org medicinals

8/7/2019 org medicinals

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ORGANIC MEDICINAL CHEMISTRY

________: the practice of medicinal chemistry is devoted to the discovery and development of new drugs________: an agent intended for use in the diagnosis, mitigation, treatment, cure, or prevention of disease in humans or in other animals________: a substance to which a drug needs to interact with to elicit a pharmacological response

________: the interaction of a drug to a specific receptor may induce or inhibit a certain pharmacologic effect________: ability of a drug to bind to the receptor________: ability of a drug to exert a pharmacologic action

FOUR FUNDAMENTAL PATHWAYS

I. ABSORPTION: the transfer of a drug from its site of administration to the systemic _______ (or to the bloodstream)

Chemical structure

Variation in particle size Nature of the crystal form Type of tablet coating

Blood flow to the absorption site

Total surface area available for absorption Contact time at the absorption surface

________: the fraction of administered drug that reaches the systemic circulation in a chemically unchanged form

II. DISTRIBUTION: the process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid)and/or the cells of the tissues.

PLASMA PROTEIN BINDING serves as a reservoir

________: binds acidic drugs________: binds basic drugs

may limit access to certain body compartments (e.g. placenta) ________: drug duration of action

TISSUE DEPOTSexample: thiopental

III. METABOLISM Converts drugs into __________, water-soluble products that are readily excretable Detoxification processes But metabolism is not always a detoxification process.

PRODRUGS are compounds that are inactive in their native form, but are easily metabolized to the active agentExamples:

Enalapril (ester form) to Enalaprilat (active form)Chloramphenicol palmitate to Chloramphenicol (active form)

FIRST PASS EFFECT drugs may be metabolized by hepatic enzymes to inactive chemicals (drug is metabolized prior to absorption) only drugs administered _______ and _______ undergo first pass metabolism

IV. EXCRETION; the main route of excretion of a drug and its metabolites is through the kidney

RENAL EXCRETION1. ________________2. ________________3. ________________

BILIARY OR FECAL EXCRETIONEnterohepatic Recirculation: drugs emptied via the bile duct into the small intestine can be reabsorbed in the intestinal lumen backto systemic circulation

ISOSTERISM: describes the selection of structural components, the steric electronic, and solubility characteristics of a drug whichmake it interchangeable with drugs of the same pharmacologic class


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ISOSTERES: compounds or group of atoms having the same number and arrangement of electrons group of atoms that impart similar physical and chemical properties to a molecule, because of similarities in size,

electronegativity, or stereochemistry compounds may be altered by isosteric replacements of atoms or groups, to develop analogues with select biologic

effects, or to act as antagonist to normal metabolitesexample: replacement of the hydroxyl group of folic acid by an amino group

DRUG METABOLISM REACTIONS

PHASE I (____________________)1. Oxidation

MIXED FUNCTION OXIDASE SYSTEM CYTOCHROME P450

o responsible for transferring an oxygen atom to the substrate o contains iron

CYP3A4 most dominant isoform of cytochrome P450 in the liverCYP2D6 antidepressants

2. Reduction plays an important role in the metabolism of many compounds containing carbonyl, nitro and azo groups carbonyl compounds are converted to alcohol derivatives while nitro and azo compounds are converted to amino

derivatives

3. Hydrolysis for drugs containing the ester functionality

PHASE II (____________________)1. Glucuronidation

most common morphine, paracetamol, chloramphenicol (Gray Baby Syndrome)

2. Sulfate conjugation

3. Glycine and Glutamine conjugation used to conjugate carboxylic acids (e.g. benzoic acid to hippuric acid)

4. Glutathione or Mercapturic acid conjugation an important pathway by which chemically reactive electrophilic compounds are detoxified free radical scavenger

5. Acetylation acetyl group utilized is supplied by acetyl CoA hydralazine (SLE), isoniazid (peripheral neuropathy)

6. Methylation inactivation of physiologically active biogenic amines does not lead to polar or water-soluble metabolites but are pharmacologically inactive


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I. LOCAL ANTI-INFECTIVES or GERMICIDES________: compounds that kill (-cidal) or prevent the growth of (-static) microorganisms when applied to living tissue________: agents that prevent infection by the destruction of pathogenic microorganisms when applied to inanimate objects

A. ALCOHOL AND RELATED C OMPOUNDS antibacterial potencies of primary alcohols (against Staphylococcus aureus) increase with molecular weight up to C8

branching _________ antibacterial potency

ALCOHOL, USP (spiritus vini rectificatus, wine spirit, ________) fermentation product from grain and other carbohydrates sources the most widely abused of all recreational drugs widely used in pharmaceutical preparations undergoes a series of _______ reactions in vivo antidote: __________

Denatured Alcohol ethanol that has been rendered unfit for use in intoxicating beverages by the addition of other substances completely denatured alcohol contains added _______ (wood alcohol) and _____ and is unsuitable for either internal

or external useRubbing Alcohol

usually contains ___% ethanol atringent, rubefacient, refrigerant, mild local anesthetic

Dehydrated Alcohol (___________)

contains not less than 99% ethanol by weight

Isopropyl Alcohol primarily used to disinfect the skin and surgical instruments rapidly bactericidal in the concentration range of 50% to 95% a 40% concentration is considered to be equal in antiseptic power to a 60% ethanol concentration

____________________ used to sterilize temperature-sensitive medical equipment and certain pharmaceuticals that cannot be autoclaved MOA: _________ of functional groups in nucleic acids and proteins by nucleophilic ring opening

FORMALDEHYDE SOLUTION (formalin)

contains not less than 37% of formaldehyde with methanol added to retard polymerization

disinfectant, embalming fluid

MOA: direct and nonspecific alkylation of nucleophilic functional groups of proteins

GLUTAROL /GLUTARALDEHYDE (Cidex)

sterilizing solution for equipment and instruments that cannot be autoclaved

Cidex is the commercial product

B. PHENOL AND THEIR DERIVATIVES

the standard to which most germicidal substances are compared is the activity of phenol

__________ defined as the ratio of a disinfectant to the dilution of phenol required to kill a given strain of the bacterium__________, under carefully controlled conditions over a given period

PHENOL (__________) was introduced as a surgical antiseptic by Sir Joseph Lister its use as either an antiseptic or disinfectant is largely obsolete Liquefied Phenol, USP (phenol containing 10%water)

CRESOL a mixture of the three isomeric cresols

THYMOL m-cresol, antifungal, used for the treatment of tinea infections

EUGENOL obtained from clove oil and other volatile oils has local anesthetic as well as antiseptic properties, and is used to relieve ___________.

