synthetic antimicrobial agents section 6 yun-bi lu, phd 卢韵碧 dept. of pharmacology, school of...

SyntheticSynthetic antimicrobial agents antimicrobial agents

Section 6Section 6

Yun-Bi Lu, PhDYun-Bi Lu, PhD

卢韵碧卢韵碧

Dept. of Pharmacology, Dept. of Pharmacology, School of Medicine, Zhejiang UniversitySchool of Medicine, Zhejiang University

[email protected]@zju.edu.cn

• Quinolones ( Quinolones ( 喹诺酮类喹诺酮类 ))

• Sulfonamides ( Sulfonamides ( 磺胺类磺胺类 ))

• Other Synthetic antimicrobialOther Synthetic antimicrobial Trimethoprim (Trimethoprim ( 甲氧苄啶甲氧苄啶 ))

Nitrofurans (Nitrofurans ( 硝基呋喃类硝基呋喃类 ))

ContentsContents

From chloroquine to nalidixic acidFrom chloroquine to nalidixic acid

Generation Example timeGeneration Example time

1 Nalidixic acid 1 Nalidixic acid 萘啶酸萘啶酸 19621962

2 Pipemidic acid 2 Pipemidic acid 吡哌酸吡哌酸 19731973

3 3 NorfloxacinNorfloxacin 诺诺氟氟沙星沙星 4 Clinfloxacin 4 Clinfloxacin 克林沙星克林沙星 1990’s1990’s

喹诺酮类喹诺酮类 (Quinolones)(Quinolones)

First generation fluoroquinolonesFirst generation fluoroquinolones

From ofloxacin to levofloxacinFrom ofloxacin to levofloxacin

Fluoroquinolones

• broad antimicrobial activity broad antimicrobial activity

• effective after oral administration effective after oral administration

• relatively few side effects relatively few side effects

• resistance to their action does not resistance to their action does not develop rapidly. develop rapidly.

FluoroquinolonesFluoroquinolones

1. Antimicrobial activity & spectrum: 1. Antimicrobial activity & spectrum:

(1) bactericidal and have significant PAE. (1) bactericidal and have significant PAE.

(2) aerobic G(2) aerobic G-- bacteria, bacteria, PesudomonasPesudomonas, , aeroaerobic Gbic G++ bacteria, bacteria, ChlamydiaChlamydia spp. spp. （衣原（衣原体）体） , Legionella pneumophila(, Legionella pneumophila( 军团菌军团菌 ) , a) , anaerobic bacteria, mycobacteria(naerobic bacteria, mycobacteria( 分枝杆分枝杆菌菌 ), multiple-resistance strains.), multiple-resistance strains.

General properties of General properties of QuinolonesQuinolones

Mechanism of actionMechanism of action

Topoisomerase Topoisomerase

DNA gyrase DNA gyrase

Key enzymes in DNA replication: bacterial DNA is supercoiled.Key enzymes in DNA replication: bacterial DNA is supercoiled.


Topo Topo isomeraseisomeraseDNA gyraseDNA gyrase

Gram (-)Gram (-) Gram (+)Gram (+)

porinporin


Fluoroquinolones:Fluoroquinolones:4 stacked molecules4 stacked molecules

DNA gyraseDNA gyraseCatalytic subuniteCatalytic subunite

DNA gyraseDNA gyraseATP binding subuniteATP binding subunite

Mechanism of resistanceMechanism of resistance

Topo Topo isomeraseisomeraseDNA gyraseDNA gyrase

Gram (-)Gram (-) Gram (+)Gram (+)

porinporin

mutation of mutation of the enzymesthe enzymes

active effluxactive effluxsystemsystem

decreaseddecreasedpermeabilitypermeability

• AAbsorption: well absorbed; bound by divalent cationsbsorption: well absorbed; bound by divalent cations– Do not administer with iron, magnesium, calciumDo not administer with iron, magnesium, calcium

• DDistribution: all distribute widely (istribution: all distribute widely (even in CSF)even in CSF), and , and most concentrate in urinemost concentrate in urine

• MMetabolism: etabolism: – hepatic metabolism diminishes the activity of hepatic metabolism diminishes the activity of

norfloxacin and ciprofloxacinnorfloxacin and ciprofloxacin– Several have predominately hepatic clearanceSeveral have predominately hepatic clearance

(Grepafloxacin, Sparfloxacin, Trovafloxacin)(Grepafloxacin, Sparfloxacin, Trovafloxacin) • EExcretion: urinary excretion predominates for the first xcretion: urinary excretion predominates for the first

generation generation fluoroquinolonesfluoroquinolones

ADME of fluoroquinolonesADME of fluoroquinolones

ADME of fluoroquinolonesADME of fluoroquinolones

• Urinary tract infections.Urinary tract infections.

