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Pathopharm 2 > Exam 3 > Flashcards

Exam 3 Flashcards

1
Q

Mechanism of action of Sulfonamide antibiotics

A

-PABA (paramino benzoic) analogs that competitively inhibit dihydropteroate synthase (DHPS) which is required for folic acid synthesis
-folic acid is needed for one-carbon biochemical reactions
-only affect bacteria that must synthesize their own folic acid

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2
Q

Are sulfonamide abx bacteriostatic or bacteriocidal?

A

bacteriostatic

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3
Q

Resistance mechanisms of sulfonamide abx

A

-Altered DHPS (enzyme for first step)
-Increased synthesis of PABA (by making more paba can outcompete sulfas)
-Increased production of NAT (N-acetyl transferase) (responsible for metabolism)-if active NAT destroys sulfonamides before they can be effective
- Alternative pathway for synthesis of essential metabolites
-All can occur via point mutation or via plasmid transfer—little piece of genetic material, usually have one gene

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4
Q

Absorption of Sulfonamide abx

A

-rapidly absorbed from GIT
-found in urine within 30 minutes

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5
Q

Distribution of sulfonamide abx

A

Well distributed throughout body tissues (including all body fluids and CSF)
Variable Vd (highest for sulfadiazine)
Variable protein binding (highest for those with lower pKa)
Possible drug interactions due to displacement from binding sites
May displace bilirubin from plasma albumin binding sites
Kernicterus in neonates—can lead to brain damage.
Readily pass through placenta, breast milk
C/I in pregnancy (late), nursing

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6
Q

Metabolism of sulfonamide abx

A

Acetylated at N4 position
Metabolites are inactive but less water soluble
Acetylation polymorphism (levels of NATs differ in pop. – Most Asian pops. fast acetylators-need higher doses, European slow-use lower doses)Excr

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7
Q

Excretion of sulfonamide abx

A

Eliminated partly unchanged and partly as acetylated metabolites in urine
Require dose reduction in significant renal failure
Marked variations in rate of renal elimination account for differences in duration of action

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8
Q

Drug interactions of sulfonamide Abx

A

May be antagonized by local anesthetics that are esters of PABA (i.e. procaine)
May potentiate warfarin, methotrexate, oral sulfonylureas, salicylates - may need dose adjustment
Contraindicated with methenamine (may form a precipitate)

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9
Q

Adverse effects of sulfonamide abx

A

Hypersensitivity
Cross sensitivity with other sulfonamide derivatives (furosemide, thiazides, sulfonylureas, carbonic anhydrase inhibitors)
Skin rashes, drug fever, toxic epidermal necrolysis, photosensitivity, Stevens-Johnson syndrome
Most common with longer-acting sulfa drugs
Crystalluria (Crystallize out easily )
Minimize by increasing fluid intake, alkalinizing urine, using drug with low pKa
Hemolytic anemia especially if G6PD-deficient
GI - nausea, vomiting, diarrhea
Hepatic necrosis
Blood dyscrasias (agranulocytosis, aplastic anemia - extremely rare)

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10
Q

Sulfonamide DOC for what?

A

Not DOC for anything
Alternate drugs for Chlamydia trachomatis, Nocardia, some UTIs with known sensitivity, some N. meningitidis

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11
Q

Rapidly absorbed sulfonamide abx

A

Sulfisoxazole (No longer available by itself)
Combined with erythromycin ethylsuccinate – (was Pediazole – now generic only)
Sulfamethoxazole-good for utis
Dose - 2 g stat, 1 g q 12 hr
Combined with trimethoprim - BACTRIM, SEPTRA
Sulfadiazine
similar activity and t1/2 to sulfamethoxazole
(Silver Sulfadiazine = SILVADENE-burn patients-sulfur ions are antimicrobial)

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12
Q

poorly absorbed sulfa sbx

A

Sulfasalazine (AZULFIDINE)
Activated by intestinal bacteria to 5-ASA + sulfapyridine
Side effects more common
Dose - 3-4 g stat, 500 mg QID for ulcerative colitis

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13
Q

Which is the DOC for prevention of burn infections?

A

silver sulfadiazine(silvadene)

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14
Q

Which topical sulfa abx can prevent burn infections but can cause metabolic acidosis due to its inhibition of carbonic anhydrase?

