Quinolones
·
Chemistry.
·
Pharmacokinetics.
·
Adverse effects.
·
Therapeutic
indications.
Chemistry
1.
The first widely used quinolone was nalidixic acid which was effective
for urinary tract infections because it is concentrated in the urine, but had
little systemic activity.
2.
It was subsequently found that fluorination of the quinolone structure
produced compounds that were up to 60x more active than nalidixic acid and kill
a wider range of organisms.
3.
Mechanism of action:
a.
The fluoroquinolones act by inhibiting bacterial (but not human) DNA
gyrase which prevents DNA supercoiling.
b.
They are rapidly bactericidal.
4.
The fluoroquinolones are:
a.
Norfloxacin.
b.
Ciprofloxacin: most antimicrobial activity.
c.
Pefloxacin.
d.
Ofloxacin.
e.
Enoxacin: least active.
Pharmacokinetics
1.
Well absorbed orally.
2.
Distribution:
a.
Widely distributed to all body tissues and fluids.
b.
Pefloxacin penetrate CSF well in presence of meningeal inflammation.
3.
Long half-lives:
a.
Norfloxacin and ciprofloxacin: 3 – 4h.
b.
Enoxacin and ofloxacin: 6 – 7h.
c.
Pefloxacin: 10 – 11h.
4.
Excretion:
a.
The fluoroquinolones are excreted by the kidneys but the extent of renal
clearance varies with different drugs being highest for olfoxacin and lowest for
pefloxacin.
b.
The half-life of pefloxacin is not significantly prolonged in renal
failure patients because of the extensive liver metabolism, but there may be
accumulation of the metabolite, norfloxacin.
c.
The fluoroquinolones are metabolized in the liver to a varied extent
being greatest with pefloxacin and less with the others.
Adverse drug effects
1.
Gastrointestinal:
a.
Nausea and vomiting.
b.
Diarrhoea.
c.
Abdominal pain.
2.
CNS:
a.
Headaches.
b.
Insomnia.
c.
Convulsions.
d.
Confusions.
3.
Allergic reactions:
a.
Rash.
b.
Pruritus.
c.
Arthralgia.
d.
Photosensitivity.
e.
Anaphylaxis.
4.
Elevation of liver enzymes.
5.
Decreased renal function.
6.
Leucopenia, thrombocytopenia and haemolysis in patients with G6PD
deficiency.
7.
Drug interactions:
a.
Antacids and sucralfate: they form a chelate complex with
fluoroquinolones reducing their bioavailability.
b.
Fluoroquinolones are inhibitors of hepatic enzymes and decrease the
clearance of the following drugs: warfarin, sulphonylureas and theophylline.
c.
Cimetidine: decrease clearance of pefloxacin and prolong its half-life.
d.
NSAIDs: increase risk of convulsions.
Spectrum of antimicrobial activity
|
|
Gram-positive |
Gram-negative |
|
Cocci |
·
Poor activity. |
·
Neisseria gonorrhoea |
|
Bacillus |
·
Poor activity against anaerobes. |
·
Salmonella ·
Shigella ·
Haemophilus ·
Pseudomonas ·
Legionella ·
Enterobacteriaeae |
Individual fluoroquinolones
1.
Ciprofloxacin:
a.
Half-life: 3h.
b.
Effective against Gram-negative organisms; has less activity against
Gram-positive organisms such as Streptococcus pneumoniae and Enterococcus
faecalis.
c.
Chlamydia and mycoplasma are sensitive but most anaerobes are not.
d.
Ciprofloxacin is indicated for infections of the urinary,
gastrointestinal and respiratory tracts, tissue infections, gonorrhoea and
septicaemia caused by sensitive organisms.
2.
Acrosoxacin:
a.
Used orally for gonorrhoea.
b.
Reserved for patients who are allergic to penicillin or resistant
strains.
3.
Cinoxacin: used for urinary tract infections, but not when renal
function is impaired.
4.
Norfloxacin: used for acute or chronic recurrent urinary tract
infections.
5.
Ofloxacin: indicated for urinary and respiratory infections and
gonorrhoea.
Nalidixic acid
1.
Spectrum of activity:
a.
Active against many Gram-negative bacteria that cause urinary tract
infection.
b.
No significant activity against Gram-positive cocci.
2.
Pharmacokinetics:
a.
Absorption after oral ingestion is good.
b.
Short half-life but prolonged in renal failure.
c.
Some are conjugated in the liver.
d.
Both metabolites and parent drug are excreted in the urine.
3.
Adverse effects:
a.
Nausea and vomiting.
b.
Abdominal pain.
c.
Cholestasis.
d.
CNS: headache, visual disturbances.
e.
Convulsions in patients with epilepsy, cerebral vascular insufficiency.