药理学-课件pharma-,folate antagonists and urinary tract antiseptics萘啶酸

Chapter

35 Quinolones,FolateAntagonists

and

Urinary

TractAntisepticsSynthetic

organic

antimicrobialsQuinolones-fluoroquinolonesSulfonamidesTrimethoprim（TMP）NitrofuransFour

generations:– generation:1962,

nalidixicacid萘啶酸–

Second

generation:1974,

pipemidic

acid

吡哌酸–

Third

generation:1980’s

fluoroquinolones–

Fourth

generation:1999 moxifloxacin

(莫西沙星),

gatifloxacin

(加替沙星)

---goodfor

respiratory

diseasesSection

1.QuinolonesNorfloxacin——诺氟沙星,氟哌酸Ciprofloxacin——环丙沙星Ofloxacin ——氧氟沙星Levoofloxacin——左氧氟沙星Lomefloxacin——洛美沙星FleroxacinSparfloxacin——氟罗沙星——司帕沙星Common

Fluoroquinolones:A.

Pharmacokinetics1.

Absorption:

Only

35-70%

of

oral

norfloxacinis

absorbed.

However,

70-90%

of

otherfluoroquinolones

are

abosrbed

after

oraladministration.2.

Distribution:

Binding

to

plasma

proteinsranges

from

10

to

40%.

All

the

fluoroquinolonesdistribute

well

into

all

tissues

and

body

fluids.Levels

are

high

in

bone,

urine,

kidney

andprostatic

tissue,

and

concentrations

in

the

lungexceed

those

in

serum.3.

Metabolism:Except

for

ofloxacin（氧氟沙星）andlomefloxacin（洛美沙星）,these

agentsareparticularlly

metabolized

to

compounds

withless

antimicrobial

activity.4.

Excretion:

The

parent

drugs

and

theirmetabolites

are

excreted

into

the

urine

wherehigh

levels

can

occur.

The

half-lives

of

thefluoroquinolones

range

from

3-5

hours,

exceptfor

lomefloxacin

which

has

a

half-life

of

8

hours.PharmacokineticsSerum

t1/2

range

from

3

hours(norfloxacin

and

ciprofloxacin)

up

to

10(pefloxacin

and

fleroxacin)

or

longer(sparfloxacin).The

relatively

long

t1/2

oflevofloxacin,moxifloxacin,

sparfloxacin,

andtrovafloxacinpermit

once-dailydosing.Oralabsorption

is

impairedby

divalentcations,

includingthose

antacids.Most

fluoroquinolones

are

eliminated

byrenal

mechanisms,

either

tubularsecretion

or

glomerular

filtration.The

exact

dose

adjustmentdependingupon

thedegree

ofrenal

impairmentandthe

specific

fluoroquinolone

being

used.Nonrenally

cleared

fluoroquinolones

arecontraindicated

in

patients

with

hepaticfailure.Structure

effects

relationshipThese

agents

are

totally

synthetic

and

are

closelyrelated

structurally

to

an

earlier

quinolone,nalidixic

acid.Nalidixic

acid,

is

a

nonfluorinated

quinolone,and

is

not

effective

against

system

infections.Fluoroquinolones（氟喹诺酮类）Chemical

StructureofloxacinB.

AntibacterialActivitybroad

spectrum,

bactericidalFluoroquinolones

have

greatly

improvedantibacterial

activity

compared

withnalidixic

acid

and

achieve

bactericidallevels

in

blood

and

tissues.They

are

active

against

a

variety

of

gram-positive

and

gram-negative

bacteria.Enterobacteriaceae

(肠杆菌科),Neisseria(奈瑟球菌属)Pseudomonas

(假单胞菌属)Haemophilus

(菌属)

Haemophilusinfluenzae（流感噬血杆菌）Campylobacter

(弯曲杆菌属)etc.1.

Excellent

activity

against

G-aerobic

bacteria2.Goodactivityagainst

G+

aerobicbacteria:p oniae

and

staphylococcus(葡萄球菌属）3.Others:mycoplasmas

(支原体)chlamydiae(衣原体)mycobacterium

tuberculosis(结核分枝杆菌)legionella(军团菌属)anaerobes

(厌氧菌)(1)group

(norfloxacin)

is

the

least

activeagainstG-

organisms.

Earlier

quinolonesdid

not

achieve

systemic

antibacteriallevels.