A

mafenide (Sulfamylon)

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15
Q

Which sulfa abx is an opthalmic solution?

A

sulfacetamide (Bleph-10)
-also available combined with prednisone as a Blephamide

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16
Q

Trimethoprim-Sulfamethoxazole (Bactrim, septra) formulation

A

5:1 SMZ:TMP in formulation yields a blood conc. ratio of 20:1 (400mg SMZ: 80mg TMP)

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17
Q

TMP reaches very high concentrations where?

A

-prostatic and vaginal fluids
-CSF
-sputum
-bile

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18
Q

Which drug causes 3 times as many dermatologic reactions as sulfisoxazole by itself?

A

Trimethoprim-sulfamethoxazole (Bactrim)

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19
Q

Which drug causes CNS toxicity in AIDS patients?

A

trimethoprim (b/c it concentrates in BBB

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20
Q

What is trimethoprim the drug of choice for?

A

Empiric tx of :
F (U) (MONUY) “Money”
Flu (H)
MOraxella catarrhalis
Nocardia
UTI (acute)
Yersenia Enterocolitica

alternate for most aerobic gm. neg. bacilli, Listeria, MRSA, M.Marinum

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21
Q

Mechanism of action of Penicillins

A

Inhibits final stage (of 3 stage process) of cell wall synthesis which involves peptide cross-linking by transpeptidases
Structural analog of D-ala-D-ala that occupies a binding site on transpeptidase (a Penicillin binding protein (PBP)).
Beta-lactam ring is opened and drug is covalently linked to serine residue.
Cell membrane remodeling continues but no cross-linking leading to cell wall weakness and cell lysis (Bacteriocidal).

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22
Q

Resistance mechanisms of Penicillins

A

Resistance Mechanisms for Penicillins
ß-lactamases
Different substrate specificities
Plasmid-mediated
Altered PBPs
Chromosomal control
Can mutate number or affinities
Porin mutation or decreased amount of porin proteins
Failure to activate autolytic enzymes in cell wall

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23
Q

Aminopenicillins

A
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24
Q

oral absorption of Penicillins

A

Oral
Include ampicillin, amoxicillin
Similar spectra, but amoxicillin is less active vs. Shigella
Gram pos. spectrum (ampicillin is DOC for Listeria monocytogenes) plus more gram neg. [E. coli, Proteus mirabilis (DOC), Eikenella corrodens (DOC), some Shigella, Salmonella, and H. flu]
Ampicillin is better than Pen G vs. Enterococcus
Considerations in choosing drug:
Amoxicillin is better absorbed than ampicillin
Less diarrhea
Food does not interfere with absorption
250-500 mg of amoxicillin T.I.D. = same amount of ampicillin given Q.I.D.
but incomplete
Pen G is acid labile (30% of oral dose is absorbed)
Best absorption with Pen V (gives 2-5 times the plasma conc. that pen G does) and amoxicillin
Destroyed by gastric juice (pH < 3 in stomach)
Decreased gastric acid production with aging, so the elderly have better absorption
Food interferes with absorption of all oral penicillins except amoxicillin
Best absorption if taken on empty stomach

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25
Q

Carboxypenicillins

A

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

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26
Q

Ureidopenicillins

A

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

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27
Q

Parenteral absorption of penicillins

A

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.

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28
Q

Distribution of penicillins

A

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

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29
Q

Excretion of Penicillins

A

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

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30
Q

Penicillins adverse effects

A

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.

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31
Q

Absorption of Cephalosporins

A

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.

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32
Q

Distribution of cephalosporins

A

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.)

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33
Q

excretion of cephalosporins

A

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

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34
Q

Adverse effects of cephalosporins

A

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

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35
Q

Clinical use of cephalosporins

A

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

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36
Q

Cefiderocol (Fetroja) IV

A

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

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37
Q

Adverse effects of Imipenem

A

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.

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38
Q

Special considerations of Imipenem

A

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

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39
Q

Macrolide ABX

A

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

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40
Q

Resistance for Carbapenems

A

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

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41
Q

Aztreonam

A

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

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42
Q

side effects of Aztreonam

A

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

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43
Q

Pharmacokinetics of Aztreonam

A

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

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44
Q

Which macrolide is acid labile ?

A

erythromycin

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45
Q

Which macrolides have increased acid stability?

