ORGANIC MEDICINAL CHEMISTRY – REVIEW NOTES

Prepared by: John Bryan G. Ruba, RPh

METABOLISM

o The biotransformation of drugs in the body

o Important in the elimination of drugs from the body
o Converts drugs to hydrophilic, inactive and nontoxic
o Liver is the primary organ
o Has 2 Phases: Functionalization & Conjugation

Phase I / ___________________
o Introduce a polar functional group (OH, COOH, NH2, SH) by:
o Direct introduction
o Modifying/Unmasking existing functionalities
o Produce a handle on the molecule for Phase II
o Reactions: Oxidation, Reduction, Hydrolysis

1. Oxidation
o Most common phase I reaction
o Undergone by Olefins, Alcohols, Aldehydes & Aromatic moieties
o ex. Phenylbutazone – ______________________→ oxybutazone
2. Reduction
o Carbonyl compounds → Alcohol derivatives
o Nitro and Azo compounds → Amine derivatives
o ex. Chloral hydrate → Trichloroethanol
Prednisone –____________________→ Prednisolone
3. Hydrolysis
o Commonly undergone by lactams, esters and amides
o ex. Aspirin → ______________________________________

Phase II / Conjugation
o Attach _____________________________________ compounds to the functional handles
o Reactions: Glucuronidation, Sulfation, Glycine & Glutamine conjugation, Glutathione, Acetylation,
Methylation
o Purpose:
1. Form excretable & inactive metabolites
2. Terminate/Attenuate activity
3. Detoxify

1. Glucuronidation
o Coenzyme: Uridine-5’-diphospho-α-D-glucuronic acid (UDPGA)
o Transferase enzyme (TE): ______________________________________
o Most common because:
o Readily available supply of D-glucuronic acid
o Numerous functional groups can combine with glucuronic acid
o The glucuronyl moiety produces hydrophilic product
o Not yet developed in neonates

2. Sulfation
o Coenzyme: 3-phosphoadenosine-5-phosphosulfate (PAPS)
o TE: ______________________________________
o Yields water soluble and inactive conjugates
o Conjugate endogenous compounds such as steroids, heparin, chondroitin, catecholamines,
thyroxine
o In ________________, sulfation is the major process.
 3. Glycine & Glutamine conjugation
o Conjugate ____________________, particularly aromatic acids & arylalkyl acids
o _______________ – common to mammals
o _______________ – humans & other primates
o Minor pathway
o Benzoic acid → ___________________ - The first mammalian metabolite discovered from
glycine conjugation

4. Glutathione
o For detoxifying chemically reactive _______________ compounds
o Glutathione is composed of 3 amino acids:
o ______________ - (-SH) is responsible for detoxification
o Glycine
o Glutamine

5. Acetylation
o For termination of activity & detoxification
o Important route of primary amino groups
o Acetyl group supplier: Acetyl-CoA
o TE: _____________________
o Undergone by sulfonamides
o Acetylation polymorphism – variation in acetylating activity
o Slow acetylators – Europeans, Caucaseans, Egyptians
o Fast acetylators – _____________________

6. Methylation
o Coenzyme: S-Adenosylmethionine (SAM)
o TE: _____________________
o Minor pathway that leads to __________________________ compounds
o Biosynthesis of _______________________________
o Inactivation of norepinephrine, dopamine, serotonin, histamine

First-Pass Metabolism / Presystemic metabolism

o When orally administered drugs are extensively metabolized before reaching the systemic circulation
o Drugs with extensive first pass effect:

Morphine Propoxyphene Salicylamine

Meperidine Propranolol
Nitroglycerin Isoproterenol
Pentazocine Lidocaine

ENZYME INDUCERS ENZYME INHIBITORS

Griseofulvin Metronidazole
Omeprazole Erythromycin (Macrolides)
Meprobamate Disulfiram, Diltiazem
St. John’s Wort Isoniazid, Indinavir
Phenytoin Cimetidine, Chloramphenicol, Ciprofloxacin
Phenobarbital Ketoconazole
Rifampicin Acute Alcoholism
Carbamazepine Valproic acid, Verapamil
Chronic Alcoholism Grapefruit juice
Cigarette smoking
 ANTI-INFECTIVE AGENTS

Terms:
o Antisepsis – appln. of agent to living tissue to prevent infection
o Decontamination – destruction or reduction in the number of microorganism
o Disinfection – chemical or physical tx on inanimate surfaces
o Sanitization – reduction of microbial load on inanimate surface to a level acceptable for public health
purposes
o Sterilization – kill or remove all types of microorganisms
o Pasteurization – kills nonsporulating microorg. By hot water @ 65C-100C
o Germicides – anti-infective agents used locally
o Cidal – kill
o Static – prevent growth

A. Alcohols & Related compounds

o SAR:
1. ↑ # of C - ↑ antibacterial activity up to C8 only
2. ↑ 9C – nonpolar ↓ water solubiity, ↓ antibacterial activity
3. Branching decreases antibacterial property (except isopropyl alcohol = more potent, cheaper,
less toxic ; 60%EtOH = 40% Isopropyl Alc)
4. Isomeric alcohol potency decrease in the order: Primary > Secondary > Tertiary
o MOA: Protein denaturation/precipitation

1. Alcohol, USP
o ethanol, grain alcohol, wine spirit, cologne spirit, spiritus vini rectificatus
o most widely abused of all recreational drugs
o commercial ethanol (95%)
o Manufactured by:
▪ Fermentation of grains and other CHOs
▪ Hydration of ethene
o Metabolism:
▪ Ethanol → Acetaldehyde → Acetic acid

Ethanol to Acetaldehyde Enzyme: alcohol dehydrogenase

Acetaldehyde to Acetic acid Enzyme: aldehyde dehydrogenase

Drugs that interfere with alcohol metabolism

1. Fomepizole
• Inhibits alcohol dehydrogenase
• Used as an antidote for methanol poisoning
2. Disulfiram
• used as a deterrent for alcohol addiction
• inhibits aldehyde dehydrogenase
• accumulation of aldehyde = extreme hangover like symptoms (nausea, vomiting,
vasodilatory flushing)
 Types of Alcohols
Absolute alcohol 95% alcohol
Dehydrated alcohol 99% alcohol, prepared by azeotropic distillation
Diluted alcohol 49-50% alcohol
Denatured alcohol EtOH rendered unfit for use in beverages by the addition of subs.
Completely denatured alcohol contains added wood alcohol and benzene unsuitable for internal
or external use
Specially denatured alcohol treated with subs. so that its use is permitted for specialized
purpose ex. Iodine in alcohol

