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Antihistamine

This document discusses antihistamines, which are drugs that reduce or eliminate the effects of histamine. Histamine is released during allergic reactions and binds to histamine receptors, causing inflammation. Antihistamines work by competing with histamine for binding sites on receptors. The document describes different types of antihistamines including first generation drugs that have anticholinergic effects and second generation drugs that are more selective. It also discusses the structures, classifications, and mechanisms of antihistamines.

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AntihistAmines Prepared by: Mr. Dharmendrasinh A Baria Assistant professor Department of Pharmaceutical Chemistry Smt. S. M. Shah Pharmacy college, Amsaran
What is an antihistamine? • A drug that reduces or eliminates the effects mediated by the chemical histamine. • Histamine is released by your body during an allergic reaction and acts on a specific histamine receptor. • True antihistamines are only the agents that produce a therapeutic effect that is mediated by negative modulation of histamine receptors (other agents may have anti-histaminergic action but are not true antihistamines) • The term antihistamine only refers to H1 receptor antagonists (actually inverse agonists) • Antihistamines compete with histamine for binding sites at the receptors. Antihistamine cannot remove the histamine if it is already bound.
What are allergies? • Allergies are caused by a hypersensitivity reaction of the antibody class IgE (which are located on mast cells in the tissues and basophils in the blood) • When an allergen is encountered, it binds to IgE, which excessively activates the mast cells or basophils, leading them to release massive amounts of histamines. • These histamines lead to inflammatory responses ranging from runny nose to anaphylactic shock • If both parents have allergies, you have a 70% of having them, if only one parent does, you have a 48% chance (American Academy of Asthma, Allergies and Immunology, Spring 2003).
Allergies Structure of Histamine Mast Cells •When it is released, histamine causes inflammation by increasing vasodilation, capillary permeability, causing smooth muscle contraction, mucus secretion, and parasympathetic nerve stimulation •Histamine is distributed in Mast Cells in all peripheral tissues of the body and basophils, which circulate in the blood
Synthesis of Histamine ■ Formed from the amino acid Histadine in a decarboxylation reaction with the enzyme histadine decarboxylase ■ Occurs primarily in mast cells and basophils
Histamine Receptors
Clinical Uses of Antihistamines ■ Allergic rhinitis (common cold) ■ Allergic conjunctivitis (pink eye) ■ Allergic dermatological conditions ■ Urticaria (hives) ■ Angioedema (swelling of the skin) ■ Puritus (atopic dermatitis, insect bites) ■ Anaphylactic reactions (severe allergies) ■ Nausea and vomiting (first generation H1- antihistamines) ■ Sedation (first generation H1-antihistamines)
Adverse effects ■ Associated with the first generation H1-antihistamines and due to their lack of selectivity for the H1 receptor and anti-cholinergic activity. Side effects are due to CNS depression: ■ Sedation ■ Dizziness ■ Tinnitus (ringing in the ear) ■ Blurred vision ■ Euphoria ■ Uncoordination ■ Anxiety ■ Insomnia ■ Tremor ■ Nausea/vomitting ■ Dry mouth/dry cough ■ Newer second generation H1-antihistamines are more selective for the peripheral histamine receptors and have far less side effects (drowsiness, fatigue, headache, nausea and dry mouth)
Structural Considerations Mole Percentage of Species at pH 7.4 3.3 96.2 0.4 ~0 N NH NH2 HN N NH2 HN N NH3 N NH NH3 pKa3 = 14 pKa1 = 9.75 pKa2 = 5.94 Dication Monocation Unionized Anion NπNτ +HN NH3 NH –N NH2 N • About 80% of histamine monocation exists in aqueous solution that binds receptors • The t tautomer (H on the t nitrogen) permits binding with the receptors However, tautomerism does not appear to be important in H1 binding but does appear to be important in the H2 interaction • Electron donating groups on C5 increase the t tautomer while electron withdrawers increase the p tautomer fraction
Sawhorse and Newman Projections trans gauche A B NH3 H H N H N HH NH3 H H NH N H H N H N HH H H NH3 NH N H H H H NH3  The trans conformer has less steric hindrance but the gauche conformer is stabilized by an ion–dipole interaction  Both conforms exist is solution  It is believed that both the H1 and H2 receptors bind the trans conformer  This is based on the observation that a– and b–methyl histamine are unable to assume the trans conformation and are weak agonists at both the H1 and H2 receptors. However, they are strong H3 agonists, thus the H3 receptor must bind Histamine in the gauche conformation.
