Pharm Flashcards
1
Q
Triple Sulfa
A
Properties:
- rapidly absorbed
- rapidly excreted
- short acting
Single dosage contains equal amounts of 3 different sulfa drugs
Reduces incidence of crystalluria
2
Q
Sulfisoxazole
A
Properties:
- highest urine solubility
- short acting
Most commonly used single sulfa
3
Q
Sulfamethoxazole
A
Properties:
- urine solubility less than sulfisoxazole
- intermediate acting
Usually administered as fix-ed ratio combination with trimethoprim
4
Q
Sulfacetamide
A
Properties:
- topical use for trachoma, 30% solutions have a pH of 7.4, which makes them non-irritating
5
Q
Silver sulfadiazine
A
Properties:
- topical use only
- elemental silver has antibacterial activity
Prophylaxis of burn patients, little or no pain
6
Q
Sulfasalazine
A
Properties:
- Split by intestinal flora to yield 5-amino-salicylate and sulfapyridine
- substitution on N1 nitrogen
Used in the treatment of ulcerative colitis and other inflammatory bowel disease, salicylate has therapeutic value
7
Q
Sulfadoxine and Pyrimethamine
A
Properties:
- rapidly absorbed
- ultra long half life (~9 days)
Used for Chloroquine-resistant falciparum malaria
High incidence of dermatitis reactions
8
Q
Sulfadiazine and Pyrimethamine
A
Properties:
- rapidly absorbed
- intermediate half life (18 hrs)
Used in treatment of toxoplasmosis
9
Q
Adverse effects of Sulfonamides
A
- drug allergy (rashes, eosinophilia, fever, Stevens-Johnson syndrome)
- renal toxicity (crystalluria)
- kernicterus (displacement of bilirubin from albumin)
- displace drugs from albumin binding sites and/or decrease clearance (oral anticoagulants, uricosuric agents, methotrexate)
- hemolytic anemia in individuals with G6PDH deficiency
10
Q
Therapeutic Uses of Sulfonamides
A
- UTI’s (E. coli)
- Nocardiosis
- Chlamydial infections, including trachoma
11
Q
Mechanism of action of sulfonamides
A
Competitive inhibitor of pteroate synthetase
reaction: pteridine + p-aminobenzoic acid (PABA) –> pteroic acid + glutamic acid
absolute selective toxicity
bacteriostatic
12
Q
Mechanism of action of trimethoprim/pyrimethamine
A
Competitive inhibitor of dihydrofolate reductase (DHFR)
reaction: dihydrofolate (DHF) –> tetrahydrofolate (THF)
absolute selective toxicity
bacteriostatic
Brand names: Bactrim, Septra
Generic form: cotrimoxazole
13
Q
Advantages of SMZ-TMP
A
- increased potency
- increased spectrum
- decreased incidence of resistance
14
Q
Therapeutic uses of SMZ-TMP
A
- UTI’s
- respiratory and ear infections (H. influenzae and Strep pneumo infections)
- Shigella and Salmonella
- Pneumocystic jiroveci pneumonia
- Toxoplasmosis and Plasmodial infections
15
Q
Adverse Effects of DHFR inhibitors (trimethoprim, pyrimethamine)
A
- crystalluria
- megaloblastic anemia (pregnancy, nutrition deficit, etc)
16
Q
Mechanism of action of fluoroquinolones
A
- inhibit bacterial DNA gyrase (topoisomerase II)
- inhibit topoisomerase IV in gram positive organisms
- bactericidal
- relatively selectively toxic
17
Q
Ciprofloxacin
A
Brand name: Cipro
Half life: 3-4 hrs
May interfere with metabolism of theophylline and warfarin
18
Q
Levofloxacin
A
Unlike other fluoroquinolones, widely distributes into tissues, bone, AND CNS
Half life: 5 hrs
ADR: QT prolongation
May interfere with metabolism of theophylline and warfarin
19
Q
Trovafloxacin
A
Not used anymore because of hepatic toxicity
20
Q
Structural features of fluoroquinolones
A
- Fluoride on C6 - confers resistance
- Halogen on C8 leads to phototoxicity
21
Q
Resistance mechanisms against fluoroquinolones
A
- point mutation of the A subunit of DNA gyrase, decreasing affinity of drug for gyrase
- efflux pump (Staph aureus, Pseudomonas aeruginosa, Mycobacteria)
22
Q
Pharmacokinetics of fluoroquinolones
A
- orally active
- widely distributed into tissues, including bone; but not CNS except for Levofloxacin
- elimination: primarily renal, of which 20% are metabolites. exception: Moxifloxacin (feces)
23
Q
Moxifloxacin
A
Unlike other fluoroquinolones, non-renal elimination. Eliminating is through feces.
