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Flashcards in Exam 4 Deck (204):
1

Describe key structural features of bacteria that are of pharmacological interest

- Peptidoglycan (peptides and surgars) cell wall for both G+ and G- bacteria: thick for G+ and thin for G-

- G- also has outer membrane LPS consisting of phospholipids and polysaccharides

- 50 S and 30 S ribosomal subunits

2

Effect of LPS on antibiotics

- Prevents / retards penetration of high MW abx (eg. Erythromycin)

3

Effect of bacteria lipid bilayer of cytoplasmic membrane on abx

- Water-soluble drugs are severely hindered

4

Effect of bacteria hydrophilic pores on abx

- Allow penetration of water-soluble molecules (eg. Sulfonamides)

5

Effect of nutrient receptor proteins on outer membrane of bacteria on abx

- Structurally-related nutrient-abx utilize these receptors. Agents similar to structure can use these.

6

Effect of teichoic and teichuronic acid (G+) on abx

- Anionic character affects rate of penetration

7

General strategies for killing/inhibiting bacteria growth

1. Disrupting coding/genetic machinery

2. Blocking protein synthesis

3. Disrupting cell wall or membrane synthesis

8

Compare and contrast bactericidal vs bacteriostatic antibiotics

- Bactericidal: agent that kills bacteria

- Bacteriostatic: agent that inhibits growth, but doesn’t kill the bacteria

9

Compare and contrast:
a. Prophylactic therapy
b. Pre-emptive therapy
c. Empirical therapy
d. Definitive therapy
e. Suppressive therapy

a. Prophylactic: tx in absence of infection to prevent dz

b. Pre-emptive: tx of high-risk infected pts who are asymptomatic

c. Empirical: tx of symptomatic pt without further testing or confirmation of organism

d. Definitive: tx with appropriate drug for identified organism

e. Suppressive: low dose tx used as secondary prophylaxis

10

List and describe possible resistance mechanisms

Acquisition of new genetic material or mutation of existing genome under pressure leads to:

1. Reduced drug entry

2. Increased drug expores

3. Expression of enzymes that destroy drug

4. Changes in expression of enzymes that activate the drug (pro-drug)

5. Impaired drug binding to original target

6. Development of new / different pathway not inhibited by drug

11

Which bacteria are commonly drug-resistant?

- Mnemonic = ESKAPE
- E: Enterococcus faecium

- S: staphylococcus aureus

- K: Klebsiella pneumoniae

- A: acinetobacter baumannii

- P: pseudomonas aeruginosa

- E: Enterobacter species

12

Peptidoglycan cell wall structure. How is it synthesized?

- Chains of repeating monomers of disaccharide subunits: NAM-NAG-pentapeptide

- Transglycosylase join monomers together: NAM-NAG

- Transpeptidase bind NAM-NAG by adding pentaglycine crosslinks bw pentapeptide residues of adjacent chains

- Wall is maintained by enzymes placed in general category of PBPs (penicillin-binding proteins). Specific beta-lactam antibiotics are selective to different PBPs.

13

Are beta-lactam compounds bactericidal or bacteriostatic?

- Bactericidal

14

Penicillin compounds.
a. Names
b. MOA
c. Main adverse effect

a. –cillin ending

b. Bind and inhibit PBPs = block synthesis and maintenance of bacterial cell wall peptidoglycan

c. Hypersensitivity (mild rash to severe anaphylaxis), other = CNS, blood, secondary infections

15

Are penicillin compounds broad or narrow spectrum? Are they beta-lactamase sensitive or resistant?

- Narrow: pen G, pen V, methicillin, nafcillin and oxacillin

- Broad: ampicillin, amoxicillin, piperacillin, ticarcillin and azlocillin

- All beta-lactamase sensitive except for methicillin, nafcillin, oxacillin

16

What is clavulanic acid? What are the side effects?

- Compound that inhibits bacterial beta-lactamase. Used in common combinations with beta-lactam antibiotics. Most commonly = amoxicillin + clavulanic acid = Augmentin.

- Side effects specific to the abx it is co-administered with

17

Cephalosporin compounds.
a. Names
b. MOA
c. Main adverse effect

a. –cef/-ceph ending

b. Bind and inhibit PBPs = block synthesis and maintenance of bacterial cell wall peptidoglycan

c. Hypersensitivity (mild rash to severe anaphylaxis), disulfiram effect (avoid etoh), other = blood

18

Are cephalosporin compounds narrow or broad spectrum? Beta-lactamase sensitive or resistant? Which are CNS penetrant?

- 4th generation = broad spectrum (G+ and G- organisms). 1st generation = narrow spectrum (G+ only).

- 1st: cefazolin, cephalexin

- 2nd: cefotetan, cefaclor, cefuroxime

- 3rd: ceftriaxone, cefotaxime, cefdinir, cefixime

- 4th: cefepime

- All are beta-lactamase sensitive except 4th generation.

- CNS penetrant = 3rd and 4th generation.

19

Monobactam compounds.
a. Names
b. MOA
c. Use
d. Main adverse effect

a. Aztreonam (only drug in this class)

b. Bind and inhibit PBPs = block synthesis and maintenance of bacterial cell wall peptidoglycan

c. G-, penetration of CSF, tx of serious pneumonia, meningitis and sepsis

d. Hypersensitivity (rashes, itch – not anaphylaxis)

20

Is aztreonam beta-lactamase resistant or sensitive?

- Resistant

21

Carbapenem compounds.
a. Names
b. MOA
c. Main adverse effect

a. –penem endings

b. Bind and inhibit PBPs = block synthesis and maintenance of bacterial cell wall peptidoglycan

c. GI (NVD), other = hypersensitivity, CV, CNS

22

What is imipenem co-administered with and why?

- Cilastatin. It is normally inactivated in the kidney. Co-administration with this drug prevents inactivation.

23

Are carbapenems beta-lactamase sensitive or resistant? Broad or narrow?

- Resistant. Susceptible for carbapenemase.

- Broad

24

Key pharmacologic effect of carbapenem drugs?

- Penetrate tissue and fluids very well including CSF. Important for use life-threatening infections.

25

Glycopeptide compounds.
a. Names
b. MOA
c. Main adverse effect

a. Vancomycin (only drug in this class)

b. Binds to D-Ala-D-Ala pentapeptide = steric inhibitor = prevents elongation of peptidoglycan cell wall

c. Skin flushing: red neck/red man syndrome, other = ototoxicity, nephrotoxicity

26

What spectrum drug is vancomycin?

- Broad for G+ and -.

27

Does vancomycin have CNS penetration effect?

- Not good penetration into CNS. Still used in meningitis tx as concentration still sufficient to get it across. Can also use intrathecally.

28

Polypeptides compounds.
a. Names
b. MOA
c. Main adverse effect

a. Bacitracin (*topical* and ophthalmic)

b. Blocks incorporation of AA and NA into cell wall

c. Hypersensitivity rxn (rare)

29

Is bacitracin broad spectrum or narrow?

- Broad

30

Phosphoenolpyruvate compounds.
a. Names
b. MOA
c. Use
d. Main adverse effect

a. Fosfomycin (only agent in class)

b. Prevents synthesis of UDP-NAM = blocking of early step in cell wall synthesis

c. Uncomplicated UTIs

d. Hypersensitivity rxn (rare)

31

Are protein synthesis inhibitor antibiotics bacteriostatic or bactericidal?

- In general these are bacteriostatic.

- Aminoglycosides are bactericidal. Macrolides are bactericidal at high concentrations.

32

Aminoglycoside compounds.
a. Names
b. MOA
c. Use
d. Main adverse effect

a. Mnemonic = Mean (aMINOglycoside) GNATS – Gentamicin, Neomycin, Amikacin, Tobramycin, Streptomycin. Also kanamycin

b. Binds 30S (maybe 50S too) = inhibits formation of initiation complex

c. Combo with beta-lactams to tx severe G- infections.

d. Nephrotoxicity, ototoxicity, other = skin hypersensitivity

33

Macrolide compounds.
a. Names
b. MOA
c. Main adverse effect

a. Mnemonic = mACErolide – Azithromycin (Z-Pak), Clarithromycin, Erythromycin

b. Binds to 50S = impaired translocation to P site

c. Drugs are prokinetic agents as motilin receptor agonists. Adverse effect = stomach cramps, NVD.

34

Tetracycline compounds.
a. Names
b. MOA
c. Main adverse effect

a. –end in cycline

b. Binds to 30S = prevents binding of new aminoacyl-tRNA to A site

c. Nutrient interaction (binds Ca = growth of bone and teeth esp in children = discoloration of teeth)*, disrupts normal flora, photosensitivity. * Don’t give in pregnancy or pediatrics. Don’t take with divalent cations (Ca, Mg, Fe etc.) as absorption reduced.