H1-Antagonists- Classification 1st Generation Antihistamines (Classical antihistamines) •Competitive inhibitors of histamine action at tissue level. •Binding is reversible and displaced by higher levels of histamine. •Additional anticholinergic activity, some possess anti- serotoninergic activity and many of them also inhibit neuronal uptake of norepinephrine. •Also have local anesthetic effect, but carry risk of irritation and sensitization.
1st Generation Antihistamines (Classical antihistamines) 1.Ethylene diamines 2.Ethanolamines (Aminoalkylethers) 3.Alkylamines (Propylamines) 4.Piperazines (Cyclizines) 5.Tricyclics (Piperidines) 6.Phenothiazine
Common Structural Features of classical first generation antihistamines ■ 2 aromatic rings, connected to a central carbon, nitrogen, or oxygen ■ Spacer between central atom and the amine, usually 2-3 carbons in length. (Can be linear, ring, branched, saturated or unsaturated) ■ The amine is substituted with small alkyl groups ■ Chirality at X and having the rings in different planes increases potency of the drug
1. Ethylene diamines Tripelenamine Pyrilamine Antazoline IUPAC: N,N-dimethyl-N-(phenylmethyl)- N-pyridin-2-ylethane-1,2-diamine IUPAC: N-(4-methoxybenzyl)- N',N'dimethyl- N-pyridin-2-ylethane-1,2- diamine IUPAC:N-(4,5-Dihydro-1H-imidazol-2- ylmethyl) -N-(phenylmethyl)aniline
2. Ethanolamines (Aminoalkylethers) Diphenhydramine Doxylamine Clemastine Orphenadrine IUPAC: 2-(diphenylmethoxy)- N,N-dimethylethanamine IUPAC: (RS)-N,N-dimethyl-2-(1-phenyl-1- pyridin-2-yl-ethoxy)-ethanamine IUPAC: N,N-dimethyl-2-[(2-methylphenyl) - phenyl-methoxy]-ethanamine IUPAC: (2R)-2-{2-[(1R)-1-(4-chlorophenyl) -1-phenylethoxy]ethyl}-1-methylpyrrolidine
3. Alkylamines (Propylamines) Pheniramine Chlorpheniramine Phenindamine Triprolidine IUPAC: N,N-dimethyl-3-phenyl-3- pyridin-2-yl-propan-1-amine IUPAC: 3-(4-chlorophenyl)-N,N-dimethyl- 3-pyridin-2-yl-propan-1-amine IUPAC: 2-methyl-9-phenyl-2,3,4,9- tetrahydro-1H-indeno[2,1-c]pyridine IUPAC: 2-[(E)-1-(4-methylphenyl)-3- pyrrolidin-1-yl-prop-1-enyl]pyridine
4. Piperazines (Cyclizines) Cyclizine Chlorcyclizine Meclizine IUPAC: 1-benzhydryl-4-methyl-piperazine IUPAC:1-[(4-Chlorophenyl)(phenyl) methyl]-4-methylpiperazine IUPAC: (RS)-1-[(4-chlorophenyl)(phenyl)methyl]- 4-(3-methylbenzyl)piperazine
Buclizine Hydroxyzine IUPAC: (RS)-1-[(4-chlorophenyl)- phenyl-methyl] -4- [(4-tert-butylphenyl) methyl] piperazine IUPAC: (±)-2-(2-{4-[(4-chlorophenyl)-phenylmethyl] piperazin-1-yl}ethoxy)ethanol
5. Tricyclics (Piperidines) Cyproheptadine Azatadine IUPAC: 4-(5H-dibenzo [a, d]cyclohepten-5- ylidene) -1-methylpiperidine hydrochloride IUPAC: 11-(1-methylpiperidin-4-ylidene)- 6,11-dihydro- 5H-benzo[5,6]cyclohepta [1,2-b]pyridine
Ketotifen IUPAC: 4-(1-Methylpiperidin-4-ylidene)-4,9-dihydro -10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one
6. Phenothiazine Trimeprazine IUPAC: N,N,2-trimethyl-3-phenothiazin-10- yl-propan-1-amine
