Organic

Medicinals
Jelly Mae T. Oviedo, RPh
Lesson Outline
⬢ Pharmacology of Drugs
⬢ Physicochemical Properties of
Drugs
⬢ Structure Activity Relationship
⬢ Antifungals
⬢ Antibiotic
⬢ Antitubercular Agents
⬢ Antibacterials

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Welcome
to the ‘hands’ and ‘legs’ of
pharmacy!

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1 Pharmacology
Pharmacodynamics - mechanism of action; what the
drug does to the body
Pharmacokinetics- LADMER; what the body does
to the drug
 “
Organic chemistry deals with the
structure, properties, and reactions
of organic compounds and other
materials that contain carbon and
involves the study of chemical
reactions. Chemistry faculty
conduct scientific studies on the
chemistry of DNA,  proteins, and
carbohydrates.

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 Physicochemical properties of the Drug
affecting biological action:
I.- release
Liberation
of drug from the dosage form
Requirements:
*must be in aqueous solution
dissolution - is the rate limiting step for absorption
*must be in unionized form
- to cross selectively permeable membrane
weakly acidic- absorbed in the stomach
weakly basic- absorbed in the intestine

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 small intestine - site of absorption of most drug
- has largest surface area due to presence of
microvilli
 Lungs - the most perfused organ
alveoli-where blood oxygenation happen

*Drugs are formulated with salts for easy absorption

Ex. Phenytoin Na, Ampicillin Na( sodium salt has
increased solubility)
Salts - used in the determination of the acidity and basicity of
the drug
Ex. Phenytoin(basic) HCl(acidic)
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 Prodrugs
-inactive in vitro but active in vivo

Importance of prodrug:
1. enhance absorption of drug (enalapril-
enalaprilat)
2. facilitate drug reaching the target site
3. alter solubility/taste of the drug
(chloramphenicol palmitate)
4. facilitate formulation of dosage form
(methylprednisolone)
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II. Absorption
- drug reaches systemic circulation

*Chemical structure
Aminoglycoside - polar; not absorbed orally thus given
parentally
-ototoxic, nephrotoxic
*Variation in particle size - dec particle, increase surface
area and absorption
*Variation in surface area
*Nature of crystalline form

Polymorphism - ability to exist in more than one crystalline form

Amorphous - randomly arrange and are more absorbed than
crystalline state
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insulin - classified according to duration of action
semilente - short acting, made up of 100% amorphous
lente - intermediate, 30% amorphous:70% crystalline
ultralente - long acting, made up of 100% crystalline
ampicillin Na - anhydrous
ampicillin Na.3H2O - hydrous (beta-lactam ring is susceptible to
hydrolysis
*Types of Tablet Coating
*Types of Tablet Matrix - modified release
III. Distribution
- to reach the target receptor site; only free drug exerts
pharmacologic action

Protein binding
albumin - basic protein that regulates the osmotic pressure,
attracts water from extravascular to blood vessels
-binds to weakly acidic drugs

alpha- acidglycoprotein - binds to weakly basic drugs

alpha- globulin
increase drug-protein binding - decrease drug distribution

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Functions of protein binding
act as buffer and transport
subject to displacement
warfarin - 95% protein bound
phenylbutazone - 98% protein bound

*two highly protein bound drugs concurrently used will have toxic
effect
Al-War + Ph -----> Al-Ph + War(toxic effect - bleeding)
Tissue depots - lipophilic drugs; adipose tissues

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Drug-Receptor interaction
- induced fit theory
agonist - has affinity and intrinsic factor
antagonist - has affinity but no intrinsic activity

Variables:
1. structural class - drugs with the same structure and receptor
2. three dimensional shape - ex. Thalidomide
3. chemical bonding - strength of intermolecular forces between
molecules

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IV. Metabolism
- to prepare drugs for excretion; convert drugs to polar,
pharmacological inactive and excretable form.
*first pass effect - drugs are metabolized prior to absorption; it is
caused by hepatocytes

2 Phases of Metabolism:
Phase 1 or Functionalization Phase - introduces a polar functional
groups (-OH, -COOH, -NH2, -SH) into a xenobiotic molecule
Enzyme system - cytochrome monooxyginase or mixed function
oxidases
CYP450-most important component
CYP3A4 - most dominant; inhibited by grapefruit

