Anti-Histaminic Drugs PDF

Anti-Histaminic Drugs Dr/ Radwan El-Haggar [email protected] ❖ Histamine is a bioamine mediator synthesized in the mast cell, basophiles and particular neuronal tract in the CNS. ❖ Histamine is synthesized from L-histadine amino-acid by decarboxylation....

Anti-Histaminic Drugs Dr/ Radwan El-Haggar [email protected] ❖ Histamine is a bioamine mediator synthesized in the mast cell, basophiles and particular neuronal tract in the CNS. ❖ Histamine is synthesized from L-histadine amino-acid by decarboxylation. COOH N NH2 Decarboxylation N NH2 N N H H L-Histadine Histamine ❖ Histamine is metabolized by histamine-N-methyltransferase or diamine oxidase or MAO-B. ❖ Histamine is released in response to immunogenic stimuli (an antigen which could be drug, injury, bacterial, viral or fungal products) or in response to non- immunogenic stimuli. ❖ Histamine is responsible for the symptoms associated with the immune response to the antigen (Hypersensitivity) itching, redness, Oedema, … etc.  ❖ There are 4 histamine receptor subtypes. H-1 Skin, brain, respiratory tract, CVS and adrenal medulla. H-2 Parietal cells of gastric mucosa and myocardial cells. H-3 CNS (histamine release and synthesis), gastric mucosa and CVS. H-4 Intestinal tissue, spleen, thymus, T cells, neutrophil and eosinophils. ❖ Tautomers of histamine for fitting at H-1 and H-2 receptors H-1 tautomer H-2 tautomer NH3 HN HN NH3 N: N: 4.5 Aͦ 3.6 Aͦ  I) H-1 receptor antagonists (Anti-allergic agents) A) 1st Generation (Classical anti-histaminics) General structure Ar and Ar` Phenyl, substituted phenyl, heteroaryl or arylmethyl Could be fused into tricyclic structure. Ar R R and R` Mainly methyl X N X O, N or CH Ar` (CH2)n R` n 2 or 3 (usually 2) ❖ This class of anti-histaminic drugs is non-specific (block other histamine receptors and therefore exert other pharmacological effects (sedative effect, anti-emetic, anti-parkinsonism). ❖ The nature of the diaryl groups, the connecting atom and the amine moiety have been used to sub-classify the anti-histaminic. 1) Amino-alkyl ether derivatives (Ethanolamines). Ar R N Ar` O R` R`` * Diphenhydramine and its analogues. 2 1 CH3 It is the prototype of this group. O-CH2-CH2 N CH3 X=H Diphenhyramine X = Cl Chloro-diphenhyramine X X = Br Bromo-diphenhyramine X = OCH3 Medrylamine 2-(Diphenyl-methoxy)-N,N-dimethyl-ethyl amine. ❖ This group of anti-histaminic drugs has severe sedative side effect as they could pass BBB so to decrease this side effect, salts were designed.  * Synthesis of diphenhydramine * Dimenhydrinate (Dramamine®). Anti-histaminic affect with decreased sedation effect. CH3 - H CH3 O N N Used as 8-chloro-theophylline salt. O-CH2-CH2 N + Cl N CH3 H3C Mainly used as anti-emetic in motion sickness and O treatment of nausea. (Dimenhyrinate = Diphenhydramine + 8-Chloro-thiophylline)  * Doxylamine. Used by itself as a short-term sedative (OTC in US), and in combination with N,N-dimethyl-2- (1-phenyl-1-pyridin- other drugs as a night-time cold and 2-yl-ethoxy)- ethanamine allergy relief drug. * Embramine. It has antihistaminic and antichloinergic effects. 2-[1-(4-bromophenyl)-1-phenylethoxy]- N,N-dimethylethanamine  * Clemastine (Tavagel®). Anti-histaminic affect with decreased sedation effect. HOOC H H3C O-CH2-CH2 Used as fumarate salt. N CH3 H COOH It has long duration of action and mainly Cl used for treatment of asthma. Additional carbon atom between the oxygen and the basic nitrogen, which is incorporated into a ring, resulted in less sedative properties. Synthesis NaCO3 H3C OH + Cl H3C O-CH2-CH2 N N - HCl CH3 CH3 Cl Cl Clemastine  2) Ethylene diamine derivatives. R * Moderate anti-histaminic effect with Ar` N N R` high frequency of CNS depression. Ar 1. They characterized by the presence of a nitrogen atom (X), and two carbons chain link between the diarylamino and the tertiary amino moieties. 2. All sharing N-benzyl-N-phenylaminolethylamino moiety (phenyl rings could be replaced by other heterocycles). 3. The terminal amino group could be part of cycle. 