2. Isopropyl alcohol
o aka: 2-propanol
o substitute for ethanol
o Prepared by sulphuric acid catalysed hydration of propylene
3. Ethylene Oxide
o C2H40
o MOA: alkylation of bacterial protein by nucleophilic opening of oxide
ring Isopropyl alcohol

o used to sterilize (gas sterilant) temperature sensitive

pharmaceuticals and equipment that cant be autoclaved
o Carboxide – 10% ethylene oxide + 90% CO2
4. Formaldehyde
o aka: Methanal, HCHO Ethylene oxide
o MOA: direct and nonspecific alkylation of nucleophilic functional
groups of proteins
o contains nlt 37% of formaldehyde
o Uses: embalming fluid, disinfectant
5. Glutaraldehyde (Cidex)
o aka: Glutarol Formaldehyde
o sterilizing solution for equipment and phcals that cannot be
autoclaved
o used in medical mission in remote areas

B. Phenol & its derivatives

1. Phenol, USP Glutaraldehyde
o aka: Carbolic acid, C6H5OH
o discovered by Joseph Lister
o SAR:
o Substitution at para position increases bacterial activity
o Activity: straight chain alkyl> branched
o Germicidal standard
Phenol coefficient = ____Dilution of a disinfectant____ Phenol
Dilution of phenol that is required
to kill a strain of Salmonella typhi
2. Liquified phenol – phenol with 10% water
3. p-chloro-m-xylenol
o aka: PC-MX, Metasep
o antibacterial & antifungal
 4. Hexachlorophene
o aka: pHisoHex
o in soaps, lotions, shampoos
5. Cresol
o Methylphenol
o From coal tar or petroleum by alkaline extraction Cresol
6. Thymol
o Isospropyl m-cresol
o from oil of Thymus vulgaris (Thyme)
o Antifungal property
7. Eugenol
o 4-allyl-2-methoxyphenol
o from clove oil
Thymol
o dental analgesic “toothache drops” , used in mouthwashes
8. Resorcinol
o m-dihydroxybenzene
o keratolytic agent
9. Hexylresorcinol
Eugenol
o in throat lozenges

C. Oxidizing agents
o effective against anaerobic bacteria
o MOA: liberation of oxygen in the tissues (peroxides)
Resorcinol

1. Hydrogen Peroxide (H2O2)

o Used for cleansing contaminated wounds
o Transient action (rapid action, short duration)
2. Carbamide Peroxide
o complex of urea and H2O2
3. Hydrous Benzoyl Peroxide (Vanoxide, Panoxyl)
o most effective topical OTC agent for acne

D. Halogen containing compounds

1. Iodine (I2) compounds
o oldest germicide in use today
o MOA: Inactivate proteins by 1. iodination of aromatic residues (phenylanalyl & tyrosyl)
2. oxidation (sulfhydryl groups)

Official iodine preparations in the USP

Iodine solution 2% in H2O with NaI
Strong Iodine Solution (Lugol’s) 5% I2 in H2O with KI
Iodine Tincture 2% in 50% alcohol with NaI

1. Inorganic iodide salts

o Admixed to increase the solubility of I2 and to reduce its volatility
o Ex. I2 + NaI
 2. Iodophors
o complexes of iodine and non-ionic surfactants
o retained germicidal properties, reduced volatility and removed irritant properties
o example: Povidone-Iodine (Betadine, [PVP]-Iodine)
- a complex with the non-ionic surfactant polymer, polyvinylpyrrolidone
3. Chlorine (Cl2) compounds
o Used for disinfection of water supplies
o MOA: chlorination of amide nitrogen atoms in proteins, oxidation of sulfhydryl groups

1. Hypochlorous acid (HClO) – active germicidal species formed when Cl2 is dissolved in water
2. Halazone
3. Chloroazodin
4. Oxychlorosene sodium

E. Cationic surfactants
o quaternary ammonium compounds that ionize in water and exhibit surface active properties
o inactivated by soaps and other anion detergents
o tissue constituents, blood, serum, and pus tend to reduce the effectiveness of these substances
o MOA: adsorb onto the surface of the bacterial cell, at which they cause lysis

1. Benzalkonium chloride (Merthiolate, Zephiran)

o new generic name of merthiolate
2. Methylbenzethonium Chloride (Diaparene)
o used to control diaper rash in infants caused by Candida albicans
3. Cetylpyridinium Chloride
o antiseptic in mouthwash and lozenges
o FDA approved for the Tx of gingivitis
4. Chlorhexidine gluconate (Hibiclens)
o Classified under biguanides
o not a cationic surfactant but share many physical, chemical and antimicrobial
properties
o used in oral surgery, mouthwash, and irrigation

F. Preservatives
o added to prevent prevent microbial contamination
o Ideal preservative
o effective at low concentrations Methylparaben
o nontoxic, compatible with other constituents of the preparation
o stable for the shelf life of the preparation
1. Parabens
o esters of p-hydroxybenzoic acid have antifungal properties
a. Methylparaben Ethylparaben
o Methyl-p-hydroxybenzoate
o Effective against molds
b. Propylparaben
o Propyl-p-hydroxybenzoate Propylparaben
o Effective against yeast
c. Butylparaben & Ethylparaben
o Preferred preservatives for drugs in oil or lipophilic bases
Butylparaben
 2. Chlorobutanol
o camphorlike aroma
o bacteriostatic agent in pharmaceuticals for injection, ophthalmic use, and intranasal
administration
3. Benzyl alcohol
o aka: phenylcarbinol, phenylmethanol
o from oil of jasmine
o preservative in vials of injectable drugs
o a/e: gasping syndrome
4. Benzoic acid
o Naturally from gum benzoin and in peru and tolu balsams
o effective as a preservative in food and pharmaceutical products at low pH
5. Sodium propionate
o antifungal
6. Sorbic acid
o Antifungal preservative in preserve syrups, elixirs, ointments, and lotions containing
components such as sugars

G. Dyes
o cationic dyes are active against gram(+) and fungi but gram (-) are generally resistant
Triphenylmethane dyes Thiazine dye

Methylene Blue (Urised)

Gentian violet (crystal violet,
methyl violet, methyl-rosaline
chloride)
- pessaries for that tx of yeast
infections (1-3%)
- anthelmintics for
strongyloides (liquid form)
-antidote for cyanide poisoning
-antiseptic property in tx of
cystitis and urethritis
-bacteriostatic
A/E: blue green color of stool

G. Mercury compounds (Mercurials)

1. Nitromersol
o at one time very popular antiseptic for skin and
Basic Fuschin ocular infections because it is nonirritating and
- mixture of chlorides of nonstaining
2. Thimerosal
rosaniline and p-rosaniline
o preservative of vaccines, antitoxins, and immune
- ingr. Of carbol fuschin aka sera
Castellani’s paint o old generic name of merthiolate
- Tx of fungi, ringworm &
athlete’s foot
 ANTHELMINTICS

o are drugs that are capable of eliminating parasitic worms or helminths

o helminths: Cestodes (tapeworms), Trematodes (flukes), Nematodes (roundworms)

