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Pharmacology > Final sweep > Flashcards

Final sweep Flashcards

1
Q

Hypothalamus secretes ——-, positive and negative effectors, respectively, of ——– by the posterior pituitary.

A

growth hormone releasing hormone (GHRH) and somatostatin (SST)

growth hormone (GH) release

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2
Q

GH is a negative regulator of —– secretion.

A

GHRH

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3
Q

Insulin-like growth factor 1 (IGF-1), produced in the liver in response to – is a negative regulator of—- release by the pituitary and a positive regulator of —- release by the hypothalamus.

A

GH,

GH

SST

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4
Q

A receptor with associated JAK kinase (as well as Src kinase) activity mediates the effects of

A

GH.

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5
Q

Follicle Stimulating Hormone-FSH —-

Luteinizing Hormone LH —–

A

Anterior pituitary

Anterior pituitary

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6
Q

Human Chorionic Gonadotropin-hCG —-

A

Placenta

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7
Q

FSH and LH Receptors are G protein coupled receptors linked to

A

Gas

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8
Q

Men
FSH —-
LH —– production

A

Spermatogenesis

Testosterone

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9
Q

FSH, LH, hCG therapeutics
Used to induce —-

Used to treat —– in cases not treatable with androgen alone.

A

ovulation that is secondary to hypogonadotropic hypogonadism,
Polycystic ovary syndrome, obesity, others

male infertility

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10
Q

Posterior Pituitary:

A

Oxytocin and Vasopressin

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11
Q

Vasopressin acts on

A

two different receptors expressed in different places - v1 and 2

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12
Q

V1 Receptors
G protein coupled receptors on ——- that mediate ——-
Linked to —–
Contraction of ——

A

vascular smooth muscle

vasoconstriction

Gaq

vascular smooth muscle

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13
Q

V2 receptors
G protein coupled receptors on —— that mediate water retention
Linked to —

A

kidney tubules

Gas

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14
Q

Clinical Uses of Vasopressin

A

Treatment of diabetes insipidous

Treatment of certain types of bleeding problems Treatment of nocturnal enuresis (bed wetting)

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15
Q

Vasopressing ant.

A

Used to treat hyponatremia (Low Na+ concentration in the blood)

Limit water retention

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16
Q

Oxytocin
Works through ——
Induces contraction of —— (Receptor numbers go up during second half of pregnancy)
Elicits —– in lactating women

A

G protein coupled receptor (Gaq)

uterine smooth muscle

milk ejection

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17
Q

Oxytocin Physiology
Lower dose: increase —– of contractions
Higher dose: sustained —–

A

frequency and force

contractions

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18
Q

Oxytocin therapeutics

A

Induce labor: If early vaginal delivery required or labor problems

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19
Q

Atosiban:

A

antagonist (of both vasopressin and oxytocin). Used to halt premature labor.

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20
Q

—– is the world’s leading cause of goiter

A

Iodine deficiency - in developed countries, autoimmune issues are the most common

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21
Q

Treatment of Hyperthyroidism

  1. Thioamides – Block —–
  2. Anion inhibitors – Block ——
  3. Iodide —–
A

hormone synthesis

I- transport into thryroid

(high concentrations inhibit transport and inhibit hormone biosynthesis)

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22
Q

If the body is low on Ca++, ——- will be released and 1) bone resorption will increase, 2) —–elimination by the kidney will decrease, and 3) —– absorption by the gut will increase.

A

Parathyroid hormone (PTH)

Ca++

Ca++

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23
Q

PTH Acts on two receptors

A

PTHR1: bone and kidney
PTHR2: CNS, pancreas, testis, placenta

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24
Q

Activation of PTHR1 receptors on osteoblasts, induces expression of —— This leads to binding and activation of osteoclasts and bone resorption.

A

RANK ligand (RANKL).

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25
Q

PTH effects on the kidney:

A
  1. Maximize Ca++ resorption, decrease PO43- resorption

2. Enhance vitamin D production

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26
Q

PTH enhances the production of —–, the active form of vitamin —. This enhances absorption of —– from the gut.

A

calcitriol

D

Ca++

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27
Q

Vitamin D produces changes in

A

gene expression, acting through a ligand activated transcription factor

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28
Q

Calcitonin is released by parafollicular cells of the thyroid in response to high serum — It counteracts the effects of —-.

A

Ca++.

PTH

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29
Q

Dental Abnormalities due to PTH issues can also be an indication of —— malfunction.

A

kidney

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30
Q

Bisphosphonates are a class of drugs that prevent the loss of —–, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treatosteoporosis

A

bone mass

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31
Q

95% of testosterone comes from —— of the testes (other 5% from adrenal gland). Some made in the ovary.

A

Leydig cells

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32
Q

Testosterone synthesis and release stimulated by —

A

LH

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33
Q

Estradiol (E2)

Major secretory product of —–

A

ovary

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34
Q

Estrone (E1) Estriol (E3)

Made in peripheral tissues from —– and other androgens

A

androstenedione

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35
Q

Natural estrogens

A

from which synthetic estrogens are derived

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36
Q

Synthetic estrogens most commonly used in

A

OCs

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37
Q

Binding of agonist(e.g. estradiol to estrogen receptor) produces a conformational change that exposes the —– region of the receptor.

A

AF-2

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38
Q

Co-activator proteins such as SRC-1 can only bind to the receptor if —- is exposed. Thus, the co-activators only bind to the receptor if —– is bound.

A

AF- 2

agonist

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39
Q

Antagonists bind perfectly well to the receptor but their binding does not lead to exposure of —. Therefore, the antagonist receptor binds to the DNA, but does not bind ——- and the antagonist does not activate transcription

A

AT-2

co-activators

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40
Q

Tamoxifen is what’s called a SERM (selective estrogen receptor modulator). It acts as an ——- in some tissues (i.e. breast) but acts as an —— in other tissues. It is speculated that things like availability of —— determines whether the SERM acts as an agonist or antagonist.

A

antagonist

agonist

co-activators

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41
Q

Fungi have 3. —– cell wall; also containing —–

A

Chitinous

ß-Glucans *

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42
Q

TYPES OF INFECTIONS

A

SUPERFICIAL, CUTANEOUS, SUBCUTANEOUS

SYSTEMIC

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43
Q

Systemic infections - subcategories

A

Opportunistic, exogenous

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44
Q
  1. Antibiosis” -
A

Life destroys life amongst lower species.

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45
Q

Ideal Antibacterial Drug

A

Stability, solubility, diffusibility, Slow Excretion, large therepeutic index

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46
Q

Sulfonamides Trimethoprim T etracyclines Erythromycin Vancomycin

A

Bacteriostatic:

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47
Q

:
Vancomycin
Quinolones Penicillins Cephalosporins Aminoglycosides

A

Bactericidal

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48
Q

Prophylaxis: Temporarily decreases most likely pathogens below ———
One quarter to one half of antibacterial drug use is for
prophylaxis.

A

critical level required to cause infection.

a) Prevent epidemic meningitis, bacterial endocarditis
b) Prosthetics - artificial valves, arteries.
c) Transplants
d) Surgery (perioperative): gunshot wound, burns, colon surgery, other surgeries.

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49
Q

Empiric Therapy: Initiation of treatment before ——- known with agents known to be effective against the most likely pathogen acquired (suspected from source of infection)

A

etiology of infection is

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50
Q

Pathogen-directed Therapy:

A

Identification of bacterial species

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51
Q

M.I.C.-

A

Minimum Inhibitory Concentration - Lowest concentration of drug which
completely inhibits growth at 24 hr.

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52
Q

b) MBC —

A

Minimum Bactericidal Concentration—(NOT AS COMMONLY USED)

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53
Q

c) Disk Diffusion Assays and E-Test for

A

determining antibiotic sensitivity

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54
Q
  1. Pharmacokinetics of antibiotic–
A

route and time course of Absorption (Ex. Vancomycin), Distribution, Metabolism (Pro-drugsdrug-drug interaction based on cyt p450 activation or inactivation), Excretion (Example: Penicillins for urinary tract infections), Toxicity.
[ADME+T]

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55
Q

Resistant bacterial strains (Antibiotic Susceptibility Data-reported in individual Hospitals and/or medical centers)ANTI-BIOGRAMS

a) Emergence of different resistant strains in different locales (hospitals) depending on
- —–.
b) Resistancecandetermine

A

:i)Choiceofdrug;ii)Howmuchdrug;iii)drugcombinations

clinical use and/or natural selection

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56
Q

Empiric Therapy for

A

serious infections of unknown etiology since no single agent

covers all potential bacterial pathogens.