A

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

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46
Q

MOA of macrolide abx

A

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).

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47
Q

resistance of macrolides

A

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

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48
Q

Clinical uses of macrolides

A

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)

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49
Q

Macrolides DOC for:

A

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.

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50
Q

Absorption of Macrolides

A

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)

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51
Q

Distribution of Macrolides

A

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.

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52
Q

Elimination of Macrolides

A

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

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53
Q

Ketolides MOA

A

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)

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54
Q

Deaths from infection account for _____ of deaths worldwide

A

1/3

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55
Q

Normal microbiome

A

–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

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56
Q

True pathogens

A

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

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57
Q

infectious microorganisms transmitted by:

A

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

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58
Q

invasion

A

invade surrounding tissues by evading the host’s defence mechanisms

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59
Q

multiplication

A

-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

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60
Q

spread

A

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

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61
Q

incubation

A

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

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62
Q

prodromal

A

-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

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63
Q

invasion

A

spreads and affects other body tissues

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64
Q

convalescence

A

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

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65
Q

Clinical manifestations of infectious disease

A

-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

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66
Q

What is the hallmark of infection?

A

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)

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67
Q

Communicability

A

ability to spread from person to person

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68
Q

immunogenicity

A

ability to produce an immune response

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69
Q

entry portal

A

how disease infects the host. where does it get in

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70
Q

mechanism of action

A

how disease damages cells

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71
Q

infectivity

A

ability to enter and replicate

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72
Q

pathogenicity

A

ability to produce diseae

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73
Q

virulence

A

capacity to cause severe disease; potency

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74
Q

toxigenicity

A

production of toxins

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75
Q

Endemic

A

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

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76
Q

epidemic

A

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

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77
Q

Pandemic

A

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

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78
Q

Bacterial infections

A

“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

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79
Q

Exotoxins

A

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

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80
Q

Endotoxins

A

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

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81
Q

Bacteria produce toxins and extracellular enzymes to destroy phagocytic cells:

A

-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

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82
Q

tissue damage from bacterial products, especially toxins or indirectly from infection or inflammation

A

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

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83
Q

Major cause of hospital acquired (nosocomial) infections and antibiotic resistance

A

staphylococcus aureus

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84
Q

B-lactamase

A

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

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85
Q

Fungal infections

A

-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

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86
Q

Systemic fungal infection usually from_____________

A

immunosuppression

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87
Q

Fungi adapt to host environment due to

A

wide temperature variations
-low oxygen
-alkaline pH

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88
Q

most common fungal infection

A

candida albicans

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89
Q

Candida albicans resides in:

A

-skin
-GIT
-mouth
-vagina

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90
Q

Parasitic and protozoan infections

A

-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

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91
Q

Parasitic infections and protozoan infections mainly transmitter through ____________.

A

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

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92
Q

How do parasitic and protozoan infections survive intracellularly

A

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

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93
Q

Most common infection worldwide

A

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

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94
Q

Basic structure of virus

A

virion=nucleic acid surrounded by capsid

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95
Q

How is virus classified?

A

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

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96
Q

the most common affliction of humans

A

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

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97
Q

virus lifecycle is completely ______

A

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

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98
Q

life cycle of virus

A

-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

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99
Q

viruses bypass immune defenses by

A

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

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100
Q

Influenza

A

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

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101
Q

MOA of AIDS

A

caused by HIV
-depletes body’s T helper cells

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102
Q

epicenter of aids pandemic is_______

A

sub-saharan africa

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103
Q

AIDS routes of transmission

A

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

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104
Q

HIV structure

A

-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

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105
Q

3 D’s of HIV

A

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

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106
Q

clinical manifestations of aids

A

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

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107
Q

Dx of aids

A

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

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108
Q

treatment of AIDS

A

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

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109
Q

Pediatric acquired immunodeficiency syndrome

A

-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

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110
Q

treatment of Pediatric acquired immunodeficiency syndrome

A

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

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111
Q

antimicrobials

A

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

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112
Q

Active immunization: vaccines

A

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

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113
Q

Attenuated

A

weakened live virus
-MMR
-varicella
-rotavirus

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114
Q

Inactivated

A

killed virus
Hep A
polio
influenza

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115
Q

Recombinant

A

Hepatitis B
HPV

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116
Q

Bacterial vaccines

A

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

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117
Q

passive immunotherapy

A

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

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118
Q

Black box warning for Telithromycin (Ketek)

A

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

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119
Q

What drugs are Lincosamides?

