Renal System- Protein Synthesis Inhibitors By Boy Bridges

Front 1

Renal System- Protein Synthesis Inhibitors by Boy Bridges

Back 1

Renal System- Protein Synthesis Inhibitors by Boy Bridges

Front 2

Five Ways We Inhibit Bacteria

Back 2

1. Inhibition of bacterial cell wall synthesis
2. Anti-metabolite activity
3. Inhibition of bacterial protein synthesis
4. Alteration of bacterial cell membrane activity
5. Inhibition of bacterial nucleic acid synthesis

Front 3

What are the drugs that inhibit protein synthesis in prokaryotic and eukaryotic ribosomes?

Back 3

-Aminoglycosides
-Tetracyclines
-Macrolides
-Chloramphenicol

Front 4

What works on the 50s site?

Back 4

Chloramphenicol (C) and macrolides (M) bind to the 50S subunit and block transpeptidation (step 2)

Front 5

What works on the 30s site?

Back 5

The tetracyclines (T) bind to the 30S subunit and prevent binding of the incoming charged tRNA unit (step 1).
The misreading step.

Front 6

What are the Aminoglycosides (AGs)?

Back 6

Streptomycin
Gentamicin
Tobramycin
Amikacin
Neomycin

*acting at the 30S ribosome

Front 7

What do you use AGs against? Why is their use more limited now?

Back 7

key role in treating serious gram neg aerobic infections.

use now limited since AGs are TOXIC , and there are safer drugs available (3rd gen cephs, imipenem)

often used in combo with cell wall synth inhibitors (extended coverage and synergistic effects)

Front 8

Frequently used (in combo with a b-lactam) for serious infections due to:

Back 8

Proteus, Serratia,
Pseudomonas (a DOC), Enterobacter
Also used frequently (in combo) for
Invasive enterococcal infections (a DOC)
Serious staphylococcal infections
Other bugs …
Yersinia pestis, Francisella tularensis (a DOC)

Front 9

Which infections?

Back 9

-Septicemia
-Nosocomial respiratory tract infections
-Complicated UTIs
-Complicated intraabdominal infections
-Osteomyelitis

Front 10

MoA of AGs?

Back 10

Irreversibly binds to 30S ribosome
-interferes with formation of initiation complex (inhibits the ribosome coming together even before the synthesis of the polypeptide chain)
-causes misreading of mRNA
-restricts polysome formation
--Blocks ability to move along mRNA and synthesize new peptide chain

Bactericidal
-Concentration-dependent killing
-AGs have a long PAE

Front 11

AG uptake in G- bacteria

Back 11

-AGs diffuse via porin channelsacross outer membrane (OM)
-Crossing the inner membrane depends on active transport (O2-dependent)
-Membrane potential drivestransport (coupled to a proton pump)
-Transport essentially blocked by
--anaerobic environment
--low extracellular pH (eg lung and bronchial secretions)

Front 12

Aminoglycoside Drug Resistance, most important to know...

Back 12

Inactivation of drug by microbial enzymes
-aminoglycoside modifying enzymes (AME)
--phosphorylation, adenylation or acetylation

Most common mechanism
-Plasmid mediated (conjugation)

Especially a problem for enterococci
-Some are also b-lactam resistant and are vancomycin resistant

Front 13

Other mechanisms of drug resistance

Back 13

Failure to permeate bacteria
-Inability to pass through porins (minor)
-Inability to pass through plasma membranes
--innate resistance in anaerobes (O2 - dependent transport)

Ribosomal mutation (altered drug binding site)
-significant only for streptomycin

Front 14

AG kinetics

Back 14

Very polar compounds
-Large water soluble molecules
-Do not cross membranes very well
--Poor absorption from GI tract (must give parentarelly)
--Pretty much excluded from cells, CSF & eye
--Usually given parenterally ... unless local GI effect desired
--To get effective levels in CSF ... give intrathecally

Front 15

How are AGs eliminated?