35

Clindamycin.
a. Class
b. MOA
c. Main adverse effect

a. Protein synthesis inhibitor, standalone

b. Binds 50S = prevents formation of initiation complex and translocates to the P site (as macrolide)

c. GI: NVD and C.diff infection (pseudomembranous colitis)

36

Cloramphenicol.
a. Class
b. MOA
c. Main adverse effect

a. Protein synthesis inhibitor, standalone

b. Binds 50S = prevents transpeptidation/peptidyl bond formation

c. Blood (suppresses RBC production), Gray Baby syndrome (infants lack glucuronic acid conjucation for metabolism of drug): gray colo, shock, vomiting and vascular collapse. Other = GI and superinfection.

37

Linezolid.
a. Class
b. MOA
c. Use
d. Main adverse effect

a. Protein synthesis inhibitor, oxazolidinones class (not important)

b. Binds P site on 50S = inhibit formation of ribosomal fMET-tRNA complex = inhibition of protein synthesis

c. Use: important for resistant bacteria (to pen, meth, vanc), primarily gram pos

d. Myelosuppression: pancytopenia or individual cell line –penias. Other = GI, drug interactions

38

Are the protein synthesis inhibiting antibiotics broad or narrow spectrum?

- Mostly broad except for clindamycin. Also linezolid effective against G+ esp resistant to pen, meth and vanc

39

Which protein synthesis inhibitor antibiotics target 30S? 50S?

- Mnemonic: buy AT 30, sell (CCEL) at 50

- Target 30S: Aminoglycosides, Tetracyclines

- Target 50S: Chloramphenicol, Clindamycin, Erythromycin (refers to Macrolide class), Linezolid

40

Sulfonamide compounds.
a. Names
b. MOA
c. Use
d. Main adverse effect

a. Sulf- containing names

b. Structurually similar to PABA (precursor to dihydrofolic acid). Compete for dihydropteroate synthase = block DHF synthesis and thus DNA synthesis

c. Use: broad against G+ and -. Combined with TMP commonly in tx of UTIs.

d. Skin (hypersensitivity, photosensitivity, Steven-Johnson syndrome – serious skin/mucous membrane eruption), other = GI, urinary tract sx.

41

Trimethoprim compounds.
a. Names
b. MOA
c. Use
d. Main adverse effect

a. Trimethoprim and pyrimethamine

b. Inhibits bacterial dihydrofolate reductase (DHFR) = impaired DNA synthesis

c. Use: Combined with SMX commonly in tx of UTIs.

d. Blood: BM suppression, megaloblastic anemia, leukopenia, granulocytopenia. Other = GI

42

Drug commonly used to tx UTIs?

- TMP-SMX. Combination of trimethoprim and sulfamethoxazole has synergistic effect.

43

Fluoroquinolones compounds.
a. Names
b. MOA
c. Use
d. Main adverse effect

a. –floxacin ending names (ciprofloxacin, levofloxacin)

b. Inhibit topo II (DNA gyrase) and topo IV = disrupts winding of DNA and separation of DNA strands in transcription and replication

c. Use:

i. Against G+: moxi-, gati-, gemi-

ii. Against G- (some G+): cipro-, levo-, o-

iii. Lease active drug: nor-

d. GI (NVD), drug-nutrient interaction (binds divalent cations and not absorbed), cardio (QT prolongation). Other = skin, bone/joints.

44

Antibiotics with drug-nutrient interactions

- Tetracyclines (-cyclines) and fluoroquinolones (-floxacin)

45

Metronidazole
a. Class
b. MOA
c. Use
d. Main adverse effect

a. Disrupts genetic machinery, standalone

b. Prodrug that is taken up and undergoes chemical reduction. Rxn metabolites bind to DNA and disrupt function and cause damage

c. Use: anaerobic bacteria (abdominal infections, C.diff). Also brain abscess. Also anti-protozoal.

d. GI (NVD), disulfiram-effect (avoid etoh)

46

Which antibiotics have disulfiram effects?

- Cephalosporins (-cef/-ceph endings) and metronidazole. Avoid etoh when on these medications.

47

Daptomycin.
a. Class
b. MOA
c. Use
d. Main adverse effect

a. Lipopeptide

b. Binds bacterial membrane (Ca-dependent process) causing depolarization.

c. Resistant bacteria

d. Musculoskeletal: myopathy, rhabdo

48

Polymyxin B.
a. Class
b. MOA
c. Use
d. Main adverse effect

a. Detergent

b. Binds to phospholipids in cell membrane (LPS specifically) = disrupts structure by punching holes

c. Use: Gram neg d/t LPS MOA. Topical to tx skin infections. Often combined with bacitracin (broad spectrum)

d. Rare, topical application

49

Mechanism for penicillin/cephalosporin drug class resistance

- expression of beta-lactamase which hydrolyzes the lactam ring of drug

- alteration of PBP binding to drug

- alteration in porin function??

50

Mechanism for aminoglycoside (eg. Streptomycin) resistance

- Changes in enzymes that destroy drug: aminoglycoside-modifying enzymes modify the abx and alter binding of drug to its target

51

Mechanism for macrolide resistance

- Transport of drug out cell

- Alterations of drug binding to 50S subunit

52

Mechanism for tetracycline resistance

- expression of efflux pump to transport drug out cell

53

Mechanism for sulfonamide resistance

- Less sensitive drug target

- Increased synthesis of PABA

- Scavenge or use other sources of folic acid

54

Mechanism for fluoroquinolone resistance

- Less sensitive drug target

- Transport of drug out of cell

55

Mechanism for chloramphenicol resistance

- Expression of inactivating enzymes

56

Mechanism for daptomycin resistance

- Reduced drug entry into organism: gene mutation (mprF) results in change in membrane charge (addition of L-lysine), it becomes overall positive repelling the abx.

57

Mechanism for metronidazole resistance

- Changes in expression of enzymes that activate the pro-drug: mutation in rdxA gene (o2-insensitive nitroreductase) decreases activation of drug.

58

Mechanism for TMP-SMX resistance

- Impaired drug binding to original target: expression of drug-insensitive enzymes dihydropteroate synthase and DHFR normally targeted by drug

59

Mechanism of vancomycin resistance

- New/different pathways activated: substitution on peptidoglycan stem and agent cannot bind

60

Skin and soft tissue bacterial infections
a. Common causes
b. Treatment

a. Causes

- Uncomplicated caused by S. aureus and Strep. pyogenes.

- Complicated caused by gram negs: E. coli and P. aeruginosa. Also MRSA.

b. Treatment

- Uncomplicated: use penicillins (eg. amp) or 1st gen cephalosporin (eg. cephalexin). If allergic, give vanc or clinda.

- Complicated: pen (eg. ticarcillin) + lactamase inhibitor (eg. clavulanate)

- MRSA: vancomycin, linezolid, daptomycin

61

What are the treatments for MRSA?

- Vancomycin, linzezolid or daptomycin

62

Bone and joint bacterial infections (acute, post-ortho surgeries, septic arthritis)
a. Common causes
b. Treatment

a. Causes

- Acute: commonly by S. aurea and Staph

- Post ortho surgeries: E. coli and P. aeruginosa

- Septic arthritis: S. aureus, S. pyogenes, Strep pneumo, N. gonorrhoeae

b. Treatment

- Acute: vanc, cephalosporin (eg. ceftriaxone of cefepime)

- Post ortho surgeries: pen (eg. Ticarcillin) + lactmase inhibitor (eg. Clavulanate)

- Septic arthritis: ceftriaxone. If MRSA: vanc, linezolid or daptomycin

63

Upper respiratory tract infections (acute, chronic, pharyngitis, pneumonia)
a. Common causes
b. Treatment

a. Causes

- Acute or chronic: commonly by Strep pneumo, H. influenzae or M. catarrhalis

- Acute pharyngitis: Strep

- Pneumonia: S. pneumoniae and M. pneumoniae = most common. Others = Klebsiella, E. coli, Enterobacter, Serratia, P. aeruginosa, Acinetobacter and MRSA


b. Treatment

- Acute or chronic: pen + lactamase inhibitor (eg. Augmentin = amoxicillin + clavulanate). If allergy: fluoroquinolone with anti-pneumococcal (levofloxacin or moxifloxacin)

- Acute pharyngitis: pen or amoxicillin

- Pneumonia-community-acquired

o Ambulatory: macrolide (erythro, azithro, clarithro)
o Resistant: fluoroquinolone with anti-pneumococcal (levofloxacin or moxiflocacin)
o Aspiration: metronidazole, clindamycin
o MRSA: vanc, linezolid, daptomycin (not technically)

- Pneumonia-hospital/healthcare-acquired

o Empiric: ceftriaxone
o MRSA: see above

64

Most common cause of UTIs? Treatment?

- E. coli

- Cystitis: TMP-SMX

- Pyelonephritis: TMP-SMX, fluoroquinolone

65

What commonly causes intra-abdominal bacterial infections? Treatment?

