org medicinals
TRANSCRIPT
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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