Nematodes
1. Piperazine
o MOA: block response of ascaris muscle to Ach → ___________________
o Tx of pinworm, roundworm
2. Pyrantel Pamoate
o MOA: deporalizing Nm blocking agent → _____________________
o should not be used with piperazine (opposite effects)
o tx of pinworm, roundworm (ascaris)
3. Thiabendazole
o MOA: inhibit _____________________ / antimitotic / antimicrotubule
o broad spectrum anthelminthic
o In veterinary practice as anthelmintic in livestock
4. Mebendazole
o MOA: _____________________________ → depleted glucose / antimitotic / antimicrotubule
o broad spectrum (whip, pin, round, hook)
5. Albendazole
o MOA: antimitotic/antimicrotubule
o broad spectrum
6. Ivermectin
o from Streptomyces avermitilis
o MOA: _________________________ → blocked interneuron-motor neuron transmission
o Tx of onchocerciasis (river blindness) – Oncocerca volvulus
7. Diethylcarbamazine (DEC)
o MOA: unknown
o Tx of _____________________

Trematodes
1. Praziquantel
o MOA: ________________________ → loss of Ca → contraction → paralysis → phagocytosis (DEATH)
o Broad spectrum
o Agent of choice for blood flukes (schistosomes)
2. Niridazole – for schistosomiasis
3. Oxamniquine
o MOA: inhibit DNA, RNA, Protein synthesis
o Tx of Schistosoma mansoni
4. Bithionol
o Agent of choice for _____________ (Fasciola hepatica) and ____________ (Paragonimus westermani)

Cestodes
1. Niclosamide
o MOA: inhibit ________________________
 ANTIPROTOZOAL AGENTS

o protozoal infections: malaria, amoebiasis, giardiasis, trichomoniasis, toxoplasmosis, P carinii pneumonia

Amoebiasis (8 DIME)

Amebicides that are effective against both intestinal & extraintestinal forms of the disease:
1. Emetine and Dehydroemetine
o alkaloids from _________________
o MOA : inhibit protein synthesis by preventing protein elongation (protoplasmic poison)
o Also used for balatidial dysentery, fascioliasis, paragonimiasis
o Limited use due toxic effects (GI, cardiovascular, neuromascular)

2. Metronidazole (Flagyl, Protostat)

o MOA: covalent binding of reactive intermediate from the reduction of 5-nitro group to the DNA
→ lethal effect
o tx of amoeba, giardiasis, trichomonas, anaerobic bacterial infections
o a/e: _______________________ (if taken with alcohol)
3. Tinidazole

Amebicides that are effective only against intestinal form:

1. 8-hydroxyquinoline
o MOA: chelation of metal ions

2. Iodoquinol
o a derivative of 8-hydroxyquinoline
o for acute and chronic intestinal amebiasis

3. Diloxanide
o Tx of asymptomatic carriers of E. histolytica
o from discovery of α-dichloroacetamides

Pneumocystis carinii pneumonia (CAP)

1. Cotrimoxazole
o __________________________________
o DOC for PCP
2. Pentamidine Isethionate
o prophylaxis for African trypanosomiasis (rapidly distributed to tissues where it is stored)
3. Atovaquone
o analog of ______________, a component of mitochondrial electron transport chain
o MOA: Interfere with the electron transport chain as it is antimetabolite for ubiquinone

Trypanosomiasis (BS MEN)

1. Eflornithine
o MOA: irreversible inactivation of ________________________________
o tx of African sleeping sickness
o myelosuppressive (→ anemia, leukopenia, thrombocytopenia)
2. Nifurtimox
o tx of South American trypanosomiasis (T. cruzi)
3. Benznidazole
o Tx of _________________________
4. Melarsoprol
o DOC for later stages of both forms of African trypanosomiasis
 5. Suramin
o _____________ derivative containing six sulfonic acid groups
o used as a long term prophylactic agent for trypanosomiasis (due to high protein binding, effect
can last up to 3 months)
Toxoplasmosis
o Sulfadiazine + Pyrimethamine – most effective therapy

Leishmaniasis
1. Sodium Stibogluconate
o MOA: inhibit phosphofructokinase
o aka Sodium antimony gluconate
o tx of ____________________

ANTISCABIES & ANTIPEDICULAR AGETNS

Scabicides – agents that control the mite Sacroptes scabei

Pediculicides – used to eliminate head, body, and crab lice

SCABICIDES
1. Benzyl Benzoate
o from _________________, also from benzyl alcohol + benzoyl chloride
o topical scabicide
2. ________________________
o antipruritic (local anesthetic action)
o 10% - lotion/cream for scabies
o A colorless, odourless oily liquid

SCABICIDES & PEDICULICIDES

1. Permethrin
o MOA: acts on nerve cell membranes → disrupt Na+ channel conductance → paralysis
o synthetic pyrethrin
o 1% lotion- for the treatment of lice ; 5% cream - for the treatment of scabies
2. Lindane
o MOA: direct contact poison, fumigant effect, stomach poison
o chlorinated benzene (________________________)
 ANTIBACTERIAL AGENTS

I. Mechanisms of Antibacterial action

1. Inhibition of cell wall synthesis

2. Inhibition of protein synthesis
3. Inhibition of cell metabolism
4. Inhibition of nucleic acid transcription and replication
5. Interactions with plasma membrane

Inhibition of cell wall synthesis

A. Beta-lactam antibiotics

PENICILLINS
a. History
o Discovered by Alexander Fleming
o Old: Penicillium notatum
o New: Penicillium chrysogenum
o Isolated by _________________ by freeze drying/lyophilization

b. Properties
o Contains an unstable bicyclic system
o Beta-lactam & Thiazolidine ring
o Nucleus: 6-Aminopenicillanic acid (6-APA)
o Precursors: Cysteine & Valine
o Shape: _____________________
c. Structure-activity relationship (SAR)
o Addition of electron withdrawing group – ______________________
o Addition of bulky groups – _________________________
o Addition of amino group – _______________________________
d. Mechanism of action (MOA)
o Irreversibly inhibits ___________________ by covalently binding to the serine residue of the active site
thus inhibiting cell wall synthesis
e. Classification of Penicillins
e.1. Narrow spectrum penicillins / Natural penicillins
1. Penicillin G
o aka ______________________
o given IV
o depot forms: Benzathine penicillin & Procaine penicillin
o DOC: Syphilis

2. Penicillin V
o aka ______________________
o given PO

e.2. Penicillinase-resistant penicillins / Antistaphylococcal penicillins

1. Methicillin
o Prototype
o s/e: ___________________
o emergence of MRSA

2. Nafcillin
o Can be given to px with renal problems
 3. Oxacillin, Cloxacillin, Dicloxacillin
o Isoxazolyl penicillins
o Contains _________________________
o Dicloxacillin – best absorbed

e.3. Broad spectrum penicillins / Aminopenicillins

1. Ampicillin
o given IV
o Prodrugs: Bacampicillin, Hetacillin, Cyclacillin
o + Sulbactam = ________________
o DOC: Listeria monocytogenes