Back 15

glomerulofiltration.
tend to concentrate in the kidney.

Front 16

In renal compromised patients ...

Back 16

-must adjust the dose / dosing frequency
-blood levels very important for this drug class
-MUST adjust dose relative to creatinine clearance
--Formal nomograms, creatinine serum levels, Cockraft-Gault formula

*very narrow therapeutic index!

Front 17

Advantages of consolidated dosing therapy (aka single daily dosing?

Back 17

-Comparable efficacy to multi-dose regimen
-Possibility of decreased nephrotoxicity
-Ease of administration and serum conc monitoring
-Reductions in administration and monitoring-related costs

Front 18

Why can you give this once a day?

Back 18

Post-antibody effect (PAE) since it's a concentration-dependent killing

Less toxic … How?
-threshold effect; less drug accum [inner ear, kidney]
-drug conc below tox threshold longer time with large qd than smaller bid, tid etc doses
-toxicity is conc- and time-dependent
--unlikely to occur until a threshold is reached and the time above that threshold is critical

Front 19

Consolidated dosing not recommend in the following settings:

Back 19

-Pregnant patients
-Osteomyelitis
-Infective endocarditis
-Patients receiving concurrent ototoxins (such as furosemide)
-Patients undergoing solid organ transplantation receiving cyclosporine or other nephrotoxic immunosuppressive drugs

Front 20

Primary toxicities include

Back 20

Nephrotoxicity [usually reversible]
Ototoxicity [often irreversible]
Neuromuscular blockade [reversible]

*Nephrotoxicity and ototoxicity are the major limitations of use
-With therapy > 5 days
-In elderly pts
-In pts with renal dysfunction
-Major dose reduction needed
-Linear relationship between … plasma creatinine conc. & drug half-life
-Tox incidence related to drug concentration

Front 21

Nephrotoxicity... reversible or no?

Back 21

THIS ONE IS IMPORTANT!!!
-Usually reversible
-Involves an acute tubular necrosis (Incidence: 8 - 26%)

The most important result may be decreased AG excretion
-Plasma AG levels increase
-Predisposes to ototoxicity

Concentration- and time-dependent

Front 22

Ototoxicity... reversible or no?

Back 22

Often irreversible
-Incidence is difficult to determine
--May be as high as 25%
-May occur even AFTER drug has been discontinued
-AGs accumulate in perilymph & endolymph in inner ear
--Occurs when plasma concs high
-Progressive destruction of vestibular or cochlear sensory cells

Front 23

How does the ototoxicity present?

Back 23

Manifest as auditory damage
-Tinnitus & high frequency hearing loss (initial)
-Vestibular damage
--Vertigo, ataxia, loss of balance

Front 24

Rare adverse effects of AGs

Back 24

Neuromuscular blockade:
Most episodes are postoperative respiratory depression
-May see acute respiratory paralysis
-May enhance effects of skeletal muscle relaxants

Pts with myasthenia gravis or neuromuscular disorders at risk (may cause muscle weakness)
-MG - ABSOLUUUUUUTE contraindication

Front 25

How can you reverse this acute respiratory paralysis problem?

Back 25

if you immediately administer calcium gluconate or neostigmine, you can reverse the effects!

Front 26

Most used AG is?

Back 26

Gentamicin:
One of most frequently used AGs
Gentamycin generally chosen first, then tobramycin or amikacin

Usually in combination with a cillin for severe infections:
Pseudomonas (a DOC)
Enterococcal (a DOC)

Front 27

Streptomycin

Back 27

Use limited by resistance & advent of newer AGs (gentamicin)

Used alone to treat tularemia and plague

Can use in combination to treat
-tuberculosis
-brucellosis (a DOC with doxycycline)
-bacterial endocarditis (with a cillin)

Front 28

Amikan: the one thing to remember about this drug...