A

Lincomycin (Lincocin)
Clindamycin (Cleocin)

unique structures called lincosamide (amino acid and sulfur-containing octose derivatives)

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120
Q

MOA Lincosamide

A

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)

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121
Q

Adverse effects of Lincosamides

A

-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

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122
Q

Lincosamide DOC

A

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

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123
Q

Which topical licosamide is ued to treat acne?

A

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

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124
Q

MOA Tetracycline

A

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.

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125
Q

Tetracycline DOC for

A

H.Pylori

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126
Q

Adverse effects of Tetracyclines

A

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

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127
Q

MOA Fluoroquinolones

A

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

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128
Q

Fluoroquinolone DOC

A

Campylobacter jejuni
Shigella
Salmonella
Pseudomonas aeruginosa causing UTIs

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129
Q

Adverse effects of Fluoroquinolones

A

-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

130
Q

Chloramphenicol MOA

A

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).

131
Q

Chloramphenicol adverse effects

A

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

132
Q

Chloramphenicol Therapeutic uses/DOC

A

-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)

133
Q

Aminoglycosides important chemical features

A

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

134
Q

MOA aminoglycosides of bacteriacidal action

A

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

135
Q

MOA of bacterial resistance of aminoglycosides

A

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

136
Q

Excretion of aminoglycosides

A

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.

137
Q

Aminoglycosides adverse effects

A

-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

138
Q

Every patient on Aminoglycosides should have peak and trough plasma concentrations determined several times a week and within 24 hours of dose change

A
139
Q

most nephrotoxic Aminoglycoside and DOC

A

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

140
Q

Aminoglycoside drugs

A

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

141
Q

Advantages Aminoglycosides

A

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

142
Q

Disadvantages Aminoglycosides

A

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

143
Q

Methenamine (Hiprex) (Urinary Tract Antiseptic) MOA

A

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

144
Q

Methanamine Adverse Effects

A

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

145
Q

Adverse effects of Nitrofurantoin

A

-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

146
Q

MOA nitrofurantoin

A

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.

147
Q

MOA Linezolid (Zyvox)

A

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.

148
Q

Adverse effects of linezolid (Zyvox)

A

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

149
Q

Which oxazolidinone is 4-115 times more potent than linezolid against staph and enterococcal organisms?

A

Tedizolid (Sivextro)

150
Q

MOA Vancomycin

A

-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).

151
Q

DOC for Methicillin-resistant S. Aureus

A

Vancomycin
general spectrum is gram positive bacteria

152
Q

Vancomycin adverse effects

A

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

153
Q

Vancomycin MOA

A

-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).

154
Q

Telavancin

A

-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

155
Q

Ortivancin (Orbactive)

A

-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

156
Q

Metronidazole (Flagyl) MOA

A

-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).

157
Q

Adverse effects Metronidazole

A

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

158
Q

Uses of Metronidazole

A

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

159
Q

Bacitracin (Baciim)

A

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.

160
Q

Mupirocin (Bactroban)

A

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

161
Q

Which drug has Conditional approval for tx of confirmed multi-drug resistant TB?

A

Bedaquiline (Sirturo)

162
Q

Which new abx is used for the tx of bacterial vaginosis?

A

Secnidazole (Solosec)

163
Q

Which drug is used for the treatment of acute bacterial skin and skin structure infections?

A

Baxdela (Delafloxacin)

164
Q

Which is siderophore-bound cephalosporin for treating drug resistant gram-negative bacteria such as pseudomonas aeruginosa?

A

Cefiderocol (Fetroja)

165
Q

Which abx are used for cutneous penetration only?

A

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

166
Q

Which abx are used for GI or abdominal and with greater risk of gm neg organisms?

A

2nd or 3rd gen cephalosporins

167
Q

Which abx is used for heart valve or joint replacement?

A

vancomycin

168
Q

Which is the most frequent severe complication of prophylactic antibiotic use?

A

pseudomembranous colitis

169
Q

Which are the most potent antibiotics at causing skeletal muscle weakness?