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Reactions:
1. Oxidation - the most common Phase 1 metabolism
a. alcohols - carboxyllic acid
primary alcohol - carboxylic acid
secondary alcohol - ketones
b. Oxidative N, O, S dealkylation to produce -NH2, -OH, -SH
c. Oxidation of aromatic moeity
arene to phenol
d. aliphatic hydroxylation

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Reactions:
2. Reduction
a. aldehydes and ketones to alcohol
ex. chloraldehyde to trichloroethanol (aldehyde
reduction)
b. Reduction of azo and nitro to NH2(amino compound)

3. Hydrolysis - major pathway for acid derivatives, esters, amides

*esters : Aspirin - esterases -> salicylic and acetic acid
*amide: lidocaine(anesthetic) - amidases

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Phase 2 or conjugation Phase
- attach a small polar, ionizable endogenous compound to
functional groups of Phase 1 to form conjugated products.

*Methylation or Acetylation - terminate or atenuate biological

activity of the drug and not generally increase water solubility.

a. Glucoronidation - most common; uses UDP- glucuronyl

transferase

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Glucoronidation is common reaction:
it increases water solubility

*Chloramphenicol - causes Gray Baby syndrome due to decrease

glucuronidation in neonates.

bilirubin - metabolite produce from destruction of old RBC

-yellow pigment responsible for the color of urine and feces
-causes jaundice(treated by an enzyme inducer
Phenobarbital)

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b. Sulfate conjugation - mostly to phenols, well developed
in neonates (main route of paracetamol conjugation in pedia)
c. Glycine or glutamine conjugation - conjugated to
aromatic acids
*benzoic acid to hippuric acid
d. Glutathiochemically reactive compounds
Glutathione - tricopeptide from gamma cysteine, an antioxidant
(protect the body from chemically active compounds and
metabolites)
Paracetamol intoxication(NAPQ) - it has 3 pathways, cause
intoxication glutathione is not available
Antidote:N-acetylcysteine provide the formation of glutathione

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e. Acetylation - primary amines or aromatic amines ; uses N-
acetyl transferase

Genetic polymorphism - difference in DNA sequence among

individuals, groups, or populations.
 slow acetylator - caucasian or egyptian
 fast acetylator - orientals or eskimos

Isoniazid - peripheral neuritis

Hydralazine - SLE like syndrome

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f. Methylation - important for the biosynthesis of many endogenous
compounds like biogenic amines (dopamine, norepinephrine, epinephrine)
- minor pathway for drugs

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V. Excretion
- major pathway/route if kidney

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Structural Activity
Relationship 23
1. Local Antiinfectives/Germicides
kills microorganism
Antiseptics - kill microorganism in living things
Disinfectants - kill microorganism in inanimate object

A. Alcohol and related compounds

SAR: *increase # C - increase antibacterial but up to C8
*increase branching - decrease antibacterial activity
1'>2'>3>
A. Alcohol and related compounds
1. Alcohol (ethanol/grain alcohol/wine spirit/spiritus vini rectificatus)
manufacturing: fermentation of grapes, hydration of ethene
*Alcohol, USP (95%)
*Dehydrated/Absolute alcohol (99%)
*Diluted alcohol (49.5-50%)
*Isopropyl alcohol (70%)
uses: astringent, rubefacient, refrigerant, mild anesthetic
*denatured alcohol - unfit for use in intoxicating beverages
contaminants:
methanol(wood alcohol) - convert to formic acid (increase concentration in
the eyes causes Snowstorm vision
benzene - causes bone marrow depression (Aplastic anemia, leukemia)
A. Alcohol and related compounds
2. Ethylene oxide -gas sterilant for equipments and pharmaceuticals
that cannot be autoclave; very toxic and carcinogenic
MOA: alkylation of functional groups in nucleic acid and proteins

3. Formaldehyde - 37% HCHO with methanol to prevent polymerization

*paraformaldehyde, formic acid
-disinfectant and embalming agent
MOA: direct nonspecific alkylation of nucleophilic functional group

4. Glutaraldehyde (Cidex) -sterilizing solution for equipment that cant be

autoclaved.
B. Phenols and their derivatives
SAR: *alkyl, aryll, halogen at para position -increase
antibacterial activity
*branching -decrease antibacterial activity