Half life: 10 hrs
ADR: QT prolongation
Can target anaerobic organisms
24
Q
Adverse effects of fluoroquinolones
A
GI (nausea, abdominal discomfort, vomiting, diarrhea)
CNS (headache, dizziness, agitation, insomnia, rarely seizures)
Allergy (rash, pruritis)
Photosensitivity
Anthropathy (damage to cartilage of weight bearing bones in adults)
Tendinitis (with concomitant steroid use)
Crystalluria (particularly at alkaline pH)
QT prolongation (risk for arrhythmias)
25
Drug Interactions of fluoroquinolones
- actacids and mineral supplements reduce oral absorption
- chelates with di and trivalent ions like magnesium, aluminum, zinc, iron. Sucralfate, a sugar derivative, contains alumni ions.
- Ciprofloxacin and Levofloxacin may interfere with metabolism of theophylline and warfarin
26
Therapeutic uses of fluoroquinolones
Urinary tract: E. coli, K. pneumoniae, Proteus, Pseudomonas aeruginosa
Prostatitis
STD's: N. gonorrhea
GI: Shigella, Salmonella, coliform infections
Resp: H. influenzae, CF, TB, anthrax
Bone/joints
Anaerobic organisms - Moxifloxacin
27
Methenamine
- urinary tract disinfectant
- spontaneously decomposes into ammonium and formaldehyde when placed in acidic water solution (must maintain urinary pH at 5.5 or less)
- safe because rate of dissociation is slow
- formaldehyde denatures proteins on the outside of an organism
28
Adverse reactions of Methenamine
- GI upset
- bladder irritation
- contraindicated in hepatic insufficiency because of ammonia production
- organic acids contraindicated in renal insufficiency because of crystalluria
- drug interaction with sulfas - formaldehyde reacts with sulfa, producing insoluble product
29
Nitrofurantoin
- Bacteriostatic against E. coli
- Rapidly excreted (half-life = 20-60 min)
- Resistance rarely develops
- Oral
- Okay to use in pregnancy
30
Nitrofurantoin adverse reactions
- NVD
- allergy (fever, chills, allergic pneumonitis in the elderly)
- neurological (vertigo, headache, nystagmus; high dose - polyneuropathy of motor and sensory nerves)
- hemolytic anemia in G6PDH deficient individuals
- colors urine brown
31
Phenazopyridine
Urinary tract analgesic, not antimicrobial
Given in early treatment of UTI
Alleviates dysuria, frequency, urgency, and burning
Colors urine orange-red
32
Mechanism of action of fosfomycin
Inhibits phosphoenolpyruvate transferase, important in muramic acid monomer synthesis for the peptidoglycan cell wall
reaction: NAG + phosphoenolpyruvate --> NAM
33
Fosfomycin
- rapidly absorbed from GI tract and excreted unchanged, achieving high concentrations in the urine
- approved for single dose therapy for uncomplicated UTI
- diarrhea = most common side effect
- no effect on fetus if given to pregnant woman
- expensive
34
Cephalosporin Structure
- Structure: 6 membered ring instead of 5
35
Carbapenem Structure (Imipenem, Meropenem, Doripenem, Ertapenem)
- Structure: Sulfur is no longer part of ring structure, it is outside of it
36
Monobactam Structure (Aztreonam)
- Structure: only one beta-lactam ring --> limited use
37
Mechanism of beta-lactam
- irreversibly inhibits the crosslinking of peptidoglycans (mimics D-ala-D-ala) in bacterial cell walls
- competitive inhibitor
- absolute selective toxicity
- bactericidal (osmotic pressure)
- requires growing culture
- activates autolysins in some organisms
bacteria are most vulnerable when undergoing cell division; they use autolysins to open cell wall and reseal during division. beta-lactam exploits this, contributing to bactericidal activity.