2. Amoxicillin
o given PO
o + clavulanic acid = _________________
o commonly used in respiratory infections

e.4. Extended spectrum penicillins / Antipseudomonal penicillins

1. Carbenicillin, Ticarcillin
o ________________________
o Carboxyl at the α-position

2. Piperacillin, Azlocillin, Mezlocillin

o ________________________
o Urea at the α-position
o Piperacillin – most potent

f. B-lactamase inhibitors
o Weak to none inhibitory activity, but are irreversible inhibitors of B-lactamase
o + Penicillins = ______________

1. Clavulanic acid
o From Streptomyces clavuligeris
o + Amoxicillin = _________________
2. Sulbactam
o Penicillic acid sulfone derivative
o + Ampicillin = ________________
3. Tazobactam
o Penicillic acid sulfone derivative
o + Piperacillin = ________________

g. Chemical degradation products

1. Penicilloyl proteins – antigenic determinant
2. Penilloic acid - major product of acid catalysed degradation of penicillin, penicillanic acid (intermediate)
3. Penicilloic acid – product of enzymatic degradation of penicillin and by weakly acidic to alkaline
 Drug Chemical name
Pen G Benzylpenicillin
Pen V Phenoxymethylpenicillin
Methicillin 2,6-Dimethoxyphenylpenicillin
Nafcillin 2-Ethoxy-1-Napthylpenicillin
Oxacillin 5-Methyl-3-phenyl-4-isoxazolylpenicillin
Cloxacillin 5-methyl-3-(2-chlorophenyl)-4-isoxazolyl penicillin
Dicloxacillin 5-methyl-3-(2,6-dichlorophenyl)-4-isoxazolylpenicillin
Ampicillin D-a-aminobenzylpenicillin
Amoxicillin D-a-amino-p-hydroxybenzylpenicillin
Carbenicillin a-carboxybenzylpenicillin
Ticarcillin a-carboxy-3-thienylpenicillin
Mezlocillin a-(1-methanesulfonyl-2-oxoimidazolidino-carbonylamino)benzylpenicillin

Chemical Structure
Methicillin

Penicillin G Penicillin V

Nafcillin Oxacillin Cloxacillin

Ampicillin Amoxacillin
Dicloxacillin

Mezlocillin

Carbenicillin Ticarcillin

Piperacillin
CEPHALOSPORINS
a. History
o ___________________ – the first cephalosporin
o Old: Cephalosporium acremonium
o New: Acremonium chrysogenum

b. Properties
o Contains an unstable bicyclic system
o Beta-lactam & Dihydrothiazine
o Nucleus: 7-Aminocephalosporanic acid (7-ACA)
o Precursors: ____________________
o Better acid stability & resistance to B-lactamase
c. Mechanism of action (MOA)
o Irreversibly inhibits transpeptidase by covalently binding to the serine residue of the active site thus
inhibiting cell wall synthesis
d. Generation of Cephalosporins
o Based on their bacterial spectrum of activity and B-lactamase resistance

First gen Second Gen Third Gen Fourth Gen Fifth Gen
Cefalexin Cefaclor Cefoperazone Cefepime Ceftibiprole
Cefadroxil Cefoxitin Ceftriaxone Cefpirome Ceftaroline
Cefazolin Cefuroxime Ceftibuten Ceftolozane
Cephalotin Cefonicid Cefdinir
Cephradine Cefamandole Cefixime
Cefpodoxime Cefotaxime
Cefprozil Moxalactam
Cefotetan Ceftidoxime
Loracarbacef Cefditoren

f. Clinical Uses
o Cefalexin – used for ________________________
o Cefazolin – _____________________________
o Ceftriaxone – New DOC: Typhoid fever
o Antipseudomonal cephs (Cefoperazone, Cefotaxime, Ceftazidime, Ceftriaxone, Moxalactam) – have
useful antipseudomonal activity

g. Side effects / Adverse effects

o Hypersensitivity
o Disulfiram-like reaction & Hypoprothrombinemia
o N-Methyl-5-thiotetrazole (MTT) containing cephalosporins
o Cefamandole, Cefotetan, Moxalactam, Cefoperazone

CARBAPENEMS

a. Properties
o Differ from penicillins in that the _____ atom has been replaced by ______ atom
o Broad spectrum of activity, including P. aeruginosa
b. Drugs
1. Thienamycin
o isolated from Streptomyces cattleya
o inactivated by _____________________
2. Imipenem
o N-formimidoylthienamycin
o + ____________ (renal dehydropeptidase inhibitor) = Tienam
3. Meropenem
o 2nd generation carbapenem
o Resistant to dehydropeptidases & B-lactamases
4. Ertapenem
o Benzoic acid contributes to high protein binding and prolongs the half life of the drug

MONOBACTAM
a. Properties
o Monocyclic B-lactams
o Inactive against ____________. Moderate activity against a narrow group
of gram negative bacteria, including P. aeruginosa.

b. Drugs
1. _________________
o isolated from Chromobacterium violaceum

B. CYCLOSERINE
o Sources: Streptomyces garyphalus, S. orchidaceus, S. lavendulus
o MOA: Prevent the formation of D-ala-D-ala (inhibits _____________________________________)
o Use: Second-line drug for tuberculosis

C. BACITRACIN
o A polypeptide from Bacillus subtilis, isolated from a fracture fragment from Margaret Tracy
o MOA: Binds to the lipid carrier
o Use: + ________________ for the topical treatment of skin infections.
o s/e: nephrotoxic & hematotoxic
o Action is enhanced by _______

D. VANCOMYCIN
o A glycopeptide from Streptomyces orientalis
o MOA: Inhibits transglycosidation, inhibits synthesis of mucopeptide polymer
o DOC: MRSA (IV), C. difficile induced Pseudomembranous colitis (PO)
o s/e: ______________________ (remedy: slow infusion)

E. TEICOPLANIN
o A glycopeptide from Actinoplanes teichomyceticus
o MOA: long alkyl chain anchors the antibiotic to the outer surface of the cell membrane
o Use: treatment of ___________________ infections

F. FOSFOMYCIN
o Synthetic derivative of ___________________
o MOA: inhibits UDP-N-acetylglucosamine enolpyruvyl transferase
o Use: UTI cause by E.coli
Interactions with Plasma Membrane

A. POLYMYXINS
o Cation polypeptides
o MOA: bind to phospholipids on the cell membrane of gram negative bacteria
o s/e: Nephrotoxic and neurotoxic
1. Polymyxin B
o source: Bacillus polymyxa
o + ______________ for skin infections
o + ___________________________ for eye infections
2. Colistin
o aka _____________
o source: Aerobacillus colistinus
o For refractory urinary tract infections & gram negative infections

B. GRAMICIDIN A
o Source: ___________________
o MOA: acts as ionophore allowing the loss of K+ ions
C. DAPTOMYCIN
o Cyclic lipopeptide from Streptomyces roseosporus
o Use: reserve agent for SSTIs