• GI and abdominal infections.GI and abdominal infections.

• Respiratory tract infections.Respiratory tract infections.

• Bone, joint and soft tissues infections, Bone, joint and soft tissues infections, OsteomyelitisOsteomyelitis..

• MeningitisMeningitis

• STD: STD: Neisseria gonorrheaNeisseria gonorrhea ( (奈瑟氏淋球奈瑟氏淋球菌菌 ))and and ChlamydiaChlamydia ( (衣原体，衣原体， Quinolone Quinolone resistance in resistance in gonorrheagonorrhea increasing) increasing)

Clinical UsesClinical Uses

•Gastrointestinal effects. Gastrointestinal effects.

•CNS side effects.CNS side effects.

•Allergic reaction.Allergic reaction.

•Hepatotoxicity, nephrotoxicity. Hepatotoxicity, nephrotoxicity.

•Joint/cartilage toxicity, TendinopathyJoint/cartilage toxicity, Tendinopathy

–Achilles tendon rupture

–Limited FDA approval for children

Adverse reactionsAdverse reactions

• NorfloxacinNorfloxacin (( 诺氟沙星诺氟沙星 ))• Ciprofloxacin Ciprofloxacin (( 环丙沙星环丙沙星 ))• Ofloxacin Ofloxacin (( 氧氟沙星氧氟沙星 ))• Levofloxacin Levofloxacin (( 左氧氟沙星左氧氟沙星 ))• LomefloxacinLomefloxacin (( 洛美沙星洛美沙星 ))• Fleroxacin Fleroxacin (( 氟罗沙星氟罗沙星 ))• Sparfloxacin Sparfloxacin (( 司帕沙星司帕沙星 ))• Clinafloxacin (Clinafloxacin ( 克林沙星克林沙星 ))• Gatifloxacin (Gatifloxacin ( 加替沙星加替沙星 ))

Fluoroquinolones agentsFluoroquinolones agents

• Quinolones ( Quinolones ( 喹诺酮类喹诺酮类 ))

• Sulfonamides ( Sulfonamides ( 磺胺类磺胺类 ))

• Other Synthetic antimicrobialOther Synthetic antimicrobial Trimethoprim (Trimethoprim ( 甲氧苄啶甲氧苄啶 ))

Nitrofurans (Nitrofurans ( 硝基呋喃类硝基呋喃类 ))

ContentsContents

Inhibitors of Folate Synthesis

2,4-Diaminoazobenzen-4’-sulfonamideProntosil

Gerhard DomagkNobel Laureate 1939

First Aid Packet carried by U.S. Soldiers in World War II

http://home.att.net/~steinert/wwii.htm

SulfonamidesSulfonamides

Antimicrobial activity:Antimicrobial activity:• A wide antimicrobial spectrum.A wide antimicrobial spectrum.• Exerting onlyExerting only bacteriostatic effect.bacteriostatic effect.

Pteridine+PABA

Blocked by sulfonamides

Dihydropteroic acid

Dihydrofolic acid

glutamate

Tetrahydrofolic acid

Blocked by trimethoprim

NADPH

NADPH

Dihydropteroatesynthase

Dihydrofolatereductasease


Mechanism of ResistanceMechanism of Resistance • A lower affinityA lower affinity for sulfonamides by the dih for sulfonamides by the dih

ydropteroate synthaseydropteroate synthase• Decreased cell permeabilityDecreased cell permeability or active efflux or active efflux

of the drugof the drug• An alternative pathwayAn alternative pathway to synthesis the es to synthesis the es

sential metabolitessential metabolites• An increased productionAn increased production of essential meta of essential meta

bolitesbolites

ADME of sulfonamidesADME of sulfonamides

• AApproximately 70%-100% of an oral dospproximately 70%-100% of an oral dose is absorbed.e is absorbed.