- E. coli, Klebsiella, Proteus and Bacteroides fragilis = gram negs

- Tx with ticarcillin + clavulanate

66

C. difficile. What abx is a culprit for its etiology? How is it treated?

- Clindamycin can be responsible for etiology

- Tx: moderate infection = metronidazole; severe infection = vancomycin. Don’t need to know difference. In general, metronidazole is best.

67

Most common cause of community-acquired bacterial meningitis in adults and children? Most common cause of neonatal meningitis? Treatment?

- Strep pneumoniae and Neisseria meningitidis in adults and children (> 2 months of age). Neonatal meningitis (

68

Treatment of sepsis syndrome?

- 3rd of 4th generation cephalosporin such as cefepime

- Piperacillin/tazobactam

- Imipenem/doripenem/meropenem

- + vancomycin

- I’m not sure exactly if all must be given.???

69

Common cause of bacterial endocarditis? Treatment?

- Staph + strep species

- Tx = ceftriaxone + vancomycin

70

Common cause of bacterial fever and neutropenia? Treatment?

- Commonly by gram pos.

- Tx = Cipro + Amoxicillin/clavunate for low risk.

71

Treatment of enterococcus infections?

- Many strains are resistant

- Tx with linezolid, daptomycin and tigecycline. This is same as MRSA treatment, except no vanc as they are typically resistant.

72

Treatment of gram-neg drug resistance bacteria such as P. aeruginosa and Acinobacter that express extended spectrum beta-lactamases or carbapenemases?

- To tx ESBL: carbapenem such as imipenem or meropenem

- To tx carbapenemases: polymyxin B of tigecycline

73

Do case studies from L50

Do case studies from L50

74

What characteristics make mycobacteria unique from other bacteria?

- Bacilli (rod-shaped), lipid-rich cell walls (mycolic acids), poor/no gram stain, acid-fast staining, replicate in macrophages, slow-growing (dormancy)

75

How is M. tuberculosis transmitted?

- Respiratory droplets

76

What are the clinical disease types of M. tuberculosis? What are the symptoms of active TB?

- Primary dz = pulmonary

- In immunosuppressed, may become disseminated

77

Compare and contrast latent vs active TB pulmonary disease in terms of:
a. Activity of organism
b. Tuberculin skin test, blood test (IFN-release)
c. CXR results
d. Sputum smear/culture
e. Symptoms
f. Infectiousness

a. Latent = inactive organism; Active = active multiplying organism

b. Positive in both

c. Latent = CXR normal usually; Active = CXR abnormal

d. Latent = smear and culture neg; Active = smear and culture pos

e. Latent = no sx; Active = general malaise, fatigue, fever, chills, night sweats, wasting, pulmonary insufficiency, cough, bloody sputum

f. Latent = not infectious; Active = infectious (called TB)

78

Drugs for TB? MOA?

- Rifamycin family (rifampin, rifabutin, rifapentine): targets RNA pol = inhibition of RNA synthesis

- Streptomycin: targets 30S ribosomal subunit = inhibition of protein synthesis

- Isoniazid: inhibits mycolic acid synthesis

- Ethambutol: targets arabinosyl transferases = inhibits cell wall synthesis

- Pyrazinamide: not known, may inhibit cell membrane/wall synthesis?

79

Is there a concern about drug resistance with TB? How is this combatted?

- 5-10% of infections are INH-resistant

- 1-2% are MDR (multi-drug) resistant

- Must ensure that at least two active TB agents be used to treat.

80

What are the M. avium complex organisms? What diseases do they cause?

- These are a group of genetically related organisms of the mycobacteria genus

- Includes: M. avium, M. intracellulare and others

- Diseases: pulmonary dz in immune-competent individuals and disseminated dz in AIDS patients. Acquired through ingestion of contaminated food and water primarily. Also through respiratory droplets.

81

How is active TB treated? Latent TB?

1. Active TB

- Initial phase: INH, rifamycin compound, pyrazinamide, ethambutol

- Continuation phase: INH and rifamycin compound

2. Latent TB

- Various combinations. INH (preferred) OR INH/RIFAPENTINE combined OR RIFAMPIN (alternate)

82

Isoniazid.
a. Clinical use
b. MOA
c. Adverse reactions
d. Resistance

a. Active and latent TB (most active drug in tx of TB)

b. Penetrates macrophages. Pro-drug, so activated by Kat G (mycobacterial catalase peroxidase enzyme). Inhibits synthesis of mycolic acid by forming covalent bond with proteins involved in synthesis.

c. Hepatitis, peripheral neuropathy (d/t structural similarity to pyridoxine). Neuropathy depends on acetylation rate (some individuals are slow and develop worse toxicity).

d. Mutation of Kat G gene. Overexpression of Inh A protein (ez involved in mycolic acid synthesis)

83

Rifampin.
a. Names of drugs belonging to this family
b. Clinical use
c. MOA
d. Adverse reactions
e. Resistance

1. Rifabutin, rifapentine

2. Active TB (first line) in non-HIV patients; latent TB (alternative to INH). Also many gram pos, gram neg and chlamydia.

3. Penetrates macrophages. Binds bacterial (only) DNA-dependent RNA pol = inhibition of RNA synthesis.

4. GI disturbances (N, V), nervous system (HA, dizziness, fatigue), hepatitis (esp w/underlying dz), harmless red-orange color to secretions (urine, feces, sweat, tears and saliva) – stains contacts. Note: inducer of cytochrome P450, so increases elimination of many drugs including many ARVs – don’t use in HIV infected patients. Use rifabutin as an alternative, which is less potent C450 inducer.

5. Point mutations in RNA pol.

84

Can rifampin be used to treat active TB in HIV patients? Why or why not?

- No. Rifampin is a strong inducer of cytochrome P450 and increases rate of elimination of many drugs including many antiretrovirals.

- Replace with rifabutin in HIV patients.

85

Pyrazinamide.
a. Clinical use
b. MOA
c. Adverse reactions
d. Resistance

a. Active TB (part of combo)

b. Penetrates macrophages. Unknown MOA. Synthetic analogue of nicotinamide. May inhibit cell membrane/wall synthesis. Pro-drug and converted to active form by bacterial pyrazinamidase enzyme. Dependent on acidic environment where mycobacteria resides in macrophage.

c. Hyperuricemia (seen in nearly all patients with some developing gouty arthritis), hepatotoxicity (rare).

d. Mutation in pyrazinamidase enzyme.

86

Ethambutol.
a. Clinical use
b. MOA
c. Adverse reactions
d. Resistance

a. Active TB (part of combo), mycobacterium avium complex

b. Inhibits arabinosyl transferase = inhibition of mycobacterial cell wall synthesis

c. Retrobulbar neuritis (reversible, impaired visual acuity and RG color blindness), hyperuricemia (less dramatic than pyrazinamide)

d. Point mutations in Arabinosyl transferase.

87

Streptomycin.
a. Clinical use
b. MOA
c. Adverse reactions
d. Resistance

a. Severe gram- infections, TB (MT) strains resistant to other drugs (in combo), M. avium complex

b. Aminoglycoside (see another flash card): targets 30S ribosomal subunit = inhibition of protein synthesis

c. Nephrotoxic, ototoxic

d. Point mutations in ribosomal proteins.

88

What is rifabutin used for?

- TB in HIV patient. Also M. avium complex infection.

89

What is the tx for M. avium complex pulmonary infections? Disseminated disease?

- Pulmonary: macrolide (clarithro, azithro), rifampin (or rifamycin), ethambutol, +/- streptomycin

- Disseminated: macrolide, rifampin (or rifamycin), ethambutol

• macrolide used to tx AIDS patient with CD4

90

Leprosy.
a. Clinical presentation
b. Bacterium responsible for disease
c. Treatment

a. Two forms

- Lepromatous: disfiguring skin lesions (nodules/plaques), absence/poor CMI response, large numbers of organisms in tissues

- Tuberculoid: mild, hypopigmented plaques/macules, strong CMI response, few organisms in tissues

b. Mycobacterium leprae

c. Dapsone, clofazimine and rifampin

91

Dapsone.
a. Clinical use
b. MOA
c. Adverse effects

a. Leprosy (in combo with other agents)

b. Structural analog of PABA = competitive inhibitor of folic acid synthesis

c. Non-hemolytic anemia in some patients, acute hemolytic anemia in pts with G6P DH deficiency

92

Clofazamine.
a. Clinical use
b. MOA
c. Adverse effects

a. Leprosy (in combo with other agents)

b. Bacterial dye with uncertain MOA, perhaps intercalates with DNA

c. Skin discoloration (red-brown to black)

93

Why is treating parasitic infections difficult?

