Exam 3 Flashcards

Question

Carboxypenicillins

Answer 1

Carboxypenicillins ticarcillin disodium(Timentin – with clavulanic acid) Combined with an aminoglycoside, ticarcillin is one of the DOCs for Pseudomonas aeruginosa Synergism and delays emergence of resistance Decreased activity vs. gram pos. organisms but includes some gram neg. (Pseudomonas, E. coli, some Proteus, Enterobacter, Serratia) Considerations in choosing drug: High activity vs. P.aeruginosa High sodium content (disodium salt) (5 meq Na+/gm) can lead to CHF

Answer 2

Ureidopenicillins Include piperacillin - (I.V.) Same spectrum as Carboxypenicillins plus many Klebsiella Usually used in combination with Aminoglycosides

Answer 3

Can get higher plasma conc. after IM injection, but peak plasma conc. decrease rapidly (pen G t1/2 = 30 min) Prolonged effect with repository forms Procaine or benzathine suspensions slowly release low but persistent levels of pen G when injected IM. (26 days duration with benzathine) Have anesthetic effect so injections are ‘painless’ Used for Strep throat, syphilis, rheumatic fever prophylaxis Give IV infusion for meningitis, endocarditis, and other serious infections Methicillin, carboxy- and ureido-penicillins are acid labile and poorly absorbed, so must be given parenterally.

Answer 4

Widely distributed in most body fluids Do not freely enter CSF but pass through inflamed meninges more readily Toxic conc. can be reached in CNS if renal impairment or if given IT (penicillin is epileptogenic). Highest protein binding with oral isoxazolyls - but not clinically significant

Answer 5

Excretion Rapid tubular secretion Blocked by probenecid t1/2 affected by renal function Incomplete renal function in neonates increases t1/2 Small amounts excreted into bile, sputum, milk High biliary excretion for nafcillin

Answer 6

Hypersensitivity Cross sensitization with all penicillins and partial cross-sensitization with cephalosporins Most severe type occurs within 30 min of exposure Exposure to PCN in the environment can induce sensitization PCN acts as a hapten formed by covalent binding of the ß-lactam ring to body proteins. This is the major determinant Skin testing can be performed with benzylpenicilloyl polylysine (Pre-Pen) Minor determinants are formed in much smaller quantities IgE antibodies directed against minor determinants usually mediate anaphylaxis.

Answer 7

Absorption Most are poorly absorbed from GI tract, so most common route of administration is parenteral. Some are available as oral preparations and most of these are almost completely absorbed and achieve serum conc. similar to those obtained after an equivalent dose of parenteral. Prodrugs (cefuroxime axetil and cefpodoxime proxetil) are incompletely absorbed (so GI SEs are more common, especially diarrhea). Most are not affected by food, however food increases bioavailability of the prodrugs.

Answer 8

Distribution 1st and 2nd generation (except cefuroxime) do not penetrate into CSF in sufficient concentration but 3rd generation do. Well distributed to most body fluids (including synovial and pericardial fluids) as well as aqueous humor of eye (for 3rd gen.)

Answer 9

Primary route is renal excretion (both GF and tubular secretion). Dosage must be altered with renal insufficiency . Biliary excretion is major route for ceftriaxone. Probenecid slows tubular secretion

Answer 10

Hypersensitivity - cross sensitivity with penicillins (5-20%) May be useful in some patients with less severe type of reaction to penicillin. Should be given with great caution or not at all to patients who had a recent severe immediate reaction to penicillin Thrombophlebitis and pain at injection site Much less with cefazolin. Pseudomembranous colitis and superinfections More common with 3rd gen. Candidiasis common N-methylthiotetrazole-containing cephs. (cefotetan) can cause disulfiram-like reaction with alcohol and bleeding problems Possible synergy with nephrotoxic drugs, especially aminoglycosides in the elderly

Answer 11

Infections where drug of choice: Gonorrhea (ceftriaxone or cefixime) Enterobacteriaceae (E. coli, Klebsiella, Proteus (indole-pos.), Providencia stuartii, Serratia (3rd gen.) H. flu meningitis (ceftriaxone or cefotaxime) Ceftriaxone for typhoid fever Surgical prophylaxis (cefazolin for most "clean" surgery; cefoxitin or cefotetan for colorectal surgery, appendectomy, hysterectomy, "dirty" surgery) Infections where reasonable alternatives: Staph. or Strep. infections in a patient mildly allergic to penicillin (caution) Nosocomial infections caused by gram neg. bacilli resistant to other antibiotics (use 3rd gen.) Cefoxitin or cefotetan for mixed infections and those due to Bacteroides fragilis

Answer 12

new type of cephalosporin a catechol-substituted siderophore siderophores are iron-containing structures that gain access to bacterial cells through specific pores, thus taking cephalosporin into bacterial cell thus gains access to cell even if porin mutation blocks normal entry mechanism Effective against carbapenem and multidrug – resistant gm neg bacilli Study has shown an increased mortality rate compared to some other antibiotic therapies

Answer 13

Adverse Effects Hypersensitivity (if patient allergic to penicillin, consider allergic to imipenem) Superinfections Seizures (elderly, or predisposed to seizures or high doses with decreased renal function) Meropenem is less likely to cause seizures.

Answer 14

Special Considerations Cilastatin - inhibits the inactivation of imipenem by dehydropeptidase I found in brush border of kidney nephron t1/2: 1 hour (given IV q 6 hr or IM q 12 hr) Elimination in urine by glomerular filtration & tubular secretion (so decrease dose or lengthen dosing interval with decreased renal function) Penetrates well into CSF, body tissues, & fluids Used with aminoglycoside for P. aeruginosa

Answer 15

Erythromycin (E-mycin) Clarithromycin (Biaxin) Azithromycin (Zithromax)

Answer 16

Carbapenem-resistant enterobacteriaceae (CRE) Almost totally resistant to Carbapenens Major concern at CDC E. Coli sp and Klebsiella sp are example organisms

Answer 17

A monobactam (single-ring ß-lactam from bacteria) Spectrum Only covers aerobic gram- bacteria Gram+ and anaerobic bacteria are resistant (aminoglycoside spectrum) Very stable to most gram (-) ß-lactamases (and does not induce them but may inhibit them) Active vs. ß-lactamase producing aerobic gram (-) bacteria, including Enterobacteriaceae, gonococci, H. flu Indications Reserved for very serious gram (-) infections resistant to less expensive drugs Effective vs pneumonia, septicemia, PID infections, intra-abdominal infections, CUTI. Cayston® is brand for inhalation use in patients with cystic fibrosis with P. aeruginosa lung infectionsSi

Answer 18

Similar to other ß-lactams Presumed safe to use in penicillin allergy Gram (+) superinfections common

Answer 19

Poor oral absorption so is given parenterally (IM or IV) Rapidly distributed Predominantly excreted in urine and can accumulate in renal failure

Answer 20

erythromycin

Answer 21

clarithromycin and azithromycin (increased T1/2, greater bioavailability, better tissue penetration, somewhat wider spectrum

Answer 22

Bacteriostatic protein synthesis inhibitor that reversibly binds to a site on 50S ribosomal subunit (also interferes with chloramphenicol which binds to the same site). Inhibits the translocation step whereby a newly synthesized peptidyl tRNA moves from the A (acceptor) site on the ribosome to the P (peptidyl or donor site) and reversibly blocks protein synthesis. Erythromycin is selectively accumulated by gram positive bacteria (up to 100 times more than in gram negative bacteria).