• DDistributing throughout all tissues of thistributing throughout all tissues of the body,e body, even ineven in CSF CSF ( sulfadiazine and ( sulfadiazine and sulfisoxazole, may be effective in menisulfisoxazole, may be effective in meningeal infections) ;readily passing thougngeal infections) ;readily passing though h the placentathe placenta..

• MMetabolized etabolized in the liverin the liver by acetylation. by acetylation.

ADME of sulfonamidesADME of sulfonamides

• EEliminated mainly liminated mainly in the urinein the urine as the as the unchanged drug and metabolic unchanged drug and metabolic product. In acid urine, the eliminated product. In acid urine, the eliminated may precipitate, thus induced may precipitate, thus induced renal renal disturbance. disturbance.

Clinical usesClinical uses

• Systemic infections.Systemic infections.

• Intestinal Intestinal infections.infections.

• Infections of burn and wound.Infections of burn and wound.

Adverse reactionsAdverse reactions• Urinary tract disturbancesUrinary tract disturbances• Hypersensitivity reactionHypersensitivity reaction• Hematopoietic system disturbancesHematopoietic system disturbances• Kernicterus (Kernicterus ( 胆红素脑病胆红素脑病 ))• HepatitisHepatitis• GI effectsGI effects

Drugs interactionsDrugs interactions• All sulfonamides are bound in varying deAll sulfonamides are bound in varying de

gree to gree to plasma protein.plasma protein.

Classification:Classification:

• Oral absorbable agentsOral absorbable agents• Short-acting agentsShort-acting agents• Medium-acting agentsMedium-acting agents• Long-acting agentsLong-acting agents• Oral nonabsorbable agents Oral nonabsorbable agents • Topical agentsTopical agents• Combination agentsCombination agents

Oral absorbable agentsOral absorbable agents

• Short-acting agentsShort-acting agents

Sulfafurazole Sulfafurazole (SIZ,(SIZ, 菌得清菌得清 ))• Medium-acting agentsMedium-acting agents

Sulfadiazine Sulfadiazine (SD,(SD, 磺胺嘧啶磺胺嘧啶 ))

Sulfamethoxazole Sulfamethoxazole (SMZ,(SMZ, 新诺明新诺明 ))• Long-acting agentsLong-acting agents

Sulfadoxine Sulfadoxine (SDM(SDM ，周效磺胺，周效磺胺 ))

Oral nonabsorbable agentsOral nonabsorbable agents

Sulfasalazine Sulfasalazine (( 柳氮磺吡啶柳氮磺吡啶 ) )

Topical agents.Topical agents.

Mafenide Mafenide (SML, (SML, 甲磺灭脓甲磺灭脓 ))

Sulfadiazine sliver Sulfadiazine sliver (( 磺胺嘧啶银磺胺嘧啶银 ))

Sulfacetamide Sulfacetamide (SA,(SA, 磺胺醋酰）磺胺醋酰）

Combination agents Combination agents Co-trimoxazole Co-trimoxazole (( 复方新诺明复方新诺明 ))

1) Features 1) Features • TrimethoprimTrimethoprim(( 甲氧苄啶甲氧苄啶 )) in combination in combination

with Sulfamethoxazole(1:5) exertswith Sulfamethoxazole(1:5) exerts a a synesynergistic effectsrgistic effects. .

• The ADME of the two agents is similar.The ADME of the two agents is similar.• Co-block essential enzymes ofCo-block essential enzymes of folate mefolate me

tabolism. tabolism.

Pteridine+PABA

Blocked by sulfonamides

Dihydropteroic acid

Dihydrofolic acid

glutamate

Tetrahydrofolic acid

Blocked by trimethoprim

NADPH

NADPH

Dihydropteroatesynthase

Dihydrofolatereductasease

2)Clinical Uses 2)Clinical Uses

• Chronic and recurrent infections in the urinChronic and recurrent infections in the urinary tractary tract

• Bacterial respiratory infectionsBacterial respiratory infections• GI infections (e.g. induced by GI infections (e.g. induced by SalmonellaSalmonella))• pneumocystis carinii pneumocystis carinii pneumoniapneumonia ( ( 肺囊虫性肺囊虫性

肺炎肺炎 ))

3)Adverse reactions

• There is no evidence that co-trimoxazole, when given in recommended dose, induced folate deficiency in normal persons.