2nd Generation Antihistamines  Antagonists at H1 receptors  Competitive antagonists though some are noncompetitive at higher doses  High therapeutic index  Poorly lipophilic - do not readily traverse blood brain barrier  Highly selective with little or no anticholinergic activity  Additional anti-allergic mechanisms of some, like inhibition of late phase allergic reaction by acting on leukotrienes or anti platelet factor activating effect
Ethylenediamines Acrivastine Cetrizine Piperazines IUPAC: (E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidin- 1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoic acid IUPAC: (±)-[2-[4-[(4-chlorophenyl)phenylmethyl]-1- piperazinyl]ethoxy]acetic acid
Piperidines Terfenadine Astemizole IUPAC: (RS)-1-(4-tert-butylphenyl)-4-{4-[hydroxyl (diphenyl)methyl]piperidin-1-yl}-butan-1-ol IUPAC: 1-[(4-fluorophenyl)methyl]-N-[1-[2-(4-methoxyphenyl) ethyl]-4-piperidyl]benzoimidazol-2-amine
Loratadine IUPAC: Ethyl4-(8-chloro-5,6-dihydro-11H- benzo [5,6]Cyclohepta[1,2-b]pyridin-11-ylidene) -1- piperidinecarboxylate
3rd Generation Antihistamines Levocetrizine Desloatadine Fexofenadine IUPAC: (±)-4-[1 hydroxy-4-[4-(hydroxyl diphenylmethyl)-1- piperidinyl]-butyl]-a, a-dimethyl benzene acetic acid hydrochloride IUPAC: 2-(2-{4-[(R)-(4-chlorophenyl)(phenyl) methyl]piperazin-1-yl}ethoxy)acetic acid IUPAC: 8-chloro-6,11-dihydro-11- (4-piperdinylidene)- 5H-benzo[5,6] Cyclohepta [1,2-b]pyridine
C C N R1 R2 X Ar1 Ar2  A protonable amine  A connecting atom X which can be O, C or N  A carbon chain, usually ethyl  Variations in the diaryl groups, connecting moiety, substituents on the connecting moiety, and substituents on the terminal nitrogen account for the differences observed in potency as well as pharmacologic, metabolic, and adverse reaction profiles. SAR
 Ar1 and Ar2 substituents  These provide bulk producing antagonistic activity  Generally two aromatic rings - phenyl, benzyl, or an isostere such as pyridyl; Pyridyl generally results in more potent compounds than phenyl  If fused must be non–coplanar as in the three ringed structures related to TCA’s and phenothiazines  Para substitution with small lipophilic groups increases potency and decreases metabolism due to decreased ring hydroxylation.  Ortho or meta substitution reduces antihistaminic activity
 This diaryl pattern is present in both first- and second-generation antihistamines. X  Atom X can be an oxygen, nitrogen, or carbon, which links the side chain to an “aromatic tail.” The nature of atom X is the basis for the structural classification of H1 antagonists. The classical H1 antagonists are divided into six classes based on what X equals:  X =C–O: (Aminoalkyl Ethers) 1. Ethanolamines 2. Propanolamines (clemastine, diphenylpyraline)  X = C: 3. Propylamines (Saturated and Unsaturated)
 X = N: 4. Ethylenediamines 5. Piperazines (Cyclizines) and Tricyclics 6. Miscellaneous: This forms the sixth class of traditional antihistamines and would include many of the newer antihistamines since they do not fall into one of the older, traditional, classes Connecting Chain  Its function is to separate the nitrogen from the rings by 5–6 Å  May be saturated, unsaturated, branched or part of a ring  Branching decreases antihistaminic potency except for the phenothiazines where β carbon branching increases antihistaminic potency.