Answer 23

Resistance (most appear to be plasmid-mediated mechanisms) Modification of target sites on ribosome (so drug can't bind) Plasmid codes for enzyme that methylates the 23S rRNA on the 50S subunit Called MLS (macrolide-lincosamide-streptogramin) resistance Becoming a significant clinical problem with S. pneumoniae and Group A S. pyogenes Some coliform bacteria may acquire a plasmid that codes for an esterase that hydrolyzes the lactone ring causing inactivation. Decreased permeability

Answer 24

General Spectrum and Clinicial Uses Primarily gram positive, esp. upper resp. tract infections (bronchitis, pneumonia (community-acquired)) Not active vs. most aerobic gram negative bacilli except erythromycin has moderate activity vs. some strains of H. influenzae and good activity vs. M. catarrhalis, Legionella, Campylobacter jejuni Erythromycin is combined with a sulfonamide (Pediazole {DC’d tradename}) for otitis media due to H. influenzae. Azithromycin and clarithromycin may be more active vs. H. influenzae than erythromycin. Includes intracellular pathogens (mycoplasma, chlamydia, spirochetes)

Answer 25

DOC for: Mycoplasma pneumoniae (or a tetracycline) Legionella pneumophila (legionnaire's disease) [+rifampin] Bordetella pertussis (whooping cough; during early course) Corynebacterium diphtheriae (eradicates carrier state) Campylobacter jejuni (if fluoroquinolones are contraindicated,e.g.,child) Ureaplasma urealyticum (a mycoplasma) Chlamydial pneumonia or conjunctivitis In general, it is an alternate to penicillin in mild-to-moderate infections when patient is allergic to penicillin (and for rheumatic fever prophylaxis). Clarithromycin or azithromycin are DOCs in penicillin-allergic patients with valvular defects undergoing dental or respiratory procedures to prevent endocarditis.

Answer 26

Absorption Different forms of erythromycin (see below) attempt to improve bioavailability & decrease gastric side effects. Free base is active form. Estolate, stearate, & ethylsuccinate forms must 1st be converted in the serum to erythromycin base before they are active. Base is incompletely absorbed and inactivated by gastric juice, so is given as enteric-coated preparations. Absorption is decreased by food, so is best taken on an empty stomach (250-500 mg QID). Esters improve acid stability and increase absorption. Stearate, Estolate, Ethylsuccinate Lactobionate or gluceptate for IV admin. Reserved for severe infections such as legionella Not used IM (pain upon injection)

Answer 27

Good into intracellular sites and body fluids (but erythromycin does not reach high concentrations in ear fluids) Excellent penetration into tissues & cells. Inadequate conc. achieved in CSF. ~70% protein-bound (clari- and azi- are less bound, estolate is most bound (96%) Concentrates in liver and in macrophages and lymphocytes.

Answer 28

Hepatic metabolism is major route of elimination. Inhibits cytochrome P-450 enzymes (CYP3A4) - so can increase effects of drugs such as anticoagulants, digoxin, carbamazepine, cyclosporine, ergotamine (ergot toxicity), triazolam, lovastatin (rhabdomyolysis), theophylline, etc. Patients on drugs metabolized by P450 enzymes should be monitored closely for serum concentrations - especially important with theophylline to prevent theophylline toxicity (may require dose reduction of theophylline). Caution in impaired hepatic function. Azithromycin does not appear to inhibit CYP3A4 as strongly

Answer 29

Fairly new class of antibiotic Similar to the Macrolides structure contains a keto group a 3 position instead of a hydroxyl group and removal of a sugar group mechanism the same as Macrolides (binds to the 50s bacterial ribosomal subunit)

Answer 30

--resident microorganisms are found in different parts of the body -produces enzymes that help digestion -produces antibacterial factors -prevents colonization by pathogens -produces metabolites: vitamin K, B vitamins

Answer 31

bypass normal defenses and cause infection can be done by inhibiting immune system themselves -infection is usually dependent on adequate numbers of microorganisms rather than a compromise of the host's defenses

Answer 32

-direct contact -indirect contact: vectors -droplet vs. airborne -vertical (btwn family members) vs. Horizontal

Answer 33

invade surrounding tissues by evading the host's defence mechanisms

Answer 34

-warm and nutrient filled environment of human tissue cause most microorganisms to multiply rapidly -viral pathogens replicate within infected cells -some bacteria are intracellular pathogens and replicate in macrophages and other cells

Answer 35

-may stay localized or enter other body areas -if immune system compromised, spreading is quick

Answer 36

-the period from initial exposure to onset of the first symptoms, could last from hours to years

Answer 37

-occurence of initial symptoms are often very mild with feelings of discomfort and tiredness. May lead to immediate more serious type of symptomatology or go quiet and major effects may not occur for over a year

Answer 38

spreads and affects other body tissues

Answer 39

-recovery occurs and symptoms decline or the disease is fatal or has a period of latency

Answer 40

-variable depending on pathogen -caused directly by pathogen or indirectly by its products such as exotoxins -fatigue -malaise -weakness -loss of concentration -generalized aching loss of appetite

Answer 41

fever -body temperature is regulated at a higher level than normal -exogenous pyrogens (i.e. lipopolysaccharide coat) -endogenous pyrogens (i.e. interleukins, triggered because of triggering of complement system)

Answer 42

ability to spread from person to person

Answer 43

ability to produce an immune response

Answer 44

how disease infects the host. where does it get in

Answer 45

how disease damages cells

Answer 46

ability to enter and replicate

Answer 47

ability to produce diseae

Answer 48

capacity to cause severe disease; potency

Answer 49

production of toxins

Answer 50

diseases with relatively high, but constant rates of infection in a particular population

Answer 51

-number of new infections in a particular population that greatly exceeds the number usually observed

Answer 52

epidemic that spreads over a large area such as continent or worldwide

Answer 53

"true" bacteria, filamentous, spirochetes, mycoplasma, rickettsia, and chlamydia various transmission routes -attach through pili (fimbriae) -surface of cells -result in direct confrontation within an individuals defense mechanisms -evasion of these defences can result in bacteremia and sepsis

Answer 54

enzymes released during growth ---damages cell membranes, activated second messengers and inhibits protein synthesis

Answer 55

-contained within cell walls of gram-negative bacteria and released during lysis of bacteria -called pyrogenic bacteria because they activate inflammation and produce fevere

Answer 56

-coat the crystalline fragment (fc) portion of an individuals antibody, preventing complement activation or phagocytosis -degrade immune cells -bind and neutralize antibodies -evade complement -cause immune suppression resistant: alter surface molecules that express antigens

Answer 57

-superantigens (triggers excessive activation of immune system, especially T cells) endotoxin shock (mainly gr - bacteria lipopolysaccharide causing massive cytokine storm)

Answer 58

staphylococcus aureus

Answer 59

an enzyme that destroys penicillin, more recently bacteria developed a resistance to MRSA

Answer 60

-large microorganisms with thick cell walls -eukaryotes -single-celled yeasts, multicelled molds or both -disease caused by fungi: mycosis -disease transmitted by inhalation or contamination of wounds -dermatophytes if infections invades skin, hair or nails

Answer 61

immunosuppression

Answer 62

wide temperature variations -low oxygen -alkaline pH

Answer 63

candida albicans

Answer 64

-skin -GIT -mouth -vagina

Answer 65

-parasites benefit at the expense of the host -parasites range from unicellular protozoa to large worms -parasitic worms (Helminths) -intestinal and tissue nematodes (i.e. hookworm, roundworm) -flukes (liver fluke, lung fluke) -tapeworms -most common cause of infection worldwide