• Hypersensitive reactions• GI effects• The effects of HIV patients• Drug interactions: warfarin, phenytoin

• Trimethoprim Trimethoprim (( 甲氧苄啶甲氧苄啶 ))

• Nitrofurans Nitrofurans (( 硝基呋喃类硝基呋喃类 ))

NitrofurantoinNitrofurantoin(( 呋喃妥因呋喃妥因 ))

Other Other SyntheticSynthetic antimicrobial antimicrobial

Antifungal agentsAntifungal agents

Section 7Section 7

Antifungal agentsAntifungal agentsOnychomycosisOnychomycosis

Fungal infections traditionally have Fungal infections traditionally have been divided to been divided to two distinct classes: two distinct classes: systemic and superficial.systemic and superficial. So, the major So, the major antifungal agents are described with antifungal agents are described with “systemic” and “topical”“systemic” and “topical”..

Antifungal agentsAntifungal agentsOnychomycosisOnychomycosis （甲癣）（甲癣）

Invasive fungal diseaseInvasive fungal disease

Ubiquitous pathogens act as opportunistsUbiquitous pathogens act as opportunistsCandidaCandida species species (( 念珠菌属念珠菌属 )) Aspergillus Aspergillus species species (( 曲霉菌属曲霉菌属 ))

Cryptococcus Cryptococcus (( 隐球菌属隐球菌属 ))

Endemic mycosesEndemic mycoses HistoplasmosisHistoplasmosis (( 组织胞浆菌病组织胞浆菌病 )) CoccidioidomycosisCoccidioidomycosis (( 球孢子菌病球孢子菌病 )) BlastomycosisBlastomycosis (( 芽生菌病芽生菌病 ))

Oral infection with Candida (Thrush 鹅口疮鹅口疮 )

www.thachers.org/ internal_medicine.htm http://vasculitis.med.jhu.edu/treatments/cytoxan.html

Invasive Aspergillosis

AA= aortic arch, a = aneurysmSC = subclavian artery

Silva ME, Malogolowkin MH, Hall TR, Sadeghi AM, Krogstad P.Mycotic aneurysm of the thoracic aorta due to Aspergillus terreus: case report and review.

Clin Infect Dis. 2000 Nov;31(5):1144-8.

• Polyenes:

Amphotercin B （两性霉素 B ）• Azoles

Ketoconazole （酮康唑）Fluconazol （氟康唑）• Allylamine

Terbinafine （特比萘芬）• Pyrimidine analogues

Flucytosine （氟胞嘧啶）

Classification of Classification of antifungal agents

Antifungal MedicationsAntifungal Medications

Amphotercin BAmphotercin B （两性霉素（两性霉素 BB ））broad-spectrumbroad-spectrum

Polyenes

1. Mechanism of action1. Mechanism of action

Amphotercin BAmphotercin B

2. Clinical Uses2. Clinical Uses::• Amphotericin B remains the drug of choice foAmphotericin B remains the drug of choice fo

r all life-threatening mycotic infections (It is ofr all life-threatening mycotic infections (It is often as the initial regimen). ten as the initial regimen).

• E.g. Cryptococcal meningitisE.g. Cryptococcal meningitis


3. Adverse reactions:3. Adverse reactions:(1) fever, chill, hyperpnea(1) fever, chill, hyperpnea （喘息）（喘息） , ,

myalgiamyalgia （肌痛）（肌痛） and hypotension, and hypotension, etetcc.. （（ ~75%~75% ））

(2) nephrotoxic(2) nephrotoxic(3) renal tubular acidosis(3) renal tubular acidosis （肾小管酸化）（肾小管酸化）

and renal wasting Kand renal wasting K++ and Mg and Mg 2+2+

(4) hematological Toxicity(4) hematological Toxicity:: hypochromic hypochromic （低血红蛋白性）（低血红蛋白性） and normocyticand normocytic （正（正常色素性）常色素性） anemia, anemia, etcetc..