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57
Q

b) Mixed Infections: Intra-abdominal—

A

potentially several organisms. Can use two

narrow-spectrum agents targeted at different organisms.

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58
Q

c) Synergism

A

(more than additive effects)

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59
Q

Quinolones-

A

DNA Gyrase A, Topoisomerase IV inhibitors

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60
Q

Sulfonamides, Trimethoprim—

A

Antifolates—inhibits folic acid synthesis

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61
Q

Rifampin-

A

RNA synthesis inhibitor

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62
Q

Nitrofurantoin—

A

Free radical generator

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63
Q

Metronidazole—

A

Anaerobic enzymatic reduction then metabolite DNA binding

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64
Q

Methenamine—

A

breaks down to form formaldehyde (alkylates DNA & protein)

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65
Q

Beta-lactams:

A

Inhibition of transpeptidation cross-linking of peptidoglycans
• Penicillins
• Cephalosporins
• Monobactams (Aztreonam) • Carbapenems (Imipenem).

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66
Q

Vancomycin

A

binds D-ala-D-ala; prevents polymerization of cell wall components

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67
Q

Bacitracin—

A

binds to and prevents functioning of lipid carrier of peptidoglycan

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68
Q

Polymyxins—-

A

cationic detergent disrupts cell membrane

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69
Q

Daptomycin—

A

lipopeptide that disrupts membrane function (newer agent)

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70
Q

Sulfonamides

Mechanism: Competitive inhibitor of —— required for synthesis of —— (See Figure 6). Generally considered to be ——.

A

Dihydropteroate synthase

folic acid

bacteriostatic

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71
Q

Sulfonamides

Selectivity: Sulfonamides are selective because bacteria must synthesize their own —– while humans utilize ——-

A

folate

dietary folate.

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72
Q

Sulfonamides

Antibacterial Spectrum: Inhibits growth of —— organisms. Resistant strains are numerous.

A

gram positive and negative

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73
Q

Sulfonamides

Clinical Uses:

A

a) Uncomplicated urinary tract infections (esp. E. coli) b) Toxoplasmosis—a parasite infection (in combination) c) Prophylactic:
→topical for burn patients
→In AIDS patients for prevention of Pneumocystis jirovecii (yeast/fungus)

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74
Q

Sulfonamides

Absorption (A):

A

Good oral absorption. Poorly absorbed forms (phthalylsulfathiazole)
used to decrease colonization density before surgery (controversial).

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75
Q

Sulfonamides

Distribution (D):

A

Widely distributed including penetration into the cerebrospinal fluid (CSF).

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76
Q

Sulfonamides

Excretion (E):

A

Renal

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77
Q

Sulfonamides

Dose Related:

A

Crystalluria–rare—> but is why bottles are labeled “take with plenty of water”
Hematopoietic: hemolytic anemia
GI Upset
Kernicterus: Sulfa drug displaces albumin bound bilirubin. Bilirubin can then pass BBB in newborn. CNS deposition leads to encephalopathy.

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78
Q

Sulfonamides

Dose Unrelated:

A

Hypersensitivity reactions ranging from mild rash to Stevens-Johnson syndrome (Fever, malaise, erythema, mucous membrane ulcerations). Photosensitivity: noted most in Southern states
Acute Kidney Injury (AKI)sulfamethoxazole

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79
Q

Trimethoprim

Mechanism:

A

Inhibitor of Dihydrofolate reductase (DHFR); structural analog of pteridine.
Bacteriostatic [Figure 12].

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80
Q

Trimethoprim

Selectivity:

A

Need much higher concentration to inhibit human compared to bacterial
DHFR [Figure 13].

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81
Q

Trimethoprim

Antibacterial Spectrum:

A

Broader spectrum of activity against both gram negative and gram positive bacteria compared to sulfonamides. Resistance associated with alterations in DHFR.

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82
Q

Trimethoprim

Clinical Uses:

A

USED ALONE OR IN COMBINATION with sulfamethoxazole [SMX] (5:1, SMX: Trimethoprim)Synergistic. Treatment of urinary tract infections, intestinal infections; Prostatitis; Pneumocystis jarovecii treatment and prevention in AIDS. Recent extensive use to treat community-acquired MRSA (resistant staph infections— see page 15);

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83
Q

Trimethoprim

Pharmacokinetics:
Absorption (A): ------
Distribution (D):-------
E): -----
Toxicity (T): ------
A

oral (G.I. absorption is good); urine conc. 100X’s that of plasma.

Wide; penetrates into CNS Excretion

Renal

Slight; blood dyscrasias. Usually associated with sulfa combination. Anemias: in patients already folate deficient. Kidney: serum creatinine increase.

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84
Q

B. ——– —Semisynthetic analog of natural product from a Streptomyces.

A

Rifampin

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85
Q

Rifampin

Mechanism:

A

Binds to and inhibits RNA polymerase–Bactericidal.

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86
Q

Rifampin

Resistance:

A

Induction of resistance is rapid; Rifampin is not usually to be used as monotherapy.

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87
Q

Rifampin

Selectivity:

A

Rifampin doesn’t bind to human RNA polymerase.

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88
Q

Rifampin

Antibacterial Spectrum:

A

potent against M. tuberculosis at both intracellular and

extracellular sites; some activity against staphylococci.

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89
Q

Rifampin

Clinical Uses:

A

First-line antituberculosis drug; used in combination with other first-line anti-tubercular drugs; some use in combination with other agents for treatment of prosthetic valve endocarditis (Staphylococcal),resistant staph infections; prophylaxis against meningococcal disease and meningitis.

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90
Q

Rifampin

Pharmacokinetics:
Absorption (A): 
Distribution (D):
Metabolism (M): 
Excretion (E): 
Toxicity (T):
A

Oral (G.I. absorption is rapid), peak levels within 2-4 hr.

Widely distributed to organs, tissues, and body fluids; also found in cerebrospinal fluid (CSF). Imparts red-orange color to urine, feces, saliva, sputum, tears [contact lenses may be affected], and sweat.Caution patients so they don’t freak out!

Liver P450 enzyme-mediated deacetylation. Metabolite retains full antibacterial activity but intestinal reabsorption is diminished. Potent inducer of hepatic microsomal enzymes (esp. CYP3A4) and can therefore increase metabolism and decrease the half-life of HIV protease and nonnucleoside reverse transcriptase inhibitors (and other drugs). Therefore, in HIV-infected patients with TB the substitution of Rifabutin (an analog) for Rifampin is indicated-Rifabutin does not induce metabolizing enzymes as much as Rifampininterferes to a lesser extent with anti-HIV therapy.

Renal (15-25%): Also rapid elimination in bile as parent and as deacetylated metabolite; daily dosing. Rifapentine (longer half-life; weekly dosing.)

Liver damage—jaundice

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91
Q

QUINOLONES

Mechanism:

A

These agents inhibit DNA replication through “poisoning” of DNA Gyrase A. Specifically these agents inhibit uncoiling function of DNA gyrase ahead of the replication fork. Quinolones also inhibit separation of newly replicated strands of DNA (decatenation) through inhibition of DNA topoisomerase IV. Bactericidal

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92
Q

Quinolones

Selectivity:

A

Mammalian DNA topoisomerase II not inhibited to same extent as DNA gyrase and DNA topoisomerase IV in bacteria.

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93
Q

Quinolones

Antibacterial Spectrum:

A

a variety of analogs are effective against either gram positive or gram negative bacteria.

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94
Q

Quinolones

Clinical Uses:

A

Urinary tract infections (UTI)(Ciprofloxacin); respiratory tract infections (RTI); Anti-tubercular (when resistance to other anti-TB drugs); Ciprofloxacin & Levofloxacin are effective against Pseudomonas aeruginosa, a gram negative bacterium. Ciprofloxacin no longer used against gram positive organisms because of rapid emergence of resistance.

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95
Q

Quinolones

Drug Resistance:

A

1) Mutations in Gyrase or Topoisomerase target 2) increased efflux pumps
3) altered porins (gram-)

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96
Q

Moxifloxacin, for treatment of ——- including better coverage against gram positive bacteria than ——-. For example: effective against Penicillin-resistant S. pneumoniae.
Moxifloxacin is not used for —— since it is not cleared by renal mechanisms.