RESORCINOL antiseptic, keratolytic


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C. OXIDIZING AGENTS

their value as germicides depend upon the liberation of oxygen in the tissues (peroxides) and their ability to denatureproteins (permanganates)

HYDROGEN PEROXIDE particularly active against anaerobic bacteria and find use in the cleansing of contaminated wounds effectiveness is somewhat limited by its poor tissue penetrability and transient action

CARBAMIDE PEROXIDE a stable complex of urea and hydrogen peroxide releases hydrogen peroxide when mixed with water

HYDROUS BENZOYL PEROXIDE (Panoxyl; 2.5%, 5%, 10%) most effective topical OTC agent for the control of acne keratolytic and keratogenic agent MOA: induces proliferation of epithelial cells, leading to sloughing and repair

D. HALOGEN-CONTAINING COMPOUNDS

IODINE one of the oldest known germicides in use today the following are iodine preparations official in the USP

____________: (2% solution of iodine in 50% alcohol with NaI)____________: (5% iodine in water with KI)____________: (2% iodine in water with NaI)

inorganic iodide salts are present to solubilize the iodine and reduce it volatility

IODOPHORS complexes of iodine and nonionic surfactants such complexes retain the germicidal properties of iodine and also reduce its volatility and essentially remove its

irritant properties

Povidone-Iodine (Betadine) a complex with the nonionic surfactant polymer, polyvinylpyrrolidone

E. CHLORINE-CONTAINING COMPOUNDS

HALAZONE used to disinfect drinking water

F. CATIONIC SURFACTANTS

quaternary ammonium compounds that ionize in water and exhibit surface-active properties

MOA: adsorb onto the surface of the bacterial cell, at which they cause lysis inactivated by soaps and other anion detergents tissue constituents, blood, serum, and pus tend to reduce the effectiveness of these substances

BENZALKONIUM CHLORIDE used as detergent, emulsifying, and wetting agent used with ___________ as a preservative

METHYLBENZETHONIUM CHLORIDE (Diaparene)

used to control diaper rash in infants caused by Bacterium ammoniagenes(causes liberation of ammonia indecomposed urine)

CETYLPYRIDINIUM CHLORIDE used as a general antiseptic available form: throat lozenges and mouthwashes FDA approved for the treatment of gingivitis

CHLORHEXIDINE (Bactidol) used as irrigation solution and as mouthwash not absorbed through skin or mucus membrane and does not cause systemic toxicity


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G. DYES

cationic dyes are active against gram-_____ bacteria and many fungi

gram-________ bacteria are generally resistant

GENTIAN VIOLET (crystal violet) available as ______________________ for the treatment of yeast infections available as _______________________ for the treatment of cutaneous Candida albicansinfections

BASIC FUCHSIN ingredient of carbol-fuchsin solution (Castellanis paint), used topically in the treatment of fungal infections, such as

ringworm and athletes foot

METHYLENE BLUE antidote for ____________ poisoning in high concentrations, it promotes the conversion of hemoglobin to ______________, which because of its high

affinity for cyanide ion diverts it from inactivating ________________. in low concentrations, it is used to treat drug-induced methemoglobinemia

H. MERCURY COMPOUNDS

MOA: reacts with _____________ (SH) groups in enzymes and other proteins

this is reversible by thiol-containing compounds such as _________ and ____________

MERCURIC CHLORIDE (__________________)

MERCUROUS CHLORIDE (__________________) were used as antiseptics

AMMONIATED MERCURY (__________________) used for skin infections

THIMEROSAL topical bacteriostatic antiseptic

II. PRESERVATIVES

used to prevent microbial contamination

IDEAL CHARACTERISTICS: effective at low concentrations against all possible microorganisms, nontoxic, compatiblewith other constituents used in the preparation, stable for the shelf life of the preparation

A. PARABENS (p-hydroxybenzoic acid) useful as preservative for liquid dosage forms have _________ properties preservative effect tends to increase with molecular weight

Methylparaben more effective against _________

Propylparaben more effective against _________ more oil-soluble so it is preferred for oils and fats

B. OTHER PRESERVATIVESChlorobutanol

employed as a bacteriostatic agent in pharmaceuticals for injection, ophthalmic use, and intranasal administration

Benzyl alcohol commonly used as a preservative in vials of injectable drugs in concentrations of 1% to 4% in water or saline

solution

Benzoic acid preservative in foods and pharmaceuticals at low pH

Sorbic acid an effective antifungal preservative


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III. ANTIFUNGAL AGENTS

A. FATTY ACIDS all fatty acids and their salts have fungicidal properties

Propionic acid present in _________ in low concentrations (around 0.01%)

Undecylenic Acid obtained from the destructive distillation of __________

B. AZOLES MOA: interacts with C-14 -demethylase to block demethylation of lanosterol to ergosterol, the principal sterol of

fungal membranes. This inhibition disrupts membrane function and increases permeability

Ketoconazole only administered _________ inhibits ______ and adrenal steroid synthesis has endocrine effects: gynecomastia, decreased libido, impotence, menstrual irregularities

Itraconazole

it lacks the endocrinologic effects of ketoconazole

Fluconazole administered orally and intravenously it has excellent penetrability into the CSF drug of choice for ______________ (Cryptococcus neoformans)