A

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)

170
Q

Which agents are used topically to kill microorganisms on tissue?

A

antiseptics

171
Q

Which agents are used to kill microorganisms on equipment (non-living tissue)?

A

disinfectants

172
Q

Common antiseptics

A

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

173
Q

common disinfectants

A

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

174
Q

Alcohols

A

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

175
Q

What are the two quaternary ammonium compounds?

A

benzylalkonium and cetylpyridinium

176
Q

Quarternary ammonium compounds -benzalkonium and cetylpyridinium moa

A

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

177
Q

Chlorohexidine (Hibiclens)

A

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

178
Q

What is iodine effective against?

A

effective against bacterial, viral and fungal organisms

179
Q

Caution with iodine in patients with this allergy

A

shellfish

180
Q

Iodine use

A

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

181
Q

iodophors

A

-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

182
Q

Hexachlorophene (pHisohex)

A

-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)

183
Q

Silver nitrate

A

-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

184
Q

Chlorine

A

-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

185
Q

Aldehydes

A

-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

186
Q

cresol

A

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

187
Q

mercurochrome and methiolate

A

-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

188
Q

Ethylene oxide

A

-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

189
Q

How many types of herpes viral infections are known to invest humans?

A

9

190
Q

What are type 1 viral infections associated with?

A

-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)

191
Q

What are type 2 viral infections are associated with?

A

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

192
Q

which antivirals are effective in genital herpes therapy, inducing more rapid healing, decreased viral titer and diminished pain

A

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

193
Q

Type 3 viral infections

A

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

194
Q

Treatment for severe cases of chicken pox

A

acyclovir

195
Q

Whhat is a recurrent infection that infects a single dermatome (skin area innervated by a single nerve)

A

varicella-zoster/shingles

196
Q

What is the flu vaccine comprised of?

A

2 “A” types and 1 “B”

197
Q

newer therapeutics to treat the flu and decrease severity and duration of infection

A

neuraminidase inhibitors

198
Q

Acyclovir (Zovirax) structure

A

-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

199
Q

Acyclovir (Zovirax) MOA

A

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

200
Q

Valacyclovir (Valtrex) is mainly used to treat ______________.

A

genital herpes type II

201
Q

What is an ester of acyclovir that is rapidly converted to acyclovir?

A

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

202
Q

Which antiviral is an oral agent used for acute herpes zoster outbreaks and is a prodrug

A

Famciclovir (Famvir)

203
Q

What is FAmciclovir metabolized by?

A

aldehyde oxidase into Penciclovir (active form)

204
Q

What is ganciclovir (Cytovene ) an analog of?

A

analog of guanosine which is a homologue of acyclovir

205
Q

What is gangiclovir used to treat?

A

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

205
Q

SE of Ganciclovir

A

granulocytopenia
thrombocytopenia
anemias
increased plasma creatinine

206
Q

what is ribavirin (Virazole) an analog of?

A

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

207
Q

MOA Ribavirin (Virazole)

A

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

208
Q

What is the 1/2 life of ribavirin?

A

40 hours
accumulates in erythrocytes

209
Q

ribavirin antagonizes the activity of what, so do not use concurrently?

A

zidovudine (AIDS)

210
Q

Which antiviral is available in aerosol form for nebulizer use?

A

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

211
Q

Which antiviral is a water soluble tricyclic amine (unrelated to any other antiviral group)?

A

amantadine

212
Q

MOA Amantadine

A

-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

213
Q

1/2 life of amantadine

A

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

214
Q

which antiviral has anticholinergic activity?

A

amantadine

215
Q

SE amantadine

A

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

216
Q

What is a structural analog of Amantadine with same MOA but eliminated mainly by hepatic metabolism not renal ?

A

rimantadine (flumadine)

217
Q

What Foscarnet (Foscavir) MOA?

A

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

218
Q

Activity of foscarnet

A

herpes
cytomegalovirus
HIV
usually given IV

219
Q

MOA Idoxuridine (Herplex)

A

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)

220
Q

Which antiviral is used for uncomplicated acute influenza viral illness and prophylaxis?