A

respiratory tract infections

Ciprofloxacin

urinary tract infection

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97
Q

Quinolones

Pharmacokinetics (General):
Rapid absorption after ——. Cations (Exs: Ca++, Mg++, Fe++ ) can ——- and limit absorption.
Rapid —- elimination
High concentrations in ——– Ciprofloxacin penetrates into ——- fluid—good for ——–.
Toxicity:

A

oral administration

chelate

renal

kidney, urine—except with Moxifloxacin which is not cleared by kidney

prostatic

prostatitis

Generally well-tolerated; avoid Ciprofloxacin in childrenpotential tendon ruptures;
Other: G.I intolerance/nausea-vomiting-diarrhea (NVD), peripheral neuropathy.

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98
Q

NITROFURANS

Mechanism:

A

DNA damage caused by formation of oxygen free radicals subsequent to reduction of nitro group.

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99
Q

NITROFURANS

Selectivity:

A

High concentrations in urine and renal interstitial fluids. Bacteria cause reductive activation more extensively than mammalian cells. Low serum concentrations prohibits use for systemic infections.

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100
Q

NITROFURANS

Antibacterial Spectrum:

A

Broad spectrum against gram positive and gram negative strains. Not effective against P. aeruginosa

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101
Q

NITROFURANS

Clinical Uses:

A

Only for treatment of urinary tract infections

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102
Q

NITROFURANS

Pharmacokinetics:

A

Well absorbed by oral route, rapidly metabolized, renal excretion. High concentrations in urine achieved-good for treatment of urinary tract infections.

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103
Q

Nitrofurans

Contraindication:

A

low creatinine clearance (poor renal function). Toxicity includes acute fever, rashes, urticaria (itching, hives-cell mediated immunity). Also, acute pleural effusions. Chronic toxicity associated with pulmonary fibrosis, often reversible.

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104
Q

METHENAMINE rarely used for

A

prophylaxis

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105
Q

METHENAMINE

Mechanism:

A

Hydrolyzed at acid pH to form formaldehyde. Acidify urine to increase selectivity (Hippuric or Mandelic acid). Denatures proteins. In addition, formaldehyde has been shown to damage DNA.

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106
Q

METHENAMINE

Clinical Uses:

A

Only for prophylaxis for lower urinary tract infections. Gram negative spectrum. Note: Methenamine is not effective against Pseudomonas, Proteus due to ability of these microorganisms to metabolize urea resulting in a rise in pH and prevention of formaldehyde generation.

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107
Q

METHENAMINE

Pharmacokinetics:

A

Oral administration and well distributed into total body water. Stomach hydrolysis is 10-30% unless tablets enterically coated. Toxicities include gastric distress, bladder irritation, crystalluria due to precipitation of acidifying agents if inadequate urine flow

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108
Q

METRONIDAZOLE: a pro-drugfor

A

Anaerobic Infections!

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109
Q

METRONIDAZOLE

Mechanism:

A

Reductive activation of nitro group specifically in anaerobic bacteria leads to free radical species and reactive intermediates that bind to and affect DNA function (replication, transcription, repair). Also activation and DNA damage activity in some protozoa. Therefore, metronidazole is a pro-drug required metabolic activation.

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110
Q

METRONIDAZOLE

Antibacterial Spectrum:

A

Bactericidal against most obligate anaerobic gram positive and gram negative bacteria. Not active against aerobes or facultative anaerobes. Active against some protozoa.

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111
Q

METRONIDAZOLE

Clinical Uses:

A

Anaerobic bacteria; some protozoans.

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112
Q

METRONIDAZOLE

Resistance:

A

Reduced activation

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113
Q

METRONIDAZOLE

Pharmacokinetics:
Absorption (A): -------
Distribution (D): --------
Excretion (E): ------
Toxicity (T): --------
A

well absorbed orally.

Widely distributed into fluid compartments; penetrates into the central
nervous system (therapeutic levels found in cerebrospinal fluid).

Renalmetabolites

Metallic taste; Disulfiram-like effect where complete metabolism of alcohol is prevented—leads to nausea, vomiting, G.I. distress if alcohol intake during therapy.
Peripheral neuropathy w/long-term use.
Also, some central nervous system neurotoxicity: dizziness, vertigo, convulsions, ataxia.

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114
Q

High internal osmotic pressure of bacteria requires a rigid cell wall to maintain integrity, shape. During growth and division bacteria require new cell wall synthesis. Therefore, inhibitors render growing bacteria susceptible to ——, with no effect on mammalian cells which do not contain cell walls.

A

osmotic rupture

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115
Q
  1. Bactericidal effects only when cells are —–.
A

growing

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116
Q

Mycoplasma lack cell walls -

A

instrinsically resistant

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117
Q

L-forms of

bacteria

A

(no cell walls); sanctuary in kidney where osmotic pressure is high.

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118
Q

Cell Wall Synthesis
1. a) ——; b) linkage of two —– [—— inhibits both steps: second line agent for treatment of tuberculosis]

  1. Linkage of—– dipeptide to three other Amino acids and
    - ——- acid to form a pentapeptide with a UDP-carrier + isoprene.

[3]. Coupling to ——.
[4]. Sugar-peptide structure linked to ——- lipid carrier is transported to —– of cell membrane.
[5]. —— added to polymer (peptidoglycan strands) via ———
a) Bacitracin binds to ——- so can’t be used as carrier. [Figure 19]
b) —– prevents transfer of sugar-pentapeptide from carrier molecule to growing peptidoglycan chain. Inhibiton of Peptidoglycan synthase [Figure 19]. Also inhibits cross-linking of peptidoglycans.
6. ——– cross-linking peptidoglycan strands by connecting penultimate D-Ala from one strand to a diaminopimelic acid unit in a sugar- peptide of an adjacent strand (E. coli).
a) Beta-Lactams: act by binding to various ———-) and inhibiting ——— reaction.
i. Many different PBP’s (MW 40,000-120,000) exist and can have other functions beside transpeptidation (endopeptidase, carboxypeptidase).
ii. Specificity of ——-due to structural similarity with D-Ala dipeptide.
iii. Resistance to —— commonly associated with production of ——– which break ring [Figure 24].

A

L-ala to D-ala
D-ala.
Cycloserine

D-Ala
N-acetylmuramic

N-acetylglucosamine

isoprenyl-phosphate
exterior

Sugar-peptide
Peptidoglycan synthase

isoprenyl phosphate

Vancomycin

Transpeptidation reaction

penicillin-binding proteins (PBP’s
transpeptidation

ß-lactams

ß-lactams
ß-lactamases

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119
Q

BETA-LACTAMS-

A

Penicillins, Cephalosporins, Monobactams, Carbapenems, ß-Lactamase Inhibitors

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120
Q

PENICILLINS

Mechanism:

A

Mimics D-ala-D-ala structure of pentapeptide on peptidoglycan and ties up transpeptidase (also called PENICILLIN BINDING PROTEIN-[PBP])—see Figures 21- 23. Bactericidal

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121
Q

PENICILLINS

SELECTIVITY:

A

Penicillins and all ß-lactams work to inhibit cell wall synthesis. Since eukaryotic cells do not contain cell walls there are no direct cytotoxic effects in the host.

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122
Q

PENICILLINS

SELECTIVITY:

A

Penicillins and all ß-lactams work to inhibit cell wall synthesis. Since eukaryotic cells do not contain cell walls there are no direct cytotoxic effects in the host.

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123
Q

Naturally Occurring Penicillins: Penicillin G, Penicillin V(semi-synthetic)
–Narrow Spectrum—

A

effective against streptococci, many anaerobes, Enterococcus, and a few gram-negative organisms (not very active against some important enteric gram negative bacteria like E. coli and Klebsiella).

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124
Q

Anti-staphlococcal (ß-Lactamase-resistant) Penicillins

Methicillin Class

  • -Narrow Spectrum—effective against infections caused by ——-
A

Nafcillin, Oxacillin, Cloxacillin, [Methicillin (no longer used in the USA)]

staphylococci and streptococci.

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125
Q

Amino-Penicillins: Ampicillin, Amoxicillin- Can be broken down by ——– –Broader Spectrum—effective against ——— not effective against ——–

A

ß-lactamases

streptococci, enterococci, and some gram negative organisms (Examples: non-ß-lactamase producing E. coli, Haemophilus influenzae);

Pseudomonas aeruginosa.

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126
Q

Anti-Pseudomonal Penicillins: Carbenicillin, Piperacillin, Ticarcillin
–Extended Spectrum—effective against

A

streptococci, and many gram negative bacteria including various Enterobacteriaceae and Pseudomonas.