3. Adverse reactions3. Adverse reactions::

(5) hepatotoxicity (5) hepatotoxicity

(6) cardiac toxicity(6) cardiac toxicity

(7) CNS side effects (7) CNS side effects

(8) hypersensitive reaction(8) hypersensitive reaction


4. Prevention of adverse reaction4. Prevention of adverse reaction::

(1) Pretreatment with oral (1) Pretreatment with oral acetaminophacetaminophen en or use of intravenous or use of intravenous hydrocortisohydrocortisone hemisuccinatene hemisuccinate. .

(2) Supplemental K(2) Supplemental K+ + is required. is required.

(3) Do physical examination termly. (3) Do physical examination termly.

(4) drug interactions(4) drug interactions



(( 脂质复合体脂质复合体 ))

(( 胶质分散体胶质分散体 ))

(( 脂质体脂质体 ))

5. New formulations of Amphotercin B :5. New formulations of Amphotercin B :

PolyenesPolyenes : :nystatinnystatin （制霉菌素）（制霉菌素）griseofulvingriseofulvin （灰黄霉素）（灰黄霉素） - - Nucleoside analogue

Allylamines:Allylamines:terbinafineterbinafine （特比萘芬）（特比萘芬） - - squalene epoxidase inhibitor ( 角鲨烯环氧化酶抑制剂 )

Topical antifungal agentsTopical antifungal agents

Imidazoles ( 咪唑类 )

• ketoconazle （酮康唑）• miconazole （咪康唑） • clotrimazole （克霉唑）

Triazoles( 三唑类 )

• fluconazole （氟康唑） • itraconazole （伊曲康唑）

Azoles antifungal agentsAzoles antifungal agents

Mechanism of action:Mechanism of action:• reduce ergosterol synthesis by reduce ergosterol synthesis by interfering interfering

with lanosterol with lanosterol （（ 1414 ）） demethylasedemethylase• inhibition of fungal cytochrome P450 enzymeinhibition of fungal cytochrome P450 enzyme

Antifungal activity Antifungal activity ::• Systemically (kSystemically (ketoconazle, fluconazole, itrac

onazole) or topically (miconazole, clotrimazol) or topically (miconazole, clotrimazole). e).


Ketoconazle Ketoconazle （酮康唑）（酮康唑） ::• the first oral azoles introduced into clinical use (sthe first oral azoles introduced into clinical use (systyst

emically or topically)emically or topically). .

• less selective for fungal P450 less selective for fungal P450

• clinical use has been limited by endocrine side effectclinical use has been limited by endocrine side effect

s, liver toxicity and the drug interactions. s, liver toxicity and the drug interactions.

• itraconazole itraconazole （伊曲康唑）（伊曲康唑） or or fluconazole fluconazole （氟康唑）（氟康唑） has replaced ketoconazle for patients who can afford has replaced ketoconazle for patients who can afford

the more expensive, newer product.the more expensive, newer product.


Itraconazole Itraconazole （伊曲康唑）（伊曲康唑） • Its antifungal spectrum is broader than kotIts antifungal spectrum is broader than kot

oconazole, and its side effects is less than oconazole, and its side effects is less than kotoconazole. kotoconazole.


FFluconazole luconazole （氟康唑）（氟康唑） • good water solubility and good CSF penetratgood water solubility and good CSF penetrat

ionion• drug interactions and side effects are also ledrug interactions and side effects are also le

ss because of its least effect on hepatic enzyss because of its least effect on hepatic enzyme of all the azoles. me of all the azoles.

• Be used in:Be used in:

(1) Candidiasis(1) Candidiasis （念珠菌病）（念珠菌病） , ,

(2) Cryptococcosis(2) Cryptococcosis （隐球菌病）（隐球菌病） , ,

(3) others.(3) others.