Ketoconazole, Itraconazole, Fluconazole for ___________ and __________ mycoses

Clotrimazole, Miconazole, Econazole for _____________ mycoses

C. NUCLEOSIDESFlucytosine

used only in combination with _____________ for the treatment of systemic mycoses and meningitis caused byCryptococcus neoformans and Candida

the combination is __________

IV. ANTIFUNGAL ANTIBIOTICS

A. POLYENESAmphotericin B

naturally occurring, produced by _______________ MOA: binds to _____________ present in the cell membrane disrupting membrane function, allowing electrolytes to

leak out from the cell, resulting in cell death

drug of choice for systemic mycoses

Nystatin first isolated from a strain of _______________________ used for the treatment of ___________infections administered as an oral agent for the treatment of oral candidiasis negligibly absorbed from the GI tract so adverse effects are rare

Natamycin obtained from Streptomyces natalensis

B. GRISEOFULVIN obtained from the mold___________________ MOA: interacts with the ___________ within the fungus to disrupt the mitotic spindle and inhibit mitosis (arrests

cell division in metaphase)


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absorption is increased by ________________

V. ANTITUBERCULAR AGENTS

ISONIAZID (Isonicotinic acid hydrazide)

MOA: inhibits the synthesis of __________, an important component of the cell walls of mycobacteria

principal adverse effect: ___________ due to the competition of isoniazid with pyridoxal phosphate for the enzymeapotryptophanase.

coadministration of ____________ prevents the symptoms of peripheral neuritis

PYRAZINAMIDE (pyrazinecarboxamide)

used in combination with other agents because resistance develops rapidly first line drug for short term treatment

adverse effect: _____________

must be enzymatically hydrolyzed to pyrazinoic acid (active form)

ETHAMBUTOL adverse effect: ______________ loss of ability to discriminate between red and green

ETHIONAMIDE structural analogue of isoniazid

used in the treatment of isoniazid-resistant tuberculosis adverse effects: gastric irritation, hepatotoxicity, peripheral neuropathies, optic neuritis

PARA-AMINOSALICYLIC ACID

acts as a competitive inhibitor for p-aminobenzoic acid in folate biosynthesis

adverse effect: severe gastric irritation

CLOFAZIMINE

basic red dye used in the treatment of leprosy, including dapsone-resistant forms

VI. ANTITUBERCULAR ANTIBIOTICS

RIFAMPIN (rifampicin)

the most active agent

obtained from _________________ enzyme ___________

toxic effects are relatively infrequent when it is taken in combination with isoniazid or ethambutol, incidence of __________ is significantly higher

adverse effect: _______________ of body secretions

CYCLOSERINE isolated from different species of Sterptomyces: S. orchidaceus, S. garyphalus, S. lavendulus

CAPREOMYCIN isolated from Steptomyces capreolus

STEPTOMYCIN

only aminoglycoside used for tuberculosis the first antibiotic effective in the treatment of tuberculosis (1944 by Waksman)

VII. ANTISCABIES and ANTIPEDICULAR AGENTS

Scabicides compounds used to control the mite Sarcoptes scabei, an organism that thrives under conditions of poor personalhygiene

BENZYL BENZOATE obtained from Peru balsam and other resins immediate relief from itching


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CROTAMINON

Pediculocides used to eliminate head, body, and crab lice

PYRETHRIN derived from ____________ plants

MOA: nerve poisoning

PIPERONYL BUTOXIDE enhances the pediculicide effects of pyrethrins

PERMETHRIN for head lice only

LINDANE (___________, Scabene, Kwildane) gamma-benzene hexachloride ADR: _____________

VIII. SYNTHETIC ANTIBACTERIALS

QUINOLONES comprise a series of synthetic antibacterial agents patterned after nalidixic acid (introduced for the treatment of UTI) 1,4-dihydro-4-oxo-3-pyridinecarboxylic acid moiety (essential for antibacterial activity) the introduction of fluorine atom forming fluoroquinolones enhances antibacterial activity Ciprofloxacin is the most potent fluoroquinolone ingestion of the fluoroquinolones with sucralfate, antacids aluminum or magnesium, or dietary supplements

containing iron or zinc can interfere with the absorption of these antibacterial agents MOA: inhibition of DNA synthesis due to the inhibition of DNA gyrase (topoisomerase) adverse effects: diarrhea, nausea, headache, dizziness, nephrotoxicity, phototoxicity

NITROFURAN and NITROHETEROCYCLIC COMPOUNDS

NITROFURAZONE employed topically in the treatment of burns

FURAZOLIDONE oral treatment of bacterial or protozoal diarrhea caused by susceptible organisms (S. aureus, E. coli, Salmonella,

Shigella, Proteus, Enterobacter, V. cholerae) CI: alcohol

NITROFURANTOIN used as a urinary antiseptic

NIFURTIMOX used in the treatment of __________infection ( ________ disease)

METRONIDAZOLE drug of choice for infections with__________________, ______________, _______________ an unpleasant ______________ is often experienced

if taken with alcohol, a ___________-like effect occurs

SULFONAMIDES Paul Erhlichs discovery of the antisyphilitic drug _____________ in 1908 Gerard Domagk studied a bright red dye, _____________________ further studies showed that __________ was metabolized in vivo to _____________ (the active drug) MOA: because of their structural similarity to ________, the sulfonamides compete with this substrate for the enzyme

________________, thus preventing the synthesis of bacterial ____________. adverse effects:

o ___________________o ___________________o ___________________

sulfonamides are usually used with folate reductase inhibitors (inhibit the enzyme dihydrofolate reductase sulfamethoxazole and trimethoprim (___________________) sulfanilamide and pyrimethamine (_____________________)


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USES1. treatment of the first attack of urinary tract infection (__________)2. in burn therapy to prevent and treat bacterial infection (________________ and mafenide)3. treatment of conjunctivitis and related superficial ocular infections (_________________)