38
Mechanisms of resistance to beta-lactams
- beta-lactamase (chromosomal or plasmid) which breaks the beta-lactam ring, rendering drug inactive
- reduced binding to Penicillin binding proteins (MRSA)
- down-regulation of porins, leading to decreased access to gram negative organisms
- increased efflux pumps found in some gram negative organisms
39
Types of Penicillins
1. Penicillin G (parenteral) and Penicillin V (oral) - broad spectrum on gram positive organisms such as: meningococci, penicillin-susceptible pneumococci, streptococci, non-beta-lactamase producing staph, syphillis, clostridia, actinomyces
2. Acid-stable or Antistaphylococcal penicillins such as methicillin (not used anymore), oxacillin (IV), nafcillin (IV), cloxicillin, dicloxacillin (oral), and isoxazolyl penicillins aka flucloxacillin - act on gram positive penicillinase producing Staph aureas.
3. Extended-spectrum penicillins such as Amoxicillin (oral) and Ampicillin (IV) - act on both gram positive and negative bacteria such as Proteus marbles, H influenza, E. coli, Listeria monocytogenes, Salmonella, Shigella, Enterococcus faecalis
4. Antipseudomonal or ureido penicillins such as Piperacillin - act on gram negative bacteria such as Pseudomonas aeruginosa, Klebsiella app, Serrate marcescens
40
Penicillin G
```
Penicillin G/V:
broad spectrum on gram positive organisms such as: meningococci
penicillin-susceptible pneumococci
streptococci
non-beta-lactamase producing staph
syphillis
clostridia (Clostridium perfringens)
N. gonorrheae
actinomyces
bacillus anthracis
cornyebacterium diptheriae
```
41
Ampicillin
Orally active
Gram pos: Listeria monocytogenes
Gram neg: E. coli, H. influenzae, Proteus mirabilis, Salmonella typhi
42
Antipseudomonal penicillins such as Carbenicillin, Ticarcillin, Piperacillin
Gram neg: Enterbacter sp, E. coli, Proteus, H. influenza, Pseudomonas aeruginosa
43
Pharmacokinetics of beta-lactams
- Distributes well
- Time-dependent killing: requires around the clock dosing, making sure plasma levels are >MIC for at least 70% of every 24 hours
- Excreted unchanged by glomerular filtration and active secretion into tubular fluid
- Short half-lives (0.5 to 1 hr)
- Penetrates into CNS only in bacterial meningitis (inflamed meninges are more permeable to penicillin, permitting rapid penetration of the drug into the CSF. However, meninges heal rather quickly and if penicillin is given late, less penicillin will enter the CNS, some organisms will remain, and leave the patient vulnerable to reinfection
Orally active: Penicillin V, Amoxicillin, Isoxozolyl
IV only: Piperacillin, Penicillin G, Methicillin, Ampicillin
44
Adverse Effects of Penicillins
- Generally safe
- Most serious adverse effect are hypersensitivities (allergies). Penicillin cross reacts with other beta lactamases so if patient as anaphylactic reaction to penicillin, do not give another beta-lactam
- Ampicillin use can produce a maculopapular rash that is NOT allergic
- Methicillin use can induce nephritis
- Neurotoxicity may provoke seizures in high concentrations (interfere with GABA receptor)
- Diarrhea may result due to disruption of normal balance of intestinal flora
- Ticarcillin use may result in decreased platelet aggregation
- Augmentin (amoxicillin and clavulanic acid) may result in a false positive for urinary glucose
- Cation toxicity (sodium is formulated with the actual penicillin molecule during drug development) - ampicillin, ticarcillin, piperacillin
45
Adjunct medications to beta-lactams
- Probenecid (inhibits renal tubular secretion of penicillins)
- Beta lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam. NOT antibacterial, only inhibits beta lactase
46
Cephalosporins
3rd generation are generally more resistant to beta lactamases than penicillins are
47
Adverse effects of Cephalosporins
Similar to penicillin: generally safe except occasional hypersensitivity reaction
Unique:
- Cefamandole and Cefoperazone can create a Disulfiram-like effect when taken with alcohol (vomiting, cardiac changes, nausea, etc)
- They can also create risk of hypoprothrombinemia (deficiency of prothrombin, which results in impaired blood clotting, leading to increased risk for bleeding)
48
First generation cephalosporin
Spectrum aimed mostly at gram positive bacteria like pen G
Cafazolin used to treat bone infections and prophylactically at a one time dose before surgery to prevent skin infection
49
Second generation cephalosporin
Similar to first generation (gram positive bacteria), but broader spectrum to include H. influenza, E. coli, Neisseria spp
Cefoxitia - for mixed infections containing both gram neg and pos bacteria
50
Third generation cephalosporin
Given parenterally
Very effective against gram neg (Neisseria spp, H. influenza), somewhat effective against gram pos BUT NOT LISTERIA (Listeria = ampicillin)
Also effective as empiric therapy of sepsis of unknown origin in both immunocompetent and immunocompromised hosts
Ceftriaxone - gets into CNS very well, relatively long half life (~7 hrs), parenterally
Ceftazidime - antipseudomonal
51
Fourth generation cephalosporin
Wide spectrum against both gram pos and neg, used first for treatment of septicemia or treatment of infection for immunosuppressed until diagnosis can be made
Cefepime - antipseudomonal
52
Carbapenems
Imipenem, Meropenem
Wide spectrum: gram pos/neg, aerobic/anaerobic, cocci/bacilli
Given parenterally only
Penetrates fluids well, including CSF in the absence of meningitis
Adverse effects: NVD, skin rashes, infusion site reactions; Imipenem is convulsant at high doses
53
Therapeutic uses of Carbapenems
- treatment of hospital-acquired resistant infections
- mono therapy for septicemia, respiratory tract infections, GU tract infections
- given to patients who cannot tolerate cephalosporins
- Meropenem is used to treat bacterial meningitis
54
Monobactam
Aztreonam
Spectrum is like aminoglycosides: gram negative aerobic bacteria
Given IM or IV
Filtered and secreted by the kidney, enters the CNS without inflammation
Injection site reactions ex) pain
Used as an alternative to aminoglycosides, penicillins, and cephalosporins
55
Vancomycin
- large tricyclic glycopeptide
- effective against gram pos bacteria only: MRSA, MRSE, strep pneumo, strep viridians, enterococcus, clostridium, listeria monocytogenes
56
Mechanism of action of Vancomycin
physically binds to the D-ala-D-ala on NAM and NAG --> inhibits cell wall synthesis
bactericidal
57
Vancomycin resistance
Bacteria can acquire vancomycin resistance by acquiring 9 genes on a transposable element present on a plasmid. Bacteria with this plasmid can change D-ala-D-ala to D-ala-D-lactate. Therefore, vancomycin can't bind.
58
Pharmacokinetics of Vancomycin
- must be administered parenterally (large molecular weight, highly charged)
- distributes well into pleural, pericardial, synovial, and ascitic fluids
- does not enter CNS unless there is inflammation - may require intrathecal administration
- filtered unchanged in the urine (not secreted)
59
Adverse effects of Vancomycin
- must administer slowly because it causes release of histamine, causing hypotension and erythema of face and upper trunk (usually give anti-histamine as pre-treatment to minimize this problem) --> Red Man Syndrome
- phlebitis
- ototoxic
- nephrotoxic
60
Therapeutic uses of Vancomycin
- MRSA causing sepsis or endocarditis
- vancomycin + gentamicin for enterococcal endocarditis in patient with serious penicillin allergy
- vancomycin + cefotaxime, ceftriaxone, or rifampin for highly penicillin-resistant pneumococcal meningitis
- resistant strains of Enterococcus faecalis and faecium have emerged
- no longer drug of choice for C. difficile pseudomembranous colitis - oral vancomycin used to be given but fear of developing resistance --> use metronidazole now
61
Macrolides
Erythromycin, Clarithromycin, Azithromycin
62
