phamaceutical chemistry of drugs used in EENT conditions

Nasal/ Ocular congestion

• vascodilation

• Smooth muscle tone of vascular: balance between the sympathetic and the parasympathetic nervous system

• Sympathetic activation: vasconstriction

• Parasympathetic activation: inhibits vasoconstriction

• Vasodilation: shift of balance to the parasympathetic over the sympathetic

• Congestion: treated by constricting the dilated vasculature, which brings cells together and reduces fluid leakage

Inflammation

• due to the release of inflammatory substance

• 4 classes ooof medication used

  • Tropical antihistamine

  • Intranasal corticosteroids

  • Leukotriene receptor antagonist

  • Mast cell stabilised

Adrenoceptor

Vascular smooth muscles nasal pathways and eye: rich in adrenergic a receptor → activation → vasoconstriction and smooth muscle contraction

3 categories of adrenergic agonist based on their MoA

• Direct acting agonist: bind directly to the adrenergic receptor and elicit intrinsic activity like NE. Can be selective to adrenergic receptor subtypes

• Indirect acting agonist: indirect mechanism → inhibiting metabolism of NE, inhibiting reuptake of NE from the synapse or increasing the release of NE from synaptic vesicles → increase the amount of NE at the synaptic cleft no selective to receptor subtypes as NE activates all adrenergic receptor

Adrenergic receptor agonist

• endogenous adrenergic agonist

• Poor oral bioavailability due to extensive metabolism by monamine oxidase and Catecholamines

Phenylephrine

Phenylethanolamine pharmacophore

• Selective α1 agonists: 2-phenolic hydroxyl moiety gives α

selectivity while decreasing β-receptor binding→ minimal

cardiac stimulatory properties

• not a substrate for COMT: longer duration of action

• oral bioavailability: less than 10% due to hydrophilic

properties and intestinal metabolism by MAO and 3′-O-

glucuronidation/sulfate conjugation

• Combination with other drugs (anti-inflammatory and

antihistamines)

• Oral decongestants: cause systemic adverse effects

(tachycardia, hypertension, and CNS adverse effect→

hypertensive patients use with caution)

Adrenaline

Oral phenylephrine: now considered ineffective → very low systemic availability

and questionable clinical efficacy — topical formulations are more reliable.

Phenylpropanolamines

Direct- and indirect-acting agonists

• Direct action: binding to both α- and β-adrenoceptors

• Indirect action: displacing NE from the synaptic vesicles o

reuptake inhibition → increasing NE concentration at the

adrenergic receptors. NE stimulates both α- and β-

adrenoceptors, indirect activity cannot be selective

Pseudoephedrine

No direct activity and fewer CNS adverse

effects than ephedrine

Widely used as a nasal decongestant

Sold as hydrochloride salt

Due to vasoconstriction effects: used with caution in hypertensive

patients. It might antagonise the actions of antihypertensive drugs such

methyldopa, carvedilol, and labetalol

Histamine

Biosynthesised in many tissues:

• mast cells, basophils, and lymphocytes: involved in allergic

and inflammatory responses

• gastric enterochromaffin-like (ECL) cells: stimulates

gastric HCl secretion

• histaminergic neurons in the CNS: functions as a

neurotransmitter

Four distinct receptors: H1–H4 (G protein–coupled receptors (GPCRs))

H₄ receptor mainly involved in immune cell chemotaxis (not targeted clinically

All the histamine receptors have some constitutive activity:

Capable of producing a biological response (basal response) in the absence

of histamine

Antihistamines

First generation:

• five chemical groups

• variable efficacy in the treatment of allergic

disorders

• numerous side effects: interaction with

cholinergic, adrenergic, dopaminergic, and

serotonergic receptors. CNS activity

(depression, sedation)

• lipophilic amines → penetrate the BBB

Ketotifen

Potent, selective dual action H1 antihistamine drug (second generation)

• Inverse agonist of H1 receptor

• Stabilizes mast cells and prevents degranulation of eosinophils

Ophthalmic drops for treatment and prevention of itching associated with

allergic conjunctivitis

Systemically: seasonal allergic rhinitis, hay fever, and asthma

Olopatadine

Dual mechanism of action

• H₁ inverse agonist (reduces histamine signalling)

• Inhibits mast-cell degranulation (↓ histamine release)

• Tricyclic structure (two aromatic rings + heterocycle)

• Zwitterionic character at physiological pH (COOH and tertiary amine)

• Increased polarity → poor CNS penetration (non-sedating)

Clinical relevance:

• First-line ophthalmic treatment

• Rapid onset + long duration

• Excellent safety profile

Azelastine

• Potent H₁ inverse agonist (reduces histamine signalling)

  • Additional anti-inflammatory effects (↓ leukotriene and cytokine release)

  Modern Ophthalmic Antihistamines: Azelastine

  • Phthalazinone core + aromatic rings

  • More lipophilic than olopatadine (missing COOH but 4-chlorobenezene)

  • Limited BBB penetration (still low sedation)

  Clinical relevance:

  • Used in topical eye drops and nasal sprays

  • Fast onset of action

  • Suitable for allergic rhino conjunctivitis

Alcafttadine

Mechanism of action

• H₁ inverse agonist (reduces histamine signalling)

• H₄ receptor blockade → reduces immune-cell recruitment

• Mast-cell stabilisation

Modern Ophthalmic Antihistamines: Alcaftadine

• Tricyclic piperidine-containing structure

• Increased receptor selectivity

• Designed for once-daily dosing

Clinical relevance:

• Prevention of ocular itching

• Particularly effective for chronic allergic conjunctivitis

Eye and ear infection: chloramphenicol

Bacteriostatic drug

• MoA: inhibition of protein biosynthesis in both bacterial and, to a lesser

extent, the host ribosomes. Binds to the 50S subparticle

• Broad-spectrum activity: gram +ve and gram –ve bacteria, including

penicillin resistant strains (H. influenza, N. meningititis and S. pneumonia)

• Serious systemic toxicity (aplastic anaemia): fatal in about 70% of cases.

Genetic predisposition → Mainly used topically for skin and eye infections

• Good penetration of CNS: diffuses well into inflamed

cerebrospinal fluid → used in meningitis in the past

• Not recommended in UTI: only 5-10% of the non metabolised

drug is excreted in urine

Chemistry and SAR of chloramphenicol

2 asymmetric centres → 4 diastereomers, BUT

only one (1R,2R) is significantly active

• p-Nitro group: can be replaced by other aryl rings or

oxygenated functional groups (EWG) →no loss of activity!!!

In vivo → reduced to aromatic amine (NH2) → aplastic

anaemia!!!

• Phenyl ring: can accept multiple-substitutions

• Conversion of C-1 OH to keto (C=O) → loss in activity

• Resistance: express a chloramphenicol acyltransferase

enzyme → acetylation (CH3CO-) of the two hydroxyl

groups → no longer bind to the ribosomes and thus are

Prodrug forms of chloramphenicol

Chloramphenicol has POOR WATER

SOLUBILITY Conversion to the C-3

hemisuccinoyl ester, which forms a water-

soluble sodium salt. This is cleaved in the body

by lung, liver, kidney, and blood esterase to

produce active chloramphenicol

Synthesis of chloramphenicol

In the past: produced by fermentation of Streptomyces venezuelae

Nowadays: simple chemical structure → several efficient total chemical syntheses

Enantioselective synthesis or Racemic synthesis

followed by separation of R,R

P-nitroacetophenone as starting material