- Parasites (protozoa and worms) are eukaryotic like humans. There are limited unique targets (enzymes only in parasite, purine salvage pathways indispensable to parasite, DHFR and microtubule disrupters which have different pharmacologic properties)

94

Treatment of giardiasis, entamoeba (amebiasis) and trichomoniasis? MOA of drug?

- Organisms possess the enzyme pyruvate:ferredoxin oxidoreductase (PFOR) not found in humans.

- Tx with metronidazole. ? MOA – Is prodrug. Enters cell, is reduced (activated) by PFOR. Reactive intermediates form which bind to and disrupt protein and DNA structure and function.

- Note: only kills trophozoite form (symptomatic dz) of entamoeba histolytica. Follow this tx with iodoquinol or paromomycin to kill non-invasive cyst forms.

95

Iodoquinol.
a. Use
b. MOA
c. Adverse effects

a. Mild/asymptomatic cases of E. histolytica (amebiasis). Severe cases are first treated with metronidazole then followed by this drug. It eliminates trophozoite and cyst forms of E. histolytica from lumen of intestine (poor absorption).

b. ?

c. GI discomfort (infrequent), take with meals. Prolonged high doses causes optic atrophy and permanent vision loss.

96

Paromomycin.
a. Use
b. MOA
c. Adverse effects

a. Mild/asymptomatic cases of E. histolytica (amebiasis). Severe cases are first treated with metronidazole then followed by this drug. It eliminates trophozoite and cyst forms of E. histolytica from lumen of intestine (poor absorption).

b. Aminoglycosidic abx. Inhibits protein synthesis in bacteria. ? about MOA in amebiasis.

c. Abdominal discomfort/diarrhea.

97

What opportunistic parasites infect the immunocompromised? Name the drugs that are used to treat each?

- Cryptosporidium parvum: nitazoxanide

- Pneumocystis jirovecii: TMP-SMX

- Toxoplasma gondii: pyrimethamine-sulfadiazine

98

Nitazoxanide.
a. Use
b. MOA
c. Adverse effects

a. Cryptosporidiosis (Cryptosporidium parvum), also giardiasis

b. Thought to interefere with PFOR (pyruvate:ferredoxin oxidoreductase) therefore disrupting anaerobic energy metabolism

c. ?

99

Drugs used to treat dormant forms of malaria (P. vivax and P. ovale)?

- Primaquine

100

Drugs used to treat erythrocytic (active) form of malaria?

- Chloroquine, quinine, mefloquine

101

Drugs used as prophylaxis tx to prevent malaria?

- Doxycycline, mefloquine, malarone

102

Antimalarial drugs. What forms of malarial disease are treated, MOA and side effects?

a. Chloroquine

- Use: clinical disease

- MOA: ? interfere with ability to detox compounds during degradation of Hb

- Side effects: HA, NV, blurred vision, dizziness, fatigue and confusion.

- Other: resistance, therefore limited usefulness in parts of world

b. Quinine

- Use: clinical disease

- MOA: localizes to digestive vacuoles, may interfere with Hb degradation or detox of products, may interfere with parasite DNA

- Side effects: cinchonism (tinnitus and temp hearing loss, HA, NV, visual disturbances), hypoglycemia

c. Mefloquine

- Use: clinical disease and prophylaxis – effective against all species of Plasmodium

- MOA: ? similar to quinine

- Side effects: neuropsych manifestations (hallucinations, vivid dreams, strange behavior) according to some reports

d. Primaquine

- Use: dormant disease (hypnozoite found in vivax and ovale infections)

- MOA: ?? activate by host, thought to interfere with mitochondrial ET and pyrimidine synthesis

- Side effects: hemolysis in persons with G6P DH deficiency (screen)

e. Malarone (combo atovaquone and proguanil)

- Use: clinical dz (Falciparum) and prophylaxis

- MOA:

o Atovaquone: ? taken with fatty meal

o Proguanil: inhibits DHFR

- Side effects: ?

f. Doxycycline

- Use: prophylaxis (primarily), clinical dz

- MOA: disrupting protein synthesis

- Side effects: photosensitivity dermatitis (sunburn), staining teeth in children (contraindicated in peds and pregnancy)

g. Artemisinin derivatives

- Use: clinical dz (combo)

- MOA: ? interacts with iron, radicals damage membrane

- Side effects: N, D

103

Benzimidazole compounds.
a. Names of drugs
b. Use
c. MOA
d. Adverse effects

a. Albendazole, mebendazole, thiabendazole. Note: all poorly soluble with little drug absorbed. Thiabendazole is more efficiently absorbed (see below).

b. Luminal nematodes (use on empty stomach). Albendazole and mebendazole used in treating ascariasis, pinworm (enterobius vermicularis), hookworm (necator americanus) and whipworm (trichuris trichiura). Thiabendazole as second line in treating strongyloidiasis (intestinal and tissue infection d/t strongyloides stercoralis) and as topical prep to treat cutaneous larval migrans caused by dog/cat hookworms.

c. Exact unknown. Inhibits mitosis.

d. Albendazole and mebendazole: GI upset. Thiabendazole: GI upset, CNS disturbances (delirium, hallucinations). Contraindicated in pregnancy and children under 2.

104

Ivermectin
a. Use
b. MOA
c. Adverse effects

a. Strongyloidiasis (intestinal and extraintestinal). Tissue dwelling nematodes (O. volvulus, L.loa and filariasis d/t W. bancofti and B. malayi)

b. Hyperpolarization in muscle cells resulting in paralysis of nematode

c. ?

105

Treatment of strongyloidiasis

- Drug of choice = ivermectin

- 2nd line = thiabendazole

106

Pyrantel pamoate
a. Use
b. MOA
c. Adverse effects

a. Drug of choice in pinworm (Enterobius vermicularis) infections. Tx entire household recommended.

b. Activates cholinergic nicotinic receptors in somatic muscle of nematodes and depolarizes. No effect on human NM function. Poorly absorbed.

c. Mild GI disturbances

107

Praziquantel
a. Use
b. MOA
c. Adverse effects

a. Tapeworm (cestode), fluke (trematode) and cysticercosis (pork tapeworm)

b. Increase calcium permeability of worm’s tegument (protein membrane covering) = depolarization. Increases immune detection and induces spastic paralysis.

c. Abdominal discomfort, HA, dizziness. Indirect effects related to immune response to dying worms = fever, rash, arthralgia and myalgia.

108

Targets of antifungal therapy

1. Fungal cell membrane (ergosterol and synthesis thereof)

2. Fungal cell wall (glucans)

3. Shared: DNA, RNA synthesis; cell division

109

Amphotericin B.
a. Clinical use
b. MOA
c. Adverse effects

a. Systemic disease from yeast (Candida and Cryptococcus); Systemic disease by molds incl. dimophics (Aspergillus, Histoplasma, Coccidioides, blastomyces, Sporothrix, mucormycoses)

b. Binds ergosterol in fungal membranes, forms pores altering membrane permeability. Note: poor CNS permeability

c. Nephrotoxicity. Infusion rxns in nearly all patients: F, chills, spasms, V, HA and HTN. Liposomal formulations are less toxic.

110

Azoles.
a. Drug names
b. Clinical use
c. MOA
d. Adverse effects

a. All –conazole endings: keto-, mico-, clotrimazole, flu-, itra-, vori-, posa-. Note: mico- and clotrimazole are topical.

b. Broad use – pathogenic yeast (Candida, crypto), systemic mycoses (histo, blasto, coccidiodo), dermatophytes (onycho-). Do we need to know breakdown of these?

- Topical azoles used for vulvovaginal candidiasis and dermatophyte infections with negligible absorption and rare adverse effects.

- Keto-: older
- Flu-: wide distribution incl. CNS, agent of choice for systemic candidiasis, crypto, coccidio. Second line for histo, blasto, sporotrich
- Itra-: poorer pharm and TI
-
c. Bind to ez responsible for converting lanosterol to ergosterol resulting in fungal cell membrane damage and leaky membrane

d. General: Minor GI. Interaction with hepatic P450.

111

Drug of choice in treating systemic candidiasis, cryptococcosis, coccidiomycosis?

- Fluconazole. Had wide distribution including CNS. Note this is common first choice.

- There are newer agents such as voriconazole and posaconazole.

112

Drug of choice in treating blastomycosis, coccidiomycosis, histoplasmosis, sporotrichosis and dermatophyte infections?

- Itraconazole. Absorption impaired by low gastric pH. Interactions with rifampin, serum digoxin and cyclosporine.

113

Treatment of choice for aspergillosis? Adverse reactions?

- Voriconazole.

- Adverse: transient visual disturbances, blurred vision, photophobia, altered color perception, hallucinations, liver enzyme abnormalities and rash

114

Clinical use of posaconazole?

- ASPERGILLUS, MUCORMYCOSES agents and Candida. Also Cryptococcus and dimorphic fungi.

115

What agent has the broadest spectrum of activity of all azoles? What agent has the highest therapeutic index of all azoles?