Mechanism of action of Macrolides
2 effects:
- bind reversibly to the P site on the 50S ribosomal subunit, causes the dissociation of the peptide t-RNA from the ribosome
- inhibits the translocation step: movement of peptide t-RNA from the acceptor to the donor site
63
Macrolide resistance
- decreased affinity of binding site because of methylation of adenine nucleotide in ribosomal RNA
- decreased penetration or increased efflux
- enzymatic inactivation of macrolide by an esterase
64
Spectrum of Macrolides
Erythromycin:
- gram positives (strep, staph, corynebacteria)
- intracellular organisms (mycoplasma, legionella, chlamydia spp, mycobacteria)
- syphillis for patients allergic to pen G
Clarithromycin: similar to erythromycin and active against H. influenza
Azithromycin: less active against strep and staph
- preferred treatment for Chlamydia trachoma's - single dose of 1 gram
65
Pharmacokinetics of Macrolides
- well absorbed orally
- given as esters or in enteric coated tablet to protect against stomach acid
- well distributed with high intracellular concentrations (azithromycin is the highest)
- does not penetrate CNS
66
Metabolism and Excretion of Macrolides
Erythromycin: extensively metabolized by CYP 450 dependent enzymes
Clarithromycin: has an active metabolite, 14-hydroxyclarithromycin
Excreted in urine and bile - biliary excretion is more important because Macrolide molecules are rather large
67
Adverse Effects of Macrolides
Erythromycin:
- epigastric distress (stimulates gastric motilin receptor)
- cholestatic jaundice
- ototoxicity at high doses
- drug interactions - inhibits the metabolism of many drugs like warfarin, cyclosporine, theophylline, digoxin
Clarithromycin: similar to erythromycin
Azithromycin - does not inhibit P450 dependent drug metabolism, mostly secreted in the bile
68
Clindamycin
Not too different from macrolides, just different in structure
Lincosamidine antibiotic
Binds to 50S ribosomal subunit and interferes with translocation
Bacteriostatic
69
Clindamycin resistance
- decreased penetrability
- decreased affinity to binding site of 50S subunit because of methylation of adenine nucleotide in ribosomal RNA
- enzymatic inactivation by an O-nucleotidyl transferase (seen in Staph aureus)
70
Clindamycin spectrum
- Strep
- Anaerobes like Bacteroides, oral anaerobes
- Toxoplasmosis in combination with pyrimethamine
- Topically for rosacea and acne
71
Pharmacokinetics of Clindamycin
- 90% bioavailability
- distributed well into the bone and body fluids, except CNS
- accumulates in macrophages and leukocytes
- crosses the placenta
- over 90% hepatic metabolism via oxidative demethylation to an active metabolite
- biliary excretion
72
Therapeutic uses of Clindamycin
- refractory bone infections
- treatment of anaerobic infections of female GU, pelvic infections, abdominal penetrating wounds
- as a substitute for amoxicillin or penicillin V for acute orofacial infections in situations where the organisms are penicillinase producing
- alternative to penicillin-sensitive patients requiring prophylaxis to prevent endocarditis
73
Adverse effects of Clindamycin
- NVD
- hypersensitivity - rashes/fever
- risk of C. diff
- Neuromuscular junction blockage at high IV doses (inhibits transmission and contraction)
74
Streptogramins and Oxazolidinones
Protein synthesis inhibitors reserved for serious life-threatening infections
--
Group A Streptogramins = macrolactones ex) dalfopristin
Group B Streptogramins = hexadepsipeptides ex) quinupristin
--
Oxazolidinone: Linezolid
75
Quinupristin/Dalfopristin
Always given together. Brand name= Synercid.
76
Mechanism of action of Quinupristin/Dalfopristin
Bind to 50S ribosomal subunit
Together, bactericidal. Separately, bacteriostatic.
Dalfopristin (Group A Streptogramins) inactivates donor and acceptor sites of peptidyltransferase, and induces a conformational change to increase the binding of Quinupristin (Group B Streptogramins) synergy!