4. treatment of chloroquine-resistant malaria (a combination of quinine, pyrimethamine and _______________)5. drug of choice for Pneumocystis carinii(Bactrim; alternative drug: pentamidine)

SULFONES mechanism of action is similar to that of sulfonamides

DAPSONE used to treat leprosy

IX. ANTIMALARIALS

have one common structural feature a quinoline ring, or a quinoline with an additional benzene added (an acridinering)

none except the cinchona alkaloids has a quinuclidine ring

CINCHONA ALKALOIDS

QUININE reserved for malarial strains resistant to other agents major adverse effect: _____________ (a syndrome causing nausea, vomiting, tinnitus and vertigo)

7-CHLORO-4-AMINOQUINOLINES

CHLOROQUINE drug of choice in the treatment of erythrocytic _______________ malaria anti-inflammatory action explains its occasional use in __________ and __________________

AMODIAQUINE highly suppressive in Plasmodium vivax and Plasmodium falciparum

has curative activity against Plasmodium falciparum

8-AMINOQUINOLINES

PRIMAQUINE effective only against the exoerythrocytic stages of malaria only agent that can lead to radical cures of the Plasmodium _________ and Plasmodium _____ malarias gametocidal for all 4 plasmodia species, transmission of the disease can be prevented

9-AMINOACRIDINES

QUINACRINE primarily used in the treatment of _________, but is also effective against tapeworm and malaria, and topically,

against leishmaniasis. should not be given with primaquine because of increased toxicity

MEFLOQUINE effective single agent for suppressing and curing multidrug-resistant forms of Plamodium falciparum

X. ANTIBATERIAL ANTIOBIOTICS

substance produced by microorganisms which has the capacity to inhibit the growth and to cause the destruction of othermicroorganisms

BETA-LACTAM ANTIBIOTICSPENICILLINS

1929: Alexander Fleming accidentally discovered the antibacterial properties of penicillin (_______________) MOA: interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linking of peptidoglycan chains)

beta lactam attached to thiazolidine ring


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nucleus: _____________________

1. Natural PenicillinsPENICILLIN G (________________)

was made available in the form of water-soluble salt of potassium, sodium, and calcium poorly absorbed from the intestinal tract, oral doses must be very large

its rapid elimination from the bloodstream led to the development of repository forms REPOSITORY FORMS (IM): _______________

_______________

PENICILLIN V (____________________) acid stable

2. Penicillinase-resistant penicillins / Antistaphylococcal penicillins: narrow spectrum

METHICILLIN (2,6-dimethoxyphenylpenicillin) prototype drug off the market due to the high incidence of ________________

NAFCILLIN (2-ethoxy-l-phenylpenicillin) relatively small amounts are excreted through kidneys, with the major portion excreted in the bile

can be given to patients with renal problems

ISOXAZOLYL PENICILLINS (Oxacillin, Cloxacillin, Dicloxacillin best absorbed)

3. Aminopenicillins: have an antibacterial spectrum similar to that of pen G but are more effective against gram-_____ bacilli

AMPICILLIN poor GI absorption more frequently administered ___________

AMOXICILLIN better GI absorption than ampicillin

HETACILLIN, BACAMPICILLIN, CYCLACILLIN prodrugs of ampicillin

4. Antipseudomonal penicillins

CARBOXYPENICILLINS (Carbenicillin, Ticarcillin)

UREIDOPENICILLINS (Piperacillin most potent, Azlocillin, Mezlocillin)

BETA-LACTAMASE INHIBITORS structurally related to the beta-lactam ring of penicillin do not have significant antibacterial activity. Instead, they bind to and inactivate beta-lactamases clavulanic acid, sulbactam, tazobactam

CEPHALOSPORINS beta-lactam attached to dihydrothiazine ring

nucleus: 7-aminocephalosporanic acid Cross-sensitivity With Penicillin Classified into 4 generations

Generation Gram Positive Gram negativeFirstSecondThird

Fourth1

stgen: Cefadroxil , Cephapirin, Cefalexin, Cephradine, Cefazoline Cephalothin

2nd

gen: Cefaclor , Cefoxitin , Cefonicid , Cefuroxime, Cefamandole Cefpodoxime , Cefprozil , CefprozilLoracarbacef , Cefotetan

3rd

gen: Cefoperazone, Ceftriaxone, Ceftibuten , Cefdinir, Cefotaxime Moxalactam , Ceftidoxime , Cefditoren


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4th

gen: Cefepime, Cefpirome

CARBEPENEMS

differ with penicillin in that the sulfur atom of the thiazolidine ring has been externalized and replaced by a carbon atom

THIENAMYCIN isolated from Streptomyces cattleya

IMIPENEM undergoes cleavage by dihydropeptidase cilastatin

MEROPENEM

MONOBACTAMS

the beta-lactam ring is not fused to another ring

AZTREONAM bactericidal

active against many gram negative organisms, including Enterobacterand P. aeruginosa

AMINOGLYCOSIDES (Streptomycin, Amikacin, Gentamicin) mycin derived from ___________ micin derived from ___________ MOA: inhibit protein synthesis at the _____ ribosomal subunit ________ with beta-lactam antibiotics Bacteri____ the highly _____ structure of aminoglycosides prevents adequate absorption after oral administration all must be given __________ to achieve adequate serum levels except neomycin (topical and oral only) adverse effects: _________ and ____________

TETRACYCLINES (Doxycycline, minocycline, tetracycline, demeclocycline) broadest spectrum antibiotic has activity against gram (+), gram (-), spirochetes, __________, _________ and __________ contain four fused rings with a system of conjugated double bonds MOA: inhibit protein synthesis at the _____ ribosomal subunit form stable complexes with _____ and _______ cations adverse effects: gastric discomfort, deposition in the bones and primary dentition causing discoloration and

hypoplasia of the teeth and a temporary stunting of growth, hepatotoxicity, phototoxicity (demeclocycline), vestibularproblems (minocycline)

