Oxymetazoline: Chemical Structure, Uses, and Mechanism of Action

Health Context of Oxymetazoline

Oxymetazoline

HEALTH CONTEXT Use: Decongestant Type: Nasal Disease: Nasal inflammation Made from: Alkylphenol

HO N HNHO N HN NASAL SPRAY

• Nasal spray decongestant (Vicks Sinex, Sudafed OM, Afrin)
• Congestion caused by rhinitis, hay fever, allergies, colds, sinus problems
• Developed by Merck in 1961

Became over-the-counter (OTC) medication in 1975

Fight-or-Flight Response and Adrenergic Receptors

Fight-or-flight response .... Adrenaline and Noradrenaline (neurotransmitters) binds to a- and ß- adrenergic receptors (adrenoreceptors), activating them to cause ...

• blood flow to muscles
• heart rate
• blood-glucose level
• alertness

Activation of Adrenergic Receptors

Fight-or-flight response .... Activation of different a- and ß-adrenergic receptors generates a different response ...

a or ß subtype Adrenalin/Noradrenalin activation causes (partial list)

a1- & a2- receptors Smooth muscle contraction vasoconstriction

B-receptors Heart rateT heart muscle contraction 1

B2-receptors Muscle contraction blood-glucose respiration

B3-receptors Lipolysis (using stored energy)

Adrenaline, Noradrenaline, and Oxymetazoline

OH HO H N HO Adrenaline (Epinephrine)

OH HO NH2 HO Noradrenaline (Norepinephrine)

Known as catecholamines Catechol is a phenol with 2 OH groups + amine)

HO HO Catechol

HO N HN Oxymetazoline - an a-adrenoreceptor / a-adrenergic agonist (agonist for a and only partially for a2)

Oxymetazoline as an Alpha-Adrenoreceptor Agonist

Oxymetazoline is an ... a-adrenoreceptor agonist ... i.e., they further activate the normal adrenaline- and noradrenaline-mediated sympathetic nervous system actions)

Agonist:

• a chemical that binds to a receptor and activates the receptor to produce a biological response

Antagonist:

• A chemical that binds to a receptor and blocks the action of the agonist

Inverse agonist:

• A chemical that binds to a receptor and induces a pharmacological response opposite to that of the agonist

Mechanism of Action in Nasal Inflammation

Arteria ethmoidalis anterior Arteria ethmoidalis posterior Nasal inflammation Arteria sphenopalatina („Sphenopalatine artery“)

Sinus sphenoidalis Veins & small arteries swell Locus Kiesselbachii Restricted airflow

Oxymetazoline Stimulates x- adrenergic receptors in nasal blood vessels

Vasoconstriction in blood vessels Opens nasal passages

Arteria palatina major („Greater palatine artery“)

Oxymetazoline also decreases mucous production

Poll: Oxymetazoline Drug Type

Join: vevox.app ID: 186-912-153 POLL OPEN What type of drug is oxymetazoline?

1. An alpha-adrenoreceptor antagonist 0%
2. An alpha-adrenoreceptor agonist 78.57%
3. A beta-adrenoreceptor agonist 14.29%
4. A beta-adrenoreceptor antagonist 7.14%
5. A beta-adrenoreceptor inverse agonist 0%

Oxymetazoline Structure and Related Decongestants

Oxymetazoline STRUCTURE Use: Decongestant Type: Nasal Disease: Nasal inflammation Made from: Alkylphenol

HO N HN

Nasal Decongestants Comparison

Nasal decongestants

HO N HN Oxymetazoline (OM) Sinex, Sudafed OM

IZ N. Xylometazoline Otrivin, Otrivine

OH HO N Phenylephrine Sudafed PE

OH H N S R N HN Naphazoline Patented in 1934

OH H S N S Pseudoephadrine (PSE) Sudafed (not PE), Sinutab

Not a complete list

OH N R S Ephedrine Also found in Ephedra plants H

Imidazole Ring Structure

Imidazole ring, numbering and saturation

HO N HN Oxymetazoline

3 N 2 4 HN 1 5 Imidazole

N HN 4,5-dihydro-1H-imidazole

Structurally Similar Compounds to Oxymetazoline

Structurally similar compounds

HO N HN Oxymetazoline (OM) Sinex, Sudafed OM

OH H HO N HO Adrenaline (Epinephrine)