Inhibition of Protein Synthesis

A. AMINOGLYCOSIDES
a. Properties
o Amino sugars joined by a glycosidic linkage
o derived from Streptomyces spp (__________) or Micromonospora spp. (__________)
o given IV (except: neomycin)
o + penicillins = _______________
o for the treatment of serious infections caused by gram-negative bacilli
b. Mechanism of action (MOA)
o Bind to ____ ribosomal subunit to prevent the reading of the mRNA
c. Drugs
1. Gentamicin
o source: Micromonospora purpurea
2. Tobramycin
o source: Streptomyces tenebravius
3. Amikacin
o semisynthetically derived from Kanamycin
o first prepared in Japan
4. Neomycin
o source: ______________________
5. Kanamycin
o source: Streptomyces kanamyceticus Structure of Amikacin
6. Streptomycin
o source: ______________________
o 1st aminoglycoside discovered
o 1st effective agent used against tuberculosis
d. Side effects
o Allergic reactions
o Ototoxicity
o most ototoxic: _______
o most vestibulotoxic: _____
o Nephrotoxicity
o most nephrotoxic: ______
o Neuromuscular paralysis

B. TETRACYCLINES
a. Properties
o Consists for 4 fused rings with a system of conjugated double bonds.
o Broadest spectrum of the antibiotics
o Have activity against gram positive & negative, spirochetes & atypical
bacteria
o *Chlortetracycline – Streptomyces aureofaciens
Structure of Tetracyclines
o DOC: _______________________
b. Mechanism of action (MOA)
o Binds to the ______ subunit of ribosomes which prevents aminoacyl-tRNA from binding to the mRNA-
ribosome complex

c. Classes of tetracyclines
Short acting Intermediate acting Long acting Very long acting
Tetracycline Methacycline Doxycyline Tigecycline
Oxytetracycline Demeclocycline Minocycline
o from S. rimosus

d. Interactions
o Products containing metals
o Dairy products and drugs containing divalent and trivalent metals
o Decreased absorption of tetracyclines due to chelation
o ____________ – antagonism

e. Side effects / Adverse reactions

o Photosensitivity
o ________________________
o taking expired tetracycline
o Tooth discoloration & Stunting of growth
o Contraindicated to pregnant women & young children

C. MACROLIDES
a. Properties
o Common chemical characteristics: Structure of
1. _________________________ Macrolides
2. _________________________
3. _________________________
b. Mechanism of action (MOA)
o Binds to the _____ ribosomal subunit, inhibiting translocation.
c. Drugs
1. Erythromycin (Ilotycin)
o source: Streptomyces erythraeus, from ____________
o Ester salts
 Estolate – lipid soluble, acid stable prodrug with better oral absorption ;
s/e: ___________________
 Ethylsuccinate – prodrug with more lipophilicity – longer duration of action
 Gluceptate – water soluble salt of glucoheptanoic acid for parenteral use
 Lactobionate - also used for parenteral means
o Substitute for penicillin in allergic patients
o Motilin agonist
o DOC: ____________________

2. Clarithromycin
o ______________________
o More stable in gastric acid and has improved oral absorption
o Use: treatment of ulcers cause by H. pylori

3. Azithromycin
o Contains a 15-membered macrocycle with N-methyl group
o Extensive tissue distribution
o Food decreases absorption
o Hydrate forms:
o Dehydrate - ____________
o Monohydrate – ___________

4. Roxithromycin
o Semisynthetic macrolide derived from erythromycin (+N-oxime side chain)

D. LINCOSAMIDES
a. Properties
o _________ containing antibiotics
b. Mechanism of action (MOA)
o Binds to 50s ribosomal subunit (same with macrolides)
c. Drugs
1. Lincomycin
o source: Streptomyces lincolnensis Structure of Clindamycin
2. Clindamycin
o 7-chloro-7-deoxy derivative of lincomycin
o potent drug for anaerobic bacteria
o a/e: Clostridium difficile induced pseudomembranous colitis
 DOC: _____________________

E. CHLORAMPHENICOL
o Source: Streptomyces venezuelae
o MOA: Binds to 50s subunit, inhibiting peptidyl transferase
o DOC: Typhoid fever (new: _______________)
o + palmitic acid = chloramphenicol palmitate (reduced bitterness)
o a/e: Aplastic anemia, _________________
o Toxicophore: ________________ group Structure of Chloramphenicol
F. STREPTOGRAMINS
o MOA: Binds to different regions of the _____ subunit and form a complex with it
1. Pritinamycin
o source: Streptomyces pristinaespiralis
o Quinupristin & Daflopristin
2. Quinupristin
o inhibits peptide chain elongation
3. Daflopristin
o interferes with the transfer of the peptide chain from one tRNA to the next

G. LINEZOLID
o classified under oxazolidinones, synthetic antibiotics
o MOA: Binds to 50s preventing the formation of the 70s complex
o DOC: ________

Inhibition of DNA Replication

A. QUINOLONES
o patterned after ____________ (NegGram)
o synthetic antibacterial agent
a. Mechanism of action (MOA)
o inhibits _____________________
b. Generations of Quinolones

Generation Drugs Activity

1st gen Nalidixic acid, Cinoxacin Moderate gram (-) act
2nd gen Ciprofloxacin, Lomefloxacin, Ofloxacin, Improved act against gram (-), has act against
Norfloxacin, Enofloxacin G(+) & Atypical microorg.
3rd gen Gatifloxacin, Gemifloxacin, Sparfloxacin, Retained gram (-) act, improved gram (+) &
Moxifloxacin, Levofloxacin atypical act
4th gen Trovafloxacin Retained gram (-), gram (+), atypical microorg,
also for anaerobic microorg

c. Structure Activity Relationship (SAR)

o Nucleus: 1,4 dihydro-4-oxo-3 pyridine carboxylic acid
o At ___, addition of groups greatly reduces or abolishes activity
o At __________, may be substituted with good effects
o At ___, + F increases antibacterial activity
o Fluoroquinolones – broad spectrum (+, -)
o At ___, + Piperazine provides activity against Pseudomonas aeruginosa
o At ___, small alkyl substitution provides greater potency
o At ___, + Halogen , side effect is photosensitivity
o Highest – Lomefloxacin
o Lowest - Sparfloxacin
d. Interactions
o Enzyme inhibitor
o Products containing divalent and trivalent metals
B. NITROFURANS
o Nitroheterocyclic compounds
o Derivatives of 5-nitro-2-furaldehyde
a. Mechanism of action (MOA)
o Inhibit __________________
b. Structure Activity Relationship (SAR)
o Nitro at 5th position – antibacterial activity
c. Drugs
1. Nitrofurantoin – used in ______
2. Nitrofurazone – used topically in ______
3. Furazolidone – used in bacterial or protozoal ______
4. Metronidazole
o Effective against trichomonas, amoeba, giardia, anaerobic bacteria
o DOC: C. difficile induced Pseudomembranous colitis