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127
Q

Group A Streptococcus Streptococcus pneumoniae (pediatric)
Pneumonia, Meningitis, Otitis Media, Bacteremia
Endocarditis, Meningitis, Epiglotitis
Sexually Transmitted Diseases (STD’s) Syphilis Urinary Tract Infections

All uses for

A

PENICILLINS

128
Q

Drug Resistance (Penicillins/ß-Lactams): 4 IMPORTANT MECHANISMS

A

1) ß-Lactamases (Gram+ and Gram-)
2) Altered PBP’s: MRSA (PBP2a)
3) Altered porins (Gram-)
4) Increased efflux (enhanced efflux pump mechanisms)

129
Q

Penicillins - Absorption: [Figure 27]

A

poor oral adsorption; only 50% with Pen-V. Food intake will decrease absorption, take penicillins before eating. Acid destruction a factor therefore give acid stable drug such as Pen-V. Short blood or plasma half-life after reaching max level within 2 hr. Much patient variability.

130
Q

Penicillins - Distribution:

A

Varies; lipid insoluble therefore no good penetration of the blood brain barrier (BBB). CSF entry increased with inflammation of meninges. Protein binding varies. Distribution can be affected by pathology of infection.

131
Q

Penicillins - Excretion:

A

Renal-by glomerular filtration and tubular secretion [Figure 28]. Plasma half-life short is (1-2 hr). Since metabolism is minor, renal impairment in patients could lead to nephrotoxicity or other adverse reaction.

132
Q

Penicillins - Toxicity:

A

Relatively nontoxic but direct toxic effects in the kidney are noted as well as hypersensitivity reactions; some G.I. toxicity with aminopenicillins.

a) Renal; electrolyte alterations, damage to kidney tubule.
b) Hypersensitivity reactions from major and minor determinants. Patients sensitive to minor determinants are more likely to have immediate anaphylactic reaction (300 die/yr in USA). Skin testing and desensitization (infrequent) have been used.

133
Q

Penicillins are —— antibacterial drugs since

A

Time-Dependent

concentrations in
the blood must be maintained for a sufficient period to inhibit cell wall synthesis and kill all bacteria. Note: Continuous infusions in a hospital setting is also an important treatment regimen.

134
Q

CEPHALOSPORINS

Mechanism and Selectivity:

A

Same as for penicillins; Bactericidal.
Generally, resistant to breakdown by ß-lactamases but there are specific cephalosporinases that breakdown ß-lactam ring of cephalosporins (Extended Spectrum ß-Lactamases [ESBL])–resistance

135
Q

CEPHALOSPORINS

Classification and Antibacterial Spectrum

A

(Many analogs–> FOCUS ON BOLDED/UNDERLINED ANALOGS)

136
Q

CEPHALOSPORINS

First, Second, Third, Fourth Generation—

A

each generation with progressively greater spectrum of activity, better activity against gram negative bacteria but effectiveness against gram positive bacteria decreases especially against Staphylococcus.

137
Q

CEPHALOSPORINS

i. First Generation:

A

Cefazolin-given by IV or IM; Cephalexin, Cephadroxil, Cefaclor-given orally; effective against gram positive organisms; Cefazolin has added activity against E. coli.

138
Q

CEPHALOSPORINS

ii. Second Generation:

A

Cefoxitin, Cefuroxime: Increased activity against gram negative bacteria compared to first generation drugs.

139
Q

CEPHALOSPORINS

iii. 3rd and 4th Generations ( and 5th):

A

3rd: Cefotaxime, Ceftazidime (only one effective against Pseudomonas); Ceftriaxone-[IM or IV, longer half-life (8 h)], Cefpodoxime, Cefdinir— >all have even greater activity against gram negative bacteria.
4th: Cefepime-effective against Pseudomonas; more resistant to ß- lactamase breakdown; only administered by IV route;
Ceftolozane-5th, Ceftobiprole-5th; Ceftaroline-5th
Pharmacokinetics

140
Q

CEPHALOSPORINS

Absorption:

A

Oral and parenteral (I.M. can be painful); I.V. (3rd and 4th generation). 3rd generation cephalosporins achieve high serum concentrations.

141
Q

CEPHALOSPORINS

Distribution:

A

Wide; 3rd and 4th generation cephalosporins can cross the blood brain barrier—penetrates into CSF.

142
Q

CEPHALOSPORINS

Metabolism:

A

Not extensively metabolized.

143
Q

Cephalosporins

Excretion:

A

Similar to Penicillins: Renal elimination via filtration and tubular
secretion; Ceftriaxone has extensive biliary excretion.

144
Q

Cephalosporins

Toxicity:

A

Like with penicillins, cephalosporins are relatively non-toxic; better tolerated than penicillins. Hypersensitivity and cross-sensitivity (1-10%) in patients who have allergic reactions to penicillin.

145
Q

CARBAPENEMS

Activity Spectrum and Use

A

i. Broad/Extended spectrum against gram- & gram+ bacteria.
ii. Stable/resistant to most ß-lactamases (but are now some Carbepenemases—
Extended Spectrum ß-lactamases–ESBLs):
CRE: Carbapenem-resistant Enterobacteriaceae—important clinically.
iii. Binds with high affinity to PBP-1 and PBP-2 of gram negative bacteria;
especially effective against Pseudomonas (exception is Ertapenem).
iv. Also effective against Acinetobacter (gram-) but resistant strains are emerging.
v. Use reserved for serious nosocomial infections (a “restricted” drug)
vi. Severe allergy to penicillins/cephalosporins precludes use of carbapenems
unless there is desensitization (cross hypersensitivity is 1-5%).

146
Q

CARBAPENEMS

Pharmacokinetics

A

i. I.V. only
ii. Renal elimination by filtration and tubular secretion.
iii. Undergoes hydrolysis in renal tubulesdiminishes effectiveness. Cilastatin
(inhibition of renal dehydropeptidase) blocks hydrolysis and is administered along
with imipenem to increase half-life.
iv. CNS toxicity can be limiting (seizures)

147
Q

MONOBACTAMS

Activity Spectrum and Use—-

A

Effective against aerobic gram negative organisms including Pseudomonas aeruginosa; essentially no activity against gram positive organisms because of poor binding to PBPs in gram positives. Very stable to action of ß-lactamases but are now many resistant gram negative strains that contain ESBLs that can break down Aztreonam.

148
Q

MONOBACTAM

Pharmacokinetics—

A

Given only I.V. or by I.M. injection. Elimination same as for penicillins. Hypersensitivity reactions are rare; cross-hypersensitivity to pens is rare.

149
Q

BETA-LACTAMASE INHIBITORS—

A

Clavulanic acid, Sulbactam, Tazobactam Suicide inactivators of β-lactamases.

150
Q

Beta lactamase inhibitors - Mechanism –

A

Inhibits ß-lactamases. Binds irreversibly to serine at active site of lactamase; suicide inactivator.

151
Q

VANCOMYCIN: Large tricyclic glycopeptide from Streptomyces orientalis
Analogs:

A

Teicoplanin-not available in the US); Telavancin: semi-synthetic lipoglycopeptide (2009);dalbavancin (2014) and orbitavancin (2014) both semi-synthetic Vanco analogs.

152
Q

Vancomycin - Mechanism(s): Binds to

A

carboxyl terminus of D-ala-D-ala and thereby:
1) Inhibits Peptidoglycan synthase (peptidoglycan polymerization after isoprenyl phosphate lipid carrier transport to cell exterior [Figure 33-34].
2) Inhibits transpeptidation reaction (cross-linking between pentapeptides)
Bactericidal (Recently considered more of a bacteriostatic drug due to resistance mechanisms in Staphylococci and Enterococci).

153
Q

Vancomycin - —– is a major problem

A

Resistance is a major clinical problem!—-[Figure 35] Due to altered D-ala-D-ala peptide structures (changed to D-ala-D-Lac or to D-ala-D-Ser) so Vancomycin doesn’t bind as avidly— [important take home message!]. Enterococcus faecium isolates becoming vancomycin resistant (VRE-type resistance). Also, there are emerging strains of Staphylococcus aureus that are vancomycin resistant (VRSA-type resistance)

154
Q

Vancomycin - Spectrum and Clinical Uses:

A

Narrow Spectrum; active against gram positive staphylococci, streptococci, E. faecalis
Large size means can’t penetrate outer membrane of gram negative bacteria.

155
Q

Vancomycin Can be used to treat

A

Methicillin resistant staphylococci (MRSA-type).

