotension, ventricular fibrillations, cardiac arrest, bronchospasm, respiratory arrest

Urticaria (due to the release of histamine) : 

Urticaria (due to the release of histamine)

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MOA : Histamine binds to specific cellular receptors located on the surface of cell membrane. Receptors are of four subtypes H1, H2, H3, H4. All types of receptors are coupled to G protein-mediated second messenger system. H1& H2 receptors are widely expressed & are targets for clinically useful drugs. H3& H4receptors are expressed in only a few cell types & their role in drug action is not clear.

Effect of histamine release (pathophysiologic release) : 

Effect of histamine release (pathophysiologic release)

Effect of histamine release (physiologic release) : 

Effect of histamine release (physiologic release)

Histamine Antagonists : 

Histamine Antagonists Physiologic antagonists: Epinephrine has smooth muscle actions opposite to histamine but by actiong on different types of receptors. It is used in conditions of massive release of histamine Histamine release inhibitors: Reduce immunologic release of histamine from mast cells Mast cell stabilizers: Cromolyn and nedocromil Beta 2 adrenergic agonists --- used in Bronchial Asthma Histamine receptor antagonists Compounds that competitively block histamine, mainly H1& H2 receptors.

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H1-Receptor Antagonists / H1Anti-histamines Generally called Anti-histamines. These drugs block H1receptors They are widely used as most of the actions are mediated by H1receptors . The older drugs– First generation cross BBB & produce sedation. The newer drugs– Second generation they do not cross / poorly cross BBB & are non-sedating sedation.

Histamine H1- Antagonists : 

Histamine H1- Antagonists Generally called Anti-histamines These drugs block H1receptors They are widely used as most of the actions are mediated by H1receptors .

Histamine H1- Antagonists : 

Histamine H1- Antagonists First Generation: The older drugs Sedating (lipophilic compounds that readily cross the blood-brain barrier) Second Generation: The newer drugs Non-sedating (poorly penetrate the blood-brain barrier)

Classification of H1-Receptor Antagonists : 

Classification of H1-Receptor Antagonists FIRST GENERATION (Sedating , Shorter DOA 4-6 hrs.) Alkylamines Chlorpheniramine Brompheniramine Ethylaminediamine: Tripelennamine Ethanolamines: Diphenhydramine Dimenhydrinate Carbinoxamine Piperazines Cyclizine Meclizine Hydroxyzine

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Phenothiazines derivatives Promethazine HCl Misc: Cyproheptadine SECOND GENERATIONNON-SEDATING, LONCER DOA (12 -24hrs) Piperidines: Fexofenadine Miscellaneous Cetirizine Loratadine Desoratadine

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Chemistry : All of the H1 antagonists are stable amines. There are several chemical sub groups. Pharmacokinetics: Well abs after oral admin. High bioavailability. PPL: 1-2hrs. OOA: 1-3 hrs Well distributed to all tissues First generation lipid soluble, penetrate BBB well, Second generation do not cross BBB readily. Plasma half life: First generation-Avg:4-6hrs , Meclizine—12-24 hrs Second generation-Avg:12-24 hrs– once daily dose. Elimination: All First generation & some Second generation—Loratadine & Desloratadine metabolized by hepatic CYP P450 enzymes--- Drug interactions with other drugs due to enzyme inhibition Cetirizine- - not metabolized excreted unchanged in urine. Fexofenadine ---not metabolized excreted unchanged in feces. DOA: Generally 24hrs. Tolerance does not develop to the effects

Pharmacokinetics: : 

Pharmacokinetics: 1- First Generation Agents: Rapidly absorbed from the GIT Widely distributed Cross blood-brain barrier Extensively metabolized by the cytochrome P450 and metabolites are active and are excreted by the kidney Duration of action 4-6 hours.

Pharmacokinetics: : 

Pharmacokinetics: 2- Second Generation Rapidly absorbed from the GIT Widely distributed Do not cross the blood-brain barrier (less lipid soluble) Elimination: Cetirizine (urine) and fexofenadine (bile)

MOA : 

MOA The drugs are competitive antagonists at H1receptors. So they block all the actions mediated through H1receptors . Also block other receptors ,which produce adverse effects A: Effects due to H1 blockade : Decreased Allergic inflammation , Itching Decreased neurotransmission in brain Increased sedation. Decreased Cognitive & psychomotor performance Increased Appetite.