MACROLIDES

common chemical characteristics: a large lactone ringa ketone groupa glycosidically linked amino sugar

MOA: inhibit protein synthesis at the ___ ribosomal subunit spectrum of activity resembles ______ but also effective against mycoplasma, Chlamydia, campylobacter, legionella

adverse effects: epigastric distress, cholestatic jaundice (_________ form of erythromycin)

ERYTHROMYCIN from Streptomyces erythreus formerly Ilotycin alternative to penicillin erythromycin base is inactivated by gastric acid esters of erythromycin base (e.g., stearate, estolate, and ethylsuccinate) have improved acid stability, and their

absorption is less altered by food

CLARITHROMYCIN more potent than erythromycin against streptococci and staphylococci clarithromycin may be given with or without food, but the extended-release form, typically given once-daily as a 1-g

dose, should be administered with food to improve bioavailability

AZITHROMYCIN


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azithromycin's unique pharmacokinetic properties include extensive tissue distribution and high drug concentrationswithin cells (including phagocytes), resulting in much greater concentrations of drugs in tissue or secretionscompared to simultaneous serum concentrations

once a day dosing should not be administered with food the elimination half-life, 40 to 68 hours, is prolonged because of extensive tissue sequestration and binding

LINCOMYCINS sulfur-containing antibiotics isolated from Streptomyces lincolnensis resemble ___________ in antibacterial spectrum and biochemical mechanism of action

CLINDAMYCIN one of the most potent agents available against non-spore forming anaerobic bacteria (_______________________) adverse effect: ____________________

POLYPEPTIDES their clinical use has been limited by their undesirable side reactions, particularly ________ most lack systemic activity (only used topically), except _______ (systemic)

VANCOMYCIN from________________ effective against ___________ staphylococci

used for potentially life-threatening antibiotic-associated colitis due to_________________ slow intravenous infusion is employed for treatment of systemic infections adverse effect: flushing (__________________)

BACITRACIN (______________)POLYMYXIN (______________) effective primarily against gram (+) organismsGRAMICIDIN (___________) useful against gram (-) organisms

UNCLASSIFIED ANTIBIOTICS

CHLORAMPHENICOL from__________________ MOA: inhibits protein synthesis at the _____ ribosomal subunit drug of choice for _________________ adverse effects:

o _____________o _____________

MUPIROCIN (___________) from Pseudomonas fluorescens used topically for impetigo, eczema, staphylococcal and beta-hemolytic streptococcal infections MOA: inhibition of RNA and DNA synthesis

CNS DEPRESSANTSGENERAL ANESTHETICS

agents that produce insensibility by successive or progressive depression of CNS function

STAGES OF ANESTHESIA1. Stage 1 (________) this is the stage proceeding up to unconsciousness. The patient is sleepy, analgesia is produced,

and some types of surgery that do not require muscle relaxation can be performed.2. Stage 2 (_________) this is the stage between unconsciousness and surgical anesthesia. Depression of higher centers

produces a variety of effects, including excitement, involuntary activity, and increased muscle tone.3. Stage 3 (__________) in this stage excitement is lost and skeletal muscle relaxation is produced. Most types of surgery

are done in this stage.4. Stage 4 (____________) respiratory and circulatory failure occur as depression of the vital centers of the medulla and

brainstem occur.

INHALATIONAL ANESTHETICS Halogenated hydrocarbons (enflurane, sevoflurane, isoflurane

_____________ most hepatotoxic______________ most potent, used in obstetric practice


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ULTRASHORT-ACTING BARBITURATES administered intravenously for the induction of anesthesia respiratory depression is marked so they are not used to maintain anesthesia unconsciousness is produced within seconds of intravenous injection and the duration of action is about 30 minutes

sodium salts of thiopental, methohexital, thiamylal

DISSOCIATIVE ANESTHESIA Ketamine induces a dissociative state wherein the patient appears awake but is unconscious and does not feel pain

ANXIOLYTIC and SEDATIVE / HYPNOTIC AGENTS

BENZODIAZEPINES MOA: binding of benzodiazepines enhances the affinity of _____________ for this neurotransmitter adverse effects: drowsiness and confusion, ataxia antidote: _________ (GABA receptor antagonist, IV only)

1. Long-acting (1-3 days) clorazepate, chlordiazepoxide, ___________, flurazepam, quazepam2. Intermediate-acting (10-20 hours) alprazolam, estazolam, ___________, temazepam3. Short-acting (3-8 hours) oxazepam, triazolam

BARBITURATES MOA: potentiate ________ action on chloride entry into the neuron by increasing the duration of opening of chloride

channels1. Long-acting (6 hours or more) metharbital, phenobarbital2. Intermediate-acting (3-6 hours) amobarbital, butabarbital, talbutal3. Short-acting (less than 3 hours) pentobarbital, secobarbital

ANTIPSYCHOTICS

PHENOTHIAZINES (________________) adverse effects: tremors, postural hypotension, constipation, urinary retention, confusion, sexual dysfunction

ANTICONVULSANT/ANTIEPILEPTIC DRUGSHYDANTOINS (phenytoin) adverse effects: _______________ ________________ (includes cleft palate, congenital heart disease, slowed growth and mental deficiency

CANCERCancer (CA)Refers to a heterogenous group of diseases.Characteristics of Cancer Cells: Infinite dividing, Lack of growth controls, Ability to invade local tissues, Ability to spread

Types of Cancer

Solid Tumors

Carcinomas-epithelial cells Sarcoma-connective tissues

Hematologic malignancies

Lymphoma-lymphatic system

Leukemia-blood-forming elements

EtiologyViruses--EBV, HBV, HPVEnvironmental and occupational exposureLife-style factorsMedicationsGenetic factors


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How CA developsA. SAFETY SYSTEMS FAILA1.Proto-Oncogenes become Oncogenes

Growth factor reaching the cell nucleus activates proto-oncogenes.