These

agents

were

useful

only

fortreatment

of

lower

urinary

tract

infections.(2)

Second

group:

pipemidic

acid

possessexcellent

G-

activity

and

treat

urinary

andbiliary

tract

infections.Third

group:

(ciprofloxacin,

enoxacin,lomefloxacin,

levofloxacin,

ofloxacin,

andpefloxacin

gatifloxacin,

and

sparfloxacin)possess

excellent

G-

activity

and

moderate

togood

activity

against

G+

bacteria.

Less

activeagainst

anaerobes.Fourth

group:

(moxifloxacin

andtrovafloxacin)

have

enhanced

G+

activity,

alsohave

good

activity

against

anaerobes.C.

Mechanisms

of

actionThe

fluoroquinolones

enter

the

cell

by

passivediffusion

through

water-filled

protein

channels(porins)

in

the

outer

membrane.Intracellular,

they

uniquely

inhibit

thereplication

of

bacterial

DNA

by

interferingwith

the

action

of

DNA

gyrase

duringbacterial

growth

and

reproduction.MechanismofactionQuinolones

block

bacterial

DNA

synthesisG-：inhibiting

DNA

gyraseG+:

topoisomerase

IVHuman:

topoisomerase

II,

low

sensitive.Bactericidal

agentsBindingofthequinolonetoboththeenzymeand

the

DNA

to

form

a

ternary

complexinhibits

the

rejoining

step

and

can

cause

celldeathby

inducingcleavageoftheDNA.Topoisomerases

can

change

theconfiguration

of

DNA

by

a

nicking,

pass-through

and

resealing

mechanismwithoutchangingitsprimarystructure.Mechanism

of

DNA

gyraseMechanism

of

topoisomerase

IVQuinolonesD.1.Altered

：Modifications

in

the

bacterial

DNA

gyrase,especially

in

amino

acids

at

the

N-terminus

ofthe

A

subunit,

have

been

associated

with

adecreased

affinity

for

the

fluoroquinolone.The

B

subunit

of

the

gyrase

is

rarely

mutated.Decreased

accumulation:Reduced

intracellular

concentration

of

the

drugsin

the

bacterial

cell

is

linked

to

two

mechanisms.One

involves

a

decreased

number

ofporinproteins

in

the

outer

membrane

of

the

resistantcell,

thereby

impairing

access

of

the

drugs

to

theintracellular

gyrase.The

other

mechanism

is

associated

with

anenergy-dependent

efflux

system

in

thecytoplasmic

membrane.-

summaryMutation

of

subunit

A:

the

ability

ofbinding

to

drugs

is

decreased.Absence of

outer

membrane

proteinporin:

decrease

the

permeability

of

theorganismIncrease

the

efflux

pump.cross-E.

Adverse

reactions1.

CNS

problems:

The

most

prominientside

effects

are

nausea,headache,

anddizziness

or

light

headedness.2.

Nephrotoxicity(肾毒性):Crystalluria

hasbeenreported

in

patients

receivingexcessively

doses

(3-4

times

normal).3.

Photoxicity:

Patients

are

advised

to

avoidexcessive

sunlight

and

to

use

sunscreen.

However,even

sunscreens

or

sunblocks

may

not

protectagainst

the

photoxicity

and

the

drug

should

bediscontinued

at

the sign

of

this

toxocity.4.

Contraindications:fluoroquinolones

shouldbe

avoided

in

pregnancy,in

nursing

mothersand

in

children

under

18

years

of

age,sincearticular(关节的)cartilage（软骨）erosionoccurs

in

immature

experimental

animals.Antacids:

comoles

compound(络合物)，reduce

theabsorbtion.Renal

hypofunction:decrement

减量Ofloxacin

氧氟沙星Enoxacin依诺沙星general

character

of

fluoroquinolonesbroad

spectrum:G-rod:include

P.Aeruginosa铜绿假单胞菌G+：

aerobic

bacteriaOthers:tubercle

bacillusmycoplasmachlamydiaanaerobesBioavailability:

80-95%t1/2

is

longHigh

concentration

in

urine2.

wellabsorbed

afteroral

administrationand

distributed

widelyThe

most

common

effects

arenausea,vomiting,and

diarrhea.