OH HO NH2 HO Noradrenaline (Norepinephrine)

NH2 NH2 Amphetamine Levoamphetamine Central nervous system (CNS) stimulant - for ADHD, obesity, narcolepsy

IZ Methamphetamine Potent CNS stimulant - recreational drug, 2nd line treatment for ADHD/obesity

Oxymetazoline Synthesis

Oxymetazoline SYNTHESIS Use: Decongestant Type: Nasal Disease: Nasal inflammation Made from: Alkylphenol

HO N HN

Starting Compound for Synthesis

Starting compound ...

• Alkyl phenol
• 'Topanol A'
• 2,4-Dimethyl-tert-butylphenol 2-tert-Butyl-4,6-dimethylphenol
• Used as an antioxidant to prevent gumming of fuels
• Compare to antioxidant excipients in simvastatin formulation

Synthesis Steps of Oxymetazoline

Synthesis of oxymetazoline

N step 1 CH2O step 2 KCN HO HO HO ZnCl2 / HCl step 3 EtOH / H+ N H step 4 H2N NH2 HO HO NH OEt oxymetazoline CI

Synthesis: Step 1 - Blanc Chloromethylation

Synthesis: Step 1

step 1 CH2O HO ZnCl2 / HCl OH + H H H 工 formaldehyde + HO H+ H H HO Step 1: Blanc chloromethylation ('Blanc reaction') HCl (g) with zinc chloride (Lewis acid) & formaldehyde HCl HO OH H HO + OH CI HO slow

Synthesis: Step 2 - Nitrile Formation

Synthesis: Step 2

N CI HO step 2 KCN HO Step 2: Formation of the nitrile (SN2) CI N= c HO

Synthesis: Step 3 - Imidate Formation

Synthesis: Step 3

N step 3 EtOH / H+ HO imidate group NH OEt HO I N H+ N+H H Et HO Step 3: Formation of the imidate NH + H Et HO HO

Synthesis: Step 4 - Imidazole Ring Formation

Synthesis: Step 4

NH OEt step 4 HO H2N NH2 1 H2N NH H2N OEt I H HO HO HO Step 4: Formation of the imidazole ring Et H H H + H N N I-Z H2N NH + N ZI N H oxymetazoline HO

Poll: Compound X for Reaction

Join: vevox.app ID: 186-912-153 POLL OPEN Which compound X would bring about the reaction shown below?

OEt -N + HN X N

1. NH3 and H2O 0%
2. EtOH 0%
3. H_NCH CH CH_NH 23.08%
4. H2NCH2CH2NH2 69.23%
5. CH3CH2NH2 7.69%

Functional Group Identification

Join: vevox.app ID: 186-912-153 Enter Text and Press Send What is the name of the functional group shown below?

OMe imidate HN R amine imine

Oxymetazoline Formulation Details

FORMULATION

HO N HN

Use: Type: Disease: Made from:

Commercial Names for Oxymetazoline

Join: vevox.app ID: 160-824-096 What is a commercial name for oxymetazoline? Enter Text and Press Send sunex paracetamol vicks oxycodone nasal spray afrin sudafed

Oxymetazoline Non-Hygroscopic Property

Join: vevox.app ID: 160-824-096 Oxymetazoline is non-hygroscopic. What does this mean? Enter Text and Press Send doesn't absorb water it's non sticky ? moisture repellent can't read horoscop water = no

Physical Properties of Oxymetazoline Hydrochloride

Physical properties

HO N HN Oxymetazoline hydrochloride

• Stable, white, crystalline solid
• Non-hygroscopic
• Sparingly soluble in water (1.4 mg/L) and alcohols
• Insoluble in diethyl ether, chloroform and benzene
• Melting point: 181-183 ℃
• pKa 11.6 (3 º imidazoline H) & pK 10.9 (phenol)

