Tetracyclines, Aminoglycosides

Question 1

Tetracyclines

Chemistry
Mechanism of Action
Mechanisms of Resistance

Answer 1

Contain 4 condensed rings with substituents
Is a basic compound–> form water soluble salts with acid
Amphiphilic
Form chelates with Ca,Mg,Fe,Al (inorgnic cations)
Light exposure–> oxidised to quinones
(= nephro- and phototoxic)

MoA
Enter bacteria: diffusion and carrier mediated transport

Inhibit 30S ribosomal subunit
Inhibit binding: aminoacyl tRNA–> ribosome mRNA
complex–> elongation of peptide chain stops–>
BACTERIOSTATIC

MoR; resistance rare
Plasmid mediated
Expression of TC efflux pumps (ex staph aur)
Expression of protection proteins-> displace TC from
ribosomal binding site (Ex. E. Coli)
Expression of FMO-> hydrolyses and inactivates TCs

Question 2

Tetracyclines

Spectrum
Pharmacokinetics

Answer 2

BROAD spectrum
G+: staphy aur, strepto, listeria, bac anthraxis

G-: neisseria, H. influenza, H. Pylori, yersinia

Spirochetes: borellia burg, treponema pallidum

Obligate IC parasites: rickettsiae, mycoplasma, chlamydia

GI absorption depends on lipid solubility
6 Hydroxy TCs: rel. hydrophilic
incompletely absorbed

6 Dehydroxy TCs: rel lipophilic
completely absorbed–> lower dose enough

DO NOT take with Ca, Mg, Fe, preps…

Vd= 1-2kg/l–> some minute accumulations; distribute
pretty evenly

Mainly renal elimination
Doxycycline: biliary elimination
Minocycline: biotransformation

Question 3

Tetracyclines

SE

Answer 3

GIT irritation
Pseudomembranous colitis
Phototoxicity
Liver injury: steatosis in preggos
Allergic reactions: rare
Depo in growing bones: CI in kiddies under 8
   complexes with Ca apatite 
   reversible inhibition of growth
   irreversible discolouration

Question 4

Tetracyclines

Drug Groups

Answer 4

6 Hydroxy TCs

6 Dehydroxy TCs

Question 5

6 Hydroxytetracyclines

Answer 5

Oxtytetracycline
incomplete GIT absorption; mainly renal elim

Tetracycline
incomplete GIT absorption; elim: bile and urine

Limecycline
completely absorbed via carrier mediated transport
eliminated mainly renally

Question 6

6 Dehydroxytetracyclines

Answer 6

Doxycycline
completely absorbed
mainly fecal elimination

Question 7

Tetracyclines

Indications: 2 Groups

Answer 7

Bacterial
   Acne
   H. Pylori Eradication (or a Macrolide)
   Cholecystitis
   Lyme Disease

Cholera
Plague
Anthrax

IC Parasite
Rickettsial
Mycoplasma
Chlamydia

Question 8

Aminoglycosides

Chemistry
Mechanism of Action
Mechanisms of Resistance

Answer 8

3 aminosugars linked by glycosidic bond
Polycations–> water soluble not lipid soluble

MoA
Uptake into bacteria: diffusion through aquaporin or
uptake via 2ary active transport (via negative charge
inside; maintained by oxidative phosphorylation)

Bind to 30S ribosomal subunit--> inhibits initiation; 
finally leading to misreading--> mutated membrane 
protein--> leaky membrane--> BACTERIOCIDAL

MoR
AG can’t enter bacteria (ex anaerobes)
AG can’t bind to 30S (ribosomal resistance)
AG converted–> inactive metabolites via
adenylation of OH
phosphorylation of OH
acetylation of OH or NH2 groups

Question 9

Aminoglycosides

Spectrum
Pharmacokinetics

Answer 9

Narrow Spectrum; mainly G-s
Enterobacteriacae (E Coli, Klebsiella, Enterobacter)
Pseudomonas

Some G+
Some enterococci
Staphyl

Poor GIT absoprtion–> IV
Largely extracellular distribution (Vd=0.25l/kg)
Accumulate in inner ear and kidney-> toxic SE
Low PPB
Elimination: mainly urinary excretion unchanged

Question 10

AGs

Toxic Effects

Answer 10

Ototoxic and Nephrotoxic; depend on cumulative dose
Ototoxicity is irreversible
Nephrotoxicity is reversible

–> hearing impairment, disturbed equilibrium

Give AGs in !!!single dose!!! to minimise nephrotoxicity
Decrease dose proportionally to decrease in GFR

Impaired NM transmission: due to Ca antagonism
Manifested only if there are other causes for NMJ impaired transmission ex Myasthenia Gravis

Question 11

Classification of AGs

Answer 11

For severe G- infections
For resistance G- infections
For topical use
For specific infections
For gonorrhoea

Question 12

AGs

For severe G- Infections

Answer 12

Gentamycin
Tobramycin
Klebsiella/ E Coli, pseudomonas, enterobacter
Sepsis, severe pyelonephritis, G- pneumonia, meningitis

Recommended Combos
E.Coli: Ampicillin or caphalosporins

NEVER mix AGs (cations) with B Lactam (anion) in one solution–> form salt. Inject separately

Gentamycin:
Osteomyelitis: locally implanted gentamycin minichip

Question 13

AGs

For resistant G- Infections

Answer 13

Amikacin

When resistance to genta- and tobramycin +

Question 14

AGs

For Topical Use

Answer 14

Neomycin
Kanamycin

Topically due to nephrotoxicity

Bladder irrigation
Outer ear infections

Question 15

AGs

For Specific Infections

Answer 15

Streptomycin

Narrow spectrum due to resistance

Tularemia
Brucelliosis
Plague
TBC

Question 16

AGs

For Gonorrhoea

Answer 16

Spectinomycin

Is not an AG but an aminocyclitol

Not bactericidal but bacteriostatic

No oto- and nephrotoxicity

2nd choice for gonorrhoea.

First choice: ceftriaxone