4. All are lipophilic enough to penetrate BBB producing sedation. 5. Fewer anticholinergic effects than aminoalkylether class.  * Phenbenzamine (Antergan®). It is the prototype of this group. N-(2-Dimethylaminoethyl)-N-benzylaniline. * Synthesis  * Tripelennamine (byribenzamine®). CH3 N N CH3 N',N'-Dimethyl-N-(phenylmethyl)- 1 2 N-(2-pyridinyl) ethylene diamine. N * Synthesis of Tripelennamine CH3 N 1) - HCl N CH3.. CH2-Cl + H2N CH3 N N 2) / - HCl N Cl CH3 Tripelennamine * Mepyramine / Pyrilamine. CH3 * Methaphenline. N CH3 N N CH3 N N CH3 H3C-O N N,N-Dimethyl-N'-pyridin-2-yl-N'-(2- S thienylmethyl) ethylene diamine. N',N'-Dimethyl-N-(4-methoxybenzyl)-N- (2-pyridinyl) ethylene diamine. * Antazoline. H 2 N N-(4,5-dihydro-1H-2-imidazolyl methyl)-N- N 3 4 (phenylmethyl) aniline. N 5 1 In addition to anti-histaminic effect, it has local anaethetic effect and is used in eye preparations. * Clemizole. Cl 1-[(4-Chlorophenyl)methyl]-2-(pyrrolidin-1-yl- methyl)benzimidazole N N N  3) Propylamine derivatives. * Pheniramine and its analogues. X X=H Pheniramine CH3 X = Cl Chlorpheniramine 3 1 N 2 CH3 * X = Br Bromo-pheniramine 2 1N Pheniramine: N,N-dimethyl-3-phenyl-3-(2-pyridinyl)propanylamine This class is 5 times more active than ethylene diamine class. Chlorpheniramine is mainly used as maleate salt. Insertion of Cl or Br atom into the p-position of the phenyl ring increases potency. The S-isomer is more active than R-isomer. Used in cough mixtures. Synthesis of chlorpheniramine maleate.  4) Piperazine derivatives. X * Cyclizine and Chlorocyclizine. X=H Cyclizine N N CH3 X = Cl Chlorocyclizine * Chlorocyclizine is more active due to increased bioavailability. * Used as anti-emetic for motion sickness. * Synthesis * Meclozine (Meclozine®). (Meclizine) Cl CH3 N N * Buclizine CH3 Cl CH3 N CH3 N Both are used as anti-emetic for motion sickness.  5) Phenothiazine derivatives. S 9 4 N * Fenethazine. 6 5 S 3 R 7 Phenothiazine N 2 8 10 1 N H3C CH3 10-(2-Dimethylamino-ethyl) phenothiazine. * Promethazine. S 10-[(2-Dimethylamino-2-methyl) ethyl] phenothiazine. N 1 CH3 2 N H3C CH3 * It is an anti-histaminic with sedative side effect. * Could be used as anti-emetic and anti-spasmodic.  Synthesis S * SAR of phenothiazine derivatives. N * For the antihistaminic activity CH3 - Benzene ring must not be substituted (promethazine). N H3C CH3 - Intermediate chain is branched (isopropyl) (promethazine). S S * The CNS sedative effect is increase by N N Cl - Intermediate chain is not branched (n-propyl) (Promazine). CH3 CH3 N N - Chloro-substitution at the benzene ring (Chlorpromazine CPZ). CH3 CH3 Promazine Chlorpromazine Anti-psychotic drugs 6) Cycloheptene and cycloheptane derivatives. S This class is considered as phenothiazine isostere in which N - The S atom is replaced by ethylene or vinyl group. R - The N atom is replaced by SP2 carbon. Phenothiazine * Cyproheptadine (Periactine®). It is the prototype of this group. * Azatadine N N CH3 N CH3 Antihistaminic with sedative effect (antipsychotic). * Ketotifen (Zaditen®). O S It is a mast cell stabilizer. Used as anti-histaminic with long duration N of action. CH3 * Olopatadine (Patanol®). File:Olopatadine.svg It is a mast cell stabilizer. It is used to treat itching associated with allergic conjunctivitis (eye allergies).  A) 2nd Generation H-1 blockers. * They are characteristic by 1. Improved peripheral H-1 selectivity. 2. Little affinity to the central muscarinic and adrenergic receptor and therefore display lower degree of side effects. 3. Long acting mainly due to formation of active metabolites. 4. Chemically unrelated. 5. More hydrophilic, so have decreased CNS side effect. * Terfenadine (Triludan®). Used for the treatment of allergic conditions (RS)-1-(4-tert-butylphenyl)-4-{4-[hydroxy (diphenyl)methyl]piperidin-1-yl}-butan-1-ol * Synthesis * Metabolism It is not used any more as in some people, it might cause life threatening arrhythmia and was replaced by its active metabolite Fexofenadine.  * Fexofenadine (Telfast®). - It is more hydrophilic so does not readily COOH cross BBB and thus causes less drowsiness N OH than the first-generation H-1 blockers. OH - Used in treatment of hay-fever and similar allergy symptoms. 4-[1-Hydroxy-4-[4-(hydroxydiphenylmethyl)-1- piperidinyl]-butyl]-α, α-dimethyl benzeneacetic acid * Ebastine (Evastin®). It is indicated mainly for allergic rhinitis and chronic idiopathic urticaria. It does not cause sedation or drowsiness Ebastine: 4-(4-benzhydryloxy-1-piperidyl) -1-(4-tert-butylphenyl)butan-1-one  * Triprolidine (Actidil®). * Acrivastine (Semprex-D®). H3C N H3C N Carboxyethenyl derivative of triprolidine N N (Increased polarity thus COOH decreased BBB penetration) Antihistaminic with sedative effect. Antihistaminic without sedative effect. * Hydroxyzine (Atarax®). * Cetirizine (Zyrtec®). O Cl O Cl O N OH N OH N N Active metabolite of hydroxyzine. Basically used as recemic mixture, but the levo-isomer is the active one (Levocetirizine)  * Loratidine (Claritin®). Cl N N N CH3 N Azatadine COOEt R R R Metabolism Hydrolysis Decarboxylation N N N Antihistaminic without COOEt COOH H sedative effect. Desloratidine (Active metabolite) The active metabolite Desloratidine is largely responsible for the anti-histaminic effect and decreased CNS side effect. N.B. the 2ry amine is protonated at physiological PH, thus do not penetrate BBB * Azelastine (Rhinolast®). File:Azelastine.svg Used for treatment of Allergic Rhinitis. Eyes drops are indicated for the local treatment of Allergic conjunctivitis * Astemizole (Hismanal®). H3C-O N NH N N Used as anti-histaminic with long duration of action. F II) H-2 receptor antagonists (Anti-Ulcer agents) Parietal cell Gastrin G +2 Ca dependent signaling pathway Proton pump + + Acetyl choline M1 M2 H H ATPase + + K K H2 c-AMP dependent Histamine signaling pathway H2-Blockers H2-blockers inhibit cAMP which inturn inhibit ATPase system that result in decrease gastric acid secretion  II) H-2 receptor antagonists (Anti-Ulcer agents) * Cimetidine (Tagamet®) It is the prototype of this group. It was largely used for treatment of heartburn and peptic ulcer. No longer used because of its serious side effects (galactorrhea in women and 1-cyano-2-methyl-3-[2-[(5-methyl-1H-imidazol -4-yl)methylsulfanyl]ethyl]guanidine gynecomastia and sexual dysfunction in men. * Synthesis  * Ranitidine (Zantac®) 1 2 H H H3C 5 O N 1 N N 2 S CH3 1 CH3 4 3 2 NO2 N-(2-[(5-[(Dimethylamino)methyl]furan-2-yl)methylthio] ethyl)-N'-methyl-2-nitroethene-1,1-diamine It 100 times more potent than Cimetidine. Nitromethylene unit replaces N-cyanoimino group in the substituted guanidine analogs, increased potency. It is commonly used for treatment of heartburn and peptic ulcer. * Nizatidine (Axid®) 3 2 H H H3C 2 N 4 N 1 N N S 1 CH3 N-[2-[[2-[(dimethylamino)methyl]-1,3-thiazol-4-yl] CH3 S methylsulfanyl]ethyl]-N'-methyl-2-nitroethene-1,1-diamine 1 5 2 NO2 * Famotidine (Famotac / Pepcid®) NH2 H2N N N SO2-NH2 S N 3-[({2-[(diaminomethylidene)amino]-1,3-thiazol-4-yl} NH2 S methyl)sulfanyl]-N-sulfamoylpropanimidamide Famotidine 15-20 times more potent than Ranitidine. Both are commonly used for treatment of heartburn and peptic ulcer.  * Lafutidine File:Lafutidine.png * Roxatidine (Roxit®) File:Roxatidine.svg Activity * Chemical name and synthesis of both  * SAR of H-2 receptor antagonists 1. Basic heteroaromatic ring, (if imidazole, free NH is essential). 2. Replacement for the imidazole ring with other heteroaromatic rings resulted in other useful analogs. 3. Flexible intermediate chain in which the NH side chain must be separated by 4 carbons or equivalent atoms (S or O) from the heterocyclic ring (the sulfur atom increases potency compared to carbon and oxygen congeners). 4. Terminal polar non-basic group (Urea like end group) N-cyanoguanidine substituent (Guanidines substituted with electron-withdrawing groups have significantly decreased basicity compared to guanidine, and they are neutral (non-protonated) at physiologic pH). 5. Nitromethylene group replaces N-cyanoimino group in the substituted guanidine analogs, increased potency.  ** Proton Pump Inhibitors (Anti-Ulcer agents) More effective than H-2 blockers in suppressing the gastric acid secretion. They irreversibly inhibit the H+/K+ ATPase enzyme. General structure of a proton-pump inhibitor Generally, Methyl or unsubstituted  Mechanism of action In the acidic conditions of the canaliculi of parietal cells, both enantiomers of omeprazole are converted to achiral products (sulfenic acid and sulfenamide configurations) which react with a cysteine group in H+/K+ ATPase, thereby inhibiting the ability of the parietal cells to produce gastric acid.  * Omeprazole (Losec®) It is the prototype of this group. Used for treatment of dyspepsia, peptic ulcer, gastroesophageal reflux and Zollinger-Ellison syndrome. As it inhibit the ATPase irreversibly, it might cause gastric carcinoma 6-Methoxy-2-[(3,5-dimethyl-4-methoxy-2- pyridinyl)- methyl sulfinyl]-1H-benzimidazole. Omeprazole contains a tricoordinated sulfonyl sulfur in a pyramidal structure and therefore can exist as either the (S)- or (R)-enantiomers. Omeprazole is a racemate, an equal mixture of the two. * Synthesis  File:ZES endo.jpg Endoscopy image of multiple small ulcers in the distal doudenum in a patient with Zollinger–Ellison syndrome * Esomeprazole (Nexium®) * Rabeprazole (AcipHex®) * Lansoprazole (Prevacid®) * Pantoprazole (Pantoloc®) Chemical Name of all  * SAR of Proton Pump Inhibitors 1. Substituted Benzimidazole, substituted pyridine and sulfinyl chain connecting the two rings are essential for activity. 2. Benzimidazole substitution with electron donating group, increases the activity. 3. Benzimidazole substitution with electron withdrawing group, decreases the activity. 4. 4-Methoxy group on pyridine ring increases the biological activity. 5. 4-fluoro alkoxy substitution on pyridine ring results in strong inhibitory activity.  III) H-3 receptor antagonists H3-antihistaminics are drugs used to inhibit the action of histamine at the H3 receptor. H3 receptors are primarily found in the brain and are inhibitory autoreceptors located on histaminergic nerve terminals, which modulate the release of histamine. Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors in the cerebral cortex. Consequently, unlike the H1-antihistamines which are sedating, H3- antihistamines have stimulant and cognition-modulating effects.  * Ciproxifan Chemical Name and Synthesis of both It is used in the treatment for sleep disorders such as narcolepsy. It also potentiated the effects of antipsychotic drugs. Could be used in the treatment of Alzheimer's disease. Suggested as an adjuvant treatment for schizophrenia. * Thioperamide It is thought to promote wakefulness and improve memory consolidation. It is also a potent H-4 antagonist. IV) H-4 receptor antagonists Mainly used as antiinflammatory and analgesic effects in acute inflammation. * JNJ-7777120 * VUF-6002 Chemical Name of both Histidine decarboxylase inhibitors Inhibit the synthesis of Histamine from L-Histidine. * Tritoqualine It used for the treatment of urticaria and allergic rhinitis  Mast cell stabilizers They block mast cell degranulation, stabilizing the cell and thereby preventing the release of histamine and related mediators. They are used to prevent breathing problems caused by asthma. They are used to prevent or control certain allergic disorders. * Nedocromil 9-ethyl-4,6-dioxo-10-propyl-6,9-dihydro-4H-pyrano[3,2-g]quinoline- 2,8-dicarboxylic acid As an inhaler It is used to prevent wheezing, shortness of breath, and other breathing problems caused by asthma. It is also useful in allergic conjunctivitis.  * Cromoglicic acid Also known as Cromolyn It prevents the release of inflammatory chemicals such as histamine from mast cells. It could be used for the treatment of allergic rhinitis and asthma. 5,5′-(2-hydroxypropane-1,3-diyl)bis(oxy)bis (4-oxo-4H-chromene-2-carboxylic acid) Synthesis  * Lodoxamide It acts as histamine mast cells satbilizer. It could be used for the treatment of allergic conjunctivitis. N,N′-(2-Chloro-5-cyano-1,3-phenylene)dioxamic acid Thank you 46