Answer 66

vectors -malaria by mosquito bites -trypanosomes by the tsetse fly -leighmania sp by sand fleas

Answer 67

-coat themselves -gene switch -antigenic variation -degrade IgG and IgA -neutralize antibodies -tissue damage from infestation and toxins

Answer 68

malaria -transmitted through bite of an infected anopheles mosquito -parasite enters the bloodstream, survives in the liver and invades the parenchymal cells -after several rounds of division, the liver cell ruptures and thousands of parasites enter the blood infecting the RBCs

Answer 69

virion=nucleic acid surrounded by capsid

Answer 70

by nucleic acid in the virion (RNA or DNA, whether it is single stranded (ss) or double stranded (ds) and whether it uses the enzyme reverse transcriptase for replication

Answer 71

viral disease -common cold -cold sores -hepatitis -HIV -SARS-COV-2

Answer 72

intracellular -attaches or binds to host cell via protein receptors -penetrates host cell via protein receptors -penetrates the host cell -releases genetic information into the host cytoplasm -RNA viruses enter the host nucleus -produce mRNA -may produce provirus DNA -DNA viruses enter the host nucleus -may integrate into the host DNA, may make mRNA

Answer 73

-translation of mRNA results in the production of viral proteins -for enveloped viruses, new virions are released through budding -viral DNA is integrated in the host cell and transmitted to daughter cells by mitosis

Answer 74

-rapid division -intracellular survival -coating with self proteins -antigenic variation -neutralization -complement evasion -immune suppression

Answer 75

highly infectious -virions attach to respiratory epithelial cells and enter by endocytosis -may be fatal for very young and old -surface proteins undergo change each year -can have antigenic drift or mutation -mutation of genes that express surface molecules -can have antigenic shift: recombination into a new virus from two different species

Answer 76

caused by HIV -depletes body's T helper cells

Answer 77

sub-saharan africa

Answer 78

blood or blood products IV drug use heterosexual or homosexual activity maternal-child transmission before or during birth

Answer 79

-gp 120 protein binds to the CD4 molecule found primarily on the surface of Th cells -typically cause a significant decrease of Th -reverses CD4:CD8 ratio normally 1-4, decreases below 1.0 in AIDS co-receptors CXCR4 and CCR5 -CXCR4 prefer T cells and form syncytium CCR 5 prefer macrophages and do not form syncytium

Answer 80

-decreased T cells -decreased thymic production of new T cells -damaged secondary lymphoid organs, especially lymph nodes

Answer 81

-serologically negative -serologically positive but asymptomatic window period: infectious but asymptomatic -fatigue, headaches, muscle aches, fever

Answer 82

atypical or opportunistic infections and/or Cancer CD4+ T-cell numbers are at or below 200cells/microL

Answer 83

Antiretroviral therappy (ART) 3 or more drugs-usually 2 drugs target reverse transcriptase (inhibits reverse transcriptase) and one if from a different class of drugs -no cure, slows progression

Answer 84

-presence of passive maternal antibody limits testing ofHIV antibodies in infants up to 18 months -CNS particularly vulnerable -developmental delays; loss of intellectual abilities -impaired brain growth or acquired microcephaly -motor deficits

Answer 85

-preserve and maintain the immune system -aggressive response to opportunistic infections -support and relief of symptomatic occurrences -antiretroviral therapy

Answer 86

prevent growth (bacteriostatic) or directly kill (bacteriocidal) microorganisms -inhibit production and function of cell wall block DNA synthesis -inhibit protein synthesis -interfere with folic acid metabolism

Answer 87

prevent initiation of disease -no not last long as infection-produced immunity

Answer 88

weakened live virus -MMR -varicella -rotavirus

Answer 89

killed virus Hep A polio influenza

Answer 90

Hepatitis B HPV

Answer 91

-conjugated (to carrier proteins) -increased immunogenicity -Hib -toxoids vaccines against bacterial toxins DtaP -extracted capsular polysaccharides: dead bacteria: meningococcal, pneumococcal

Answer 92

-preformed antibodies are administered to individuals -useful for Hep A and B and rabies

Answer 93

also acts as a cholinergic antagonist leading to a Black Box warning to avoid use in Myasthenia gravis patients

Answer 94

Lincomycin (Lincocin) Clindamycin (Cleocin) unique structures called lincosamide (amino acid and sulfur-containing octose derivatives)

Answer 95

Binds reversibly to 50S subunit of bacterial ribosome and inhibits protein synthesis (bacteriostatic), similar to the macrolides Some bacteria may acquire a plasmid that codes for an enzyme that methylates bacterial RNA in the 50S subunit (so it can't bind; cross-resistant with erythromycin - MLS resistance)

Answer 96

-diarrhea (2-20% -pseudomembranous colitis (10% -caused by necrotizing exotoxin release by clindamycin-resistance c. dif -D/C immediately when significant diarrhea or colitis develops! -superinfections , esp vaginal yeasts after use of vaginal cream -skin rash in 10% of patients (Steven-Johnsons) -IV admin causes local thrombophlebitis

Answer 97

-not DOC for anything -alternative therapy for Bacteroides fragilis infection outside CNS (metronidazole is drug of choice) -anaerobic infections in pcn allergic patients -

Answer 98

Cleocin T Cleocin T (topical) and vaginal cream can cause pseudomembranous colitis (5% of dose absorbed systemically from vagina)

Answer 99

The 30S subunit of the bacterial ribosome is their site of action. In order to gain access to the gram negative bacterial ribosome, 2 processes are required: passive diffusion through hydrophilic pores formed by the porin proteins in the outer membrane. energy-dependent active transport system that pumps tetracyclines through the inner cytoplasmic membrane. Upon entering the cell, TCNs bind to the 30S subunit of bacterial ribosomes and inhibit protein synthesis by blocking the binding of the aminoacyl tRNA to the acceptor (A) site on the mRNA-ribosome complex (amino acids are thus not added to the growing peptide chain). Inhibitory effects are REVERSIBLE when TCN is removed. TCNs are primarily bacteriostatic at therapeutic concentrations, and concurrent therapy with bactericidal agents such as penicillins and cephalosporins may be antagonistic. Entry into gram positive organisms less well understood, but also requires an energy-dependant pump. Minocycline most active, followed by doxycycline. Tetracycline and oxytetracycline least active.

Answer 100

GI: N/V/ abdominal discomfort, diarrhea (may be lessened with taking with food) -Esophagitis and esophageal ulceration (drink full glass of water to reduce risk) -possible that drug-induced diarrhea could be due to superinfection of bowel such as pseudomembranous colitis-life threatening with TCN than PCN because of broad spectrum -Candida Albicans -hepatotoxicity-Contraindicated in pregnancy! -renal toxicity -Fanconi Syndrome -permanent brown discoloration of teeth in children under 8 (calcium depsited in newly formed teeth or bone) -vestibular toxicity-minocycline -Phototoxicity -Benign intracranial hypertension (pseudotumor cerebri)-reversible

Answer 101

Inhibits DNA gyrase A Topoisomerase, which are responsible for breaking and rejoining DNA strands necessary for DNA replication Eukaryotic cells do not contain DNA gyrase Less mutational selection than with older quinolones Resistance becoming a problem with Serratia and Pseudomonas in some hospitals Bacteriocidal

Answer 102

Campylobacter jejuni Shigella Salmonella Pseudomonas aeruginosa causing UTIs

Answer 103

-hypersensitivity -seizures (rare) -GI symptoms -CNS symptoms -Cartilage deterioration (arthropathy) in young animals-not recommended in children (<18) or during pregnancy or nursing -peripheral neuropathies potential serious side effect-nerve damage may become permanent -Photosensitivity -superinfections with strep and candida -abn liver function tests -disturbance of blood glucose -reports of crystalluria-ensure hydration -increased risk of tendinitis or tenon rupture in p older than 60 yrs taking steroids and p with kidney, heart or lung transplane -may exacerbate muscle weakness in patients with MG

Answer 104

Natural compound, first isolated in 1947. Simple structure (now made synthetically) containing a nitrobenzene, propanediol, and dichloroacetic acid portion. Acetylation by chloramphenicol-acetyl-transferase on the propanediol portion results in resistance (loss of binding to site). Relatively broad spectrum includes gram-positive,gram-negative aerobes and anaerobes and intracellular pathogens. However, therapeutic uses are severely limited because of its potential to cause serious, fatal blood dyscrasias. Use only for serious infections (ex. Meningitis, typhus, thyphoid fever, Rocky-Mountain spotted fever).