Back 28

-Has the broadest spectrum ... and is quite resistant to inactivating enzymes of bacteria
Used when other AGs fail

-Primarily used for pseudomonas and other serious infections caused by organisms resistant to other AGs

Front 29

Neomycin: the one thing to know about this is...

Back 29

it's the MOST TOXIC

Systemically ... most toxic of the AGs
1o used ORALLY ... to sterilize the gut
Only used systemically ... when organisms very resistant to other agents

Available OTC in many combo preps for topical use

Front 30

Recap: Aminoglycosides

Back 30

30s
3 mechanisms of inhibition
Toxicity: Renal, Ototoxicity

Front 31

Tetracyclines

Back 31

4 rings
acting at the 30S ribosome

-A family of closely related antibiotics
-Similar antimicrobial, pharmacological & therapeutic properties
-Antimicrobial spectrum is one of the broadest
-Use decreasing due to resistance
-Differ mainly in their pharmacokinetics (either than that they're pretty much the same)

Front 32

Spectrum of use?

Back 32

Broad spectrum
-wide range of aerobic and anaerobic G+ & G- bacteria
-intracellular bacteria (eg, Chlamydia, Rickettsia, mycoplasma p.)
-some protozoa (eg Plasmodium)

*since it's such a broad spectrum, resistance is a problem
**AGs don't cross plasma membrane (intracell), but these can

Front 33

Name 2 tetracyclines and their uses

Back 33

Doxycycline & minocycline
-2 of the most widely prescribed drugs

Doxycycline
-preferred in patients with poor renal function (excreted in bile)

Minocycline
-for meningococcal carrier state ( only drug in class that enters CSF in therapeutic amounts)

Front 34

Dox is DoC for...

Back 34

DOC or alternative for Mycoplasma p., chlamydia, Rickettsiae, Lyme disease

DOC for bacillus anthracis (ANTHRAX) ... Ciprofloxacin other DOC

Plague, tularemia, brucellosis,malaria prophylaxis (doxycycline)

GI infections ..... Cholera

Front 35

Tetracyclines: Reversible or no? and other characteristics

Back 35

Bacteriostatic

Binds 30S ribosomal subunit - reversible
-Prevents tRNA binding to acceptor site
-Prevents addition of amino acids to growing peptide chain

*because it's reversible, the bacteria have developed a unique mechanism of toxicity

Front 36

Cell entry: Active/Passive diffusion/transport?

Back 36

passive diffusion (porin OM)
active transport (plasma membrane)

Front 37

Tetracyclines Resistance

Back 37

Primary mechanisms:
-efflux pumps
-*ribosome protection
--proteins that interfere with tetracycline binding
--they dislodge drug from the ribosome &  the apparent kd of drug binding to the ribosome

-alter the binding site (ribosomal RNA)

Cross-resistance among tetracyclines:
-general exception: tigecycline

Front 38

wait, so what is ribosome protection?

Back 38

bacteria makes a protein, and the protein competes for the binding with the drug OR it'll kick it off (if it's already bound)

since it has a better binding affinity, it will get on the binding site quicker than the drug can.
*binds to the site but it doesn't affect protein synthesis

Front 39

Tetracyclines Pharmacokinetics

Back 39

GI absorption is variable:
-Tetras form stable ‘chelates’ with cations (e.g. Ca, Mg, Al, Fe including Fe or Zn supplements)
-Don’t take them with milk, antacids or Pepto-Bismol
--tetras can irritate the GI tract, so pts may want to
-For some ... food can decrease absorption (NOT doxy or minocycline)

Tetracyclines effective orally, IV, and topically

Front 40

Again, which tetra gets into CSF?

Back 40

Only minocycline gets into CSF in therapeutic concentrations

Front 41

Where does the calcium chelation concentrate?