Brand Names of Oxymetazoline Products

Brand names

Oxymetazoline is the active ingredient in a number of decongestant nasal spray (DNS) products:

• Vicks Sinex
• Sudafed OM
• Afrin (USA)

12 ALLERGY-NASAL ALERGIAS-NASALES DEx 1.99 540 741 33 26) 60 MucinexDM SUDAFED" SUDAFED" SUDAFED" SUDAFED !! 441 Certainty Clear Otil Mucinex 140 1971 13% 1290 1299 1000 TYLENOL - Advil Ça 719 Advil Advil PR 5 HUMIDIFIER 5 745 WarmMist 17 12% 120 1799 1719 124 FITH 89 130 1749 2 120 12-40 66 70 Vaporizer Certainty Customer Service 999 62

Oxymetazoline Dosage Information

Dosage

HO N HN

• Provides rapid relief from blocked nose for up to 12 hours

Doses for adults and children over the age of 12:

• 1 to 2 sprays in each nostril
• Every 6 to 8 hours

• Do not use for children under 12 years
• Do not use for more than 7 days, unless told to do so by your prescriber.

Nasal Spray Formulation

Formulation

NASAL SPRAY Nasal Spray Pump mist, anti-drip: 0.05% (0.5 mg mL-1) Alternatively, injected into the vein

Non-Active Ingredients in Oxymetazoline Nasal Spray

Non-active Ingredients

Purpose Alcohol (96%) Solvent Puified water Solvent Monosodium phosphate Buffer Disodium phosphate Buffer Methyl hydroxybenzoate (methylparaben, methyl 4-hydroxybenzoic acid, methyl ester of p-hydroxybenzoate) Preservative (antifungal agent) Cetrimide (mixture of quaternary ammonium salts, incl. cetrimonium bromide CH3(CH2)15N(CH3)3+ Br) Antiseptic (antibacterial) Levomenthol (L-menthol) Cooling effect* Camphor racemic Cooling effect* & decongestant Eucalyptol Reduces mucous hypersecretion & reduces inflammation *Excipients

Cooling Effect Excipients

O (R)-camphor (S)-camphor Camphor racemic 1,7,7-Trimethylbicyclo[2.2.1]heptan-2-one Strong, menthol-like odour

Eucalyptol (main component, 90%, of eucalyptus oil) 1,3,3-Trimethyl-2- oxabicyclo[2.2.2]octane Mint-like odour

Oxymetazoline Side-Effects

Oxymetazoline SIDE-EFFECTS Use: Decongestant Type: Nasal Disease: Nasal inflammation Made from: Alkylphenol

HO N HN

Common and Rare Side Effects

Common Very rare Dryness or irritation of the nasal mucosa Allergic reactions (skin rash, itching) Nausea Blurred vision Headache Irregular or fast heartbeat Local burning sensation Rhinitis medicamentosa (Rebound congestion)

Contraindications for Oxymetazoline Use

Contraindications

Do not take oxymetazoline if patient suffers from:

• Allergic to any of the ingredients
• Have heart or blood vessel disease
• If taking monoamine oxidase inhibitors (for depression) or have taken them in the last 14 days
• Overactive thyroid
• Glaucoma
• Prostate problems
• If pregnant or breastfeeding (unless recommended by prescriber)
• Methyl hydroxybenzoate (E218) may cause allergic reactions (possibly delayed)

Over-use and Rhinitis Medicamentosa

over-use ... Over-use (see dosage) of oxymetazoline can lead to Rhinitis medicamentosa:

• A rebound effect where stuffy nose becomes worse after having relief previously
• Name comes from the fact that congestion caused by the medication
• Rhinitis means inflammation inside the nose
• The condition can be reversed by stopping the treatment for a couple of weeks (first week is difficult, but other decongestants, such as oral antihistamines, oral steroids or a saline spray, can be used)
• If not stopped, chronic sinusitis (inflammation of sinuses) and other serious, long-term problems can result

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