- Posaconazole = broadest spectrum – Newer!

- Fluconazole = highest TI of all – more common first choice

116

5-Flucytosine.
a. Clinical use
b. MOA
c. Adverse effects

a. Besides being anti-neoplastic, part of combo therapy for systemic Cryptococcal infections (including meningitis – has CNS penetration). Occasionally for systemic candida infections.

b. Transported into fungal cell by cytosine permease. Converted into 5-FU. Disrupts protein synthesis and inhibits DNA synthesis.

c. BM suppression: anemia, leukopenia, thrombocytopenia.

117

Echinocandins.
a. Drug names
b. Clinical use
c. MOA
d. Adverse effects

a. –fungin endings: caspo-, mica-, anidula-

b. Primarily to tx invasive Candida and Aspergillus infections (esp in those that don’t respond to other anti-fungal agents - $$$)

c. Inhibit synthesis of beta-glucan, essential component in most fungal cell walls

d. Well tolerated as selective.

118

Griseofulvin.
a. Clinical use
b. MOA
c. Adverse effects

a. Oral agent for dermatophyte infections (second line – has been replaced by azoles and allylamines)

b. Concentrates in keratin precursor cells, MOA unclear – may interfere with microtubule function/mitosis

c. Well tolerated. HA, hepatoxicity, GI distress. Increases warfarin metabolisms, decrease effectiveness of OCPs.

119

Terbinafine.
a. Clinical use
b. MOA
c. Adverse effects

a. Allylamine drug. Topical and oral. Oral is first line in treatment of onychomycosis. Topical (terbinafine and naftifine) are available for treatment of tinea cruris (jock itch), tinea corporis (ringworm) etc.

b. Inhibits the enzyme squalene epoxidase, step in ergosterol synthesis. Concentrates largely in skin, hair and nails.

c. Rare: GI, HA, elevated LFTs

120

Nystatin.
a. Clinical use
b. MOA
c. Adverse effects

a. Topical agent only (including ointments, creams, oral suspensions rinse). Use against most species of Candida – oropharyngeal and vaginal.

b. Similar to MOA of amphotericin B, which is binds ergosterol in fungal membranes, forms pores altering membrane permeability.

c. Toxic, unpleasant taste.

121

55 yo obese woman with adult-onset DM has been receiving amoxicillin for tx of acute exacerbation of chronic bronchitis. After 1 week of therapy, pt develops dysuria and increased urinary frequency. UA shows 25 WBCs/hpf, and a Gram-stain of urine shows budding yeast. Which treatment is most appropriate for her Candida?
a. Oral ketoconazole
b. Oral fluconazole
c. Topical clotrimazole
d. Oral itraconazole
e. Oral 5-flucytosine

- Answer = B (oral fluconazole) – well absorbed, drug of choice for invasive candidiasis

122

34 yo male presents with fever, cough, dyspnea, and bloody sputum. The patient is currently completing his 2nd round of chemo for NH lymphoma. A CXR reveals diffuse alveolar infiltrates on the right lobe and small cavitary lesion on left lobe. Bronchoalveolar lavage reveals septate hyphae, branching at ~45% (V-shaped). Which of the following drugs would be most appropriate?
a. Flucytosine
b. Terbinafine
c. Griseofulvin
d. Nystatin
e. Voriconazole

- Answer = E. Tx of choice.

123

Describe relationship between HSV thymidine kinase, HSV DNA polymerase, and acyclovir.

- Acyclovir’s MOA: this is a nucleoside analogue that requires phosphorylation by HSV thymidine kinase then acts as a competitive inhibitor of the viral DNA polymerase = chain termination when incorporated into viral DNA

124

Acyclovir
a. Clinical use. What is prodrug?
b. MOA
c. Adverse effects

a. Oral: genital herpes, varicella zoster; IV: severe/disseminate mucocutaneous herpes, neonate infections, HSV encephalitis, VZV in immunocompromised

- Note: prodrug = valacyclovir w/3-5 x greater oral bioavailability. Use = primary/recurrent genital herpes, varicella in older children and adults, zoster and orolabial herpes.

b. This is a nucleoside analogues that requires phosphorylation by HSV thymidine kinase then acts as a competitive inhibitor of the viral DNA polymerase = chain termination when incorporated into viral DNA

c. Nephrotoxicity and neuro effects esp w/ dehydration; N, HA, diarrhea

125

Are antiviral resistance or pharmacokinetics of antivirals important?

Are antiviral resistance or pharmacokinetics of antivirals important?

126

Foscarnet
a. Clinical use
b. MOA
c. Adverse effects

a. HSV, VZV infections resistant to acyclovir; CMV retinitis, CMV colitis, CMV esophagitis. **IV only

b. Analogue of pyrophosphate and blocks release in catalytic cycle. Doesn’t required phosphorylation by thymidine kinase to act!

c. Renal impairment, blood chem changes

127

Ganciclovir
a. Clinical use. What is pro-drug?
b. MOA
c. Adverse effects

a. CMV retinitis, colitis, pneumonitis and esophagitis. Reduces risk of CMV disease in transplant recipients. *IV, oral or IM

- Note: pro-drug = valganciclovir (metabolized to ganciclovir in liver and intestines) w/ higher oral bioavailability.

b. Requires initial phosphorylation by viral kinase (CMV UL97) then acts as competitive inhibitor of the viral DNA polymerase = chain termination upon incorporation into viral DNA.

c. Myelosuppression, BM toxicity, CNS toxicity. With IV use: phlebitis, anemia, rash, fever, liver enzyme abnormalities, NV, eosinophilia.

128

Trifluridine
a. Clinical use. What is pro-drug?
b. MOA
c. Adverse effects

a. Ocular administration to tx keratoconjunctivitis and recurrent epithelial keratitis d/t HSV-1 and 2. Not for systemic administration.

b. Phosphorylation, then competitive inhibitor of thymidine for incorporation into newly synthesized genomes.

c. ?

129

When should influenza anti-virals be given?

- Within 48 hours to have impact on disease progression.

130

Steps in influenza virus life cycle and viral enzymes inhibited by oseltamivir, zanamivir, peramivir, amantadine, and rimantadine.

- Neuraminidase inhibitors oseltamivir, peramivir and zanamivir interfere with virion release from infected cells

- M2 protein inhibitors amantadine and rimantadine block nucleocapsid release

131

Oseltamivir
a. Clinical use
b. MOA
c. Adverse effects

a. Influenza A & B viral infection. Give within 48 hours of symptoms. Approved for 1+, chemoprophylaxis. Oral.

b. Inhibitor of neuraminidase = prevention of spread of progeny virions. Prodrug, metabolized in liver.

c. N, V, abdominal pain, HA, fatigue, diarrhea. Rarely: rash and neuropsych events.

132

Zanamivir
a. Clinical use
b. MOA
c. Adverse effects

a. Influenza A & B viral infection. Give within 48 hours of symptoms. Chemoprophylaxis. Same as oseltamivir except for children 7+. Inhalation.

b. Neuraminidase inhibitor = prevention of spread of progeny virions.

c. Cough, bronchospasm, temp. decrease in pulm. function. Nasal/throat discomfort. Contraindicated in pts with pre-existing pulm. Dz.

133

Peramivir
a. Clinical use
b. MOA
c. Adverse effects

a. Acute uncomplicated influenza within 48 hours of symptoms. IV.

b. Neuraminidase inhibitor = prevention of spread of progency virions.

c. GI, rash, Steven Johnson syndrome, hyperglycemia, HTN, delirium, hallucinations, psychosis

134

Amantadine and rimantadine
a. Clinical use
b. MOA
c. Adverse effects

a. Susceptible influenza A patients. Give within 48 hours of symptoms. Oral.

b. Inhibits influenza A M2 protein = prevent formation of nucleocapsid

c. N, anorexia; mild neuro symptoms

135

Ribavirin
a. Clinical use
b. MOA
c. Adverse effects

a. Aerosolized: severe RSV respiratory illness; Oral (w/pegylated IFN +/- other HCV inhibitor) for chronic hep C illness

b. Phosphorylated by adenosine kinase. Interferes with synthesis of guanosine triphosphate; inhibits viral mRNA capping; inhibits RNA dependent RNA pol of RSV and hep C virus.

c. Hemolytic anemia, depression, fatigue, rash, cough, insomnia, pruritus, nausea. Contra: pregnancy, anemia, ischemic vascular dz, severe renal dz.

136

Discuss the use of combination therapy in the treatment of chronic hepatitis C infections and be able to identify the MOA for each class of anti-HCV drugs.