Back 41

Chelates with calcium:
-concentrates in bone and teeth

Front 42

Tetra Elimination

Back 42

All eliminated by GF to some degree

Doxycycline and minocycline are less dependent on kidneys for elimination:
--excreted in bile
--no dosage adjustment with compromised renal function

Front 43

Tigecycline uses

Back 43

Very broad spectrum antibiotic

Effective in resistant organisms
-MRSA, Staph epidermis, penicillin-resistant streptococcus pneumoniae (PRSP), vancomycin-resistant enterococcus (VRE)

Same mechanism of action as other tetracyclines

Front 44

Is tigecycline affected by major tetracycline resistance mechanisms (ribosomal protection and efflux)?

Back 44

nope! it's not affected.

other things:
-Poor oral absorption, given IV

-Treatment of complicated skin and skin structure infections and intraabdominal infections; community-acquired pneumonia

-Biliary excretion
--Not effective for UTIs!

Front 45

Adverse reactions of tetras, GI

Back 45

Gastrointestinal:
-Oral dosing
-Can cause GI distress (Pts may want to grab antacids!!)
-NVD
-Need to distinguish diarrhea due to direct effects from pseudomembranous colitis

Front 46

Adverse reactions of tetras, bones and teeths

Back 46

Tetracyclines bind to calcium:
-Readily bind in newly formed bone or teeth in young children

-Children may develop permanent brown discoloration of teeth
--Risk if used during last half of pregnancy up to 8 years of age

-May cause deformity or inhibit bone growth
--Drug deposited in bone during gestation throughout childhood may retard skeletal development and bone growth

Front 47

other adverse reactions

Back 47

Liver Toxicity:
-Rare but can be fatal
-Occurs more commonly with tetracycline and minocycline and less often with doxycycline

Local Tissue Toxicity:
-Directly irritating to tissues …
--IV: thrombophelbitis (frequent with prolonged use)
--IM: painful (avoid route)

Front 48

Photosensitization, Vestibular Reactions, superinfections and PC

Back 48

Photosensitization
sensitivity to sunlight (sunburn)

Vestibular Reactions
may be produced by minocycline
ataxia, dizziness, NV

Superinfections

Pseudomembranous colitis

Front 49

Ok, fine, so who don't you give these drugs to?

Back 49

To decrease the incidence of toxic effects, observe the following precautions in the use of tetracyclines:

-Do not administer to pregnant patients

-Do not use for treatment of common infections in children younger than 8 years of age

-Discard unused supplies of these drugs

Front 50

Fanconi Syndrome:

Back 50

Outdated and degraded drug can cause Fanconi syndrome
Characterized by NV & renal tox - proximal tubular function of the kidney is impaired causing polyruia, polydipsia, proteinuria, acidosis, glycosuria and aminoaciduria.

Front 51

Name the Protein Synthesis Inhibitors acting at the 50S ribosome

Back 51

Chloramphenicol
Macrolides
Lincosamides
Streptogramins
Oxazolidinones

Front 52

Chloramphenicol use

Back 52

-Rarely used
--Reserved for life-threatening infectionsdue to resistance or allergies to safer drugs
---rickettsial infections (typhoid fever or rocky mountain spotted)
--meningitis
--anaerobic infections

Front 53

MoA of Chloramphenicol

Back 53

Broad spectrum
Bacteriostatic
Binds reversibly to 50S
inhibits peptidyltransferase (peptide bond formation)

Front 54

Chloramphenicol Toxicity

Back 54

Hematological Toxicity:

Bone marrow suppression:
-Anemia, leukopenia, thrombocytopenia
-Dose-dependent

Idiosyncratic response:
-rare with no rhyme or reason
Serious and fatal blood dyscrasias
-Aplastic anemia leads to fatal pancytopenia
-Risk does not contraindicate where use may be life-saving

Front 55

Chloramphenicol Adverse Effect:
Gray syndrome

Back 55

Gray syndrome (if exposed to excessive drug)or gray baby syndrome:
-New born infants (especially if premature)
-Gray color, shock, hypothermia, vomiting, flaccidity
-Can be fatal within 2 days of initial symptoms (40% mortality rate)

Mechanism:
-lack of glucuronyl transferase activity (glucuronic acid conjugation)
-- it's a phase 2 metabolism pathway that's lacking

Front 56

Go ahead and name the Macrolides

Back 56

Erythromycin
Clarithromycin
Azithromycin

**good substitudes for penicillins (effective against many of the same organisms as Pen G)

Front 57

Clarithro and azithromycin are the DoC for which gram negative bacteria?