1. Phenol
- is also termed by Joseph Lister as carbolic acid
-sterile standard from which most germicides are compared

Phenol coefficient - measures disinfectant potency

- ratio of dilution of disinfectant to the dilution of
phenol required to kill a strain of S. typhi
B. Phenols and their derivatives
1. Phenol
*creosol (Lysol) - methyl phenol
*liquid phenol - phenol with 10% water
*resorcinol - keratolytic
*thymol - fungicidal for treatment of tinea infection
-extracted from Thymus vulgaris
MOA: low concentration - precipitation of bacterial protein
high concentration - lysis of bacterial cellwall
C. Oxidizing agent
MOA: *liberation of nascent O (peroxides)
Allotropes - special kind of polymorphism
O - nascent oxygen (active against anaerobes)
O2 - oxygen
O3 - ozone
*denaturation of proteins (permanganate)
soap and water - best cleansing for contaminated wounds

1. Carbamide peroxide
- combination of urea and H2O2
- antiseptic and disinfection
C. Oxidizing agent
2. Hydrous Benzoyl Peroxide (Panoxyl)
-keratolytic and keratogenic for pimple and acne
MOA: induces proliferation of epithelial cells that would lead to sloughing
repair
D. Halogen containing compounds
Fluorine - is the most powerful oxidizing agent

1. Chlorine
-water disinfectant; strong oxidizing agent
*NaOCl - bleaching diisinfectant
*Halazone - disinfect drinking water
D. Halogen containing compounds
2. Iodine
*iodine tincture - 2% iodine in 50% alcohol with NaI
*strong iodine solution (lugol's solution) - 5% iodine in KI solution
*Iodine solution -2% iodine in NaI
*Iodophores - nonionic surfactant complexes I2
e.g. povidone ioodine (Betadine) - has PVP as solubilizing agent
MOA: iodination/chlorination and oxidation of the sulfhydryl group
E. Quaternary ammonium compounds/Cationic surfactant
1. Benzalkonium chloride
-disinfectant; emulsifying agent and wetting agent

2. Methylbenzethonium chloride (Diaperene)

-control diaper rash
*urine has bacteria that converts urea to ammonia
-Bacterium ammoniagenes
-Candida albicans
3. Cetylpyridinium Cl
-for manufacturing of mouthwashes and lozenges

4. Chlorhexidine
-irrigation and mouthwashes
F. Dyes
Cation dyes - active against g(+) bacteria and fungi

1.Gentian violet/Crystal violet

-hexamethyl-p-rosanilin Cl
-use in vaginal suppositories for yeast
-antihelminthic in Strongyloides and oxyuriasis

2. Basic fuchsin
-ingredient of carbol fuchsin (castellani's paint)
-treatment for fungal infection like ringworm and athlete's foot

3. Methylene blue
-antidote for cyanide poisoning
G. Heavy Metals
-due to oligodynamic action

1. Silver
-bind to sulfydryll group
-ability of the metal to inhibit the growth of microorganism
*Silver nitrate
-gonococcal opthalmitis newborn
-obsolete, the current treatment now is Erythromycin and
Tetracycline
*Silversulfadiazine (Flammazine,SIlvadine)
-used for burn infection prevent P. Aeroginosa
G. Heavy Metals
2. Mercury - “Messenger of God”
Hg2Cl2 - mercurous chloride (calomel)
HgCl2 - mercuric chloride (corrosive sublimate
HgCl - ammoniated mercury (white precipitate)
*Thiomersal(Methiolate)
-bacteriostatic; preservative for vaccines and antitoxin

MOA: reaction with -SH group in proteins

Antidote: BAL
H. Preservatives
-prevent microbial contamination
-apply to multiple close vials (max 30ml)

1. Paraben
-para-hydroxybenzoic acid
-preservative in liquid dosage form; antifungal properties
*methylparaben - molds
*propylparaben – yeasts