Answer 105

due to inhibitory effect on protein synthesis in mitochondria -bone marrow disturances-toxic erythroid bone marrow depression -aplastic anemia-not dose related -possible genetic predisposition -GI -Superinfection -Gray Baby syndrome -fatal in 40% of cases -when premie or neonate given too much -2-9 days after therapy started -result from toxicity due to failure to lower the dose enough to take into account the infant’s reduced capacity to conjugate CA to the glucuronide and to inadequate renal excretion of unconjugated drug -skin turns ask-gray color -caution in infants and limit dose

Answer 106

-only when benefits clearly outweight risks DOC for: -rickettsial diseases -typhoid fever -if PCN allergy, DOC for N. meningitidis and H. influenza meningitis -Rocky Mountain Fever (also Tetracycline)

Answer 107

AGs are strongly basic and exist as polycations and remain charged at physiological pH. OH and NH2 groups can be modified by bacterial enzymes. Can undergo chemical interaction with drugs bearing negative charges when mixed together (leading to inactivation by some acidic drugs). So, never mix penicillin (neg.) and AG (pos.) in the SAME IV bottle - give them separately. Can also occur with heparin, amphotericin B, and some cephalosporins

Answer 108

Irreversible inhibitors of protein synthesis that are bactericidal. Residual bactericidal activity may persist after serum conc. falls below the minimum inhibitory concentration (MIC) (post-antibiotic effect). Events involved in action: Passive diffusion through outer membrane Energy and oxygen-dependent transport across cytoplasmic membrane (inhibited by divalent cations, low pH, anaerobic conditions) Bind to receptor proteins on the 30S ribosomal subunit Interfere with initiation complex of peptide formation Cause misreading of mRNA message

Answer 109

Plasmid-mediated enzymes (acetylases, adenylases, phosphorylases) that can inactivate AGs. Alteration of the energy and oxygen dependent transport system so that the targets become inaccessible, i.e., AG can't penetrate the inner membrane. Mutation of ribosomal protein so as to prevent binding, especially of streptomycin

Answer 110

Excretion Mainly excreted by glomerular filtration. 3-5% is reabsorbed by kidney proximal tubules. Plasma half-life is about 2 hours and is highly variable depending on the status of renal function. The t1/2 is significantly increased with deteriorating renal function AND IT IS CRITICALLY IMPORTANT TO ADJUST DOSAGE IN RENAL FAILURE. Accumulate in proximal tubular cells and the t1/2 there is significantly longer than the plasma half-life.

Answer 111

-skeletal muscle weakness -Ototoxicity -Nephrotoxicity -potentiates NMBs-inhibits presynaptic Ach release at NMJ and diminishes postsynaptic receptor sensitivity -patients with MG or hypocalcemia susceptible-IV calcium or neostigmine effected antidote

Answer 112

-Gentamycin DOC: -in combo with Pen G or ampicillin for enterococcal endocarditis -with tetracycline for Brucella

Answer 113

Neomycin-most nephrotoxic (not Parenteral route) Gentamycin-most nephrotoxic Tobramycin Amikacin-broadest spectrum of AG Streptomycin Kanamycin-reserve tuberculostatic agent Plazomicin (Zemdri)

Answer 114

Chemical stability Rapid bactericidal action (most organisms) Experience over many years Rare allergic SEs Synergism with ß-lactams No pseudomembranous colitis (when used parenterally)

Answer 115

Nephrotoxicity and ototoxicity Lack of activity vs. anaerobes Low conc. in CSF Variable pharmacokinetics Lack of correlation between administered dose and measured serum conc. Inactivation by some drugs

Answer 116

hydrolyzed in acidic urine to formaldehyde and ammonia -formaldehyde is bacteriacidal in urine at pH <5.5 -used for chronic recurrent lower UTI

Answer 117

N/V -GI irritation with high doses -acid salts contraindicated in renal failure -mandelate salt can cause crystalluria -acid salts can precipitate urate crystals in urine -hepatic insufficiency -antagonistic with sulfonamides

Answer 118

-C./I in severe renal impairment (leads to toxicity) -hypersensitivity -lung toxicity (acute reaction is a pneumonitis) -chronic use may cause irreversible interstitial pulmonary fibrosis -neurodisorders: drowsy, headache, vertigo -polyneuropathy with demyelination and degeneration -hemolytic anemia (if G6PD-deficient) Colors urine brown -tx course should not exceed 2-weeks

Answer 119

Synthetic nitrofuran that requires activation (by bacterial enzymes) to reactive intermediate. Damages bacterial DNA Actvity is higher in acid urine. Well absorbed orally but excreted into urine so fast that systemic antibacterial effects are not seen. Urinary levels decrease and serum levels increase as renal function decreases.

Answer 120

Inhibits protein synthesis by binding to a site on the bacterial 23S ribosomal RNA of the 50S subunit; thus preventing the formation of a functional 70S initiation complex, an essential step in the bacterial translation process. This mechanism is somewhat unique among antibiotics, and this agent does not show cross-resistance to other antibiotics. Resistance development has been noted, due to point mutations in the bacterial 23 rRNA. Due to this compounds usefulness at treating vancomycin-resistant and methicillin-resistant infections, it should not be used as first line therapy to avoid the development of resistant organisms.

Answer 121

most common: N/V/D -can cause serotonin toxicity when combined with SSRI -weak reversible MAO inhibitor so avoid foods rich in tyramine -can lead to HTN crisis -bone marrow suppression -thrombocytopenia -ocular neuropathy -lactic acidosis

Answer 122

Tedizolid (Sivextro)

Answer 123

-large tricyclic glycopeptide Considered bacteriostatic normally, but bacteriocidal for rapidly dividing organisms. Also, for E. faecalis, cidal if given with streptomycin. Inhibits cell wall synthesis by irreversibly binding to the pair of D-ala molecules of cell wall precursor units. Resistance has emerged in Enterococcus faecium due to an alteration of vancomycin’s target (see below).

Answer 124

Vancomycin general spectrum is gram positive bacteria

Answer 125

may penetrate CNS if meninges inflamed -chills, fever, rash -rapid infusion=”red neck syndrome” (flushing over upper chest, urticarial rash, tachycardia, hypotension) due to release of histamine (pretx with antihistamine) -ototoxicity and nephrotoxicity (esp. if renal impairment) -rapid infusion <30 min associated with profound hypotension and cardiac arrest

Answer 126

-large tricyclic glycopeptide Considered bacteriostatic normally, but bacteriocidal for rapidly dividing organisms. Also, for E. faecalis, cidal if given with streptomycin. Inhibits cell wall synthesis by irreversibly binding to the pair of D-ala molecules of cell wall precursor units. Resistance has emerged in Enterococcus faecium due to an alteration of vancomycin’s target (see below).