A

zanamivir (Relenza)

221
Q

MOA of Zanamivir (Relenza)

A

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

222
Q

neuramidase inhibitors effective for

A

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

223
Q

Tamiflu (Oseltamivir phosphate)

A

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

224
Q

Peramivir (Rapivab)

A

-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

225
Q

adverse effects of peramivir

A

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

226
Q

Remdesivir (Veklury)

A

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

227
Q

Other tx of covid -19

A

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

228
Q

is hep B cureable?

A

no -is manageable

229
Q

Which hepatitis virus have vaccine to prevent

A

Hep A and B

230
Q

Is Hep C curable?

A

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

231
Q

HIV believed to have arised from chimpanzee virus that jjumpted species in Africa, evidence of first human infected_____

A

early 1900s

232
Q

Current understanding of molecular events in replication cycle of HIV-1

A
  1. virus entry
  2. reverse transcriptase
  3. integration
  4. gene expression
  5. assempbly
    6 budding
    7 maturation
233
Q

First step in HIV 1 replication cycle

A

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

234
Q

approx _____mllion people living with aids in 2018

A

37.9 million

235
Q

approx______died of AIDS complications in 2018

A

770,000

236
Q

________new infections of AID occur each year in US

A

50,000

237
Q

Florida has the ______highest infection rate in US

A

3rd

238
Q

major routes of HIV transmission

A

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

239
Q

only HIV where is associated with transmission

A

blood
breast milk
vaginal fluid
semen

240
Q

within 1-3 weeks of infection ____ to ____% of individuals develop flu-like illness known as HIV disease which can last from days to more than 10 weeks but usually less than 14 days

A

40-90%

241
Q

seroconversion or presence of HIV antibodies can usually be detected between ___ and ____ days after initial infection

A

22-27

242
Q

Acute infection with GIV occurs in about 1 in 10 to 1 in 100 CD4 T cells as detected by measuring viral RNA in cell

A
243
Q

what are the hallmarks of aids

A

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

244
Q

T helper cells

A

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

245
Q

What is the most sensitive of all diagnostic assays of HIV

A

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

246
Q
A
247
Q

Entry inhibitors of HIV

A

Enfuvirtide (fuzon)h
hypersensitvity reactions most common

248
Q

CCR5 antagnoist in HIV

A

maraviroc (Selzentry)
black box warning for hepatotoxicity

249
Q

integrase inhibitor for HIV

A

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

250
Q

protease inhibitors in HIV

A

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

251
Q

SE of protease inhibitors

A

GI upset
hyperlipidemias
hyperglycemia

252
Q

When should antiretroviral therapy be initiated?

A

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

253
Q

nucleoside/nucleotide reverse transcriptase inhibitors

A

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

254
Q

Carcinomas

A

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

255
Q

Sarcomas

A

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

256
Q

Leukemia

A

-cancer of cells of blood

257
Q

Lymphomas

A

-cancer of cells of immune system

258
Q

transformation to cancer cell

A

-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)

259
Q

Telomeres

A

-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

260
Q

carcinogens (Cancer causing)

A

-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

261
Q

What is the cause of cancer induction?

A

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)

262
Q

Cancer associated with Hepatitis B

A

Hepatoma

263
Q

Cancer associated with epstein-barr virus

A

burkitt’s lymphoma

264
Q

cancer associated with papilloma virus

A

cervical carcinoma

265
Q

cancer associated with Human T -cell leukemia (RNA virus)

A

leukemia

266
Q

viral oncogenes are mutated forms of cellular _________ found in normal cell

A

proto-oncogenes

267
Q

only ______viruses contain oncogenes, not _____Viruses

A

Only RNA viruses contain oncogenes, not DNA viruses.

268
Q

Apoptosis

A

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?).

269
Q

Cyclophosphamide (Cytoxan) MOA

A

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

270
Q

What is the most widely used alkylator?

A

cyclophosphamide (Cytoxan)

271
Q

uses of cyclophosphamide (cytoxan)

A

-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

272
Q

Toxicity of Cyclophosphamide (Cytoxan)

A

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

273
Q

What is a symmetrical bis-substituted methanesulfonic acid ester

A

busulfan (Myeleran)

274
Q

MOA of busulfan

A

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

275
Q

Uses of Busulfan

A

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

276
Q

Which agent is excrete in urine as methanesulfonic acid?

A

busulfan (Myeleran)

277
Q

Toxicity of Busulfan (Myeleran)

A

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

278
Q

Anthracyclines (doxorubicin, daunorubicin) mechanisms:

A
  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
279
Q

toxicities of anthracyclines (doxorubicin, daunorubicin)

A

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).