2. Chlorobutanol
- bacteriostatic in pharmaceutical for injection
-ophthalmic use and intranasal administration
H. Preservatives
3. Benzyl alcohol
-preservative in vial of injected drugs
-applied in lotion and ointments for treatment of various pruritic
conditions
4. Benzoic acid
-antiseptic in lotions, ointment and mouthwashes
-most effective as preservative in food and pharmaceutical at low
pH
5. Sorbic acid
- use to preserve syrup, elixirs and lotions containing components
such as sugar that support mold growth
ANTIFUNGALS:
A. Synthetic
1. Fatty acids - fungicidal
*Undecylenic acid -destructive distillation of castor oil
2. Azole
MOA: inhibit CYP450 enzyme of fungi
a. Imidazoles - topical (Ketoconazole, Clotrimazole)
b. Triazol - oral/parenteral:
*Fluconazole - only parenteral with CSF penetration
DOC: Cryptococcal meningitis and prophylaxis cryptococal
infection in AIDs
*Voriconazole - invasive aspergiloses
*Itraconazole - blastomyces, sporothrix, chromoblastomyces
ANTIFUNGALS:
3. Allylamines
MOA: inhibition squalene epoxidase
increase squalene - damages fungal cell membrane
*Terbinafine(Lamisil), Naftifine - ringworm, athlete's foot, jock itch

4. Nucleoside antifungal
-sugar base with nucleic acid
*Flucytosine -serious systemic infection by Candida
and Cryptococcus with Amphotericin B
cyrosine permease - found in fungal cellwall that allows the drug to
enter
ANTIFUNGALS:
B. Antibiotic antifungal
1. Polyene antibiotics
SAR: conjugated bond system in macrocyclic lactone ring
MOA: bind with sterols in fungal cell membrane to causes
disorganization and loss of cell constituent like K ions

a. Amphotericin B (Fungizole)
-obtain from S. nodosus
-DOC for serious systemic fungal infection
A/E: nephrotoxic, pain at the injection site
ANTIFUNGALS:
b. Nystatin(Mycostatin)
-obtained from S. nourseie
-topical used for oral thrush
c. Natamycin(Nataci)
-obtained from S. natalensis
2. Griseofulvin
MOA: acts on microtubule inhibiting cell division of fungus
-obtained from P. griseufulvum
-absorption increase with fatty foods and meals
-from basal to corneum
-treatment for systemic tinea infection
 Antitubercular Agents
acid fast microorganism - due to presence of mycolic acid
-M. tuberculosis, M. leprae
Intensive Maintenance
I. NEW - 2 months RIPE 4 months RI
2. RESISTANT - 2 months RIPE 1 month RIP, 5 months RI

1. Isoniazid (isonicotinic hydrazide)

MOA: ninhibit synthesis of mycolic acid
A/E: peripheral neuritis -give Vit B6
Antitubercular Agents
2. Ethambutol
MOA: inhibit incorporation of mycolic acid in cell wall
inhibit arabinosyl transferase
S/E: optic neuritis/retrobulbar
3. Pyrazinamide (pyazone carboxamide)
A/E: hyperuricemia, arthralgia, hepatotoxic
4. Rifampicin
-from S. meditteranei
MOA: inhibit DNA dependent RNA polymerase
-most active agent in clinical use for treatment of tuberculosis
-enzyme inducer
A/E: hepatotoxic, reddish-orange secretion
Antitubercular Agents
5. Streptomycin
-first aminoglycoside used for tuberculosis
6. Amikacin
- resistant to streptomycin
7. PAS
-similar to sulfonamide
8. Ethionamide
-structural analogue of Isoniazid; for isoniazid resistant
9. Cycloserine, Capreomycin
Antileprosy: *Dapsone, *Rifampicin
*Clofazamine - treatment for lepromatous leprosy
*Thalidomide - treatment for multiple myeloma angiogenesis
Antibacterial
I. Drugs acting on Cell membrane
(Peptidoglycan)
Beta-lactam - a four membered cyclic amide
- useful for microorganism actively dividing like g(+) and
anaerobes
MOA: inhibit of cell wall synthesis by binding to PBP
PBP - responsible from transpeptidation and cross-linking of cell
wall
PENICILLINS
1. Natural Penicillin - discovered by Alexander Fleming
from P. notatum - new source was P. chrysogenum
isolated by Florey and Chain
*6-aminopenicillanic acid-beta-lactam-thiazolidine ring
A/E: allergies caused by penicilloyl proteins, an antigenic
determinants
Antibacterial
1. Natural Penicillin
a. Pen G - benzyl penicillin given IV
b. Pen V - phenoxymethylpenicillin given
orally for minor infection
c. Repository forms - depot preparations;
given IM with prolonged drug concentration
e.g. Benzathine(1month) and
Procaine(1week)
SAR: *6-APA - is prone to hydrolysis
*e-withrawing group in acyl side chain -
acid resistance
Antibacterial
2. Penicillinase Resistance Penicillin
isoxazolyl penicillin p- also known as antistaphylococcal penicillin
SAR: *inc steric hindrance by a-carbon of acyl group - inc B-lactamase
resistant