156
Q

VANCOMYCIN

Pharmacokinetics:
Absorption:
Metabolism/Excretion:
Toxicity:

A

Given I.V. Not absorbed from G.I. Vancomycin used orally to treat pseudomembranous colitis resulting from toxin released from Clostridium difficile. Extensive use of many oral antibacterial agents such as Fluoroquinolines, clindamycin (see under Protein synthesis inhibitors), cephalosporins and others may alter the normal intestinal flora and increase the risk of developing C. difficile (Gram positive anaerobe) diarrhea since this organism is not killed. Oral use of Vancomycin is effective against C. difficile but results in rapid emergence of resistant enterococci. Another agent, Metronidazole (which incorporates into and damages bacterial DNA), is a good alternative to treat moderate pseudomembranous colitis through its bactericidal activity against C. difficile. Alternatively, can use Fidaxomicin (transcription inhibitor of protein synthesis), a new Macrolide [expensive]. For severe colitis, Vancomycin is still best choice. [See lecture by Dr. Wardlow 1/24/17-“Gastrointestinal (GI) & Intra- abdominal Infections” for more therapeutic details).

Not metabolized, renal excretion; half-life is 6-9 hr.

Hearing loss is dose-related and often related to underlying renal impairment in patient which leads to slower elimination (uncommon). Some renal toxicity noted (5- 10% of patients). Red man syndromeerythematous rash on neck/face if Vanco infused too quickly.

157
Q

BACITRACIN:

A

mixture of polypeptides produced by B. subtilis containing both D- and L-
amino acids.

158
Q

Bacitracin - Mechanism:

A

Binds to isoprenyl-phosphate lipid carrier, inhibits dephosphorylation and utilization.

159
Q

Bacitracin - Spectrum and Clinical Uses:

A

Inhibits gram positive cocci, some activity against gram negatives.
Superficial skin infections, ophthalmic infections.–>used in creams, ointments.

160
Q

Bacitracin - Pharmacokinetics:

—– absorbed, only administered —–. If given I.V. causes ——–

A

Poorly

topically

severe renal damage

161
Q

POLYMYXINS (type B and E)—Effective against

A

gram negative

bacteria

162
Q

Polymyxins - Mechanism:

A

Acts as bactericidal cationic detergent; disrupts cell membrane of gram negative bacteria (results in holes in membrane, cytoplasm leaks out). Selectivity (Gram negative):  Not effective against gram positive organisms because cell wall so thick that structural integrity is maintained. Bactericidal

163
Q

Polymyxins - Pharmacokinetics:
Absorption -
Toxicity:

A

Topical, oral
Poor G.I. absorption
Nephrotoxicity is dose-related. In patients with renal disease can be slower elimination and neurotoxicity. Incidence of nephrotoxicity and neurotoxicity is low.

164
Q

DAPTOMYCIN

Mechanism:

A

Insertion of lipophylic tail into cell membrane causes membrane depolarization, potassium ion efflux, and disruption of DNA, RNA, and protein synthesis. Bactericidal (rapid action—1 h).

165
Q

DAPTOMYCIN

Spectrum and Clinical Uses:

A

FOR GRAM POSITIVE INFECTIONS ONLYWhy?: Binds to LPS layer in gram negative bacteria and can’t get to plasma membrane. Effective against most gram positive pathogens. Also, effective against resistant isolates including vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). Not effective in lung infections (inactivation by pulmonary surfactants).
Currently approved for use in serious skin and skin structure infections: Ex.) wound infections, ulcer infections, major abscesses. Recently approved for endocarditis caused by S. aureus but resistant strains are emerging.

166
Q

DAPTOMYCIN

Pharmacokinetics (Daptomycin is a concentration-dependent agent): Absorption:

Distribution:
Toxicity:

A

I.V.—once a day dosing due to 8 hr half-life and maintained antibacterial action

limited to plasma and vascular tissues.

Very little—reversible skeletal muscle enzyme alterations.

167
Q

DAPTOMYCIN

Pharmacokinetics (Daptomycin is a concentration-dependent agent): Absorption:

Distribution:
Toxicity:

A

I.V.—once a day dosing due to 8 hr half-life and maintained antibacterial action

limited to plasma and vascular tissues.

Very little—reversible skeletal muscle enzyme alterations.

168
Q

VI. INHIBITORS OF PROTEIN SYNTHESIS mech

A

Direct synthesis inhibition or decreased fidelity in reading genetic code. Still much controversy about specific mechanisms.

169
Q

Aminoglycosides: Bind to

A

proteins in interface between 30S and 50S; also some AG’s bind to 30S and/or 50S separately. Streptomycin binds only to 30S.

170
Q

Aminoglycosides –Interfere with —– attachment.

–Blocking activity of —– complex.

A

tRNA

initiation

171
Q

Tetracyclines: Bind to

A

30S and block binding of tRNA to mRNA (A site). Reversible

172
Q

Chloramphenicol:

A

Bind to 50S. Inhibits Peptidyl transferase by preventing attachment of amino acid end of aminoacyl-tRNA to the “A” site.

173
Q

Clindamycin:

A

Binds to 50S. Binds to same site as Chloramphenicol since can be displaced by from bound site by chloramphenicol.

174
Q
  1. Erythromycin (MACROLIDES):
A

Binds to 50S close to Clindamycin and chloramphenicol site. Inhibits translocation, causes release of oligo-peptidyl tRNA.

175
Q
  1. Quinupristin:
A

Binds 50S. Stimulates dissociation of the peptidyl-tRNA. Dalfopristin: Binds 50S. Prevents binding of aa-tRNA to acceptor site.

176
Q

Quinupristin/Dalfopristin = only used in

A

combination

177
Q
  1. Linezolid:
A

Binds 50S. Blocks formation of initiation complex.

178
Q

AMINOGLYCOSIDES

Antibacterial Spectrum: Effective against

A

gram negatives especially pseudomonal species. Some activity against gram positive organism (S. aureus) in combination with beta-lactams or other agents that disrupt cell wall and allow aminoglycosides to enter. Some anti-tubercular actions.

179
Q

Streptomycin:

i. Original aminoglycoside, used in past for

A

tuberculosis (better agents now available–>requirement for administration by intramuscular injection—hurts!). Recently Streptomycin used again for drug resistant tuberculosis.

180
Q

ii. Penicillin/Streptomycin for endocarditis when is resistance to .

A

gentamicin

181
Q

Kanamycin:

i. Not used in

A

U.S.A. More active, less toxic agents. Resistance is problem.

182
Q

Neomycin:

A

i. Topical use for treament of burns, wounds, infected dermatoses. ii. Oral use as a preparatory treatment before bowel surgery.

183
Q

Ototoxicity:

A

Cochlear (hair cell death followed by degeneration of

auditory nerve fibers). Irreversible. Also, reversible vestibular toxicity.

184
Q

ii. Nephrotoxicity (reversible): relates to

A

proximal tubular cell accumulation of aminoglycoside to high cellular concentrations (via
binding to phospholipids).
a) risk increases with age, renal disease, prior drug therapy.

185
Q

iii. Neuromuscular Blockade:

A

skeletal muscle weakness, respiratory

depression. Important in patients with Myaesthenia Gravis.

186
Q

Aminoglycosides are

A

Concentration-Dependent drugs (in contrast to
penicillins which are time dependent agents). Therapeutic efficacy is dependent on serum concentration which is reflective of how much
drug will enter cells and bind to targeted ribosomal
sites.

187
Q

Aminoglycosides exhibit a considerable

A

POST-ANTIBIOTIC EFFECT (PAE).

188
Q

Tetracyclines - Antibacterial Spectrum and Clinical Uses:

A

a) Effective against Rickettsiae, Mycoplasma, Chlamydia, Protozoa, and a variety of gram-positive and gram-negative bacteria—-hence became known as first “Broad-Spectrum” antibiotics.
b) Second line therapy currently due to resistance and toxicities: Acne, outpatient mycoplasma, Urethritis.
c) Resistance: decreased influx, increased efflux pump, decreased binding to ribosomes, enzymatic inactivation

189
Q 
Tetracyclines - Pharmacokinetics:
Absorption: 
Distribution: .
Excretion: 
 Toxicity:
A

Primarily used by oral route.
i. Partially absorbed in stomach, upper G.I
ii. Chelates calcium, magnesium, other metal ions. Therefore, don’t administer with
glass of milk, magnesium hydroxide (antacids

Volume of distribution (Vd) is larger than body water space reflecting lipid solubility of each agent.

i. Bone sequestration extensive.
ii. Some penetration into CNS; crosses placenta

Urine and feces.

i. Binds to bone and teeth. Yellow/brown teeth. Retards bone growth. Don’t
administer in pregnancy or to young children.
ii. G.I. (NVD=nausea, vomiting, diarrhea)
i. Fanconi syndrome: renal tubular dysfunction after oral administration of
outdated/degraded tetracyclines.
ii. Photosensitivity →sunburn reaction; especially with doxycycline.