280
Q

Pharmacokinetics of anthracyclines

A

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

281
Q

Uses of doxorubicin (Adriamycin)

A

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

282
Q

Which agent chelates iron and other metals (from syringe needles) so keep from prolonged contact with metal?

A

doxorubicin

283
Q

Which agent if given too rapidly causes erythematous streaking along proximal veins
-single IV injection q 21-28 days

A

doxorubicin

284
Q

uses of duanorubicin (daunomycin, rubidomycin, cerubidine)

A

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

285
Q

Bleomycin (Blenoxane) structure

A

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

286
Q

MOA bleomycin (blenoxane)

A

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).

287
Q

uses of bleomycin (blenoxane)

A

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

288
Q

Toxicities of bleomycin

A

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

289
Q

beomycin pharmacokinetics

A

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.

290
Q

Methotrexate MOA

A

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.

291
Q

uses of metotrexate (mexate)

A

-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.

292
Q

toxicities of methotrexate

A

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

293
Q

pharmacokinetics of methotrexate

A

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)

294
Q

What is an analog of uracil with a fluorine atom at the 5-position

A

5- fluorouracil

295
Q

MOA of fluorouracil

A

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.

296
Q

uses of 5-fluorouracil

A

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.

297
Q

toxicitiies of 5-fluorouracil

A

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.

298
Q

5-fluorouracil pharmacokinetics

A

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.

299
Q

which anticancer agent is isolated from the periwinkle plant?

A

vincristine (oncovin) and Vinblastine (velban)

300
Q

MOA vincristine (oncovin) and Vinblastine (velban)

A

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.

301
Q

general effects of vincristine and vinblastine

A

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

302
Q

MOA Paclitaxel, Docetaxel (Taxotere), Carbazitaxel (Jevtana)

A

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

302
Q

Which anticancer agents are obtained from the pacific and European yew trees (bark fungus)

A

Paclitaxel, Docetaxel (Taxotere), Carbazitaxel (Jevtana)

302
Q

Uses of cisplatin

A

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.

302
Q

Uses of Paclitaxel, Docetaxel (Taxotere), Carbazitaxel (Jevtana)

A

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

303
Q

SE of Paclitaxel, Docetaxel (Taxotere), Carbazitaxel (Jevtana)

A

N/V
alopecia
neutropenia
anemia
thrombocytopenia

303
Q

MOA of cisplatin (platinol)

A

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.

304
Q

Toxicities of cisplatin

A

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.

305
Q

pharmacokinetics of cisplatin

A

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

306
Q

carboplatin

A

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.

307
Q

Patients treated with the vinca alkaloids, cisplatin etc should be questioned about:

A

about possible peripheral neuropathies, and patient positioning controlled carefully.

308
Q

Patients received what should be assessed for signs of cardiac myopathy

A

doxorubicin, duanorubicin

309
Q

Patients taking what should be assessed for pulmonary, dysfunction, which can be worsened by increased oxygen tension?

A

bleomycin, busulfan

310
Q

Patients given what anticancer agent should be carefully monitored if succinylcholine is used for muscle relaxation?

A

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

311
Q

Patients receiving cisplatin, methotrexate should be assessed for what insufficiency?

A

renal

312
Q

anticancer agents associated with cardiac toxicity

A

Busulphan
cisplatin
cyclophosphamide
daunorubucin
5-fluorouracil
paclitaxel

313
Q

anticancer agents associated with pulmonary toxicity

A

Methotrexate
bleomycin
busulphan
cyclophosphamide
cytarabine
carmustine
docetaxel
paclitaxel

314
Q

anticancer agents associated with renal toxicity

A

Methotrexate
L-asparginase
carboplatin
ifosfamide
mitomycin-C

315
Q

Anticancer agents associated with hepatic toxicity

A

Actinomycin D
methotrexate
androgens
L-asparginase
busulphan
cisplatinum
azathiopine

316
Q

Anticancer agents associated iwth CNS toxicity

A

Methotrexate,
cisplatin
interferon
hydroxyurea
procarbazine
vincristine
docetaxel
paclitaxel

317
Q
A

Pathopharm 2 (4 decks)

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