a. Methycillin (2,6-dimethoxyphenyl penicillin)

- first semisynthetic phenicillin with staphyloccocus resistance
-acid labile; renal toxicity
b. Oxacillin (5-methyl-3-phenyl-4-isoxazolyl penicillin)
- given IV
c. Cloxacillin (Oxacillin + Cl)
-given orally
Antibacterial
3. Extended Broad Spectrum
SAR: introduced an ionized polar group into a-position of side chain benzyl
Carbon of Pen G - act against g(+) bacilli, P. aeruginosa

a. Aminopenicillin
- orally active; with g(-) activity
*Ampicillin (a-aminobenzyl penicillin)
*Bacampicillin
*Amoxicillin (a-amino-para-hydroxypenicillin)
Antibacterial
4. Antipseudomonal penicillin
*Carbenicillin - with carboxyllic group
-act against Pseudomonas, Kleibsiella, Enterobacter
*Azlocillin, Piperacillin, Mezlocillin - ureidopenicillin (with
urea group)
Antibacterial
CEPHALOSPORIN
(7-aminocephalosphoranic acid)
SAR: beta lactam ring + dihydroxythiazine ring - greater
resistant to acid hydrolysis and beta lactamase
Antibacterial
CARBAPENEMS
- broadest spectrum of all beta lactams
1. Thienamycin
-prototype; obtained from S. cattleya;
-unstable and hydrolyze by renal dihydropeptidase(DHP)
2. Imipenem
- for Enterobacter species
- commercially available with Cilastatin (inhibit renal DHP)
3. Meropenem
- not metabolized by renal DHP
- more active against Pseudomonas aeruginosa
4. Ertapenem
- similar to Meropenem but with longer half-life
Antibacterial
MONOBACTAM
d. Astreonam - no g(+) activity
Antibacterial
B-LACTAMASE INHIBITOR
-suicide drugs
1. Clavulanic acid + Amoxicillin (Augmentin)
2. Sulbactam + Ampicillin (Unasyn)
3. Tazobactam + Piperacillin (Tazocin)
Antibacterial
GLYCOPEPTIDE ANTIBIOTICS
1. Bacitracin
-from B. subtilis from bone of Margaret Tracey
MOA: inhibit mucopeptide cell wall synthesis

2. Vancomycin
- obtained from S. orientalis
- treatment for pseudomonas colitis; MRSA
- not orally absorbed and given IV
A/E: Redman's Syndrome - a hypersensitivity caused by rapid infusion
Tx: Diphenhydramine
Antibacterial
I. Drugs acting on Cell membrane (Peptidoglycan)
II. Acting on Plasma membrane
polypeptides - renally toxic

1. Gramicidin
- obtained from B. brevis
MOA: act as ionophores that allows uncontrolled movement of ions
across cell membrane

2. Polymyxin
- obtained from B. polymyxa; used topically for g(-) bacteria
Antibacterial
I. Drugs acting on Cell membrane (Peptidoglycan)
II. Acting on Plasma membrane
III. Acting on protein synthesis
- all are bacteriostatic except Aminoglycoside
1. Aminoglycoside
MOA: prevention of initiation complex
-misreading of codons
*Neomycin - nephrotoxic; topical
SAR: 3 rings of amino sugars linked glycosidically
ring 1 - essential for activity; polar in nature which given parenterally
A/E: ototoxic, neurotoxic, nephrotoxic
Antibacterial
I. Drugs acting on Cell membrane (Peptidoglycan)
II. Acting on Plasma membrane
III. Acting on protein synthesis
- all are bacteriostatic except Aminoglycoside
2. Tetracycline
MOA: blocks aminoacyl tRNA
- renally excreted except Doxycycline
-broadest spectrum of all antibacterials
-for atypical microorganism
-bacteriostatic action against g(+), g(-), spirochete, mycoplasma,
ricketsia, chlamydia
*Doxycycline - prophylaxis for leptospirosis
Antibacterial
I. Drugs acting on Cell membrane (Peptidoglycan)
II. Acting on Plasma membrane
III. Acting on protein synthesis
- all are bacteriostatic except Aminoglycoside