CA: Proto-oncogenesOncogenes

A2.Tumor Supressor Genes Stop Working Tumor Suppressor Genesgenes that halt cell cycle, preventing further cell division.

A3.Cell Cycle Clock MalfunctionsCell cycle Clockcollection of interacting proteins in the nucleus that control cell division

If conditions are right: activate proto-oncogenes

If conditions are not right: tumor suppressor genes produce proteins that inhibit the cell p53 (tumor suppressor gene) Apoptosis (programmed cell death)

A4.Cells Achieve Immortality Life span: 40 cell divisions This life span is controlled in part by telomeres, protective segments at the ends of the cells DNA.

Telomerase

B.Cells Break Free and SpreadB1.Tumor forms

A tumor is a mass of cells not dependent upon an extracellular matrix These cells can grow on top of each other, creating a mass of abnormal cells. Angiogenesis

B2.Tumors Spread lymphatic or hematogenous spread The unique receptors on the surface of a cell may also play a role in where tumors metastasize.

Some tissue types share similar surface receptors, enabling cancerous cells to move between them and proliferate.

Detection and Diagnoses1. Warning signs of CA

Change in bowel or bladder habitsA sore that does not healUnusual bleeding/dischargeTIndigestion or difficulty swallowingON

2.Guidelines for Screening: Mammography, FOBT, Pap smear3. Tumor markers

Biochemical indicators of neoplastic proliferation

Carcinoembryonic antigen (CEA)

Alpha-fetoprotein (AFP)

Prostate specific antigen (PSA)

4. Tumor Biospy5. Imaging Studies

X-rays, CT scan, MRI, Positron Emission Tomography (PET)

Staging Categorizing patients according to the extent of the disease

TNM staging AJC staging

Survival Depends on the : tumor type, extent of the disease, therapy received.


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6/10 patients survive more than 5 years.

Not all patients who survive are cured. Complete response or remission

Cell Life CycleA. PHASES OF THE CELL CYCLE

M phase

G1 phase S phase G2 phase

G0

RecruitementChemotherapy, Surgery, radiation

B. CELL GROWTH KINETICS Cell growth fraction Cell cycle timeAverage time for a cell that has just completed mitosis to grow and again divide and pass through mitosis

Tumor doubling time

Tumor Cell Burden Number of tumor cells in the body

109

cells

Each cycle of cancer chemotherapy kills a certain percentage of tumor cells

Phase-specific Agents M phase

G1 phase S phase

G2 phase

Effective for high fraction malignancies E.g. hematologic malignancies

Phase-nonspecific Agents

Alkylating agentsex . cisplatin

Antitumor antibiotics Use: For low and high fraction malignancies

Cell cycle-nonspecific agents

Nitrosoureas Radiation

OBJECTIVES of Chemotherapy

Curee.g.leukemia

Remission induction Consolidation therapy

Palliation

Adjuvant chemotherapy Neoadjuvant chemotherapy

Indications Neoplasms are disseminated and not amenable to surgery Supplement to surgery and radiation to attack micrometastases

Undifferentiated, high growth fractions

Basis for dosingbody weight, AUC, BSA Reasons for Combination Chemotherapy

Overcoming or preventing resistance Cytotoxicity to resting or dividing cells

Biochemical enhancement of effect

Rescue of normal cells Eg.

CMF (breast CA)Cyclophosphamide, methotrexate, 5-FU

POMP (ALL)Prednisone, oncovine (Vincristine), Methotrexate, Purinethol (Mercaptopurine) Which to combine?

Different toxicities, Different Sites of Action, Different MOA


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Administration Route varies

Intrathecally:

1.

2. 3. 4.

Chemotherapeutic AgentsCLASSIFICATION

a. Alkylating Agentsb. Antitumor Antibioticsc. Antimetabolitesd. Plant Alkaloidse. Hormonesf. Enzymesg. Biologic Enzyme Modifiersh. Tyrosine kinase inhibitorsi. Miscellaneous Agents

A. Alkylating Agents

Mechlorethamine

MOA: ALKYLATION cause cross-linking and abnormal base-pairing of DNA strands Inhibit DNA replication

Cytotoxic, mutagenic, carcinogenic Divided into subclassifications

Nitrogen Mustards

Mechlorethamine Indications: Hodgkins lymphoma (MOPP)

PK: Unstable, IV

ChlorambucilDOC for CLL Cyclophosphamide

Ifosfamide

Closely related mustard agents Unique:

(1)can be taken orally(2) cytotoxic only after administration of their alkylating species

Indications:

Cyclophosphamide: most commonly used alkylating agent Burkitts lymphoma and breast CA

Cyclo: Non-CANephrotic syndrome, intractable RA Adverse effects:

Bone marrow depression

Toxic metab (ifosfamide)

Germ cellsamenorrhea, testicular atrophy, serility

Neurotoxicity (ifosfamide)chloroacetaldehyde Secondary malignancies

MelphalanEthylenimenes/MethylmelaminesThiotepa, (triethylene thiophosphoramide), Altretamine(hexamethylmelamine)Alkyl sulfonatesBusulfanNitrosoureasCarmustine (BNCU), Lomustine (CCNU), Semustine (methyl CCNU), StreptozocinTriazenes-Dacarbazine (DTIC)Platinum Coordination Complex Carboplatin, Cisplatin**Cisplatin and Carboplatin

Indications:


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+ vinblastine and bleomycin: Solid tumors (metastatic CA)

+cyclophosphamide: ovarian CA Alone: bladder CA

Carboplatin:

cannot be vigorously hydrated kidney dysfunction

neuro- or ototoxicity

Adverse effects:

Cisplatin Severe, persistent vomiting

Nephrotoxicity (dose-limiting)

Carboplatin Mild nausea and vomiting

Not nephro-, neuro-, or ototoxic

Myelosuppression (dose-limiting)

Substituted Urea hydroxyureaOthers Procarbazine, Temozolamide

**Procarbazine Indications: Hodgkins disease Adverse effects:Bone marrow depression (major toxicity), Neurotoxic, Disulfiram-like reaction, Inhibits MAO