190
Q

TIGECYCLINE

Mechanism:

A

Same as Tetracyclines: Binds to 30S ribosomal unit. Bacteriostatic
Spectrum: Broad spectrum against gram positive and negative bacteria including
anaerobes. Tigecycline is not affected by the main Tetracycline resistance mechanisms: 1) increased efflux pump specific for Tetracycline; 2) ribosomal alterations leading to diminished binding. Therefore, this new agent may be useful against multiple organisms when there is resistance to tetracyclines and/or to ß-lactams, and vancomycin.

191
Q

Tigecycline - Clinical Use:

A

Complicated intra-abdominal and skin and skin structure infections. Not approved for bacteremias because poor serum levels are achieved.

192
Q

Tigecycline - Toxicity:

A

Nausea is important limiting toxicity.

193
Q

CHLORAMPHENICOL: a ——- analog (Streptomyces and synthetic) Antibacterial Spectrum and Clinical Uses:

A

nitrobenzene

EXTREMELY LIMITED CLINICAL USE BECAUSE OF POTENTIALLY FATAL SIDE EFFECT: APLASTIC ANEMIA

194
Q

Chloramphenicol - b) Resistance:

A

acetylation of drug; decreased uptake, change in ribosome structure

195
Q

Chloramphenicol - Pharmacokinetics:

Absorption:

A

rapid, complete by oral route but no oral preparation available in U.S.A. Distribution: throughout body compartments.

i. enters CNS (50% of blood level)-lipid soluble
ii. peak levels 2-3 hr., half-life 1.5-3.5 hr. [Figure 44]

196
Q

Chloramphenicol - Pharmacokinetics:

Metabolism and Excretion:

A

i. Hepatic metabolism to glucuronide (80-90% of dose). [Figure 43]
ii. Renal elimination [Figure 43]

197
Q

Chloramphenicol - Pharmacokinetics:

Toxicity:

A

i. Aplastic anemia-irreversible; 1-30,000 but fatal 80% of the time.
ii. Grey baby syndrome-Historical Teaching point
a) Neonates can’t glucuronidate chloramphenicol which accumulates. [Figure 44] Inhibition of mitochondrial protein synthesis.
b) Abdominal distension, vomiting, pallid cyanosis –high mortality.

198
Q

MACROLIDES

Antibacterial Spectrum and Clinical Uses:

A

a) Bacteriostatic and some Bactericidal activity against mostly gram positive bacteria.
b) Effective against Mycoplasma pneumoniae, Legionnaire’s disease,Chlamydial infections,
other respiratory infections, pneumonias. c) Middle ear and sinus infections in children.

199
Q

MACROLIDES

Resistance:

A

a) 50S ribosome target modification—methylation
b) Enhanced efflux pump
c) Chromosomal mutations in 50S
d) Macrolide hydrolysis by esterases (Enterobacteriaceae)

200
Q

MACROLIDES

Pharmacokinetics: Absorption:

A

oral

i. Erythromycin is acid labile; give as enteric coated tablet.
ii. Clarithromycin is acid stable

201
Q

MACROLIDES

Pharmacokinetics absorption - Distribution:

A

i. rapid, extensive, accumulates in tissues—gets into the CNS.

202
Q

MACROLIDES

Pharmacokinetics absorption - Metabolism and Excretion:

A

i. Extensive liver metabolism; excretion in bile (Erythromycin, azithromycin); Clarithromycin eliminated by kidney

203
Q

Macrolides - Toxicity:

A

Fairly safe

i. mild G.I. upset, nausea, abdominal cramps. ii. Hypersensitivity: fever, rash.

204
Q

KETOLIDE

Mechanism:

A

Same as for Macrolides—binds to components of 50S ribosomal subunit.

205
Q

KETOLIDE

Antibacterial Spectrum and Clinical Uses:

a) Treatment of ——: Effective against gram positive and gram negative bacteria causative for community acquired pneumonia (CAP). Examples:Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae.
b) Effective against ——– since: 1) can still bind to 50S even when this target is altered resulting in macrolide binding alterations and macrolide resistance; 2) efflux pumps that impart macrolide resistance don’t affect Telithromycin.

A

respiratory tract infections

macrolide-resistant strains

206
Q

KETOLIDE

Pharmacokinetics: Absorption:

A

oral
Distribution:
i. rapid, extensive, accumulates in many tissues.

207
Q

KETOLIDE

Metabolism and Excretion:

A

i. Extensive liver metabolism; eliminated by kidney and in bile. ii. May interfere with metabolism of other drugs

208
Q

KETOLIDE

Toxicity:

A

Liver Toxicity revealed after-market

209
Q

CLINDAMYCIN

Antibacterial Spectrum and Clinical Uses:

A

a) Effective against Gram positive bacteria; staphylococci, streptococci (but not enterococci), and anaerobes. Notable activity against S. pyogenes (Group A strep).
b) Treatment of penicillin-resistant anaerobic infections, other infections insensitive to other antibacterials. Note: METRONIDAZOLE also for anaerobic infections (see above).
c) Topical treatment of acne in patients intolerant of tetracyclines.

210
Q

Clindamycin - Pharmacokinetics: Absorption:

A

good; oral.

211
Q

Clindamycin - Distribution:

A

penetrates most tissues, including bone.

212
Q

CLindamycin - Toxicity:

A

i. Hypersensitivity: rashes, diarrhea.
ii. Pseudomembranous colitis caused by toxin from C. difficile which is
resistant to Clindamycin. (toxicity in up to 10% of patients—can be severe). Can be life-threatening. If C. difficile then treat with Metronidazole.

213
Q

QUINOPRISTIN/DALFOPRISTIN

Antibacterial Spectrum and Clinical Use:
a) Effective mainly against —- organisms
b) Useful for —– Enterococcus faecium (VRE-type). Also, effective
against MRSA-type resistance.
c) Individually these drugs are —– but when used together they are —–.
Conformational changes in ribosomes induced by dalfopristin increases binding affinity for quinipristin: Bind to distinct but closely related sites on the 50S ribosomal subunit of bacteria.
Pharmacokinetics:
a) —- only
b) Toxicities include ——- (muscle pain); also nausea/vomiting

A

gram positive

Vancomycin-resistant

bacteriostatic

bactericidal

IV

phlebitis and myalgias

214
Q

LINEZOLID

Antibacterial Spectrum and Clinical Uses:
a) Broad activity against —- isolates (staphylococcus, streptococcus, enterococcus). Poor activity against —–
b) FDA approved for use against —— Enterococcus faecium; also effective against MRSA infections. Recent reports of resistance in VRE, MRSA strains].
Pharmacokinetics:
a) —— forms available
b) Toxicities: some mild ——- (hematological side effect); increasing reports
of peripheral and optic neuropathies especially with therapy beyond 4 weeks; thrombocytopenia; serotonin syndrome when used in combination with serotonin reuptake inhibitors.

A

gram positive

gram negative organisms and anaerobes

Vancomycin-resistant

IV and oral

myelosupression

215
Q

MUPIROCIN –Natural product mono-carboxylic acid Mechanism: Inhibits

A

isoleucyl tRNA synthetase;

bacteriostaticbactericidal

216
Q

MUPIROCIN

Antibacterial Spectrum and Clinical Uses:
a) Topical mainly for —– and some —– bacteria. b) Skin infections including

A

Gram positive

gram negative

MRSA; nasal decolonization

217
Q

Fungi differ from bacteria in that they are

A

eukaryotes, have 80S ribosomes compared to bacterial 70S ribosomes. Therefore, many antibacterial agents are ineffective.

  1. Fungi are slow growing, much larger than bacteria.
  2. Fungi have rigid cell wall (chitin/glucans) instead of mucopeptide cell walls in bacteria.
218
Q

Fungi contain —– instead of cholesterol (mammalian) in cell membranes. Basis of selective action of Polyenes, Azoles.

A

ergosterol

219
Q

Fungal infections occur in ——- tissues, or in skin, nails, hair. Difficult to treat since antifungal agents are ——-. Therefore, drugs are not distributed, retained well.