Answer 127

-semi-synthetic derivative of vancomycin -approved for MRSA and other gram + microorganisms -not considered first line due to higher rates of kidney damage and teratogenicity in animal studies

Answer 128

-another semi-synthetic derivative of vancomaycin -approved for gram _ skin and soft tissue infxn -major advantage is very long half life (250 hrs) and >90% protein binding allowing for single dose therapy

Answer 129

-nitroimadazole derivative The nitro group is activated by intracellular electron-transport proteins, ferredoxins, in anaerobic microorganisms to chemically reactive intermediates which can then react with DNA and can lead to increased degradation of existing DNA, altered DNA helical structure, increased strand breaks, and inhibition of DNA synthesis. (Anoxic or hypoxic conditions are required for the formation of cytotoxic metabolites).

Answer 130

GI disturbances -Metallic taste -neurotoxicity: contraindicated in active CNS disease -disulfuram like reaction with alcohol -reddish-brown urine -reversible neutropenia -high doses are mutagenic and carcinogenic in animal studies should only be used if clearly needed in pregnant patients -may potentiate anticoagulant effet of warfarin and potentiate toxicity of lithium

Answer 131

IV tx of anaerobic infections esp meningitis due to Bacteroides fragilis -DOC (oral) for C.diff, H. pylori (in combo with tetracycline and bismuth) DOC for Gardnerella vaginalis Oral admin for amebiasis, diardiasis and genital infections Trichomonas vaginalis

Answer 132

Polypeptide antibiotic that is extremely nephrotoxic when used parenterally; now current use is restricted to topical application (active against gram positive bacteria and Neisseria, H. influenzae, T. pallidum). Eradicates sensitive bacteria from open infections and can be used topically for conjunctivitis. Usually combined with neomycin and polymixin (Neosporin). Inhibits bacterial cell wall synthesis (binds to a precursor of the cell wall and forms an unusable complex, acts at a step before the one inhibited by vancomycin). Advantage over other topical antibiotics: rarely causes hypersensitivity. Orally is an alternate to metronidazole or vancomycin for C. difficile.

Answer 133

Unique structure and mechanism of action: Reversibly binds to bacterial isoleucyl-tRNA synthase and blocks protein synthesis. Only covers gram positive bacteria, including methicillin-resistant S. aureus. Used in treatment of impetigo caused by Staph aureus or Strep pyogenes Long-term topical therapy has resulted in emergence of resistant staphylococci. No systemic absorption, so few local SEs

Answer 134

Bedaquiline (Sirturo)

Answer 135

Secnidazole (Solosec)

Answer 136

Baxdela (Delafloxacin)

Answer 137

Cefiderocol (Fetroja)

Answer 138

1st generation cephalosporin less risky, mostly gm. pos organisms

Answer 139

2nd or 3rd gen cephalosporins

Answer 140

vancomycin

Answer 141

pseudomembranous colitis

Answer 142

Polymyxin B and colistimethate (Polymyxin E) -site of action believed to be prejunctional --not antagonised with either calcium or neostigmine -significant potentiation with neuromuscular blockers -also be cautious of skeletal muscle weakness seen with Telithromycin (Ketek)

Answer 143

antiseptics

Answer 144

disinfectants

Answer 145

-alcohols (ethyl or isopropyl) -Quarternary ammonium compounds -iodine compounds -chlordexidine -hexachlorophene -silver nitrate -mercurous compounds

Answer 146

-alcohols (ethyl or isopropyl) -aldehydes (formaldehyde and glutaraldehyde) -cresol -chlorine -ethylene oxide -heat

Answer 147

-antiseptic and disinfectant -isopropyl slightly more effective than ethyl -considered bacteriocidal (mostly) -repeated wiping increases efficacy -ineffective against most fungal or viral organisms

Answer 148

benzylalkonium and cetylpyridinium

Answer 149

alters cell membrane permeability -used as preservatives and to sterilize surgical equipment -effective at killing most bacteria and many fungal and viral organisms as well (not mycobacterium tuberculosis) -mixed with alcohol to increase efficacy

Answer 150

-bactericidal against most -disrupts cell membranes -alcohol increases efficacy -used as hand wash as it adheres well to skin, but is not well absorbed

Answer 151

effective against bacterial, viral and fungal organisms

Answer 152

most commonly as skin antiseptic but must be applied for 1-2 minutes to assure good action-usually left, not rinsed off -local toxicity fairly low, but care must be used in allergic patients -causes skin staining

Answer 153

-combination of an organic molecule carrier with iodine -povidone-iodine most common -free iodine concentration low enough that little staining is observed -not as effective as most iodine solutions -commonly used in hand soaps and surgical swabs

Answer 154

-no longer used much due to easy absorption and severe dermatological, neurological and possible teratogenic effects -neonates especially susceptible -hand wash effective against most gram-positive organisms -adheres well to skin providing continued action -prescription only (for acne)

Answer 155

-used as a cautic, astringent and antiseptic -bactericidal and often used in eyes of new borns of mothers with gonococcal infections -also used on burns and other wounds

Answer 156

-commonly used for instrument and general disinfection including biologic spill clean up -hypochlorites (such as bleach-sodium hypochlorite, NaOCl) most widely used -usualy concentration 5-6% -broad antimicrobial spectrum and rapid action -additional chlorine-releasing agents include chloramine-T, chlorine dioxide and sodium dichloroisocyanurate MOA likely amino acid oxidation

Answer 157

-effective against bacterial, viral and fungal organisms -glutaraldehyde more effective than formaldehyde -requires several hours exposure for maximum effectiveness -acts by precipitating proteins in the organism -reacts with any proteins so not as good as antiseptic, main use as disinfectant

Answer 158

-benzene analog -bactericidal against most organisms including mycobacterium tuberculosis -phenol derivative, -causes burns to skin and limited to disinfectant uses

Answer 159

-poor efficacy -allergic reactions and poisoning (oral) mercurochrome listed by FDA as "not generally recognized as safe and effective" as an over the counter antiseptic and forbidden for sale across state lines -thiomersal only used as a preservative in some multiuse products such as a few vaccines, tattoo ink, antivenins, some ophthalmic and nasal preps

Answer 160

-used as a disinfectant (gas sterilization) -requires a treatment chamber to hold instruments for several hour contact period required -air-out plastic components sterilized by this method to allow ethylene oxide to out-gas from material

Answer 161

-infection of the mouth, face, skin, esophagus or brain (acyclovir to treat oral or IV) ex. fever blister of type 1 herper infection Type 1 encephalitis SE of herpes type 1 potentially fatal can be treated with acyclovir keratoconjunctivitis-serious eye infection that can result in blindness (use trifluridine (Viroptic or Idoxuridine (Herplex)

Answer 162

-infections of the rectum, genital areas, skin of lower body or menininges ex. genital herpes

Answer 163

acyclovir and valacyclovir immunocomromised patients more susceptible to type II infections and may cause meningitis, skin and mucous membrane infections

Answer 164

varicella-Zoster-->chicken pox -characterized by fever and skin lesions that can lead to scarring

Answer 165

varicella-zoster/shingles

Answer 166

2 "A" types and 1 "B"

Answer 167

neuraminidase inhibitors

Answer 168

-purine nucleoside analog similar to purine -antiviral activity mainly limited to herpes viruses esp. type 1 -varicella-zoster is less sensitive but there is still some activity against it -in-vitro acyclovir is 100 x more active than vidarabine and 10 times more active than idoxuridine against herpes type 1