- Mechanism

a. Viral polyprotein must be cleaved by HCV NS3/4a enzyme (protease)

b. Genome replication via HCV NS5A and B (RdRp)

1. Ribarivin (w/pegylated IFN +/- other HCV inhibitors)

- MOA: interferes with synthesis of guanosine triphosphate; inhibits viral mRNA capping; inhibits RNA dependent RNA pol of hep C

2. Paritaprevir and Simeprevir

- MOA: HCV NS3/4A inhibitor (protease inhibitors)

3. Ledipasvir and Ombitasvir

- MOA: HCV NS5A inhibitor (genome replication step)

4. Sofosbuvir and Dasabuvir

- MOA: HCV NS5B (RNA pol inhibitor)

** Besides this, should we remember anything else about HCV treatments?

137

Describe the life cycle of HIV and classes of drugs with names and the mechanism of action

1. Attachment of virus to cell using co-receptor

- Co-receptor antagonist: maraviroc

2. Fusion of virus to cell

- Fusion inhibitors: enfuvirtide

3. Reverse transcription of viral genome

- NRTIs (nucleoside reverse transcriptase inhibitors): zidovudine, lamivudine, abacavir, tenofovir disoproxil, emtricitabine

- NNRTIs (non-nucleoside reverse transcriptase inhibitors): nevirapine, efavirenz

4. Integration of viral genome into host’s

- Integrase inhibitors: raltegravir, elvitegravir, dolutegravir

5. Genome replication, transcription, budding

- No class of drugs here

6. Protein cleavage (transformation from immature to mature virion)

- Protease inhibitor: ritonavir, atazanavir, darunavir

138

Abacavir
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. NRTI

b. Naïve and experienced HIV patients

c. Oral

d. Common with NRTIs – lactic acidosis, fatty liver dz, lipodystrophy. Other = allergic rxn (life-threatening and associated with HLA-B5707 – do genetic screening), rash, fever, nausea, vomiting, diarrhea, dyspnea, fatigue, pancreatitis, increased cardiac event risk, reduced efficacy of methadone.

139

Lamivudine
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. NRTI

b. Naïve and experienced HIV patients. Short term safety for pregnant mothers and neonates. Also approved for Hep B infections w/interferon.

c. Oral

d. Common with NRTIs – lactic acidosis, fatty liver dz, lipodystrophy. One of least toxic ARV drugs in treating HIV. High doses have GI and CNS effect.

140

Emtricitabine
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. NRTI

b. Naïve and experienced HIV patients. Contraindicated for oral solution include young children, pregnant women, patients with renal or hepatic failure.

c. Oral

d. Common with NRTIs – lactic acidosis, fatty liver dz, lipodystrophy. Other = HA, N, D, rash, hyperpigmentation of palms and soles.

141

Tenofovir
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. NRTI

b. Naïve and experienced HIV patients. Trials suggest reduction in transmission. Approved for use in chronic hep B infections w/interferon.

c. Oral. Disoproxil form is water soluble prodrug.

d. Common with NRTIs – lactic acidosis, fatty liver dz, lipodystrophy. Other = GI (more common in lactose intolerant), HA, asthenia, renal and bone toxicity, Fanconi syndrome (rare), crosses placenta, decreased bone density and fetal growth in primates.

142

Zidovudine (AZT)
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. NRTI

b. Tx naïve and experienced HIV infected patients. Reduction in vertical transmission. PEP.

c. Oral.

d. Common with NRTIs – lactic acidosis, fatty liver dz, lipodystrophy. Other = myelosuppression so avoid co-administration with other myelosuppressive drugs eg. Ganciclovir; fatigue, malaise, nausea, HA, insomnia, asthenia, nail hyperpigmentation

143

Efavirenz
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. NNRTI

b. Naïve and experienced HIV patients

c. Oral (on empty stomach)

d. Common with NNRTIs – rash, Steven Johnson syndrome, hepatotoxicity, drug-drug interactions d/t cytochrome P450. For this drug: CNS, HA, nausea, teratogenic in primate. Contraindicated in pregnancy.

144

Nevirapine
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. NNRTI

b. Naïve and experienced HIV patients, prevention of vertical transmission.

c. Oral

d. Common with NNRTIs – rash, Steven Johnson syndrome, hepatotoxicity, drug-drug interactions d/t cytochrome P450. For this drug: nausea, headache.

145

Atazanavir
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. Protease inhibitor

b. Naïve and experienced HIV patient. Approved for use in children over 6.

c. Oral. Enhanced with food, requires acid for absorption. Contraindicated with PPIs.

d. Common with PIs – hyperlipidemia, lipodystrophy, hepatotoxicity, GI intolerance, increased risk for bleeding, drug-drug interactions d/t cytochrome P450. For this drug: neuropathy, skin rash, cardiac effects.

146

Ritonavir
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. Protease inhibitor

b. Booster to increase half-life of co-administered ARV drug d/t CYP3A4 effect.

c. Oral.

d. Common with PIs – hyperlipidemia, lipodystrophy, hepatotoxicity, GI intolerance, increased risk for bleeding, drug-drug interactions d/t cytochrome P450. For this drug: neuropathy.

147

Darunavir
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. Protease inhibitor

b. Naïve and experience HIV patients

c. Oral. Coadminister with enhancer such as ritonavir or cobicistat

d. Common with PIs – hyperlipidemia, lipodystrophy, hepatotoxicity, GI intolerance, increased risk for bleeding, drug-drug interactions d/t cytochrome P450. For this drug: increased serum amylase.

148

Maraviroc
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. Co-receptor antagonist, CCR5 receptor inhibitor

b. CCR5 tropic virus. Must screen for tropism before use.

c. Oral.

d. Cough, URT infections, postural hypotension, arthralgia, myalgia, abdominal pain, sleep disturbance, allergic reaction, increased cardiac events in those with underlying dz.

149

Enfuvirtide
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. Fusion inhibitor

b. Experience patients with evidence of HIV replication even with ARV tx.

c. SubQ injection. Only parenterally delivered ARV agent.

d. Painful erythematous nodule at site of injection, insomnia, HA, dizziness, nausea, eosinophilia, allergy, increased risk for bacterial pneumonia??

150

What is the only parenterally delivered ARV agent for HIV tx?

- Enfuvirtide via subq twice daily

151

Identify which ARV drugs alter the activity of the cytochrome P450 enzyme

- NNRTIs

- Protease inhibitors

152

Raltegravir
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. Integrase inhibitor

b. Tx experienced and naïve HIV pt

c. Oral

d. Insomnia, HA, diarrhea, nausea, dizziness, fatigue, CK elevation, myopathy, rhabdomyolysis

153

Elvitegravir
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. Integrase inhibitor

b. Tx experienced and naïve HIV pt

c. Oral. Requires co-administration with drug like cobicistat to increase half-life.

d. N, D, elevation of lipase, HA, fatigue, insomnia, depression, rash

154

Dolutegravir
a. Class/MOA
b. Use
c. Route
d. Adverse effect

a. Integrase inhibitor

b. HIV patients at least 12 years of age and weighing at least 40 kg

c. Oral.

d. Insomnia, HA, hypersensitivity rxn, elevation of serum aminotransferases and fat redistribution syndrome

155

Identify the extra screening tests used prior to prescribing abacavir and maraviroc

1. Abacavir: has side effect of life-threatening allergic reaction associated with HLA-B5707. Must genetically screen for this.

2. Maraviroc: effective only in CCR5 tropic virus. Must screen to see if virus is specific to this co-receptor.

156

Describe how emtricitabine and lamivudine differ from one another

1. Lamivudine: tx naïve and experienced HIV pts, short term safety for pregnant mothers and neonates, used in tx chronic Hep B

2. Emtricitabine: tx naïve and experienced HIV pts, contraindicated (oral soln) in young children and pregnant women, not used in tx chronic Hep B

157

Describe the typical drug class combinations that are utilized for initial HIV treatments

- Std of care = combinations of at least three ARV drugs at least from two different classes.

- Initial therapy preferred:

a. 1 PI (ritonavir boosted) + 2 NRTIs

b. 1 II + 2 NRTIs

158

Identify the antiretroviral drugs that are typically reserved for patients who have not responded to initial therapies

- Enfuvirtide, a fusion inhibitor.

159

Describe cellular and molecular events that contribute to development and maintenance of the inflammatory process

- Injury/noxious stimulus activates immune cells

- Transient vasodilation

- Increased permeability

- Activation of molecular inflammatory mediators: bradykinin, substance P, histamine, 5HT, arachidonic metabolites (via cyclooxygenase – PG, TXA, prostacylins)

- Stimulation of mast cells, infiltration of leukocytes and activation of phagocytosis

- Tissue degeneration and fibrosis

160

Describe functions of PGE2 and PGI2

- Increase edema and vascular permeability

- Modulate lymphocyte function

161

Location and function of COX-1 vs 2?

- COX-1: constitutively expressed, housekeeping functions, synthesis of PG in stomach mucosa that protects stomach lining from gastric acid

- COX-2: inducible, produces inflammatory molecules including PGI2 in vascular endothelium. Also required for normal renal function.