Inhibition of Cell Metabolism

A. SULFONAMIDES
a. History
o Discovered by ______________
o Studied a bright red dye, _________, which was metabolized in vivo to sulfanilamide
a. Mechanism of action (MOA)
o Inhibits _____________________, thus preventing folic acid synthesis
o Active form: Ionized
b. Structure Activity Relationship (SAR)
o para amino group is essential for activity and must be unsubstituted
o The aromatic ring and the sulphonamide functional groups are both required
o Both the sulphonamide and amino group must be directly attached to the aromatic ring
o The aromatic ring must be para-substituted only
o The sulphonamide nitrogen must be primary or secondary
d. Side effects / Adverse effects
o _________________________
o _________________________
o _________________________
o _________________________
o _________________________
e. Other antimetabolites (PYRIMIDINES)
1. Trimethoprim
o MOA: _________ dihydrofolate reductase inhibitor
2. Pyrimethamine
o MOA: _________ dihydrofolate reductase inhibitor
f. Drugs / Drug combinations
1. Sulfalazine
o Prodrug of ___________________
o Used in ulcerative colitis
2. Co-trimoxazole
o _________________________ (synergistic combination)
o Uses: 1st attack of UTI, P.carinii pneumonia (DOC)
 3. Co-trimazine
o Sulfadiazine + Trimethoprim
4. Sulfadiazine + Pyrimethamine
o Used in _______________
5. Sulfadoxine + Pyrimethamine
o Used in _____________
6. Silver sulfadiazine + Mafenide
o Used in ___________

B. SULFONES
o MOA: inhibit dihydropteroate _____________
1. Dapsone
o Used in leprosy
o Contraindicated in G6PD deficiency, may cause hemolytic anemia

Miscellaneous agents
METHENAMINE (Urothropin)
o Urinary antiseptic used in UTI
o _______________ release in low pH is required for antibacterial effect
 Given with acidifying agents (NH4Cl) to optimize the effect
o Certain bacteria produce urease, causing resistance
 Give acetohydroxamic acid (Lithostat) – ___________________
 ANTIMYCOBACTERIAL DRUGS
TUBERCULOSIS

FIRST LINE DRUGS

o Rifampicin, Isoniazid, Pyrazinamide, Ethambutol, Streptomycin DRUGS

1. Rifampicin (Rifampin, R)
o Source: S. meditirranei
o MOA: ______________________
o most active agent in clinical use for TB patients
o S/E / Interactions: red-orange secretions, hepatoxicity,
enzyme inducer
2. Isoniazid (H)
o aka Isonicotinic acid hydrazine, INH
o MOA: inhibit synthesis of mycolic acid
o S/E: peripheral neuropathy, hepatoxicity Isoniazid
o AD: Give ______________________
3. Pyrazinamide (Z)
o aka Pyrazinecarboxamine, PZA
o MOA: unclear
o first line drug for short term treatment
o prodrug of pyrazinoic acid
o S/E: ________________________ Pyrazinamide
4. Ethambutol (E)
o MOA: inhibits __________________ inhibiting the formation of
mycobacterial cell wall
o S/E: optic neuritis (blue-green vision)
5. Streptomycin
o first and oldest antibiotic effective in the tx of TB Ethambutol

SECOND LINE DRUGS

1. Capreomycin
o Source: S.capreolus
o s/e: ototoxicity, nephrotoxicity
2. 4-Aminosalicylic acid
o aka para-aminosalicylic acid, PAS
o MOA: inhibits dihydropteroate synthetase
o One of the very first drugs used for tuberculosis
3. Ethionamide
o Analog of isoniazide Streptomycin
o s/e: hepatotoxicity
4. Cycloserine
5. Respiratory fluoroquinolones

LEPROSY
Drugs:
1. Clofazimine (Lamprene)
o A phenazine red dye 2. Dapsone
o MOA: bind to nucleic acids 3. Rifampicin
o Used in _________________________________
o s/e: brownish-black skin discoloration
**For tuberculoid leprosy (mild), dapsone + rifampicin is given. However, for lepromatous leprosy (severe), clofazimine is
added to the regimen.
 ANTIFUNGAL DRUGS
A. POLYENES
o Structure: contains conjugated double bonds in macrocyclic lactone rings
o MOA: forms __________________on the cell membrane
o Drugs:
1. Amphotericin B
o source: Streptomyces nodosus
o Oldest antifungal
o DOC for the treatment of
_______________________
o S/E: nephrotoxicity
2. Nystatin
o source: Streptomyces noursei
o DOC for candida infections
3. Natamycin
o source: Streptomyces natalensis

B. AZOLES
o MOA: : inhibits ________________________ to block demethylation of lanosterol to ergosterol.
o SAR:
1. Imidazole or 1,2,4-triazole ring bonded by a N-C linkage
2. 2 or 3 aromatic rings increases potency
3. Addition of halogen increases potency
o Groups of azoles (based on structure):
o ___________ - Ketoconazole, Itraconazole, Fluconazole Posaconazole, Voriconazole
o ___________ – Clotrimazole, Miconazole, Econazole

For systemic fungal infections:

1. Ketoconazole (Nizoral)
o Used in systemic fungal infections (before), topical (now)
o needs acidic pH to be absorbed
o s/e, interactions: hepatoxicity, antiandrogenic effects, enzyme inhibitor
o reduced production of testosterone, impotence, loss of libido, gynecomastia, dec. sperm
count
2. Itraconazole (Sporanox)
o Alternative to _______________
o Not hepatotoxic, no adrenal suppression
o Needs acidic pH to increase absorption
3. Fluconazole (Diflucan)
o Lipophilic (crosses BBB)
o DOC & Prophylaxis for ____________________
4. Posaconazole
o Broad acting synthetic antifungal
o Structurally similar to Itraconazole
o a/e: gastrointestinal disturbances (n/v, diarrhea), headaches
5. Voriconazole
o Broad acting synthetic antifungal
o Structurally similar to Fluconazole
o DOC for invasive aspergillosis
o a/e: ________________________, hepatotoxicity

For superficial fungal infections:

6. Clotrimazole (Canesten) 8. Econazole
7. Miconazole (Daktarin) 9. Tioconazole
C. ALLYLAMINES
o MOA: inhibit _____________________
o Drugs:
1. Naftifine (Naftin)
2. Terbinafine (Lamisil)
3. Tolnaftate (Tinactin)

D. OTHER ANTIFUNGALS
1. FLUCYTOSINE
o Nucleoside antifungal (Pyrimidine antimetabolite)
o Prodrug of _________________
o Used in combination with Amphotericin B in Cryptococcal meningitis
o MOA: _______________________
2. GRISEOFULVIN
o Source: Penicillum griseofulvum
o MOA: “mitotic spindle/microtubule poison” – inhibiting mitosis
o DOC for refractory ringworm infections of the body nails, hair, feet
o Long duration of treatment (3-6 mos)
o Poor bioavailability
o Solutions: 1. ____________ 2. ______________________________________

E. ECHINOCANDINS
o MOA: inhibits synthesis of _________________, thus inhibiting fungal cell wall synthesis
o Potent against Aspergillus & most Candida species
o s/e: flushing (rapid infusion)
o Drugs: Anidulafungin, Caspofungin, Micafungin