4. Macrolides
SAR: macrocyclic lactone ring sugar/ketone aminosugar - activity
*Erythromycin
- prototype; drug of choice for Legionnaire's disease and diphtheria
-alternative to penicillin for g(+) bacterial infection, mycoplasma,
chlamydia, campylobacter, legionella
A/E: GI discomfort (estolate form), acute cholestatic jaundice
Antibacterial
I. Drugs acting on Cell membrane (Peptidoglycan)
II. Acting on Plasma membrane
III. Acting on protein synthesis
- all are bacteriostatic except Aminoglycoside

5. Lincosamide
- obtained from S. lincolnensis
- active against g(+) and nonspore forming anaerobes
*Clindamycin - treatment for anaerobe infection above diaphragm
A/E: pseudomembranous colitis
Antibacterial
I. Drugs acting on Cell membrane (Peptidoglycan)
II. Acting on Plasma membrane
III. Acting on protein synthesis
- all are bacteriostatic except Aminoglycoside
6. Streptogramins
- for g(+) cocci and MRSA
Antibacterial
I. Drugs acting on Cell membrane (Peptidoglycan)
II. Acting on Plasma membrane
III. Acting on protein synthesis
- all are bacteriostatic except Aminoglycoside
7. Oxazolidinediones
*Linezolid - for g(+), MRSA, Vancomycin-resistant
Antibacterial
I. Drugs acting on Cell membrane (Peptidoglycan)
II. Acting on Plasma membrane
III. Acting on protein synthesis
IV. Acting on Nucleic Acid
1. Quinolones
-patterned after Nalidixic acid
MOA: inhibit DNA gyrase (responsible for DNA supercoiling)
SAR: *4-dihydro 4-oxopyridine carboxyllic acid - essential for activity
*F at position 6 - enhance g(+) activity
*Piperazinyl at position 7 - act against Pseudomonas
*Halogen at position 8 - phototoxicity
*Ciprofloxacin - drug of choice for UTI; for pseudomonas
Antibacterial
I. Drugs acting on Cell membrane (Peptidoglycan)
II. Acting on Plasma membrane
III. Acting on protein synthesis
IV. Acting on Nucleic Acid
2. Metronidazole
- drug of choice for trichomonas, amoebiasis and giarda infection
- for anaerobe infection below the diaphragm
- has metallic taste and disulfiram-like effect
Antibacterial
I. Drugs acting on Cell membrane (Peptidoglycan)
II. Acting on Plasma membrane
III. Acting on protein synthesis
IV. Acting on Nucleic Acid
2. Metronidazole
- drug of choice for trichomonas, amoebiasis and giarda infection
- for anaerobe infection below the diaphragm
- has metallic taste and disulfiram-like effect
Antibacterial
I. Drugs acting on Cell membrane (Peptidoglycan)
II. Acting on Plasma membrane
III. Acting on protein synthesis
IV. Acting on Nucleic Acid
V. Drug acting on Cell Metabolism:
1. Sulfonamides
-parent drug is Prontonsil dye
MOA: inhibit dihydropteroate synthase
A/E: crystalluria(acidic), Steven Johnson's Syndrome
*Cotrimoxazole(Bactrim, Septra)
Trimetoprim + Sulfamethoxazole (static+static=cidal)
Clinical Use:
1. Treatment and prophylaxis of P. jirovecii and P. carinii
DOC: Cotrimoxazole, Alternative: Pentamidine
2. First attack of UTI
3. Burn therapy - Silver sulfadiazine(Flamazine), Mafenide
4. Chloroquine resistant malaria
- Sulfadoxime+Pyrimethamine (Fansidar)
5. Conjunctivitis and ocular infection - Sodium
sulfacetamide

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THANKS! 69