- Inflammation, pain, fever results in activation of these enzymes

162

Name main functional characteristics and clinical uses of NSAIDS including main MOA

- Analgesia, antipyretic, anti-inflammatory

- Main MOA = COX-1/2 inhibitor decreasing PG production

163

Difference between acetylsalicylic acid and salicylic acid?

- Aspirin = ASA. Absorbed in GI tract and hydrolyzed to salicylic acid, a reversible COX inhibitor. ASA itself is an irreversible inhibitor.

164

ASA (aspirin)
a. Clinical use
b. MOA
c. Adverse effects

a. Antipyretic, acute rheumatic fever, analgesia (mild pain), prophylactic protection against: platelet hyper-aggregation, CAD, MI, post-op DVT

b. Analgesic, antipyretic, antiinflammatory, anti-coagulant. Low dose effects = analgesic, antipyretic; high dose effects = anti-coagulant

- Analgesic: inhibition of COX-2 therefore inhibition of PG

- Anti-inflammatory: inhibition of COX-2 therefore inhibition of PG

- Anti-pyretic: blocks production of PGE2 in CNS to reset temp control at hypothalamus, results in dilation of superficial blood vessels = sweating

- Anti-coagulant: inhibition of TX synthesis and inhibition of platelet COX-1

c. GI upset/irritation (d/t COX-1 inhibition) – take w/food or milk; platelet inhibition (increased bleeding time), hepatic/renal toxicity (decreased renal BF), hypersensitivity/pruritus, tinnitus, Reye’s syndrome encephalopathy

165

What are the non-selective COX inhibitors? What are the selective COX inhibitors – to what COX enzyme?

- Non-selective: aspirin, ibuprofen, indomethacin, ketorolac, naproxen, oxaprozin, piroxicam, sulindac

- Selective to COX-2: celecoxib, etoricoxib, meloxicam

166

Why were COX-2 selective inhibitors developed? What are their advantages over non-selective NSAIDs? What is the major down-fall of these drugs? When would you rx COX-2 selective NSAIDs?

- Why, advantages? Able to selectively block COX-2 and achieve the good effects, ie. anti-inflammatory, while still allowing COX-1 housekeeping isoform. Essentially you get analgesia, antipyretic and anti-inflammatory effects with less GI adverse effects. No impact on platelet aggregation.

- Down-fall? Incidence of CVA thrombotic events with these – eg. Rofecoxib (Vioxx)

- Celecoxib for RA and osteoarthritis. Has black box warning.

167

How is acetaminophen different from NSAIDs in terms of the effects it produces? Use? What is the major acetaminophen safety concern?

- It is analgesic and antipyretic. Has no anti-inflammatory properties and does not inhibit platelet aggregation. Also no GI tract irritation as traditional non-selective NSAIDs. MOA unknown.

- Use for mild/moderate pain, extensively in elderly and children.

- Safety concern: hepatotoxicity at high doses (necrosis then liver failure). Also interactions with ethanol and INH via P450.

168

Describe the pathophysiology of gout.

- Increased productions/decreased excretion of uric acid leads to hyperuricemia. There are recurrent episodes of acute arthritis d/t deposits of uric acid crystals in joints and cartilage. Inflammation results in phagocytosis of crystals. Low pH produced by leukocytes leads to increased uric acid crystallization.

169

Identify treatment strategy and specific agents used to treat acute gouty attack.

- NSAIDs = first line, primarily indomethacin. Don’t use ASA as it causes retention of uric acid. Previously, colchicine was the primary treatment – it reduced pain/inflammation and inhibited leukocyte migration and phagocytosis. Had side effect of GI upset including diarrhea.

- Corticosteroids if patient cannot tolerate NSAIDs

- Also intra-articular steroid injection

170

Identify Identify treatment strategy and specific agents used for gout prophylaxis. MOA?
treatment strategy and specific agents used for gout prophylaxis. MOA?

- Xanthine oxidase inhibitors (blocks conversion of xanthine to uric acid): Allopurinol, febuxostat

- Uricosuric drugs (increase renal clearance by inhibiting tubular absorption): probenecid, sulfinpyrazone

171

Identify treatment strategy for RA in terms of drugs that treat symptoms vs. drugs that slow the progression of RA.

1. Symptomatic treatment w/o slowing progression

- NSAIDs and glucocorticoids

2. Symptomatic treatment w/slowing progression

- DMARDS, slower acting in comparison to NSAIDs

172

DMARDs.
a. What is the first line DMARD for tx of RA? MOA?
b. Advantages and disadvantages?
c. Which DMARD was the first agent indicated for both symptomatic improvement and retardation of structural joint damage in RA? MOA?
d. Which anti-malarial agents can be used in rheumatic disease?
e. What are biologic DMARDs? MOA?

a. Methotrexate (MTX) – inhibits AICAR transformylase to increase EC adenosine and inhibit T-cell activation, cytotoxic to proliferating lymphocytes following antigen exposure.

b. Advantages and disadvantages:

- Advantages: symptomatic and progression retardation in RA.

- Disadvantages: toxicity, expensive, slow-acting

c. Leflunomide – inhibits ribonucleotide synthesis and causes cell cycle arrest.

d. Chloroquine and hydroxychloroquine

e. Biologics

- Etanercept: cytokine receptor fusion protein

- Infliximab: anti-TNF chimeric monoclonal antibody

- Anakinra: IL-1 cytokine receptor decoy

173

What is the current hypothesis on pathophysiology of migraine?

- Vasodilation of dural vasculature occurs (why??) leading to pain and further nerve activation. Leads to cortical spreading depression? And sensitization of trigeminal pain pathway.

174

What strategies and drug classes are used for preventive therapy of migraine? Adverse effects?

1. Beta-blockers: propranolol (beta1,2) and metoprolol (beta1) = tx of choice

- Adverse: reduced energy, tired, postural symptoms, contraindicated in asthma

2. Antidepressant: amitriptyline

- Adverse: drowsiness
3. Anticonvulsant: valproic acid (divalproex), topiramate

- Drowsiness, weight gain, tremor, hair loss, hematologic/liver abnormalities, teratogenic

175

What strategies and drug classes are used for tx of acute migraine attacks? MOA? Advantages and disadvantages/adverse effects?

1. Non-specific:

- Analgesic: ASA, naproxen, ibuprofen, acetaminophen *Limit to 2-3 days otherwise drug overuse can “transform” migraine into a more severe chronic disorder

- Opiate analgesic: meperidine, butorphanol, oxycodone, hydromorphone if severe (rarely). Be careful of dependence, tolerance and also transforming migraine into more severe chronic disorder.

- Antiemetic: metoclopramide, chlorpromazine, prochlorperazine. D2 antagonists. Metoclopramide is also weak 5HT3 antagonist.

2. Migraine-specific:

a. Ergot derivatives: ergotamine, dihydroergotamine

- MOA: vasoconstriction d/t stimulation of alpha-adrenergic and 5-HT (1D) receptors (latter specific to cerebral vasoconstriction)

- Advantages/disadvantages: + : effective, low cost, high experience; - : complex pharmacology/pharmacokinetics; adverse: GI upset

b. Triptans: sumatriptan, zolmitriptan, -triptan ending

- MOA: selective 5-HT (1D) and (1B) receptor agonists

- Advantages/disadvantages: + over ergot: selective, simple pharmacokinetics, efficacious and established safety; - : higher cost, contraindicated for use in presence of CV dz (mimics angina); adverse: N, dizziness, drowsiness, muscle weakness

176

General uses of immunosuppressants

- Transplants: prophylactic tx and acute rejection episodes

- Autoimmune dz

- Inflammatory diseases

177

What are the general adverse effects common between immunosuppressants?

- ID and malignancy

178

Glucocorticoids
a. MOA
b. Uses
c. Adverse reactions

a. MOA

- Genomic effects: binds to cytosolic receptor and translocates to nucleus, binding directly to DNA activating or inhibiting expression. Inhibits TFs and decreases production of immunoregulatory and inflammatory cytokines

- Non-genomic: intercalates into cell membrane to alter ion transport resulting in rapid immunosuppression

- Overall: rapid decrease in peripheral blood lymphocytes, downregulates pro-inflammatory cytokines (IL-1, IL-6, TNF-alpha, IFN-gamma), inhibits IL-2 production by T cells needed for their proliferation, reduce neutrophil chemotaxis and lysosomal enzyme release

b. Prevent transplant rejection, GVHD, block cytokine storm caused by tx with muromonab CD3 and antithymocyte globulin, treat autoimmune diseases

c. Growth retardation, increased infection risk, poor wound healing, HTN, avascular necrosis of bone, cataracts, hyperglycemia, adrenal crisis upon discontinuation

179

Define nomenclature used to describe prednisone equivalent

- Defined: amount of prednisone or its equivalent. Below all are per day dosing

- Low dose: 7.5 mg, but 30 mg, but 100 mg

- Pulse therapy: >=250 mg

180

Cyclosporine.
a. Characteristics
b. MOA
c. Uses
d. Adverse reactions

a. Polypeptide, calcineurin inhibitor

b. Complex with cyclophilin then binds to calcineurin prevent the dephosphorylation of NFAT, a TF required for IL-2 transcription for example. Mainly suppresses T-cell mediated immunity.

c. Prophy for transplant, GVHD after HSC transplant, RA (unresponsive to MTX), psoriasis. Usually combined with other agents. *note: not generally given to renal transplant patients before procedure d/t nephrotoxicity

d. Nephrotoxicity * see above, HTN, hyperlipidemia, neurotoxicity (tremors), swollen/painful gums, hirsutism, skin cancer risk, avoid with grapefruit juice which inhibits CYP3A and MD efflux pump.