Back 57

Enhanced Gram Neg activity for...
-Campylobacter Jejuni
-H Pylori
-Shigella spp.

Front 58

WHO are the macrolides DoC for?

Back 58

-children
-pregnant females
*bones suck up tetracyclines and risk developmental bone defects

-patients allergic to penicillin
-outpatient CAP
-URIs

Front 59

Macrolides are also useful of DoC for

Back 59

-mycoplasma pneumoniae
-chlamydia
-Bordetella pertussis
-Campylobacter (enteritis)

Front 60

MoA of Macrolides

Back 60

-bacteriostatic

-reversibly binds 50s ribosome
--inhibits peptide chain elongation
--inhibits translocation of peptidyl tRNA from A to P site

Front 61

Why is there resistance to macrolides?

Back 61

Ribosome Modification!
-methylase alters the macrolide binding site on the bacterial ribosome

Active efflux pump

Front 62

Compare erythromycin to the newer microlides?

Clarithro vs erhythro in freq of doses?

Why is Azithro different from the other 2?

Back 62

-newer macrolides are more acid-stablile than eryth...improved oral absorption, tolerance, and pharmacokinetic properties

-clarithro has less freq dosing that erythro (better for compliance)

-Azithro differs from erythro and clarithro mainly in PK -long half life.
-- once a day dosing, decrease tx time

Front 63

Drug interactions of Macrolides

Back 63

Inhibits CYP34A
--Azithro does NOT inhibits

P450 inhibition basis for interactions with
-theophylline, oral anticoagulants, corticosteroids, digoxin, cabamezpine

Front 64

GI effects (mainly with erythromycin)

Back 64

GI effects
-anorexia, NVD
-Epigastric distress
-primary reason to stop erythro
-DIRECTLY stimulates GI motility (motilin receptors)
-lower incidence with clarithro

Front 65

What do you see with erythro in the estolate dose form?

Back 65

(the best absorbed salt form)

you see Cholestatic Hepatitis
-fever, jaundice, impaired liver function

Front 66

What is an example of a lincosamide, and what is the spectrum of clinical use?

Back 66

Clidamycin is a lincosamide, and it's used for the treatment of anaerobic and streptococcal and staphylococcal infections (skin and soft tissue)

-gram negs are intrinsically resistant

Front 67

MoA of Clindamycin

Back 67

binds to 50S ribosome
-binds close to erythromycin and chloramphenicol binding sites (possible competition)
-inhibits the transpeptidase reaction

bacteriostatic

Front 68

How is there resistance to clinda?

Back 68

Alteration of ribosomal binding site
-primarily by methylation (like the macrolides)
-cross resistance may be seen with erythro

Front 69

Where does clinda go? where doesnt it go?

Back 69

-does not cross BBB

-penetrates/accumulates well into BONE!
-good against anaerobic bugs
-may also achieve excellent penetration into ABSCESSES

Front 70

Adverse effects of clindamycin

Back 70

-DIARRHEAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

Front 71

CLASSICALLY, clindamycin is associated with...

Back 71

psuedomembranous colitis, but any antibiotic can cause the condition. cephalosporins account for a large % of cases b/c of its freq use

Front 72

Name the streptogramins

Back 72

Quinupristin and Dalfopristin.

-used together. not separately. these are the big guns vs the nasty things. the most expensive drugs of all the antibiotics (500 bucks a day)

Front 73

What do we use this quinupristin/dalfopristin combo against?