F. TOPICAL AGENTS FOR DERMATOPHYTOSES

1. FATTY ACIDS
o Propionic acid
o Sodium Caprylate – from caprylic acid, component of coconut & palm oils
o Undecylenic acid – from destructive distillation of ____________
o Salicylic acid (SA) & Benzoic acid (BA) – ______________________
 PARASYMPATHETIC SYSTEM

o aka cholinergic system

o Neurotransmitter: Acetylcholine (ACh)
o Receptors: Muscarinic (M), Nicotinic (N)
o Metabolism: Acetylcholinesterase (AChE)

Biosynthesis of acetylcholine:
1. ___________ → ____________ enzyme: serine decarboxylase
2. ___________ → ____________ enzyme: choline-N-methyltransferase
3. ___________ → ____________ enzyme: choline-acetyltransferase (ChAT)

Metabolism of acetylcholine:
1. Ach → choline + acetic acid enzyme: ________________________

Cholinergic agonists
o ACh – prototype
o Problems:
1. Prone to hydrolysis
2. Non-selective
o Requirements:
1. Stability to stomach HCl and esterases
2. Selectivity for cholinergic receptors
o SAR: Acetylcholine
1. Addition of carbamate – less prone to susceptibility
o ______________
• More stable ester, resulting to long acting effect
• Used for glaucoma
2. Addition of alkyl group – less prone to susceptibility & more selective to muscarinic than
nicotinic
o ______________
• More selective on muscarinic over nicotinic receptors & more stable
• Used for the diagnosis of asthma
3. Combination of the 1 & 2
o ______________
• More selective on muscarinic over nicotinic receptors & more stable
• Used to stimulate GIT and urinary bladder after surgery

Bethanechol

Carbachol
Methacholine
 SYMPATHETIC SYSTEM

o aka adrenergic system

o Neurotransmitters: Norepinephrine, Epinephrine
o Receptors: Alpha, Beta
o Metabolism: Monoamine oxidase (MAO) & Catechol-o-methyl transferase (COMT)

Biosynthesis of neurotransmitters:
1. Tyrosine → L-DOPA
2. L-DOPA → Dopamine
3. Dopamine → Norepinephrine
4. NE → Epinephrine
enzyme: Tyrosine hydroxylase
enzyme: Aromatic L-amino acid decarboxylase
enzyme: Dopamine β-hydroxylase
enzyme: Phenylethanolamine N-methyltransferase (PENMT)

Metabolism:
1. Norepinephrine/Epinephrine –MAO & COMT->->-> Vanillylmandelic acid (VMA)
2. Dopamine –MAO & COMT->->-> Homovanillic acid (HVA)

Structure-Activity Relationship (SAR)

1. Parent structure: _____________________
2. _________atoms separate the aromatic ring & the amino group
3. Optical isomerism: ____ configuration – more potent
4. Substitution on N: Increase in size and bulkiness
- Increased ________ activity, _______________ activity
5. Substitution on alpha carbon
- Blocked oxidation by MAO, increased _____
- Increased oral absorption, CNS activity
- +methyl → _____________
6. 3’&4’ OH groups – maximal α & β activity, provides ____________ activity.
7. w/o 3’&4’ OH groups – resistant to ________ (increased DOA), provides indirect activity
8. 3’-OH – important for _________ ex. Phenylephrine
9. 4’-OH – important for _________ ex. Albuterol

Beta-blockers – chemical class: _______________________

 CNS DEPRESSANTS

Benzodiazepines
o Most widely used anxiolytic
o MOA: Increase the FREQUENCY of GABA-mediated chloride ion channel opening.
o SAR:
o Benzene ring A fused to a 7-membered diazepine ring
B
RING A
o At 7, + EWG substituent(↑EN = ↑activity)
o Positions 6, 8,and 9 should not be substituted.
RING B
o At 5, + phenyl ring promotes activity
o At 3, +/- OH has pharmacokinetic properties
o saturation of 4=5 or shift to 3,4 = reduced activity

RING C
o + EWG at ortho position = ↑activity ; at para position = reduced activity

Triazolobenzodiazepines
▪ BZD fused with triazolo ring
▪ short acting
▪ ex. Triazolam, Alprazolam

Imidazolobenzodiazepine
▪ BZD fused with imidazolo ring
▪ short acting
▪ ex. Midazolam

Barbiturates
o Was used extensively as sedative hypnotic
o MOA: increase the DURATION of GABA mediated chloride ion channel opening
o SAR:
o Nucleus: 2,4,6-trioxohexahydropyrimidine (Barbituric acid)
o At 5, +alkyl/aryl groups confers activity
o At 2, if S replaces O → Thiobarbiturates
▪ More lipid-soluble (very high lipid water partition
coefficient)
▪ Rapid CNS penetration
▪ Short duration of action
▪ Ex. Thiopental
 ANTIPSYCHOTICS
Typical antipsychotics
1. Phenothiazines
o Aliphatic – Chlorpromazine, Promazine, Triflupromazine
o Piperidine – Thioridazine, Mesoridazine, Piperacetazine
o Piperazine – Fluphenazine, Perphenazine, Trifluoperazine
o Butyrophenone – Haloperidol, Droperidol

2. Thioxanthene – Thiothixene, Chloprothixene, Flupenthixol

Potency: Butyrophenones = Piperazine > Piperidine ≥ Thioxanthenes >>> Aliphatics

Atypical antipsychotics
1. Dibenzoxazepine – Loxapine
2. Dibenzodiazepine – Clozapine
3. Dibenzothiazepine – Quetiapine
4. Benzisoxazole – Risperidone
5. Thienobenzodiazepine – Olanzapine
6. Dihydroindolone – Ziprasidone
7. Dihydrocarbostyril – Aripiprazole
8. Benzamide - Amisulpride

Phenothiazines
o SAR
o 6-6-6 system, two benzenes are linked by sulphur and nitrogen
o At 2, + EWG substituent(↑EN = ↑activity)
o Position 10 and amino nitrogen must be separated by a 3-carbon chain
▪ 2 carbon chain (↑antihistaminic & anticholinergic effect)
▪ Ex. Promethazine
o Amine is always tertiary

Butyrophenones
o SAR
o At C-4, + tertiary amino group, essential for neuroleptic activity
▪ Highest activity if cyclic form
o p-fluoro, aids activity (Fluorobutyrophenones)
o modification of the 3 carbon propyl chain decreases neuroleptic potency.
 ANTIDIABETIC AGENTS

INSULIN
o Produced by B-cells of the pancreas
o Promotes the absorption of glucose
o Hexamer: form for the storage
o Monomer: form that is absorbed and interacts with the
insulin receptor

Categories of Insulin:

