Lec 37-38

What molecule is this

Histamine

Know the pKa of the amines – i.e. which one is the most basic and which is least basic?

The most basic amine is the primary amine on the alkyl chain (9.4)

The ring amines have a pka of 5.8

Know which form of histamine is most likely to penetrate membranes and why.

The unprotonated form (not a body pH)

How do H1 vs H2 antihistamines differ in what they are used to treat?

H1 antihistamines treat allergic inflammation

H2 antihistamines treat gastric hypersecretory disorder

How many histamine receptors are known and are they G-coupled proteins or ion channels?

There are 4 receptors and they are G coupled protein receptors

Understand histamine biosynthesis – what functional groups, co-enzyme and enzyme are involved?

Histidine is turned into Histamine via PLP L histidine decarboxylase

Histamine is broken down through two pathways – understand what are the major metabolites, and how are these metabolites excreted?

N methylation pathway:

Histamine → N methylhistamine→N methylimidazole acetic acid via N-methyltransferase and MAOB & aldehyde dehydrogenase

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Oxidative pathway:

Histamine → Imidazoleatic acid →Imidazoleacetic acid riboside

via Diamine oxidase and phosphoribosyl transferase

Understand the process of histamine release and hypersensitization.

1)B cells recognize an antigen then divide into memory and plasma cells

2)Plasma cells make antibodies

3)Antibodies bind to mast cells , mast cell is “primed”

4)Now, if we have antigen they bind to the antibodies leading to mast cell activation, leading to release of mediators (histamine) than go interact with other things that cause allergy symptoms

Know the result of agonist action on each histamine receptor type on the effectors and messengers.

finish later (table)

Cromolyn

Inhibitor of Histamine Release (Mast cell stabilizer)

Inhalation, eyes

Pemirolast

Inhibitor of Histamine Release (Mast cell stabilizer)

Eyes

Nedocromil (Alocril) & Lodoxamide (Alomide)

Inhibitor of Histamine Release (Mast cell stabilizer)

ophthalmic solution

Season allergic conjunctivities

How do first and second generation H1 receptor antihistamines differ from each other in terms of side effects. How do they generally work?

First generation- Sedation (get into CNS better)

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Second generation- Non sedating, peripherally selective

H1 receptor antihistamines MOA

inverse agonists

Produce the opposite response of an agonist

Know the pharmacophore of first generation H1 receptor antihistamines. This means that if you were given a lineup of structures (real or fictional) you can apply the rules to pick out an active vs inactive first generation H1 receptor antihistamine.

Two aryl groups

X = N, CHO, CH2N, CH

Spacer (CH2)

R1,R2= usually small alkyl group

Understand that the pharmacophore of first generation H1 receptor antihistamines overlap with the pharmacophore of anticholinergics and why this is relevant.

We see anticholinergic effects associated with antihistamines because of this ( dry mouth, blurred vision, tachycardia, urinary retention, constipation)

Recognize name/structure of benedryl

First gen H1 receptor antihistamine

Used for allergic conditions

Short half life

Wide safety margin

Sedation is a side effect

Understand the SAR of first generation H1 receptor ethanolamine-based antihistamines.

As the size of the R2 position increases the anticholinergic affects increase and the antihistamine effects decrease

Recognize name/structure of clemastine

first generation H1 receptor ethanolamine based antihistamine

Relief of symptoms associated with allergic rhinitis

Less sedative than diphenhydramine

R,R isomer is most potent

. Know what the alkylamines/propylamines are used for therapeutically and what advantages they possess over ethanolamine-based antihistamines (slide 17). Recognize the names/structures of these.

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Triprolidine, Pyrrobutamine, Dimenthindene

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Longer half lives

Extended duration of action

Fewer CNS side effects

Decrease anticholinergic effects

Decreased antiemetic effects

What are piperazine-based first generation H1 receptor antihistamines used for? Recognize structure/names for these.

Cyclizine, Hydroxytinze, Cetirizine

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Vertigo, motion sickness

Significant antihistamine and anticholinergic effects

Drowsiness

hydroxyzine → itchy skin

Know what functional group of Visteril is metabolized to give Zyrtec and what functional group results.