Back 73

-effective against G+ bacteria resistant to methicillin (MRSA), Quinilones, Vancomycin...when you see bacteremia and skin/soft tissue infections

-Strept pneumoniae resistant to penicillins

-Vancomycin-resistant Enterococcus FAECIUM (VRE), but NOT FAECALIS. DoC for faecium.

Front 74

MoA of Quinupristin? Dalfopristin?

Back 74

Quinupristin- binds at the same site as macrolides

Dalfopristin- directly interferes with polypeptide chain formation
-binds near quinupristin; synergistically enhances binding of quinupristin

Bactericidal- net result of cooperative and synergistic bind of both drugs

MEGAZORD

Front 75

Drug interactions of quinupristin and dalfopristin

Back 75

potent INHIBITOR of CYP3A4
-appropriate caustion and monitoring recommended for drugs in which the terapeutic index is narrow

Front 76

Resistance of dalfopristin? quinupristin?

Back 76

Dalfopristin-
-enzymatic inactivation
-efflux pump
-produces resistance to drug combo

Quinupristin-
-binding site modification by methylase
-enzymatic inactivation
-can render combo bacteriostatic

-lose dalfo, lose everything...lose quinu, become bacteriostatic

Front 77

Unique side effects are

Back 77

Athralgia and myalgia

-can have injection site problems, but you always give it via central line to avoid this.

Front 78

Go ahead and name an oxazolindinone and the spectrum

Back 78

Linezolid, a protein synthesis inhibitor acting at the 50S ribosome.

spectrum similar to quinupristin and dalfopristin (gram pos) INCLUDING E. faecalis.

Reserved for multidrugresistance Gram pos bacteria

Front 79

Clinical use of linezolid

Back 79

MRSA and MSSA (a DOC)

tx of skin and soft tissue infections

Infections due to vancomycin-resistant enterococcus (VRE), a DoC

Front 80

MoA of Linezolid

Back 80

-bind to 50S to block formation of initiation complex (stops the 50 and 30 from coming together to form the 70)
-mostly 'static' (cidal for strep)

Front 81

Resistance for linezolid

Back 81

mutation of rRNA binding site. not methylase, but an actual genomic mutation, so the drug will not recognize the binding site.

Front 82

Since linezolid is a MAO inhibitor, what do you want to avoid?

Back 82

-tyramine-rich foods
-can cause sudden/severe HTN

-adrenergic or serotonergic drugs (SSRIs) aka antidepressants

*MAO works in synapses to NTs and metabolizes them. Maintains balanced level. If you inhibit MAO, you don't break them down, you get higher levels. For tyramine, inhibiting MAO increases the amount that hits the bloodstream, which can cause NE release, which can cause acute hypertensive crisis.

Front 83

What are the mild adverese effects

Back 83

-myelosuppression
-thrombocytopenia
-anemia, leukopenia

Front 84

Daptomycin...spectrum and clinical use

Back 84

-spectrum similar to vanco
-against all gram pos bacteria
-enterococcus faecalis and faecium
-staph auerus (including MRSA)

Clinical use:
-complicated skin (structure) infections
-bacteremia, endocarditis

Front 85

MoA of daptomycin

Back 85

UNIQUE!

Binds to bacterial membranes
-rapid depolarization
-loss of membrane potential, leading to cell death.

-bactericidal (conc-dependent)

Front 86

How does it work? What is it dependent on? what does it bind to?

Back 86

-Binds to cytoplasmic membrane
-Forms complexes in Ca-dependent manner
-Complex formation causes rapid loss of cellular potassium and membrane depolarization
-DNA, RNA and protein synthesis inhibition

Front 87

How is daptomycin cleared?

Back 87

RENALLY cleared. dosage adjustment required for renally impaired.

No clinically significant drug-drug interactions

Not effective for the tx of pneumonia (binds to surfactant)

Front 88

Side effect of daptomycin

Back 88

-myopathy (skeletal muscle damage)
-look for CPK elevations
-use with caution in pts receiving other drugs assoc with myopathy

-superinfection and/or pseudomembranous colitis