Occasionally,

headache,

dizziness,insomnia,

skin

rash,

photosensitivity,

or

abnormalliver

function

tests

develop.3.Lessadverse

reactionsand

well

tolerated--May

damage

growing

cartilage

(软骨)and

cause

an

arthropathy

(关节病),

notmended

for

use

in

patients

under

18years

old.--they

are

excreted

in

breast

milk,contraindicated

for

nursing

mothers.--Avoided

during

pregnancy,

allergicdisorders,

and

history

of

epilepsy.4.

Clinical

UsesUrinary

tract

infections:areeffectiveeven

when

causedbymultidrug-resistantbacteria,

eg,

pseudomonas假单胞菌.Bacterial

diarrhea

caused

by

shigella

(志贺菌属),

salmonella

沙门氏菌,

toxigenic

Ecoli,

or

campylobacter

(弯曲杆菌属).(3)Infections

of

soft

tissues,bones,andjoints,including

those

caused

by

multidrug-resistant

organisms

such

as

pseudomonas

andenterobacter

(肠杆菌).(4)

Treatment ofp onia

and

otherupper

respiratory

tract

infections,Legionella军团杆菌,chlamydia衣原体

and

mycoplasmap

onia.5.

AnnouncementsCartilaginous

tissue

damage

(childhood)pregnant

womenlactation

womenchildren

<18yCNS

adverse

reactions

epilepsyDrug

interactionmetabolism

of

following

drugs

will

be

inhibitedTheophylline:Coffeine:oral

anticoagulantenoxacin>ciprofloxacin>pefloxacin.But

ofloxacin

influences

less

to

these

drugs.Investigative

trends

of

quinolonesIncrease the

antibacterial

activityElevaeight

stabilityDegrade

photosensitivityreactionsafety1.

Ciprofloxacin（环丙沙星）This

is

the

most

potent

of

the

fluoroquinolonesand

has

an

antibacterial

spectrum

similar

to

thatof

norfloxacin.Ciprofloxacin

finds

use

in

the

treatment

ofpseudomonas

infections

associated

with

cystic（腔囊的）fibrosis.Ciprofloxacin

is

particularly

useful

in

treatinginfections

caused

by

many

enterobacteraceae（肠杆菌）and

other

gram-negative

bacilli.2.

Norfloxacineffective

against

both

gram-negative(including

pseudomonas

aeruginosa)and

gram-positive

organisms

intreatingcomplicated

andplicated

urinarytract

infectionsand

prostatitis,but

not

in

systemicinfections.Section

2

sulfonamidesOverview:

In

the

1930s,

Domagkdemonstratedth hemotherapeutic

agentcould

influence

the

course

of

a

bacterialinfection.The

drug

was

prontosil

(百浪多息，磺胺类药),adyewhich

provedto

bea

pro-drug,inactive

invitro

and

needing

to

be

metabolized

in

vivo

togive

the

active

product-sulfanilamide.Basic

structureSO2

NHR1NHR2---sulphanilamide

对氨基苯磺酰胺---para-NH2

is

essentialgroup

forantibacterialactivity.Structure-function

relationshipR1

replace，action

increase,

oral

easyabsorbed,

used

in

systemic

infections；R2

replace，oral

hard

to

absorb,

usedinintestinal

infections:SO2

NHR1NHR2ClassificationUsed

in

systemic

infections:Short-acting:

SIZ

(磺胺异噁唑)Medium-acting:

SD,SMZ

(磺胺甲基异噁唑)Long-acting:

SDM

(磺胺多辛)Used

in

intestinal

infections:sulfasalazine

(SASP,柳氮磺吡啶)Used

in

local

infections:

SD-Ag,SA-Na(磺胺醋酰钠),SML

(磺胺米隆)Antimicrobial

ActivityBroad-spectrum;G-

and

G+

bacteriaChlamydia

trachomatis

(沙眼衣原体)BacteriostaticagentsThe

action

on

synthesisofFolateFolate

is

requiredfor

DNA

synthesis

inboth

bacteria

and

in

humans.Human

cannot

synthesis

itbut

obtain

itfrom

thediet

andhave

evolvedatransport

mechanismfortaking

it

upintothecells.The

action

on

synthesis

ofFolateMany

bacteria

must

rely

ontheirability

to

synthesize

folate

from

PABA(p-aminobenzoic),

pteridine

(蝶啶）,andglutamate.ogueSulfanilamide

is

a

structuralofp-aminobenzoicacidand

blocksynthesis

of

folic

acid

inbacteria.Mechanismof

actionmammalDihydropternatesynthaseDihydrofolateredu

eSulfonamides

are

similar

to

PABA,

and

compete

withthis

substrate

for

the

dihydrofolate

synthetaseTrimethoprim

(TMP),

a

potential

inhibitor

of

dihydrofolateredu

epteridineglutamatedihydrofolatesynthetasedihydrofolatereductansetetrahydrofolateEasyty

notsufficient，permanent

drug-acquireddrug-crossstructural

change

or ty

increaseof

dihydropteroicacid

synthasedrug

destroy

or

deactivationproduction

and

utilization

of

PABAincreasemetabolic

pathway

change:

utilizeextrinsic

source

folic

acidMechanismof

Clinical

UsesUrinary

tract

infection:Oral

absorbable

agents:

Sulfisoxazole(SIZ)and

sulfamethoxazole

(SMZ)Meningococcalmeningitis:SD,

choiceBacterial

dysentery(痢疾):SMZUlcerative

colitis溃疡性结肠炎,enteritis肠炎,and

other

inflammatory

bowel

disease:Oral

nonabsorbable

agents:sulfasalazine(SASP

,柳氮磺吡啶);Topical

use

for

trachoma

(沙眼)

andconjunctivitis(结膜炎)

:

SA-Na

(磺胺醋酰钠);Prevent

infections

of

burn

wounds:SD-Ag,SML

(磺胺米隆).Adverse

ReactionsUrinary

tract

disturbance:Precipitate

in

urine,

especially

atneutral

or

acidpH,producingcrystalluria,hematuria血尿,even

obstruction,and

the

various

types

ofnephrosis

or

allergic

nephritis.

This

is

rare

withthe

more

soluble

sulfonamides

(eg,SIZ).Preventive

measurepH:

sodium

bicarbonate

to

alkalinize

theurineDrink

waterAcute hemolytic

anemiaProvoke

hemolytic

reactions

in

patientswhose

red

cells

are

deficient

in

glucose-6-phosphate

dehydrogenase.Hematopoietic

DisturbancesCausehemolyticoraplasticanemia,granulocytopenia,

thrombocytopenia,orleukemoid

reactions(白血病样反应).(4)Allergy:Fever,skin

rashes,exfoliative

dermatitis

剥脱性皮炎,photosensitivity,urticaria

(荨麻疹),There

are

the

cross-allergenic

in

allsulfonamides

and

their

derivatives,includingcarbonicanhydrase

inhibitors,thiazides,

furosemide,bumetanide布美他尼,torsemide

(托拉塞米),diazoxide

(二氮嗪),and

the

sulfonylurea

hypoglycemicagents.GI:

nausea,

vomiting,

and

diarrhea

are

themost

common.Kernicterus核黄疸:unconjugated

bilirubindeposits

in

basal

ganglia

andhypothalamus

of

newborn

and

preterminfant.Drug

interactions(5)

OthersPharmacokinetic

aspectsMost

sulfanilamides

are

readily

absorbed

inthe

gastrointestinal

tract

and

rea

aximumconcentrations

in

the

plasma

in

4-6

hours.They

are

usually

not

given

topically,

mainlybecame

of

the

risk

of

sensitization

andallergicreactions.The

drugs

pass

into

inflammatory

exudate（渗出物）and

cross

the

placental

and

blood-brainbarriers.Section

3

Trimethoprim

(TMP)TMP

resembles

the

pteridine

moiety

offolate.Bacterial

dihydrofolate

redu eismanytimes

more

sensitive

to

TMP

than

is

theequivalent

enzyme

in

humans.CharacteristicsIt

is

sometimes

given

asa

mixture

withsulfamethoxazole(磺胺甲噁唑,SMZ)in

acombination

called

cotrimoxazole复方新诺明.Since

sulfonamides

affect

anearlierstage

in

the

same

metabolic

pathway

inbacteria,

i.e.

folate

synthesis,

they

canpotentiate

the

actionof

TMP.Mechanismof

actionmammalDihydropteroatesynthaseDihydrofolateredu

ePharmacokinetics:(1)

Usually

given

orally,

alone

orincombination

with

sulfamethoxazole

(has

asimilar

half-life),

also

be

givenintravenously.(2)

TMP

is

absorbed

well

from

the

gut

anddistributed

widely

in

body

fluids

and

tissues.It

reaches

high

concentrations

in

the

lungsand

kidneys

and

fairly

high

concentrationsin

the

cerebrospinal

fluid

(CSF).Trimethoprim(3)

About

40%

of

TMP

is

pro