Rapid acting insulin

• Insulin Lispro (Humalog)
o Lysine and Proline exchanged at positions B28 and B29
o Stabilized by cresol preservative into hexamers
• Insulin Aspart (Novolog)
o Formed by replacement of Proline at B28 w/ Aspartic acid
• Insulin Glulisine (Apidra)
o Glutamic acid replaces lysine at B29 and Lysine replaces asparagine at B3

Short acting insulin

• Regular Insulin
o Soluble crystalline Zn insulin
o Only IV

Intermediate acting insulin

• Neutral Protamine Hagedorn/ NPH/ Isophane Insulin
• Suspension of insulin in a complex w/ Zn and protamine in PO43- buffer
• Insulin Zn suspension
• Mixture of crystallized and amorphous form of insulin in acetate buffer

Long acting insulin

• Insulin Glargine (Lantus)
• Asparagine at a-21 is replaced with Glycine
• Insulin Detemir (Levemir)
• Terminal threonine is dropped and myristic acid is attached to the B29 lysine
• Insulin Degludec (Tresiba)
• Threonine at B30 is removed and the lysine at B29 is conjugated to hexadecanoic acid
 ANTINEOPLASTIC DRUGS

Tumor/Neoplasm – collection of abnormally profilerating cells

o Benign neoplasm – does not invade surrounding tissues
o Malignant neoplasm – invade and metastasize to all parts of the body

Phases of Cell cycle

1. G0 phase or Resting phase – the cell is not committed to division
2. G1 phase – RNA & proteins are synthesized. Cells grow larger.
3. S phase – DNA synthesis & replication occurs
4. G2 phase – DNA synthesis ceases. RNA & other enzymes (e.g.
topoisomerase I & II) are produced to prepare for cell duplication
5. M phase or mitosis – cell divides into 2 daughter cells

Antineoplastic agents – prevent, inhibit or halt the development of a neoplasm or

tumor.
o Cell cycle non-specific agents
• are not dependent on the cell being in a particular phase of the cell
cycle for them to work - they affect cells in all phases of the cell cycle
o Cell cycle specific agents
• act on the cells in a specific phase

I. CELL CYCLE NON-SPECIFIC AGENTS

A. Alkylating agents

MOA: alkylation of reactive species on DNA

Classification Drugs Notes
Cyclophosphamide/Ifosfamide
Mechlorethamine, Melphalan,
tox: hemorrhagic cystitis due to
Nitrogen mustards Chlorambucil, Bendamustine,
metabolite Acrolein
Ifosfamide, Cyclophosphamide
AD: MESNA
Ethyleneimine - Thiotepa
Methylmelamines - Altretamine
Alkyl sulfonate Busulfan
Nitrosureas Carmustine, Streptozocin
Triazenes Dacarbazine, Temozolomide
Methylhydrazine Procarbazine
Cisplatin
Platinum coordination Cisplatin, Carboplatin, Oxaliplatin a/e: nephro- & ototoxicity
complexes
AD: Amifostine

B. Antibiotics
o Anthracyclines & Anthracenedione
• Anthracyclines – Doxorubicin, Daunorubicin, Epirubicin, Idarubicin
• Anthracenedione – Mitoxantrone
• MOA: inhibit topoisomerase II & intercalate DNA
• S/E (Anthracyclines) – Cardiotoxicity AD: Dexrazoxane
 o Others
• Dactinomycin/Actinomycin D (Streptomyces spp)
▪ MOA: intercalates between GC base pairs of DNA
• Plicamycin (S. plicatus)
• Mitomycin C (S. caespritosus)

II. CELL CYCLE SPECIFIC AGENTS

G1–phase specific
1. L-asparaginase
o source: E. coli
o MOA: hydrolyzes asparagine to aspartic acid and ammonia, thus depriving the tumor cells of
asparagine, which is needed for protein synthesis
2. Prednisone (Corticosteroids)

S–phase specific
1. Camptothecin derivatives
o MOA: inhibit Topoisomerase I
o Drugs: Topotecan, Irinotecan
o S/E (Irinotecan): cholinergic diarrhea (mgt: Atropine or Loperamide)
2. Hydroxyurea
o MOA: inhibits ribo-nucleotide reductase (RNR - conversion of ribo- to deoxyribonucleotides)
3. Antimetabolites
o MOA: inhibit enzymes necessary for folic acid, DNA or RNA synthesis
1. Folic acid analogues - Methotrexate, Pemetrexed
• Methotrexate toxicity: myelosuppression AD: Leucovorin/Folinic acid
2. Pyrimidine analogues - 5-Fluorouracil, Capecitabine, Cytarabine, Gemcitabine, 5-Azacytidine
3. Purine analogues - 6-mercaptopurine, Fludarabine, Cladribine, Pentostatin

G2–phase specific
1. Bleomycin
o source: S. verticillus
o MOA: binds to DNA, generates free radicals
o toxicity: pulmonary toxicity (pulmonary fibrosis)
2. Epipodophyllotoxins
o semisynthetic derivatives of podophyllotoxin, isolated from mayapple root
o MOA: inhibits Topoisomerase II
o Drugs: Etoposide, Teniposide

M–phase specific
1. Taxanes
o Isolated from the bark of pacific yew tree (Taxus brevifolia)
o MOA: stabilize microtubules, inhibit depolymerization
o Drugs: Paclitaxel, Docetaxel
2. Vinca alkaloids
o source: Catharanthus roseus leaves
o MOA: inhibit tubulin polymerization and microtubule formation
o Drugs: Vincristine, Vinblastine, Vinorelbine

III. HORMONAL THERAPY

1. Glucocorticoid receptor agonist Prednisone
2. Selective Estrogen Receptor Modulator Tamoxifen for premenopausal px w/ HR(+) breast ca
3. Selective Estrogen Receptor Downregulator Fulvestrant
4. Aromatase inhibitors - Anastrazole, Letrozole, Exemestane for postmenepausal px with HR(+) breast ca
IV. TARGETED THERAPY
1. Monoclonal antibodies
o target growth factor receptor and inhibit cell growth
o example drugs (-mab):
• Trastuzumab – HER-2/neu inhibitor
• Bevacizumab – inhibits human vascular endothelial growth factor (VEGF), preventing
angiogenesis
2. Tyrosine kinase inhibitors
o inhibits tyrosine kinase and prevents phosphorylation of kinase substrate by ATP
o example drugs (-tinib):
• Erlotinib – EGFR inhibitor
• Imatinib – BCR-ABL kinase inhibitor

Antineoplastic agents Toxicity

REFERENCES:
1. Wilson & Gisvold’s Textbook of Organic & Pharmaceutical Chemistry 12 th edition by John Beale, John Block
2. An Introduction to Medicinal Chemistry 4th edition by Graham Patrick
3. Basic & Clinical Pharmacology 14th edition by Bertram Katzung
4. Goodman & Gilman’s The Pharmacological Basis of Therapeutics 13 th edition
5. Review notes (Manor review center & UIC review)
6. Module 1 summary by Kathreen Mae D. Cascabel
7. PACOP reviewers (Blue, Green, Pink, Red)