Basic aliphatic amine  Must be able to accept a proton (basic) at physiological pH  R1 and R2 : Potency order is 3° > 2° > 1°  Quaternization does not increase antihistaminic but does increase anti-cholinergic activity  May be incorporated into a heterocycle which is although larger, the heterocycle constrains  Dimethyl is the optimum configuration  Larger substituents decrease antihistaminic potency due to steric hindrance unless they are part of a heterocycle structure when the ring constrains the two ethyls so they are still active
 The H1 antagonists do not occupy the same area or space as the natural receptor substrate  Only the protonated nitrogen binds the same anionic site as Histamine  The aromatic tail binds adjacent to the Histamine binding site thus produces the nonspecific conformational perturbation of the receptor. This changes the shape of the receptor decreasing the affinity for Histamine  It seems that sites outside may be chiral because steroselectivity is observed with some H1 antagonists  As previously discussed the optical isomers of α-Methyl histamine are equipotent as agonists Receptor Interaction
Histamine H2-Antagonists Guanylhistamine N C NH NH2CH2CH2 NHN H N C S NH2CH2CH2CH2 NHN H N C S NH2CH2CH2CH2CH2 NHN H N C S NHCH3CH2CH2CH2CH2 NHN H N C S NHCH3CH2–S–CH2CH2 NHN H H3C Metiamide N C NH NHCH3CH2–S–CH2CH2 NHN H H3C N C N NHCH3CH2–S–CH2CH2 NHN H H3C CN SK&F 91581 SK&F 91863 Burimamide Cimetidine ™ I a b c d e f g  Guanylhistamine provided the lead.  Extension of the side chain increased anti H2 potency but some agonist activity remained. Replacing the basic guanidino group with the neutral thiourea yielded effective H2 antagonists.  Burimamide lacked agonist action but was not orally absorbed  In Metiamide (1) reduce the pKa of the ring N, reduced ionization, increased membrane permeability and absorption and 10X more potent than Burimamide, (2) cause the t tautomer to predominate which interact with H2  But caused kidney damage and granulocytopenia, possibly due to the thiourea so was replaced by the isosteric guanidine. This compound being highly basic was 20 times less potent  Replacement of this group with strong electron withdrawer but more lipophilic cyano derivative yielded Cimetidine.
 Need an aromatic ring with n electrons next to the side chain. The imidazole ring is not required (the other H2 antagonist don’t have it) but if it is present the t tautomer should predominate. The t tautomer is promoted by electron donors at position 5 and electron withdrawers at position 4.  The terminal nitrogen group should be polar but not basic for maximal potency  Separation of the ring from the nitrogen group by 4 atoms gives maximal potency.  Cimetidine is an extremely successful drug in the treatment of ulcers.  Note the electron donor methyl at C5 and electron withdrawing side chain at C4 Also the non basic cyano guanidine terminal nitrogen group.  However, cimetidine has several disadvantages. It is an inhibitor of CYP, which leads to many drug–drug interactions. It exhibits anti-androgenic action and can cause gynecomastia. Further it has 60 to 70% oral bioavailability. SAR C H3C NH N S H N H N CH3 N N Cimetidine
CH3 CH3 N NO2 O S H N H N CH3 HC Ranitidine NS N NH2 NH2 N H N H S SO2NH2 Famotidine CH3 CH3 N NO2 S N S H N H N CH3 HC Nizatidine Nizatidine is also a thiazole derivative similar to Ranitidine (5–18 X Cimetidine), but more bioavailable, 90%, with no antiandrogenic or enzyme inhibition. Ranitidine is a furan derivative, an isostere of the imidazole with n electrons on the oxygen, with 50% bioavailability. It is 4 - 10 X potent than Cimetidine with a longer DoA. Further, it is a weaker CYP inhibitor. The tertiary amine side chain allows the formation of salts. Famotidine, a thiazole derivative, is 9–15 X potent than Ranitidine or 40–60 X than Cimetidine. No cases of gynecomastia have been reported. It is a weak inhibitor of CYP. Like Ranitidine salts can easily be prepared for this compound. but its absorption is incomplete with only 40 to 50% bioavailability.
 Cationic Histamine binds to the receptor via the formation of three hydrogen bonds  The cationic nitrogen and t–nitrogen of the imidazole ring are hydrogen donors and the p–nitrogen acts as a proton acceptor  Participation of the ammonium group in the hydrogen bonding inevitably leads to a decrease of the positive charge on the ammonium group  This decrease in positive charge induces a tautomeric change in the imidazole ring resulting in a stronger binding of the p–nitrogen and proton release by the t– nitrogen  The net result is a proton shift at the receptor surface which is believed to trigger the H2 stimulating effect  This mechanism calls for the presence of a hydrogen atom in position 3 of histamine, and recall that 3–methylhistamine is unable to stimulate the receptor. Histamine H2 Receptor Interaction
H3-Receptor Antagonists HN N Thioperamide N NH S HN N N N O Cl GR-175737 HN N N O GT-2016  Potential for treating asthma, migraine, hypertension, septic shock, and in learning and memory degenerative disorders like AD  Thioperamide and its congeners (4(5)-substituted imidazole derivatives) are examples of the potent and selective H3 receptor antagonist  Some of the more prominent new H3 receptor antagonists are GT-2016, and GR- 175737, which show receptor affinities in the low nanomolar range.  None of this class of compounds is in clinical use; however, few are undergoing further pharmacologic evaluation as potential therapeutic agents.