A

poorly vascularized

poorly soluble

220
Q

Fungi cause ——– (antigens, polysaccharides);

A

cellular immune response

221
Q

granulomatous reaction–may interfere with ——-In general, short term low toxicity therapy for bacteria; long term thus —— therapy for fungi.

A

drug penetration.

higher toxicity

222
Q

Griseofulvin—

A

Mitosis Inhibitor

223
Q

5-Flucytosine—

A

DNA/RNA Synthesis Inhibitor

224
Q
  1. Cell Membrane Disruption:
A

Ergosterol Binding: Amphotericin B, Nystatin, Natamycin

225
Q

Imidazoles:Triazoles:

A

14α-sterol Demethylase Inhibitors

226
Q

Allylamines,Benzylamines:

A

Squalene Epoxidase Inhibitors

227
Q

Cell Wall Synthesis:

A

ß-(1,3)-Glucan synthase Inhibitors

228
Q
  1. Protein Synthesis: ——– synthetase Inhibitor
A

Leucyl-tRNA

229
Q

Potassium Iodide–only for

A

mucocutaneous sporotrichosis

230
Q

POtassium iodide - —— administration. Readily absorbed from G.I. Distributed in extracellular fluids. Excretion by kidney. Toxicity is acne, nausea, diarrhea.

A

Oral

231
Q

GRISEOFULVIN

Antibiotic produced by

A

Penicillium griseofulvin. Fungistatic; can be fungicidal.

232
Q

GRISEOFULVIN

——- inhibitor. Binds to tubulin dimers and prevents polymerization into ——; metaphase arrest. In addition, disruption in cytoplasmic microtubules leads to abnormal ——— of treated organisms.

A

Mitotic

microtubules

shape function

233
Q

Griseofulvin is avidly taken up into —— or precursor cells. Therefore, these tissues (stratum corneum, and outer epidermis) become resistant to ——

A

keratinocytes

fungal infection.

234
Q

Griseofulvin is taken up into fungi by an ——- mechanism. Resistance, though rare, is proposed to be related to decrease ——-

A

energy dependent

transport into cells.

235
Q

GRISEOFULVIN e) Absorption:

A

Orally Poor; improved G.I. absorption when taken along with fatty meal. Peak serum level in 4 hr.

236
Q

Griseofulvin - f) Distribution:

A

Keratinocytes

237
Q

Griseofulvin - g) Metabolism, Excretion:

A

Liver demethylation, glucuronidation. 99% out in feces.

238
Q

Griseofulvin - h) Toxicity:

A

Well tolerated but during long-term patients can experience: headaches, memory lapse, skin rashes, photosensitivity reactions, porphyria. Possibly teratogenic, carcinogenic.

239
Q

FLUOROCYTOSINE

Synthetic analog of —- (1957). First tested as —– agent.

A

cytosine

anticancer

240
Q

FLUOROCYTOSINE

—–. Effective against Candida, Cryptococcus, Aspergillus. Effective in combination with Amphotericin B to treat ——-. Combination also with Azoles. Prophylactic in AIDS.

A

Fungicidal and fungistatic

cryptococcal meningitis

241
Q

FLUOROCYTOSINE

Mechanism of Action:

A

Transported into cells by cytosine permease. Cytosine deaminase action to form 5-FU; anabolism to form 5-FdUMP (FUdRMP) and/or 5-FUTP (FURTP) resulting in inhibition of thymidylate synthesis and/or incorporation into RNA respectively (see Figure 2). Inhibition/alteration of DNA/RNA synthesis

242
Q

FLUOROCYTOSINE

Absorption, Distribution:

A

Well absorbed orally; peak serum level 4-6 hr; half-life 3-5 hr. Wide distribution. Low protein binding, crosses into CNS. Therefore, good for treatment of cryptococcal meningitis.

243
Q

FLUOROCYTOSINE

Metabolism, Excretion:

A

Not metabolized; glomerular filtration; 90% out unchanged in urine.

244
Q

FLUOROCYTOSINE

Toxicity:

A

Similar to 5-FU; bone marrow depression (BMD), neutropenia, thrombocytopenia. Careful with AIDS patients on AZT.

245
Q

FLUOROCYTOSINE

Drug Resistance:

A

Incidence with 5-FC is very high. Transport alterations, cytosine deaminase alterations, anabolic enzymes altered.
Combination chemotherapy with Amphotericin B.
rate of emergence of resistance to 5-FC is less.
Synergy; increased accumulation of 5-FC through membrane holes created by Amphotericin B
decrease Ampotericin B dosage and toxicity.

246
Q

AMPHOTERICIN B

Mechanism of Action:

A

Fungicidal: Interaction with membrane sterols (Figure 8) to form pore/alter membrane fluidity. Amphotericin B binding to ergosterol in fungal cell membranes can cause a loss of K+, alteration in membrane associated Na/K ATPase activity, loss of selective membrane permeability, inhibition of amino acid uptake.

247
Q

AMPHOTERICIN B

Selectivity of Amphotericin B for fungi is due to >100-fold lower binding affinity for human —–. Bacteria membranes do not contain —-. Ampho B is not active against bacteria (exception is Mycoplasma which do contain sterols).

A

cholesterol

sterols

248
Q

AMPHOTERICIN B

Clinical Use: First, best choice for treating

A

systemic fungal infections: Candidiasis, histoplasmosis, Coccidiomycosis, Blastomycosis, aspergillus, cryptococcoses.

249
Q

AMPHOTERICIN B

Absorption, Distribution:

A

Usually given I.V. or topically due to low
solubility, poor GI absorption. Poor distribution to CNS. (Figure 9) Infusion over several hours; slowly. Avoids cardiac arrhythmias,
ventricular fibrillation.
Rapidly sequestered in tissues; slowly released. Initial half life is 24 hr. Second phase half-life of 15 days.

250
Q

AMPHOTERICIN B

Metabolism, Excretion:

A

Not metabolized. Ampho B is 90% protein bound. Slow renal excretion (5%/day). Major excretion extra-renal.

251
Q

AMPHOTERICIN B

T oxicity:

A

i. Nephrotoxicity: Dose-related reversible; Total dose related irreversible (Calcium phosphate precipitation in tubules). Follow BUN, creatinine; interrupt therapy if signs of renal impairment. Can use mannitol infusion to maintain urine flow.
1) Hypokalemia, hypomagnesemia, tubular acidosis
2) Glomerular damage-hyalinization, wall thickening; hypersensitivity reaction.
3) Renal tubule degeneration
4) Sodium loading can prevent limit some Ampho B-related renal damage.

252
Q

AMPHOTERICIN B

Drug Interactions

A

i. Rifampin plus Amphotericin B . Rifampicin not normally toxic to fungi since can’t enter cells. In presence of Amphotericin B, Rifampicin cytotoxicity is increased (Figure 10).
ii. 5-FC plus Amphotericin B for Cryptococcal meningitis.
iii. Synergism or Additivity with Ampho B+Triazoles.

253
Q

AMPHOTERICIN B

Drug Resistance
i.

A

Resistance is rare. Alteration of sterol content, or change in sterol composition so less binding of Amphotericin B. (Candida, Cryptococcus).

254
Q

AMPHOTERICIN B

Fungizone:

A

Amphotericin B/bile salt (deoxycholate) formulation for better dissolution.

255
Q

Amphotericin B - Liposomal Ampho B and Amphotericin B lipid complex (ABLC)
allow for

A

increase in therapeutic concentrations in specific organs such as liver, lungs. May allow reduction in toxicity; decrease in time required for treatment.

256
Q

Amphotericin B - Sterol complex with Ampho B can decrease

A

vein necrosis at site of injection.

257
Q

NYSTATIN

Specific topical treatment for

A

candidiasis; thrush, esophaginitis, vaginitis.

258
Q

NYSTATIN

c) Absorption, Distribution:

A

Poor oral absorption, breaks down rapidly. Restricted to GI distribution

259
Q

NYSTATIN

d) Metabolism, Excretion:

A

Neglible metabolism, slight kidney excretion.

260
Q

NYSTATIN

e) T oxicity: .

A

minimal

261
Q

AZOLES

A

Largest Class of antifungals

262
Q

AZOLES

Broad spectrum, fungistatic at low

A

concentrations, fungicidal at

higher concentrations.