Quinupristin prevents the translocation step
77
Quinupristin/Dalfopristin Resistance
- methylation of 23S RNA binding site, prevents binding of quinupristin
- bacterial enzymatic inactivation; particularly dalfopristin
- increased efflux
78
Pharmacokinetics of Quinupristin/Dalfopristin
- must be given IV
- penetrates macrophages and PMNs
- undergoes extensive non-enzymatic conversion to non-active products (does not require P450)
- excretion: 80% bile, 20% urine
- short half lives:
Quinupristin 0.8 hr
Dalfopristin 0.7 hr
79
Adverse effects of Quinupristin/Dalfopristin
- Injection related: pain, inflammation, edema, reactions (incompatible with saline)
- NVD, headache, myalgia, arthralgia
- marked drug reactions because of CYP3A4 (ex) cyclosporine levels should be monitored)
80
Therapeutic use of Streptogramins
Treatment of vancomycin resistant Enterococcus faecium (NOT faecalis)
81
Mechanism of action of Linezolid
Binds to site on 50S subunit similar to chloramphenicol, prevents formation of 70S initiation complex
Resistant strains of S. aureus bind less antibiotic but there is no cross-resistance with other antibiotics
Bacteriostatic
82
Linezolid spectrum of action
Gram positive and anaerobic organisms (similar to vancomycin)
- approved for nosocomial pneumonia, community-acquired pneumonia, skin infections, vancomycin resistant enterococcal infections, MRSA
Has interactions with SSRI's - if taken together can cause serotonin syndrome
83
Tetracyclines
Structure: 4 fused six-membered unsaturated rings
84
Mechanism of action of Tetracyclines
- inhibits protein synthesis by binding to the 30S subunit: blocks access of the amino acyl-t-RNA to mRNA-ribosome complex at the acceptor site
- active uptake mechanisms by susceptible organisms imparts some selective toxicity
- greater affinity of non-host ribosomes since intracellular rickettsiae and chlamydiae are treatable
85
Spectrum of action of Tetracycline
- Broad: both bacteria and Rickettsia are susceptible
- intracellular diseases like Lymes Disease, Mycoplasma pneumonia, Chlamydia, cholera, Ricketssia rickettsia
- bacteriostatic
- similar spectrum to erythromycin - Mycoplasma pneumonia, Chlamydia app, Legionella spp, Ureaplasma, Rickettsiae
- treatment of acne vulgaris and rosacea
86
Tetracycline resistance
- resistance is widespread, transposable, and commonly permanent because multi-drug resistance gene cassettes exist
- most important: active efflux
- enzymatic inactivation
- decreased affinity of target
87
Pharmacokinetics of Tetracycline
- orally active - range from 30% bioavailability for chlortetracycline to 95% for doxycycline
- dairy products and ions chelate tetracyclines and produce a non-absorbable complex
- binds to tissues undergoing calcification like teeth and bones
- penetrates tissues well: high concentrations in the liver and the kidney
- crosses the placenta
- Minocycline has high concentration in tears and saliva , often given to carriers of meningococcus
88
Elimination of Tetracycline
- metabolized to varying extents, especially glucuronide formation
- all undergo enterohepatic circulation and renal excretion except doxycycline glucuronide, which is excreted in bile but does not get reabsorbed; goes out via feces
89
Adverse effects of Tetracycline
- GI distress
- deposition in bone and primary dentition during calcification --> contraindicated in children less than 8 y/o
- hepatotoxic in pregnant women
- phototoxicity
- vestibular disturbance with Minocycline
- Azotemia (abnormally high levels of nitrogen containing compounds like urea, creatinine, etc in the blood; related to insufficient filtering of blood by the kidneys) and Fanconi-like syndrome (disease of proximal renal tubules of the kidney in which glucose, aa, uric acid, phosphate, and bicarbonate are passed into the urine) with outdated preparations
90
Drug interactions with Tetracyclines
- antacids
- increased digoxin toxicity in 10% of patients
- increased Warfarin activity due in part to decreased intestinal flora which produce vitamin K
91
Mechanism of action of Chloramphenicol
- Works in a similar area as macrolides and clindamycin
- interferes with translocation and peptidation, which inhibits formation of the growing peptide chain
- REVERSIBLE binding to site
- NO2 group on benzene ring = very reactive, plays into chloramphenicol's adverse effects
92
Chloramphenicol resistance
- enzymatic conversion to an inactive product via acetylation