Answer 169

inhibits viral replication by inhibiting DNA synthesis -acyclovir is phosphorylated in the cell by viral thymidine kinase to acyclo-GDP and acyclo-GTP by normal cellular enzymes -acyclo-GTP inhibits viral DNA polymerase by competing with deoxyguanosine triphosphase in addition, some acyclo-GTP gets incorporated into viral DNA strand where it causes termination of synthesis of strand -resistant strains have been identified but these have so far been less active than parent strains

Answer 170

genital herpes type II

Answer 171

valacyclovir (Valtrex) =better bioavailability -normally given BID for 5 days to decrease pain and increase healing rate of an outbreak

Answer 172

Famciclovir (Famvir)

Answer 173

aldehyde oxidase into Penciclovir (active form)

Answer 174

analog of guanosine which is a homologue of acyclovir

Answer 175

human cytomegalovirus competitively inhibits viral DNA polymerase by substituting for deoxyguanosine triphosphate

Answer 176

granulocytopenia thrombocytopenia anemias increased plasma creatinine

Answer 177

purine nucleoside analog that inhibits replication of DNA and DNA viruses (wide spectrum) -not recommended for single stranded RNA viruses where RNA strand acts as a messenger -RNA

Answer 178

phosphorylated to ribavirin monophosphate (RMP) which is a strong inhibitor of inosine monophosphate dehydrogenase, an enzyme needed for the conversion of inosine monophosphate to xanthosine monophosphate which is needed for the synthesis of guanine nucleotides -therefore intracellular GTP decreased -also inhibits viral RNA polymerase (via RTP) by competing for GTP and ATP sites on enzyme

Answer 179

40 hours accumulates in erythrocytes

Answer 180

zidovudine (AIDS)

Answer 181

ribavirin shortens the duration of viral pneumonia infections in children, also some improvement seen in young adults with influenza infections

Answer 182

amantadine

Answer 183

-binds to membrane-channel protein (M2) on type A -blocks late-stage assembly of influenza type A -does not affect viral attachment, penetration, or RNA dependent RNA polymerase activity

Answer 184

16 hours needs to monitor dosing in elderly if any signs of renal impairment

Answer 185

amantadine

Answer 186

high plasma concentrations lead to CNS toxicities (nervousness, confusion. hallucinations, seizures, coma) -up to 5% of patients without renal failure report some CNS side effects, such as insomnia and loss of concentration -SE can be decreased by dividing single daily dose into BID dosing -useful for prophylaxis of type A influenza but vaccine is better

Answer 187

rimantadine (flumadine)

Answer 188

inhibits viral DNA polymerase and reverse transcriptase by binding to these enzymes

Answer 189

herpes cytomegalovirus HIV usually given IV

Answer 190

resembles thymidine in structure and is phosphorylated in cells. triphosphate is incorporated into viral and mammalian DNA and more susceptible to breakage -mainly used for DNA viruses (ex. herpes and poxviruses)

Answer 191

zanamivir (Relenza)

Answer 192

neuraminidase inhibitor, which is a viral enzyme responsible for breaking the bond of newly synthesized viral particles in the host cell therefore new viruses cannot be released and viral spread is curtailed

Answer 193

both Type A and B influenza infections available as inhaled powder : 2 puffs BID x 5 days

Answer 194

-neuraminidase inhibitor -ethyl ester prodrug converted in body as active form

Answer 195

-neuraminidase inhibitor -same uses as zanamivir and oseltamivir but not for influenza prophylaxis -approved for patients over 18 -only IV dose form, given by single IV infusion -elimination unchanged via renal excretiona

Answer 196

diarrhea most common-8% -rare but serious skin reactions (steven johnson) -temporary psychiatric reactions (delirium and hallucinations) reported

Answer 197

broad spectrum antiviral originally designed for use to treat ebola -FDA approved in oct 202 for covid treatment but science mixed

Answer 198

regeneron approved under EUA is monoclonal antibody that decreases severity -molnupiravir-may be released in late 2021, given early may decrease disease severity by 50%. acts to decrease viral replication

Answer 199

no -is manageable

Answer 200

Hep A and B

Answer 201

yes but costs high multiple antivirals in therapy most common: Harvoni, Mavyret, Zepatier

Answer 202

early 1900s

Answer 203

1. virus entry 2. reverse transcriptase 3. integration 4. gene expression 5. assempbly 6 budding 7 maturation

Answer 204

interaction of viral envelope proteins with specific host-cell surface receptors and other accessory factors -these interactions lead to fusion of viral and cell membranes so that viral nucleoprotein complexes enter the target cell cytoplasm. These complexes are rapidly transported to host cell nucleus where the reverse transcriptaze enyme orchestrates the synthesis of a DNA copy of the viral RNA genome. The integrase protein IN directs integration of viral DNA associated with these complexes into host chromosomal DNA to form provirus

Answer 205

37.9 million

Answer 206

circumstances that promote exchange of blood or body fluid containing HIV HIV has been documented in: -blood products -semen --vaginal secretions -breast milk -tears urine CSF vsaliva

Answer 207

blood breast milk vaginal fluid semen

Answer 208

immune deficiency and increased susceptiblity to opportunistic infections -due to infection of CD4+ lymphocytes, the major target of HIV CD4+ T lymphocytes are functionally known as T helper cells

Answer 209

participate by helping B cells to manufacature antibodies in stimulating T cytotoxic cells (CD8+_ to kill virus-infected cells and tumor cells and in activating macrophages to eliminate intracellular pathogens such as mycobacterium species thus with destruction and/or inactivation of T helper cells both cell-mediated and humoral immunity are significantly compromised which increases susceptibility to opportunistic infections and eventually causes death

Answer 210

HIV RNA detects HIV infection 3-5 days earlier than P24 antigen test another test=HIV p24 antigen-protein can be detected prior to development of HIV antibodies

Answer 211

Enfuvirtide (fuzon)h hypersensitvity reactions most common

Answer 212

maraviroc (Selzentry) black box warning for hepatotoxicity

Answer 213

raltegravir (Isentress) -appears well tolerated , may lead to increased risk of depression

Answer 214

Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir Saquinavir-cariac problems-QT and PR prolongation Tipranavir-black box warning for hepatotoxicities and intracranial hemorrhage

Answer 215

GI upset hyperlipidemias hyperglycemia

Answer 216

if CD$+ t cells drop below 350 cells/mm3 also start ARV if HIV positive and opportunisic infection apparent or if pregnant

Answer 217

abacavir didanosine emtricitabine lamivudine stavudine tenofovir Zidovudine all increase risk of lactic acidosis espiecially in cases of renal dysfunction lactic acidosis raises risks in anesthesia

Answer 218

-cancer of cell sheet or epithelia (skin, intestinal tract) -accounts for 90% of cancer

Answer 219

-cancer of supporting tissue (bone, muscle, blood vessels)

Answer 220

-cancer of cells of blood

Answer 221

-cancer of cells of immune system

Answer 222

-production of excess lactic acid via anaerobic glycolysis (Fermentation) -lack of contact inhibition -loss of cell-cell adhesion -decreased serum requirements -different gene expression (transcription) -immortalized (telomeres?) -cause tumors when injected into certain animals (like mice)

Answer 223

-ends of chromosomes -act as some sort of clock for cell aging -Haylflick limit (40-60 divisions) -needed to prevent loss of DNA from lagging strand replication -eventually a gene is lost and cell dies -not active in most cells, but reactivated in cancer cells who can activate telomerase which rebuilds telomeres

Answer 224

-radiation: ultraviolet or other forms -chemicals which mutate DNA (chemical mutagens, or carcinogens) or substances which are converted in the body by enzymes to create carcinogens -viruses-both DNA and RNA viruses

Answer 225

DNA alteration -usually change in somatic (non-sex cells) -principle change is the alteration of a gene into an oncogene (a gene that causes cancer, not known how yet)

Answer 226

burkitt's lymphoma

Answer 227

cervical carcinoma

Answer 228

proto-oncogenes

Answer 229

Only RNA viruses contain oncogenes, not DNA viruses.

