Med chem Exam 4: Antihistamine H-1 part 1

Histamine occurs in

plants as well as in animal tissues and is a component of some venoms and stinging secretions

In humans, histamine is a

biogenic amine

Histamine, at physiological pH, 96 % correspond to the

monocation Na

in solution, histamine exists in what form

tautomeric

In aqueous solution histamine the tautomer percentage Nτ/Nπ is

4.2 at the imidazole ring

at lower pH a higher percentage of Histamine in

dicationic species is found

Histamine is synthesized from the essential amino acid

L -histidine

what is the enzyme responsible for L-histidine to histamine

histidine decarboxylase

what is an important cofactor is producing histamine

pyridoxal phosphate

where is histidine decarboxylase

gastric mucosa parietal cells, mast cells, basophils, and CNS

how does histamine get released from mast cells

IgE crosslinking, complement allergy inducing drugs

how does histamine get released from platelets, basophilic, leukocytes

IgE crosslinking, complement allergy inducing drugs

Histamine gets released from enterochromaffin-like cells in the stomach by

somatostatin and gastrin

how does histamine get released from the CNS

activation of N-methyl-D-aspartate, U opioid, dopamine D2, and serotonin receptors

Histamine plays a crucial pharmacological role

Fighting off allergen as part of your immune response, Chemical messenger between your body and your brain

what is histamines role in digestion

promotes stomach acid release to aid digestion

as a NT, histamine influences

wakefulness, memory, and immune responses

When histamine is released, it interacts

with specific receptors in the brain, affecting various neurological functions

histamine has a differential expression which means

it changes according to the stage of the cell in differentiation and microenvironmental influences

Severe allergic reaction (e.g., peanuts) causing a dangerous histamine response; can be life-threatening.

Anaphylaxis

Scombroid poisoning

Food poisoning from spoiled seafood with very high histamine

Some kinds of fish contain naturally high levels of the

chemical histidine, which can be converted to histamine by bacteria

Mild reactions to allergens like pollen; may cause hives, sinus congestion, watery eyes, and rashes

Localized allergic reactions

Eating too much histamine in one meal (over ~50-100 mg/kg)can trigger symptoms; tolerance varies between people

Histamine overload

Sensitivity to even small amounts of histamine; symptoms can include abdominal pain, diarrhea, headaches, fatigue, hives, sinus issues, heart palpitations, and low blood pressure

Histamine intolerance

Histamine Termination

Cellular uptake and Desensitization cellular

how is histamine metabolized to be terminated

N-methylation and oxidative deamination

what are two enzymes that metabolize histamine

Diamine oxidase Aldehyde dehydrogenase and N-methyltransferase

what are the two major metabolites of histamine

Imidazoleacetic acid riboside and N-Methylimidazole acetic acid

what of type GPCR is H1

Gq, increase IP3 and DAG

what of type GPCR is H2

Gs, increase cAMP

what of type GPCR is H3 and H4

Gi, decrease cAMP

referred to drugs that block (antagonist) the actions of histamine at H1 receptors

Histamine Antagonist H-1 antihistamines

discovered that piperoxan could protect animals from bronchial spasm induce by histamines

Bovet

Main Pharmacological use of antihistaminic H-1 is to

treat allergic reactions

what is the general structure of histamine

tertiary amine with an heteroatom and 2 R groups

The X atom of antihistamine agents

This substituent is often a heteroatom as nitrogen, saturated carbon-oxygen moiety or simply a carbon.

distance between N and X atom of antihistamine agents

This distance can be varied from two to three carbons, with two providing optimal activity

what are the two R groups of an antihistamine

it is a methyl group, but for some drugs the amine can be part of a heterocyclic system

what optimal pka of the amine in a antihistamine agent is

8.5 to 10

used extensively for the treatment of seasonal allergies, insect bites and stings, and rashes. However, it also has antiemetic, antitussive, sedative, and anti parkinson properties

Diphenhydramine

Diphenhydramine has also been shown to be implicated in a number of neurotransmitter systems that affect behavior including

dopamine, norepinephrine, serotonin, acetylcholine, and opioid

what are the different salt formulations of diphenhydramine

tannate, citrate, hydrochloride

diphenhydramine is used in combo with 8-chlorotheophylline (stimulant)

as the anti-nausea drug, marketed as Dramamine

FDA warns that taking higher than recommended doses of Benadryl can lead to

serious heart problems, seizures, coma, and death

sold as an OTC for cough and cold, do not use in children under 4, S configuration is more active

Carbinoxamine maleate

what does the extra Cl on Carbinoxamine maleate and clemastine fumarate do

increases lipophilicity

It is indicated for the relief of symptoms associated with allergic rhinitis, or the management of mild, uncomplicated allergic skin manifestations of urticaria and angioedema

Clemastine fumarate

what is the duration of action of Clemastine fumarate

5-7 hours and persist 10-12 hour

common side effects of Clemastine fumarate

Dry mouth, fixed dilated pupils, excitement, flushing of the face, and fever are common side effects

it is commonly used as a sleep aid. This drug is also used to relieve symptoms of hay fever (allergic rhinitis), hives (rashor itching), and other allergic reactions, as well as morning sickness

doxylamine succinate

It is also the most powerful OTC sedative available in the United States, and more sedating than many prescription hypnotics

anti-allergy power is superior to all except diphenhydramine

Doxylamine Succinate

Pyrilamine (Mepyramine) is found as OTC combination products for

colds and menstrual symptoms

Pyrilamine rapidly

permeates the brain and so often causes drowsiness as a side effect. It is used as maleate

pyrilamine is a histamine H1 receptor

inverse agonist

Pryilamine binds to a G protein couple form of the receptor

and promotes a G protein-coupled inactive state of the H-1 receptor that interferes with the Gq/11-mediated signaling

Pyrilamine binds in the effector cell

surface, resulting in suppression of histaminic edema, flare, and pruritus

Inverse Agonist

Drug that binds to the same receptor as an agonist but produces the opposite response

antagonist

Drug that binds to a receptor and blocks/disrupts the interaction and function of both agonist and inverse agonist.

what is the receptor binding of inverse agonist

Binds only to receptors with constitutive (baseline) activity

what is the receptor binding of antagonist

Binds to receptors with constitutive activity and ligand-induced activity

binding sites of inverse agonist

Can bind only to the active site of the receptor

binding sites of antagonist

Can bind to the active site and allosteric sites of the receptor

Thonzylamine has been found in OCT combo products with

clofedanol or phenylephrine for temporary relief of symptoms of common cold, hay fever

contains a piperazine and treats common allergies

Chlorcyclizine hydrochloride

Chlorcyclizine hydrochloride has some local anesthetic and

anticholinergic, and anti-serotonergic properties, and can be used as an antiemetic

it is used in the symptomatic treatment of motion sickness and control of vertigo associated with vestibular system diseases

Meclizine