263
Q

AZOLES

b) Mechanism of Action:

A

Bind through ring nitrogen (N-3 or N-4) to heme of cytochrome P450 (CYP51) and inhibit the lanosterol C14-demethylase system. Figure 14. Interfere with ergosterol synthesis. Associated with Fungistatic activity.

264
Q

AZOLES

Note: Selectivity:

A

100-fold greater binding affinity to fungal cell lanosterol C14-demethylase compared to mammalian enzyme. Triazoles have greater specificity compared to imidazoles.
i. Alterations of fatty acid metabolism
ii. Accumulation of toxic peroxides, inhibition of respiration
iii. Alteration of membrane Na+/K+ ATPase; as membrane fluidity,
integrity is changed.
Note: These effects (i.-iii.) associated with Fungicidal activity.

265
Q

AZOLES

c) Drug-drug interactions:

A

Inhibitors/substrates of liver P450 enzymes. PK effects; cardiovascular effects

266
Q

Azoles - d) Resistance:

A

Overproduction/mutation in C14-demethylase; drug effux

267
Q

KETOCONAZOLE

Limited clinical use:

A

supplanted by itraconazole (triazole) systemically based on spectrum of activity, PK properties, adverse effects.
Topical; First Oral Antifungal: dermatophyte, mucosal, some systemic infections.
i. mucocutaneous candidiasis
ii. candidiasis of mouth, esophagus, vagina
iii. systemic candidiasisvariable effectiveness

268
Q

KETOCONAZOLE

b) Absorption, Distribution:

A

i. Variable absorption orally, pH dependent; requires low pH in
stomachanti-acids interfere with absorption.

269
Q

KETOCONAZOLE

c) Metabolism, Excretion:

A

P450 liver metabolism; inactive metabolites

excreted in bile, small amount in urine. 90% protein bound.

270
Q

KETOCONAZOLE

d) Toxicity:

A

GI, NV; hepatotoxicity, anti-androgenic effects; gynecomastia.

271
Q

CLOTRIMAZOLE

A

Oral, skin, vaginal infections

272
Q

CLOTRIMAZOLE

b) T opical:

A

Dermatophytes, Candidiasis

273
Q

CLOTRIMAZOLE

c) T oxicity:

A

Induces liver enzymes

274
Q

MICONAZOLE

T opical:

A

Dermatophytes

275
Q

MICONAZOLE

c) Toxicity:

A

Itching, burning, cramps, headache

276
Q

FLUCONAZOLE

Oral treatment of

A

dermatomycoses, oropharyngeal and vaginal

candidiasis.

277
Q

FLUCONAZOLE

b) Treatment and prophylaxis of

A

cryptococcal (meningitis) esp. AIDS patients. Allows outpatient treatment.

278
Q

FLUCONAZOLE

c) Absorption, Distribution:

A

Good, high serum concentrations achieved (oralpH independent and IV). Penetrates meninges (inflamed)60-80% CSF level compared to serum. Low protein binding, wide distribution.

279
Q

FLUCONAZOLE

d) Metabolism, Excretion:

A

Excreted unchanged in urine and feces.

280
Q

FLUCONAZOLE

e) Toxicity:

A

Minor, low incidence of GI upset, nausea, elevation of hepatic enzymes.

281
Q

FLUCONAZOLE

f) Resistance:

A

altered demethylase enzyme; increased efflux.

282
Q

ITRACONAZOLE

Oral and IV:

A

treatment of histoplasmosis, blastocycosis, aspergillosis. Broader spectrum of activity compared to ketoconazole.

283
Q

ITRACONAZOLE

b) Absorption, Distribution:

A

low pH in stomach required; does not cross blood brain barrier efficiently.

284
Q

ITRACONAZOLE

c) Metabolism, Excretion:

A

Liver metabolism, bile excretion.

285
Q

ITRACONAZOLE

d) Toxicity:

A

Hepatotoxicity, GI distress

286
Q

ITRACONAZOLE

e) Drug-drug interactions:

A

Substrate/inhibitor of P450s; multiple interactions

287
Q

VORICONAZOLE

Oral and IV:

A

treatment of invasive aspergillosis, other systemic fungal

infections.

288
Q

VORICONAZOLE

b) Absorption, Distribution:

A

Oral—pH independent like with fluconazole; does cross BBB-into CNS.

289
Q

VORICONAZOLE

c) Metabolism, Excretion:

A

Liver metabolism, urinary excretion of metabolites

290
Q

VORICONAZOLE

d) Toxicity:

A

Hepatotoxicity, visual hallucinations (transient)

291
Q

VORICONAZOLE

e) Drug-drug interactions:

A

Substrate/inhibitor of P450s; multiple interactions.

292
Q

POSACONAZOLE

Oral and IV:

A

Broad spectrumaspergillosis, candidiasis other infections

293
Q

POSACONAZOLE

b) Inhibits

A

C14-demethylase isoforms CYP1A and CYP51B in Aspergillus

294
Q

POSACONAZOLE

c) Fewer interactions with

A

P450s and hence fewer drug-drug interactions.

295
Q

POSACONAZOLE

d) Toxicity:

A

Hepatotoxicity, thrombocytopenia

296
Q

EFINACONAZOLE

Topical for

A

onchomycosis (nail and nail bed)

297
Q

EFINACONAZOLE

b) Inhibits

A

C14-demethylase

298
Q

EFINACONAZOLE

c) T oxicity:

A

application site dermatitis

299
Q

ALLYLAMINES

Treatment of

A

skin and nail infections. Tolnaftate also (thiocarbamate). Synthetic compounds that inhibit 1st step in ergosterol synthesis (Fig. 14).

300
Q

ALLYLAMINES

Accumulation of squalene is

A

fungicidal (as a result of epoxidase inhibition).

301
Q

ALLYLAMINES

Selectivity:

A

Host Squalene epoxidase much less affected.

Topical use for dermatophytes. Terbinafine available for oral dosing.

302
Q

ALLYLAMINES

Terbinafine:

A

90 day treatment; potential liver toxicity (LFT testing required).

303
Q

ECHINOCANDINSCASPOFUNGIN (2001), MICAFUNGIN (2005),

CELL WALL:

A

INHIBITION OF ß-GLUCAN SYNTHASE ANIDUFUNGIN

304
Q

ECHINOCANDINSCASPOFUNGIN (2001), MICAFUNGIN

Development of these semisynthetic lipopeptides initiated because of need to

A

better treat systemic fungal infections especially in light of emerging resistance to Amphotericin B, Triazoles, and 5-FC.

305
Q

ECHINOCANDINSCASPOFUNGIN (2001), MICAFUNGIN

b) Clinical Activity:

A

Systemic candidiasis, aspergillosis, antifungal prophylaxis in bone marrow transplants.

306
Q

ECHINOCANDINSCASPOFUNGIN (2001), MICAFUNGIN

c) Mechanism:

A

Osmotic lysis due to loss of cell wall integrity (inhibiton of ß(1,3)-glucan synthase (Figure 18).

307
Q

ECHINOCANDINSCASPOFUNGIN (2001), MICAFUNGIN

d) Absorption,Distribution:

A

IV only; poor CNS penetration; highly protein bound.

308
Q

ECHINOCANDINSCASPOFUNGIN (2001), MICAFUNGIN

e) Metabolism/Excretion:

A

Livercleavage of peptide bonds, slow excretion in bile and urine.

309
Q

ECHINOCANDINSCASPOFUNGIN (2001), MICAFUNGIN

f) Toxicity:

A

Well tolerated; some fevers, allergic histamine release.

310
Q

ECHINOCANDINSCASPOFUNGIN (2001), MICAFUNGIN

g) Drug-drug Interactions:

A

minimal due to weak P450 interactions.

311
Q

TAVABOROLEInhibition of

A

Leucyl-tRNA synthetase

312
Q

TAVABOROLE

a) Mechanism:

A

Inhibits ability of Leucyl-tRNA to be attached to leucine. Tavaborole forms a covalent adduct (through the boron atom) with the tRNA for leucine in complex with the leucyl-tRNA synthetase enzyme. Protein synthesis is inhibited since amino-acyl tRNA for leucine is not formed.

313
Q

TAVABOROLE

b) Specificity:

A

Mammalian enzyme has different structure than fungal enzyme at a critical amino acid recognition or “editing” site.

314
Q

TAVABOROLE

c) Clinical Activity:

A

Topical for onychomycosis of nails in 10% formulation along with ciclopirox. Good nail penetration.

315
Q

TAVABOROLE

d) Toxicity:

A

None noted.

Pharmacology (19 decks)

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