B. Antitumor AntibioticsAnthracyclines

Daunorubicin (daunomycin) Doxorubicin (Adriamycin, hydroxydaunorubicin) Epirubicin

Idarubicin

AnthracendionesMitoxantrone

Other Agents

Bleomycin Indications: +vinblastine or etoposide: testicular tumors

excretion: renal

Adverse effects: Unusual: Myelosuppression is rare

Dactinomycin (Actinomycin D)

Indication +surgery and vincristine: Wilms tumor + methotrexate: Gestational choriocarcinoma

Plicamycin (Mithramycin)

C. Antimetabolites

Structural analogs of naturally occuring substrates for biochemical reactions. MOA: inhibit DNA synthesis Adenosine analogsCladribine, Fludarabine

Folic Acid Analogs (Folate antagonists)Methotrexate Indications: ALL, Choriocarcinoma, Burkitts lymphoma in children, Breast CA, Head and neck CA, Osteogenic CA

PK GI, IM, IV, intrathecally Excretion: crystalluria (important to keep the urine alkaline)

Adverse effects:

Common: stomatitis, myelosuppression, erythema, rash, urticaria, alopecia, vomiting, diarrhea

Purine analogs (Purine antagonists)Mercaptopurine, Thioguanine

6-Mercaptopurine Indication: Maintenance of remission in ALL

Metabolism: Liver


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6MP6-methylmercaptopurine or thiouric acidExcretion: kidney

Adverse effects: N&V, diarrhea, bone marrow suppression

Pyrimidine analogs (Pyrimidine antagonists)Capecitabine, Cytarabine (ARA-A, cytosine arabinoside), Fluorouracil,Gemcitabine

5-FluorouracilIndications

Slowly growing solid tumorsColorectal, breast, ovarian, pancreatic and gastric CATopically: basal cell CA

PK: Severely toxic to GITopically, or IV

Toxicities:Ulceration of the GI mucosa, dermopathy (hand foot syndrome)

CytarabineCytosine arabinoside or Ara-AIndications:

+ TG or daunorubicinAcute nonlymphocytic Leukemia

PKNot effective PO: ara-UIV, intrathecal

Excretion: Ara-C and Ara-U, renally

**Fludarabine Unnatural purine nucleotide (5phosphate of 2-fluoro-adenine arabinoside) Alter both DNA and RNA synthesis Indication:

Chronic lymphocytic leukemia

Hairy cell leukemia PK: IV Adverse effect: myelosuppression (dose-limiting)

**6-Thioguanine Another purine analog

Indication: + daunorubicin and cytarabine=acute nonlymphocytic leukemia

Cross-resistance with 6-MP and 6-TG

Same toxicities as 6-MP Difference: not converted to thiouric acid

D. Plant AlkaloidsVinca Alkaloids

MOA:Mitotic spindle=chromatin + microtubules

Examples:Vinblastine, Vincristine, Vindesine, Vinorelbine

Vinca rosea (vincristine, vinblastine)Vicristine (Oncovin)Acute lymphoblastic leukemia, Wilms tumor, Ewings sarcoma, Hodgkins and Non-hodgkins lymphoma

Vinblastine (+bleomycin and cisplatin)Metastatic testicular CA

PKMetabolism: liverExcretion:

Adverse effects:Shared: phlebitis, cellulitisUnique:

Vinblastine: more potent myelosuppressantVicristine:

Camptothecins Ex: Irinotecan (CPT-11), Topotecan


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Podophyllotoxins Ex: Etoposide (VP-16), Teniposide (VM-26)**Etoposide

VP-16

Indications: Oat cell CA of the lung Refractory testicular CA

Adverse effect:

Myelosuppression (dose-limiting

Taxanes Ex: Docetaxel (Taxotere), Paclitaxel (Taxol)

Taxol Indication PK: Metabolism: Liver; Excretion:

Adverse effects: Hypersensitivity, neutropenia

E. Hormones Androgens--Fluoxymesterone, testosterone

Antiandrogens--Flutamide, nilutamide Antiestrogens--Tamoxifen, Toremifene

Aromatase inhibitors--Aminoglutethamide Corticosteroids--Dexamethasone, Prednisone Estrogen/Nitrogen mustard--Diethylestradiol, Ethinyl Estradiol

GnRH or LHRH--Goserelin, Leuprolide

Progestins--Medroxyprogesterone, Megestrol

Hormone-sensitive tumors1. Hormone-responsive2. Hormone-dependent3. Both

PrednisonePotent anti-inflammatory with less mineralocorticoid activityMOA: unknownIndication: lymphoma, ALLCushings syndrome: lymphocytopenia

Tamoxifen Not effective for pre-menopausal women Indication:

PK: Oral

Adverse effects: Hot flashes, nausea, vomiting, skin rash, vaginal bleeding and discharge

**Estrogen E.g. ethinyl estradiol or diethylsilbestrol Indication: prostate CA

MOA: block LH production, thus decreasing the synthesis of androgen in the testes

Adverse reactions: Thromboemboli, MI, stroke, hyperCa Women: loss of libido, menstrual changes

Men: gynecomastia, impotence

**Leuprolide and Goserelin

Analogs of GnRH Results to reduction of androgen and estrogen synthesis

Indication: Prostatic CA

PK: Leuprolide (SC daily or IM monthly)

Goserelin (IM monthly) Adverse effects:

Imoptence, hot flashes and tumor flare


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**Flutamide Indication: Prostatic CA

Always administered in combination with leuprolide or goserelin PK: Administred orally, excreted through kidney Adverse effects: gynecomastia, GI distress

**Aminoglutethimide 2nd line therapy for the treatment of metastatic breast CA MOA:

Inhibits adrenal synthesis of pregnenolone from cholestreol

Inhibits estrogen production

PK: PO, metabolized by hepatic Cytochrome P-450 system

Adverse effects:

CNS depression, maculopapular rash

F. EnzymesAsparaginase--Enzyme that degrades asparagines, Tumor cells lack the ability o synthesize asparagines

MOA: degrades asparagine

Indication:

(+ vincristine and prednisone): Childhood ALL Route: IM or IV Adverse effects:

Hypersensitivity

Decrease in clotting factors

Liver abnormalities Seizures coma

TOXICITIES1. Bone Marrow Suppression--Neutropenia, throbocytopenia, anemia

most common dose-limiting SE of CA chemotherapyNeutropenia (NC1,500/mm3

PC>100,000/mm3

Severe: Carmustine, Cytarabine, Daunorubicin, Paclitaxel Little or No: Asparaginase, Bleomycin, Vincristine

2. Dermatologic Toxicity: Alopecia, Local necrosis Skin changesdryness, sensitivity to light

3. GI toxicities Nausea, vomiting

Very highly emetogenic: Carmustine, Cisplatin, Cyclophosphamide, Dacarbazin, Mechlorethamine, Streptozocin Stomatitis

Fluorouracil, Methotrexate

Diarrhea (Fluorouracil, Irinotecan) Constipation (Vincristine) Anorexia

Taste changes

4. Chills and feverBleomycin, Monoclonal antibodies5. Pulmonary toxicity

Irreversible and fatal


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s/sx: shortness of breath, nonproductive cough, low-grade fever

Bleomycin, Busulfan, Carmustine, Mitomycin

6. Cardiac toxicity= Acute, Chronic: Daunorubicin, Doxorubicin ; Give: (+ Dexrazoxane)

7. Hypersensitivity reactions

Aparaginase, Carboplatin, Cisplatin, Etoposide, Paclitaxel, Etoposide8. Neurotoxicity

Vincristineautonomic and peripheral neuropathies Cisplatinperipheral neuropathy and ototoxicity

CytarabineCerebellar toxicity

9. Hemorrhagic cystitis Cyclophosphamide, Ifosfamide Toxic metabolite:

Acrolein

To minimize:

Mesna

10. Renal toxicity:

serum crea and BUN, electrolyte abonormalities Cisplatin, ifosfamide, Methotrexate

Adequate hydration, osmotic diuresis with mannitol

11. Hepatotoxicity: liver function tests, jaundice, hepatitis liver function tests, jaundice, hepatitis Asparaginase, Cytarabine, Mercaptopurine, Methotrexate

12. Secondary Malignancies: Solid tumors, leukemia, lymphoma

Cyclophosphamide, Etoposide, melphalan, mechlorethamine13. Infertility: Cyclophosphamide, chlorambucil, mechlorethamine, melphalan

Minimizing Adverse Effects

Remove patients marrow prior to treatment Promote diuresis Methotrexate: megaloblastic anemia

Leucovorin, 5-formyltetrahydrofolic acid

Human granulocyte colony stimulating factor (filgrastim)

Other Therapeutic Modalities Surgery

Diagnostic

Therapeutic Radiation therapy

Stomatitis, N&V, diarrhea, myelosuppression


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1. Which of the following viruses has been associated with the development of cervical CA?A. Hepatitis B virus B. Human Papilloma Virus C. Epstein-Barr Virus D. HIV

2. If you suspect adenocarcinoma of the colon, which of the following tumor markers would be most helpful?A. CEA B. AFP C.PSA D.HCG

3. Which of the following is the most frequently used in drug dosing because it provides an accurate comparison of activityand toxicity, and correlates with cardiac output (which determines renal and hepatic blood flow), thus affecting drugelimination?

A. body weight B. AUC C. BSA D. NOTA

4. All of the following chemotherapeutic agents can be administered intrathecally EXCEPT:A. methotrexate B. cytarabine C. hydrocortisone D. thiotepa E. vincristine

5. The rationale for combination chemotherapy includes all of the following EXCEPTA. biochemical enhancement of effect

B. rescue of normal cellsC. overcoming or preventing resistanceD. biochemical nullification of effectE. cytotoxic to both resting and dividing cells

6. Which of the following agents is notorious for causing cardiotoxicity?A. Doxorubicin B. Bleomycin C. Both A and B D. NOTA

7. Which of the following class of antineoplastic agents have the adverse effect of causing secondary malignancies?A. antitumor antibiotics B. Alkylating Agents C. Antimetabolites D. Hormones

8. Which phase is targeted by the Antimetabolites?A. G1 phase B. S phase C. Mitosis D. None, they are phase nonspecific

9. What is the most serious toxicity commonly associated with Bleomycin?A. cardiotoxicity B. nephrotoxicty C. pulmonary fibrosis D. nausea and vomiting

10. Which of the following subclassification of Antineoplastic Agents, readily penetrate the CNS, hence, they find usefulapplication for brain tumors?

A. Nitrogen mustard C. Nitrosoureas (Carmustine, Lomustine)B. Busulfan D. Platinum Coordination compounds

11. Which of the following is associated with risk of endometrial CA developmentA. Tamoxifen B. Paclitaxel C. Vincristine D. Vinblastine

12. What is given together with cylophosphamide to serve as a protectant for the bladder?A. Dexrazoxane B. Mesna C. Leucovorin D. NOTA

13. The top four most commonly diagnosed cancers include all of the following EXCEPT:A. lung B.prostate C. Colon and rectum D. Thyroid E. Breast

14. How do antimetabolites exert their cytotoxic effect?A. inhibiting DNA synthesis by sliding between DNA base pairs.B. Inhibiting RNA synthesis by sliding between RNA base pairs.C. Acting as false metabolites in the microtubules.D. Acting as flase substitutions in the production of nucleic acids.E. Promoting microtubule assembly and stabilization.

15. When does the neutrophil nadir associated with chemotherapy agents generally occur?A. during administration of the chemotherapyB. 1-2 days after therapyC. 10-14 days after therapy


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D. 1 month after the therapyE. When the platelet count begins to rise

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