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B: Effects due to Blockade of other receptors Anticholinergic Effects due to blockade of Muscarinic receptors A/E – dry mouth , urinary retention , sinus tachycardia. (most marked with Diphenhydramine & promethazine) Alpha-1 adrenergic receptors blocking Effects---- A/E Hypotension , Increased dizziness ,Reflex tachycardia. (most marked with promethazine) Serotonin receptors blocking Effect (cyproheptadine)--- Increased appetite. Also useful in controlling smooth muscle menifestation of Carcinoid syndrome & cold induced urticaria. Local anesthesia . Diphenhydramine can block Na+ channels . Other actions. Inhibition of nausea & vomiting by effect on CTZ & Vestibular pathways

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Therapeutic Uses Allergic reactions: First dugs to prevent or treat the symptoms of: Allergic Rhinitis- Urticaria ---Acute & chronic Seasonal Rhinitis & Conjunctivitis (Hay fever) Serum Sickness– (Urticarial & edematous lesions) Mild Allergic drug reactions For Anaphylaxis DOC is Epinephrine because other mediators are also involved & patient is serious.H1 antagonists may be added as adjucnts or second line drugs Atopic dermatitis —mainly due to sedative effect Diphenhydramine is used The choice of agent depends upon how critical is requirement of wakefulness – Driving , operating machinery .Office work, studies etc. Second generation drugs are less/ non-sedating ,but expensive First generation drugs are markedly sedating ,but cheap

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Motion Sickness & Nausea: Inhibition of nausea & vomiting by effect on CTZ & Vestibular pathways--- due to blockade of central H1 & Muscarinic pathways---(Dimenhydrinate ,Cyclizine, Meclizine & Hydroxyzine) Vestibular disturbance: Meniere’s syndrome and Vertigo (Cyclizine, Meclizine) Inhibition of vertigo by effect on CTZ & Vestibular pathways- Nausea & Vomiting of pregnancy / Morning sickness ( should be avoided due to teratogenic effects in rodents.) Parkinsonism (Diphenhydramine ) due to blockade of central Muscarinic receptors in Nigrostriatal pathways. Somnfacients: Not DOC ,but first generation drugs are sometimes used due to sedative properties. Important: Ineffective in bronchial Asthma as other mediators are also involved. Release inhibitors like Cromolyn are useful.

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Adverse Effects of H1 Antagonists ON CNS Sedation: Blockade of neurotransmitter effect of Histamine in the CNS --- Sedation Marked with Ist generation Anti-histamines as they readily cross BBB. Second generation do not cross BBB readily – so no sedation or mild with Cetirizine Other CNS effects :Tinnitis , fatigue , dizziness , lassitude , In-coordination & tremors In children Excitement & convulsions sometimes. Orthostatic Hypotension , Increased dizziness ,Reflex tachycardia. due to Alpha-1 adrenergic receptors blocking Effect. (most marked with promethazine)

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Anti-muscarinic effects Dryness of mouth, throat, respiratory passages Constipation Urinary retention Blurred Vision Sinus tachycardia Drug Allergy: with topical use Cardiac Arrhythmias: Fatal ventricular arrhythmia occurred with Astemizole & Terfenadine.-- so withdrawan. The same A/E may be seen with newer drugs if used with enzyme inhibitors.

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Drug Interactions: 1. With CNS depressants ----- ↑CNS depressants like alcohol 2. With anti-muscarinic drugs--- ↑ anti- muscarinic A/E 3.With α-blocking drugs--- marked postural hypotension. 4. With Macrolides, ketoconazole, itraconazole, grape fruit juice --- due to enzyme inhibition of CYP3A4 → ↑Concentration of H1 antagonists---- marked A/E

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Overdosage. The effects of overdosage of older agents resemble Atropine poisoning & treated in the same way. Newer drugs may produce cardiac arrhythmia if used with enzyme inhibitors. C/I: Consider D/I For first generation consider how critical is requirement of wakefulness – Driving , operating machinery .Office work, studies etc