- decreased affinity --> cross resistance - changing the binding site so that chloramphenicol can't bind as well also makes the macrolides and clindamycin have decreased affinity for the 50S binding site
93
Spectrum of Chloramphenicol
similar to tetracyclines
- H influenzae
- acute typhoid fever
- Rickettsial infections (Rocky Mountain Spotted fever)
- anaerobic infections
94
Pharmacokinetics of Chloramphenicol
- orally active; can be given parenterally as well
- well distributed; can enter CNS in the absence of inflammation
- crosses the placenta
- extensive metabolism by the host - ultimate product is glucuronide
- excreted in urine
95
Adverse effects of chloramphenicol
- Hematological:
~hemolytic anemia in G6PDH deficiency
~reversible anemia, leukopenia, thrombocytopenia - dose related; occurs during therapy
~irreversible idiosyncratic aplastic anemia; probably allergic in origin ; no immediate solution --> why doctors in the US don't give this drug that much. Since it is allergic in origin, reaction depends on how many times you've been treated with chloramphenicol. The more exposure, the bigger the risk of developing aplastic anemia
- gray baby syndrome: decay of chloramphenicol in neonates is much slower than for older children --> exposure to high concentration for high amounts of time --> mitochondria can no longer utilize oxygen --> baby becomes blue gray, lethargic and does not thrive
- drug interactions because of CYP 450 inhibition: caution in patients on warfarin, phenytoin (anti-seizure med)
96
Therapeutic uses of Chloramphenicols
- anaerobic infections due to Bacteroides fragilis
- Typhoid fever and H. influenzae meningitis when first line therapy fails or cannot be employed
- pneumococcal or meningococcal meningitis in penicillin-allergic patients
- Rickettsial diseases as a substitute for tetracycline
97
Mechanism of Aminoglycosides
- binds to 30S subunit and prevents initiation of protein synthesis
- blocks further translation and causes premature termination
- causes misreading of mRNA codon
- entry across bacterial cell membrane occurs via an active transport system that requires oxygen
98
Aminoglycoside Resistance
- does not affect anaerobes by default (requires oxygen dependent transport system to get into bacterial cell membrane)
- decreased affinity at the 30S subunit binding site
- plasmid associated inactivating enzymes that can acetylate, adenylate, or phosphorylate the aminoglycoside
- -> resistance to one class of aminoglycosides does not necessarily confer resistance to all of them:
ex) There is only one acetylation enzyme that does not work very well at inactivating Kanamycin
ex) None of the acetylation, phosphorylation, or adenylation enzymes work well at inactivating Amikacin
99
Spectrum of Aminoglycoside
- Streptomycin - M. tuberculosis
- Gentamicin, Tobramycin, Amikacin - gram neg aerobic bacteria like Pseudomonas
- aminoglycosides are frequently combined with beta-lactams to treat serious, life threatening infections (synergistic - beta lactic increases the permeability of those organisms to aminoglycosides --> get higher amounts of aminoglycosides into the bacteria)
100
Pharmacokinetics of Aminoglycoside
- must be given parenterally
- dose-dependent killing: once a day dose is better than multiple doses throughout the day
- distribution is in the extracellular fluid; does not enter CSF
- crosses the placenta
- concentrated in the renal cortex and endolymph
- dependent on glomerular filtration for elimination; excreted unchanged; no secretion
- therapeutic monitoring
101
Adverse effects of Aminoglycosides
- ototoxicity - can cause problems in either cochlear or vestibular portions of CN 8
- fetal auditory toxicity (contraindicated in pregnancy)
- renal toxicity - not only are aminoglycosides dependent on renal fxn but they can impair it as well - need to monitor
- neuromuscular paralysis - can cause death from paralysis of diaphragm
102
Patient factors affecting dosing of aminoglycosides
- age: renal fxn decreases with age
- obesity: since the drug is water soluble and stays in the extracellular fluid, if you base dosage on weight, you might give incorrect dose since obese person has a lot of fat and a lower proportion of ECF
- renal function
- pregnancy: potential fetotoxic effects
- hepatic function: aminoglycosides are not metabolized so liver function does not have to be considered when dosing someone