181

Tacrolimus.
a. Characteristics
b. MOA
c. Uses
d. Adverse reactions

a. Antibiotic, calcineurin inhibitor

b. Inhibitor of calcineurin, prevents dephosphorylation of NFAT, a TF required for IL-2 transcription for example. Mainly suppresses T-cell mediated immunity.

c. Prophy of allograft rejection in solid-organ transplantation.

d. Nephrotoxicity, HTN, DM, neurotoxicity, avoid with grapefruit juice which inhibits CYP3A and MD efflux pump.

182

Azathioprine.
a. Characteristics
b. MOA
c. Uses
d. Adverse reactions

a. Purine antimetabolite/anti-proliferative drug

b. Metabolized to 6-mercaptopurine, which is converted to additional metabolites. Some incorporated into DNA inhibiting lymphocyte proliferation. Also, de novo purine salvage pathway blocked. This cannot be overcome in lymphocytes.

c. Prevention of organ transplant rejection, RA, other autoimmune diseases (Crohn’s, MS, ITP, autoimmune hemolytic anemias). *monitor CBC and liver function when on this drug

d. BM suppression *see above, hepatotoxicity, increased susceptibility to infections (esp VZV and HSV), increased risk for lymphoma

183

Mycophenolate mofetil.
a. Characteristics
b. MOA
c. Uses
d. Adverse reactions

a. Anti-metabolite, anti-proliferative drug

b. Prodrug that is hydrolyzed to MPA (mycophenolic acid). This is selective inhibitor of IMP DH required for de novo synthesis of guanine nts, prevents lymphocytes from proliferating as they require this pathway.

c. Prophy of transplant rejection (usually administered with glucocorticoids and calcineurin inhibitor), off lab for SLE

d. Hematologic, GI upset, infections with CMV, congenital abnormalities

184

Sirolimus.
a. Characteristics
b. MOA
c. Uses
d. Adverse reactions

a. Antimetabolite, anti-proliferative drug

b. Binds FKBP and inhibits MTOR (a protein kinase: mammalian target of rapamycin), therefore blocking cell-cycle G1-S transition in lymphocytes.


c. Prophylaxis of organ transplant rejection (in combo with glucocorticoids and low dose calcineurin inhibitor). Also used in renal transplant patients (w/glucocorticoids and mycophenolate) since calcineurin inhibitors are nephrotoxic.

d. Hematologic, hypokalemia, GI upset, delayed wound healing, infections, neoplasms.

185

Antithymocyte globulin
a. Characteristics
b. MOA
c. Uses
d. Adverse reactions

a. Biological: rabbit serum containing purified gamma globulin specific to human thymocytes

b. Antibodies that bind to many CD markers on T lymphocytes causing depletion of circulating lymphocytes by: complement and inhibition of lymphocyte function

c. Induction immunosuppression, prophylactic immunosuppression, tx of acute rejection of solid organ transplants

d. Initially (fever, chills, malaise, hypotension d/t release of inflammatory cytokines) – premedicate with glucocorticoids to minimize this; serum sickness, anaphylaxis, hematologic changes, malignancy, infection

186

Muromonab-CD3
a. Characteristics
b. MOA
c. Uses
d. Adverse reactions

a. Biological mouse antibody

b. CD3 is T cell marker important in activation of the cell. Antibodies cause depletion of T-lymphocytes through complement and prevent T cell activation.

c. Reverse glucocorticoid-resistant transplant rejection. Note this is one time use as neutralizing antibodies can be made against murine antibodies by patient. 2nd time use is contraindicated.

d. Cytokine storm within 30 mins of use (fever, chills, malaise, hypotension) – premedicate with glucocorticoids, tremor, NVD, myalgia, arthralgia, generalized weakness, anaphylaxis, pulmonary edema, ARDS, cardiac arrest, infections, neoplasms

187

Anti-TNF alpha
a. Names of drugs and MOA
b. Uses
c. Adverse reactions

a. Names and MOA

- Infliximab: monoclonal ab containing a human constant region and murine variable region

- Adalimumab: recombinant human IgG1 monoclonal ab

- Etanercept: contains ligand-binding portion of human TNF-alpha R fused to Fc portion of human IgG1

- MOA: prevents TNF-alpha binding to receptors and binding directly to cytokine.

b. RA in patients who have not adequately responded to MTX alone. Crohns dz, UC, ankylosing spondylitis, psoriasis

c. Serious infections, lymphomas and other malignancies

188

Herbal medication/supplement with primary intended use of treating and preventing common cold? Potential mechanism?

- Echinacea (MOA: increase cytokine production, inhibits COX, increase number of immune cells in blood)

189

Herbal medication/supplement with primary intended use of treating and preventing HTN? Potential mechanism?

- CoQ10, garlic (MOA: inhibition of ACE, increase NO bioavailability and H2s production = decreased vasoconstriction and enhanced vasodilation)

190

Herbal medication/supplement with primary intended use of treating and preventing hyperlipidemia

- Garlic, Fish oil

191

Herbal medication/supplement with primary intended use of treating and preventing cognitive decline? Potential mechanism?

- Ginkgo biloba (for AD, dementia) – (MOA: restoration of cortical 5-HT1A receptors in aging rats)

192

Herbal medication/supplement with primary intended use of treating and preventing neurodegenerative diseases

- CoQ10 (PD), Ginkgo biloba (for AD, dementia)

193

Herbal medication/supplement with primary intended use of treating and preventing insomnia

- Melatonin

194

Herbal medication/supplement with primary intended use of treating and preventing joint dysfunction

- Glucosamine and chondroitin

195

Herbal medication/supplement with primary intended use of treating and preventing depression? Potential mechanism?

- St. John’s Wort (MOA: inhibit reuptake of serotonin, DA and NE at nerve terminals)

196

Herbal medication/supplement with primary intended use of treating and preventing BPH (benign prostatic hypertrophy). Potential Mechanism?

- Saw Palmetto (MOA: inhibits 5alpha reductase induced conversion of testosterone into DHT, blocks DHT from binding androgen receptors)

197

Herbal medication/supplement with primary intended use of treating and preventing liver disease

- Milk Thistle

198

Herbal medication/supplement with primary intended use of treating and preventing migraine

- CoQ10, butterbur, feverfew

199

Herbal medication/supplement with primary intended use of treating and preventing statin-induced myopathy

- CoQ10

200

Herbal medication/supplement with primary intended use of treating and preventing fatigue (boosting mental and physical performance)

- Ginseng

201

Identify criteria that should be followed when choosing bw brands of dietary supplements.

- Select formulations that have been studied in clinical trials – Evidence-based resources

- Select formulation that have been independently tested for quality – NSF, USP labels

- Use standardized botanicals containing specific quantity of active ingredients

202

Describe potential reason for conflicting results between clinical trials on efficacy and safety of dietary supplements.

- Different growth conditions of active ingredients altering concentration

- Not all standardized to known active ingredients

- Not always known the chemical(s) that produce beneficial effect

- Different brands – effects between these may not be comparable

203

Which dietary supplement/herbal medication can cause the following:
a. Increased bleeding risk in patients on warfarin
b. Increase immune system activity
c. Decrease reproductive system function
d. Induce mania in psychiatric patients
e. Increase risk of seizures in seizure-prone individuals

a. Ginkgo biloba, garlic, ginseng, glucosamine/chondroitin, feverfew, not melatonin (decreases PT time) or CoQ10 (similar to vit K) which would cause clotting right

b. Echinacea, ginseng

c. Melatonin (decreases sperm quality and reduces LH hormone in women)

d. St. John’s Wort

e. Ginkgo biloba

204

Which dietary supplement/herbal medication can potentially decrease serum drug levels by inducing cytochrome p450 enzymes?

- St. John’s wort = inducer hepatic CYP enzymes and decrease serum concentration of those agents metabolized by it. This one was emphasized!

- Not Echinacea = potential CYP 34a inhibitor, which would increase serum drug levels