Answer 230

a built in, signal induced mechanism that causes self-destruction of cells. Appears to occur in most normal cells after a specific number of divisions (Telomeres?).

Answer 231

cross-linked DNA Bioactivated by cytochrome P-450 to the active metabolites, phosphoramide mustard and acrolein.

Answer 232

cyclophosphamide (Cytoxan)

Answer 233

-Hodgkin's, lymphomas, leukemias, lung, breast, ovarian carcinomas, multiple myeloma, Burkitt's lymphoma. -One of primary agents for childhood neuroblastomas and retinoblastomas -Used in combination with methotrexate and 5-fluorouracil as adjuvant therapy after surgery for breast carcinoma

Answer 234

Toxicity: N/V are common and usually delayed (may occur 8 hours later) Hemorrhagic cystitis - due to binding of acrolein to bladder lining -May minimize by adequate fluid intake and frequent bladder emptying DLT is bone marrow depression (leukopenia), recovery by 21 days. Alopecia, immunosuppression, pulmonary fibrosis; water retention (due to inappropriate secretion of ADH) Inhibition of pseudocholinesterase, increases Succinylcholine duration

Answer 235

busulfan (Myeleran)

Answer 236

DNA cross-linking -alkylating agent -no action other than myelosuppression (1st on granulocytes, then platelets, erythrocytes; eventually pancytopenia results) -no cytotoxicity to lymphoid tissues or GI epithelium

Answer 237

-chronic myelocytic (granulocytic) leukemia (CML) -polycythemia vera

Answer 238

busulfan (Myeleran)

Answer 239

-DLT is bone marrow depression -N/V, alopecia, lung fibrosis, impotence, sterility

Answer 240

1. Inhibition of topoisomerase II 2. Binding with DNA to inhibit RNA and DNA synthesis 3. Oxygen radical production 4. Membrane binding and alteration of ion transmembrane flow

Answer 241

DLT for doxorubicin and daunorubicin is cardiomyopathy (due to oxygen radicals), a unique toxicity. 2 forms: 1) brief, acute, reversible or 2) chronic, cumulative, dose-related Unprotected myocardial cells are subject to induction of ferric iron-dependent and oxidative stress due to oxygen-radical formation. Can be minimized by giving vitamin E (antioxidant) or iron chelators. The piperazine derivative of EDTA, dexrazoxane (ZINECARD), is an effective "rescue agent" for cardiac cells; it does not interfere with antitumor effects. Dexrazoxane is a prodrug that readily crosses myocardial cell membranes and is rapidly hydrolyzed to ferric iron-chelating metabolites. Dexrazoxane's cardioprotective action is thought to be due to displacing Fe+3 from its complex with anthracyclines. (When Fe+3 is reduced to Fe+2, oxygen radicals are converted back to oxygen so myocardial cells are spared drug-induced oxidative stress).

Answer 242

both drugs eliminated by metabolism to less active metabolites so decrease dose if hepatic dysfunction -given IV

Answer 243

Soft tissue, osteogenic and other sarcomas; lung, bladder, breast, ovarian, thyroid cancers; Hodgkin's, lymphomas, acute leukemias Usually used as part of combination regimens

Answer 244

doxorubicin

Answer 245

doxorubicin

Answer 246

Acute leukemias, some solid tumors in children Also available as a liposomal formulation (DAUNOXOME) approved as first-line treatment for advanced Kaposi's sarcoma.

Answer 247

Copper-chelating glycopeptide isolated from Streptomyces Found as a complex with copper bound in a coordinate complex (core of 4 nitrogens binds metals), then is converted to an iron complex by metallothionein which traps copper

Answer 248

Causes DNA strand breaks - free radicals Metallo-bleomycin complex is activated in presence of oxygen and reducing agents, then transfers an electron from iron to molecular oxygen - forming activated oxygen species. (The amino terminal S tripeptide binds to DNA and the complex partially intercalates).

Answer 249

Testicular tumors, head and neck, skin cancers, lung, Kaposi's sarcoma, lymphoma, Hodgkin's.

Answer 250

DLT is pulmonary fibrosis. N/V, fever, skin toxicity, anaphylactic-like reaction

Answer 251

Inactivated by bleomycin hydrolase in normal tissues - but low amounts in tumors, skin , and lung. May be given IV, IM, SQ, IP, or intraarterial. 2/3 excreted in urine by GF; if renal impairment, at high risk for pulmonary toxicity - so reduce dose.

Answer 252

an analog of folic acid, so, it can "fool" the cell into trying to incorporate it as though it was folic acid. Methotrexate is a dihydrofolate reductase (DHFR) inhibitor. enters cells by a high affinity active transport system (higher rate of influx in tumor cells) and is converted by the enzyme folylpolyglutamyl synthetase (FS) to methrotrexate polyglutamates in which up to 6 glutamyl groups are added in t -peptide linkage. Due to the highly ionized nature because of the free carboxyl groups, they are highly retained in the cell. FS activity is higher in cancer cells vs normal cells - so may account for selectivity. (FS activity is also high in liver cells and these can retain methrotrexate polyglutamates for several months; hence, hepatotoxicity). Methotrexate and methotrexate polyglutamates (PGs) inhibit human DHFR. The PGs also inhibit thymidylate synthase (TS) and folate-dependent enzymes of de novo purine biosynthesis.

Answer 253

-Acute lymphocytic leukemias (ALL) in children. - Carcinomas of breast, head and neck, gastric, bladder, some sarcomas. -Can be used in high doses for osteogenic sarcomas along with "rescue" of host toxicity by leucovorin (folinic acid, citrovorum factor). -Also used intrathecally in high dose with leucovorin for meningeal leukemias. (Repeat dose Q 4days til no cancer cells in CSF, leucovorin counteracts toxicity of methotrexate that escapes into systemic circulation). -Also used for psoriasis (abnormally rapid proliferation of epidermal cells) and sometimes for immunosuppression (prevention of graft-vs-host reaction). -Also used for refractory rheumatoid arthritis (methotrexate is a DMARD (disease modifying antirheumatic drug) that is usually given once a week, sometimes along with NSAIDS. In addition to stopping pain symptoms, methotrexate can stop the disease from involving more joints, joint disability, and joint destruction.

