[Mid] Med Org: Anti-infective Agents

John Lister

1867 Introduced phenol) for antiseptic principles (Lister’s principle caused dramatic decrease in postsurgical infections)

Used phenol (carbolic acid) as wash for the hand

Pre on the incision site and on bandages applied to wounds

Paul Ehrlich

- father of chemotherapy

- Disciple of Robert Koch, began to work with set of antibacterial dyes and antiparasitic organic arsenicals

- His goal is to develop compounds that retain anti-microbial activity at the expense of toxicity to human host

- Magic bullets (antimicrobial activity at the expense of host toxicity)

- At this time, only few comunds can treat infectious diseases and none are effective in treating severe gram (+) and gram (-) infections

- discovered that the anti-microbial properties of dyes are parallel to staining activity (first demonstration of selective toxicity

- began work with a set of antibacterial dyes and anti-parasitic organic arsenicals

Compound 606 (Salvarsan)

FIRST anti-syphilitic drug

Selective toxicity

Main tenet of modern antimicrobial therapy

the property of certain chemicals to kill one type of organism while not harming another

1920s

most successful anti-infective agents based on Group-IIB element mercury and the group-VA elements arsenic and antimony

basis for anti-infective agent

H.W. Thomas

1920 when he discovered the most successful anti-infective agents based on the group-IIB element mercury and the groupVA element arsenic and antimony, Atoxyl

Atoxyl

(sodium arsanilate and arsphenamine)

was used for sleeping sickness

Dyes: gentian violet, methylene blue

Somewhat effective were a few chemical conjurers of the quinine molecule

Some of these agents represented significant achievements in anti-infective therapy but they also possess some important limitations

Heavy metal toxicity tx w/ mercury, arsenic, antimony

gentian violet, methylene blue

dyes of Atoxyl

Germicides

anti-infective agents that are used locally

Antisepsis

application of an agent to living tissue for the purpose of preventing infection

Disinfection

chemical or physical treatment that destroys most vegetative microbe or viruses, but not spores, in or inanimate surface

Decontamination

destruction or marked reduction in the number of activity of microorganism

Sanitation

reduction of microbial load on an inanimate surface to a level considered acceptable for public health purposes

Sterilization

a process intended to kill or remove all types of microorganism, including spores, and usually including viruses with an acceptable low probability of survival

Pasteurization

a process that kill non-sporulating microorganism by hot water or steam at 65-100°C

3 Major Classification of Anti-Infectives

1. Chemical type of the compound

2. Biological property

3. Therapeutic indication

Antiseptics

applied to living tissue

- must have low toxicity that it can be used directly on skin or wounds

- bactericidal

- bacteriostatic

Cidal

compound that kills

Static

prevent the growth

Disinfectant

- applied to inanimate objects

- exerts a rapidly lethal action against all potentially pathogenic microorganism and spores

Coagulation and Denaturation of Cell Protein

Local anti-infectives mechanism of action

Formalin, Phenol, Alcohol

Strong coagulators

Iodine, Cresol, Phenol

Denaturants

Ideal Anti-infective

• Low-enough toxicity that it can be used directly on skin or wounds

• Exert a rapid and sustained lethal action

• Low surface tension so that it will spread into the wound

• Retain activity in the presence of body fluids (pus)

• Non-irritating to tissues

• Non-allergenic

• Lack systemic toxicity

• Not interfere with healing

Group Classification of Anti-infective Agents

1. Alcohol and related compounds

2. Phenol and derivatives

3. Oxidizing agents

4. Halogen containing compounds

5. Cationic surfactants

Protein and Carbohydrate Precipitation

Alcohol MOA

Alcohol SAR

• MW Up to 8 carbon atoms (octanol) increases antibacterial potency

• Increased chain length increases membrane penetration

• Branching decreases antibacterial potency

Ethanol

"grain alcohol"

"rectified spirit"

"spiritus vini rectificatus"

"wine spirit"

• Grain fermentation

• sulfuric acid catalyzed hydration of ethene

• Oxidized to acetaldehyde causing N&V vasodilatory flushing

• disulfiram blocks aldehyde dehydrogenase

Commercial ethanol

95% ethanol; forms azeotrope with water at 78.2°C

Ineffective against spores

Ethanol limitation

Ethanol uses

• Solvent

• fuel

• CNS depressant

• antipyretic 25%

• germicidal 60-90%

• disinfectant 70%

Ethanol medicinal use

• Injected near nerves and ganglia to alleviate pain

• low narcotic potency

Ethanol internal use

• Mild sedative

• carminative “FLATULENT“

• weak vasodilator

Ethanol pharmaceutical use

Preparation of spirits, tinctures, and fluid extracts

Spirits

Ethanol as sole solvent

Tinctures

Hydroalcoholic mixtures

Fluidextracts

Alcohol used as cosolvent

Denatured alcohol

• Unfit for human use

• used in alcohol lamps

Denaturants

Wood alcohol, acetone, benzene

Completely denatured alcohol

Contains wood alcohol and benzene

2-propanol C₃H₈O

Isopropyl alcohol chemical name

Rubbing alcohol

• Isopropyl alcohol 68-72%

• astringent

• rubefacient

• mild local anesthetic

Preparation:

H₂SO₄-catalyzed hydration of propylene

Rubbing alcohol

• Astringent

• rubefacient

• mild local anesthetic

Isopropyl alcohol preparation

Sulfuric acid catalyzed hydration of propylene

Isopropyl alcohol

• Skin disinfectant

• surgical instruments

• bactericidal 50-95%

• 40% is equivalent to 60% ethanol

Azeotropic isopropyl alcohol

Used on gauze pads for skin sterilization before injections

Dehydrated alcohol

• Absolute alcohol

• NLT 99% w/w ethanol

Dehydrated alcohol preparation

Azeotropic distillation of ethanol and benzene

Diluted alcohol

41-42% alcohol by weight

Glycerin

“Glycerol” “1,2,3-propanetriol”

• polyhydric alcohol

• solvent

• humectant

Ethylene oxide

• Gas sterilant

• used for temperature-sensitive equipment

• explosive at 3-80% in air

Carboxide

10% ethylene oxide and 90% CO₂

non-explosive

carcinogenic

Carboxide MOA

• Alkylation of nucleic acids and proteins

• nonselective

• toxic and carcinogenic

Formaldehyde synonyms

Formol

methanal

formalin

Formaldehyde

• Irritating to mucous membranes

• hardens skin

Formaldehyde uses

Disinfect rooms clothing and surgical instruments

contains not less than 37% formaldehyde

Formaldehyde MOA

Nonspecific alkylation of amino hydroxyl acid and sulfhydryl groups

Glutaraldehyde

Superior to formaldehyde

active against all microorganisms including spores and viruses

Glutaraldehyde synonyms

“Glutarol”

“Cidex®”

“pentanedial”

Glutaraldehyde

Sterilization of equipment not suitable for autoclaving

Commercial glutaraldehyde

– 2% solution

– buffered pH 7.5-8

– retains 80% activity after 30 days

Phenol

- Protein precipitant

- standard for germicidal comparison

Phenol coefficient

Ratio of disinfectant dilution to phenol dilution killing Salmonella typhi

Carbolic acid

Phenol synonyms

Phenol uses

• Germicide

• local anesthetic but caustic

• antipruritic

• antiseptic

• wound cauterization

Phenol SAR

• Para- alkyl aryl or halogen substitution increases activity

• straight chain more effective than branched

• soluble 1:15 in water

Liquefied phenol

• Phenol with 10% water

• used in pharmaceutical preparations

P-chlorophenol

• Used with camphor

• phenol coefficient about 4

Chloro-m-Xylenol

“PCMX“; “Metasep“

Non-irritating antiseptic

broad antibacterial and antifungal

2% shampoo

Chloro-m-Xylenol uses

Tinea infections

athlete's foot

jock itch

Eugenol

• Local anesthetic

• antiseptic mouthwash

• dental analgesic

Hexachlorophene

• 2,2-methylenebis 3,4,6-trichlorophenol

• effective against G+ bacteria

Hexachlorophene

2-3% soaps, creams, lotions, shampoos

Hexachlorophene SAR

• Biphenolic compounds more potent

• chlorine increases potency

Hexachlorophene toxicity

Neurotoxic in infants and burn patients

Cresol

Mixture of ortho-, meta-, and para- methylphenols

Chlorocresol

• 4-chloro-3-methylphenol

• slightly soluble in water

• preservative at low concentrations

Thymol

• Isopropyl m-cresol

• from oil of thyme

• fungicidal

• used for tinea

Resorcinol

m-dihydroxybenzene

• weak antiseptic

• 1-3% solution

• 10-25% paste for skin diseases

Hexylresorcinol, USP

• Antiseptic

• mild anesthetic

• throat lozenges

• phenol coefficient 98%

Oxidizing agents

• Effective against anaerobes

• used in contaminated wounds

• poor tissue penetration

Oxidizing agent MOA

Liberation of oxygen

Hydrogen peroxide

• Short acting germicide

• enzyme destroyed in wounds

Carbamide peroxide

• Urea hydrogen peroxide complex

• 12.6% in anhydrous glycerin

Carbamide peroxide

• Oral ulcerations

• dental care

Benzoyl peroxide

• Unstable

• keratolytic

• acne treatment 5-10%

Benzoyl peroxide MOA

Epithelial proliferation causing sloughing and repair

Halogen compounds MOA

Iodination and oxidation of proteins

Iodoform

• Triiodomethane

• bactericidal

• fungicidal

Elemental iodine

• Oldest germicide

• used as tincture and liniment

Iodine tincture

2% iodine in 50% alcohol with sodium iodide

Lugol solution

5% iodine in water with POTASSIUM iodide

Povidone iodine

Polyvinylpyrrolidone complex

10% iodine

non-toxic

non-irritating

non-staining

Hypochlorous acid

• Active germicidal species

• formed when chlorine dissolves in water

Halazone sodium

Disinfects drinking water

Chlorazodin

Azochloramid®

• wound dressing

• long-lasting antiseptic due to extremely slow reaction with water

Oxychlorosene sodium

• Broad spectrum

• 0.1-0.5% solution

• used in urology and ophthalmology

Cell wall Lysis

Cationic surfactants MOA

Quaternary NH4+ compounds

• cationic head hydrophobic tail

• broad G+ and G– coverage

Cationic surfactant

ADVANTAGES:

• Broad spectrum

• water soluble

• stable

• non-staining

• non-corrosive

DISADVANTAGES:

• Inactivated by soaps

• blood

• pus

• not active against spores