The hydorxy group on the end of the side chain is metabolized to a carboxylic acid

What is significant about Zyrtec in terms of its side effect profile compared to Visteril?

Second Generation H1 receptor antihistamine

“Nonsedating”

Know the general pharmacophore of the tricylic antihistamines, how they are used, and examples by structure/name.

Promethazine: Sometimes combined with codeine for cough

Cyproheptadine: Appetite stimulating, used for anorexia nervosa

Know the profile of second generation H1 receptor antihistamines vs first generation H1 receptor antihistamines.

Improved H1 selectivity

Decreased affinity for adrenergic and or serotonergic receptors

Act mostly in periphery

Little to no sedative effects

Decreased anticholinergic effects

May possess anti allergic effects apart from antihistamine activity

Vary widely in structure

Most are administered once daily

toxicity associated with terfenidine/Seldane.

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Second gen H1 antihistamine

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In presence of other CYP3A4 substrates high concentrations of parent drug can result leading to hERG K+ channel inhibition which leads to prolonged QT interval leading to ventricular arrhythmias

How does hERG potassium channel inhibition effect heart rhythm?

prolonged QT interval of heart leading to ventricular arrhythmias

In the absence of CYP3A4 metabolism, does terfenidine/seldane have antihistamine activity?

No, its active metabolite is Allegra

. Recognize the structure/name of terfenidine and Allegra. What is the benefit of Allegra vs terfendiine/Seldane?

Allegra is not associated with hERG problem

Allegra is the metabolite of terfenidine

Recognize Zyrtec as a second generation piperazines and what therapeutic advantage it has over its parent drug.

2nd gen H1 receptor antihistamine

“Nonsedating”

Active metabolite of hydroxyzine (1st gen)

Zyrtec

2nd generation H1 receptor antihistamine

Acid metabolite of 1st gen antihistamine, hydroxyzine

No cardiotoxicity

Commonly combines pseudoephedrine

Know the origin of xyzal. Recognize the name/structure of xyzal and its use.

The enantiomer of zyrtec

claritan, clarinex and rupafin

Second gen H1 antihistamines

Nonsedating, selective peripheral H1 inverse agonist activity

Long duration- once daily use

Clarinex is metabolite of claritin and rupafin

Recognize the structure/names of topical H1 receptor antihistamines and what they are used for.

Olopatadine, Ketotifen, Epinastine, Levocabastine, Emedastine

Eye drops

How are H2 receptor antihistamines used and what is their mechanism of action?

Alleviate over production of gastric acid

Inverse agonists

Understand the approaches to anti-ulcer agents summarized in class and how they work.

1) H2 receptor antihistamines

2) Proton pump inhibitors

3)Anticholinergics

4)Prostaglandin analogs

Know that the H2 receptor is cAMP dependent and that agonists increase cAMP production.

H2 receptor activation leads to a cAMP pathway that promotes the formation of HCL in the gastric lumen

What are the roles of prostaglandins in regulation of gastric acid secretion.

Balance the pro acidic mechanisms by:

1)Dampening the cAMP pathway in the parietal cells ti inhibit acid secretion

2)Increasing production of cytoprotective mucus and bicarbonate in superficial epithelial cells → pH 7

How do NSAIDS affect ulcer formation?

Block Prostaglandin Production

Block Bicarbonate Production

Block Mucus Production

Recognize the structure/name of cimetidine, how it is used and the role of bioisoterism in its development.

Thiourea replaced with N cyanoguanidine (bioisosterism)

H2 receptor antihistamines

cimetidine, zantac and Pepcid AC

OTC used to treat gastric acid hypersecretion, acid indigestion, heartburn

Prilosec, Nexium, prevacid, and protonix

Proton Pump Inhibitors

Treat gastric ulcers, GERD, gastric hypersecretion, erosive esophagitis

How do PPIs work

The PPI forms a disulfide bond with the proton pump which inactivates the pump

. What concern is there with prolonged use of proton pump inhibitors?

Increase risk of hip, wrist and spine fracture in patients of age 50 or older

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Maybe bc:

PPIs interfere with absorption of iron, calcium , mg which are important to bone formation- inhibited pump is similar to pump in bone reabsorption