Answer 254

DLT is mucositis. Oral and intestinal epithelium are more sensitive than bone marrow cells. (swelling and vacuolization of intestinal mucosal cells within 6 hrs., desquamation of epithelial cells, plasma extrudes into lumen of bowel, (hemorrhagic enteritis) and within 24 hours, there is loss of proliferating bone marrow cells). Both of these toxicities are usually almost completely reversed in 2 weeks. Bone marrow depression, alopecia, interstitial pneumonitis, nephrotoxicity, hepatotoxicity, defective oogenesis or spermatogenesis (impaired fertility), toxic to developing embryo and induces abortion. Teratogenic

Answer 255

Readily absorbed from GI. (High doses are incompletely absorbed and are given IV (with rescue). 50% bound to plasma proteins; may be displaced by other drugs such as sulfonamides, salicylates, tetracycline, phenytoin, etc. - Use caution if given concomitantly. More than 50% excreted in urine unchanged (glomerular filtration and active tubular secretion). Caution if impaired renal function (prolonged bone marrow suppression in delayed excretion of methotrexate). Minimal metabolism, but with high doses, metabolized to 7-OH-methotrexate which is nephrotoxic (less soluble, precipitates in renal tubules). High doses can precipitate in renal tubules in acid urine - so must maintain output of large volume of ALKALINE urine. Decreased excretion and consequent severe myelosuppression can be caused by drugs that reduce renal blood flow (NSAIDS), by nephrotoxic drugs (cisplatin), or weak organic acids (aspirin, penicillin) Several routes of administration - oral, IM, IT, IV (as high-dose with leucovorin rescue)

Answer 256

5- fluorouracil

Answer 257

Converted enzymatically to FdUMP which inhibits TS (a covalent stable ternary complex is formed with 5,10-methylene FH4, FdUMP, and TS). 5-FU is also activated to FUTP which may be incorporated into RNA, and to FdUTP which may be incorporated into DNA. Some of the enzymes required for its activation are found in higher concentration in tumor cells. 3 different pathways can activate it, and these depend on cellular pools of enzymes and substrates. Normal cells can be "rescued" from toxicity of high doses of 5-FU by administering uridine (mechanism is not clear but involves differences in uridine uptake or activation in normal vs. tumor cells; ultimately expands UTP pools and decreases incorporation into RNA). Methotrexate increases 5-FU activity when given PRIOR to 5-FU. Leucovorin also increases formation of the ternary complex.

Answer 258

stomach, colon, bladder, prostate, pancreas, breast, and ovarian (10-30% response rate) cancers. more effective when used in combination. topically for premalignant skin lesions and superficial basal cell carcinomas. Used as 2% solution or 5% cream (EFUDEX) to treat actinic keratoses (sun cancer of the skin) caused by basal cell or squamous cell cancers. Is usually curative for this when used topically. Can also be used for severe psoriasis.

Answer 259

Toxicities (Dependent on route): Continuous infusions - usually delayed - 1st is anorexia, nausea, then stomatitis and diarrhea (mucosal ulceration of GI may cause a fulminant diarrhea, shock, and death); these are warning signs that a sufficient dose has been given. If they occur, 5-FU should be discontinued, since myelosuppression is not evident until day 9 - 14. Bolus dose - Myelosuppression (leukopenia maximal at 9 - 14 days), alopecia, skin eruptions and pigmentation are common reactions. Intrathecal - neurological (acute cerebellar syndrome), cardiac toxicity. Except for topical use for skin cancers, 5-FU normally administered IV, either as rapid IV injection or continuous IV infusion over 24 hours. Various dosage regimens have been used.

Answer 260

Incomplete and unpredictable absorption if oral (so is given IV) Readily enters CSF Metabolic degradation, especially in the liver - inactivated by dihydrouracil dehydrogenase which reduces the pyrimidine ring. Also found in other tissues, including intestinal mucosa. Some patients may be deficient in this enzyme, so are highly sensitive to 5-FU. First course should be given in hospital to see how patient reacts.

Answer 261

vincristine (oncovin) and Vinblastine (velban)

Answer 262

Spindle poisons Cell cycle specific; act at M phase (cause mitotic arrest at metaphase) Bind to tubulin, drug-tubulin complex adds to ends of microtubules, terminates their assembly, and causes depolymerization of microtubules resulting in mitotic arrest at metaphase and dissolution of the mitotic spindle. This interferes with chromosome segregation.

Answer 263

Unpredictable oral absorption - so given IV Fatal if given intrathecally Rapid, extensive binding to plasma proteins and tissues. Metabolized in liver and excreted into bile and feces - reduce dose if hepatic impairment. Varying terminal t1/2 - ranges from 25 hr (vinblastine) to 85 hr (vincristine). Take precautions to avoid extravasation during IV administration. Rapid action - so may need allopurinol to prevent hyperuricemia

Answer 264

function as mitotic spindle positions (lock dividing cells in metaphase)

Answer 265

Paclitaxel, Docetaxel (Taxotere), Carbazitaxel (Jevtana)

Answer 266

Testicular tumors (curative, comb. with BLEO and VINBL); broad activity, esp. carcinomas of the bladder, head and neck, ovarian (comb. with cyclophosphamide + doxorubicin, i.e., CAP), cervical, lung, esophagus, neuroblastoma, retinoblastoma.

Answer 267

Paclitaxel and Docetaxel approved for breast, head, neck, lung cancers Paclitaxel also used for Kaposi’s sarcoma and restenosis (recurrent narrowing of coronary stents). Taxus® is a drug-releasing coronary stent. Docetaxel also used for prostate cancers Carbazitaxel used for prostate cancers

Answer 268

N/V alopecia neutropenia anemia thrombocytopenia

Answer 269

After hydrolysis, loses chlorides, and forms activated platinum species that reacts with DNA and proteins, forming cross links. Intrastrand (adjacent N7 guanines on the same strand) is most prevalent; interstrand is slower and less prevalent. Also protein-DNA cross links. Can react with other nucleophiles, e.g., SHs of proteins - causing unusual toxicities.

Answer 270

Severe, intense N/V (premedicate with antiemetics) in all patients. DLT is nephrotoxicity (can minimize with hydration and diuresis). Rescue agents are those with high affinity for heavy metals, e.g., sodium thiosulfate, diethyldithiocarbamate (DDTC, a disulfiram metabolite). Usually given 2 hours after cisplatin, to decrease renal and GI effects but not antileukemic. -Ototoxicity (hearing loss at high frequency range) esp. with repeated doses and in children. Electrolyte disturbances (decreases plasma Mg, Ca, K, PO4) -Mild BMD, hyperuricemia, neurotoxicity (peripheral neuropathy), anaphylaxis.

Answer 271

Given IV (diluted in dextrose, saline, and mannitol, with hydration to prevent renal tox.) 90% protein bound Inactivated intracellularly by sulfhydryls Poorly penetrates CNS

Answer 272

Second Generation Compound Considered somewhat less nephrotoxic than Cisplatin N&V also less than with Cisplatin and easier to control. Main uses are ovarian, head, neck, and lung cancers. Longer half-life than Cisplatin, with the half-life of platinum-plasma protein complex up to 5 days. Urine elimination of 70% of Carboplatin dose in 24 hours unchanged mechanism appears to be the same as Cisplatin Bone marrow suppression is the primary DLT Anaphylactic reactions also reported, even on initial dose.

Answer 273

about possible peripheral neuropathies, and patient positioning controlled carefully.

Answer 274

doxorubicin, duanorubicin

Answer 275

bleomycin, busulfan

Answer 276

cyclophosphamide -the inhibition of pseudocholinesterase may last several weeks following last treatment -consider non-depolarizer instead

Answer 277

Busulphan cisplatin cyclophosphamide daunorubucin 5-fluorouracil paclitaxel

Answer 278

Methotrexate bleomycin busulphan cyclophosphamide cytarabine carmustine docetaxel paclitaxel

Answer 279

Methotrexate L-asparginase carboplatin ifosfamide mitomycin-C

Answer 280

Actinomycin D methotrexate androgens L-asparginase busulphan cisplatinum azathiopine

Answer 281

Methotrexate, cisplatin interferon hydroxyurea procarbazine vincristine docetaxel paclitaxel