FlucytosineFlucytosine （氟胞嘧啶）（氟胞嘧啶）

5-FC

5-FC

5-FU

FdUMP

dUMP

dTMP

Inhibition of DNA synthesisInhibition of DNA synthesis

Inhibition of Protein SynthesisInhibition of Protein Synthesis

FdUMP

FUTP

5-FC, 5-fluorocytosine; 5-FU, 5-fluorouracil; FdUMP, 5-fluorodeoxyuridine;FUMP, 5-fluorouridine monophosphate; FUDP, 5-fluorouridine diphosphate;FUTP, 5-fluorouridine triphosphate; dUMP, deoxyuridine monophosphate;dTMP, deoxythymidine monophosphate

5-FC

FlucytosineFlucytosine ：： Mechanism of actionMechanism of action

Cytosine permease

Cytosine deaminase

Phosphorylation

Conversion to deoxynucleosides

Ihibition of thymidylate synthaseIhibition of thymidylate synthase

Substitution for uracilSubstitution for uracil

• a a norrow-spectrumnorrow-spectrum antifungal drug. antifungal drug.

• drug resistance occurs rapidly whedrug resistance occurs rapidly whe

n flucytosine is used alone. n flucytosine is used alone.

• flucytosine is flucytosine is usedused predominantly predominantly ii

n combination with amphotericin Bn combination with amphotericin B

for therapy of crypotococcal meninfor therapy of crypotococcal menin

gitis in AIDS patient, gitis in AIDS patient, etcetc..

FlucytosineFlucytosine

Adverse reactionsAdverse reactions::• depressing the function of bone madepressing the function of bone ma

rrowrrow (leading to leukopenia and thr (leading to leukopenia and thrombocytopenia, ombocytopenia, etc.)etc.). .

• Plasma levels of hepatic enzymes aPlasma levels of hepatic enzymes are elevated (reversible).re elevated (reversible).

• rash, nausea, vomiting, diarrhea. rash, nausea, vomiting, diarrhea.

FlucytosineFlucytosine

Antiviral agentsAntiviral agents

Section 8Section 8

Essential Characteristics of VirusesEssential Characteristics of Viruses

• Genome (RNA or DNA) packaged in a Genome (RNA or DNA) packaged in a protein coreprotein core

• Intracellular parasitismIntracellular parasitism– No ribosomes or mitochondriaNo ribosomes or mitochondria– Utilize cellular machinery for synthesis of Utilize cellular machinery for synthesis of

macromoleculesmacromolecules

• Antiviral therapies targetAntiviral therapies target– Entry into cellsEntry into cells– Virus utilization of cellular machineryVirus utilization of cellular machinery– Or stimulate immune clearanceOr stimulate immune clearance

Specific Antiviral Therapy forSpecific Antiviral Therapy for

• Respiratory VirusesRespiratory Viruses– Influenza, Respiratory Syncitial Influenza, Respiratory Syncitial

VirusVirus

• HerpesvirusesHerpesviruses– HSV 1 & 2, VZV, CMV, EBVHSV 1 & 2, VZV, CMV, EBV

• RetrovirusesRetroviruses– HIV-1, HIV-2, HTLV-1HIV-1, HIV-2, HTLV-1

• Chronic HepatitisChronic Hepatitis– Hepatitis B and CHepatitis B and C

• PapillomavirusesPapillomaviruses ( ( 乳头瘤病毒乳头瘤病毒 ))

General schema of virus replication

Adsorption

Penetration

Uncoating

Protein and nucleic acid synthesis

Assembly

Release

Target cell

Virus particle

Adsorption

Penetration

Uncoating

Protein, nucleic acid synthesis,

Assembly

Release

Sites of Antiviral Drug ActionDocosonal (H)Chemokine receptor

blocking agents-(HIV)

AmantidineRimantidine (A)

Nucleoside analogues(H, HBV, HIV)

Nucleotide analogues(CMV, HBV, HIV)

Non-nucleoside Reverse transcriptase inhibitors

(HIV)Antisense oligonucleotides

(CMV)

Oseltamivir Zanamivir (I)

A Influenza AE EnterovirusesI Influenza A or BH Herpes virusesCMV CytomegalovirusHBV Hepatitis B virusHIV HIV

HIV Protease inhibitors

AAmantadinemantadine ( ( 金刚烷胺金刚烷胺 ))

• Inhibitors of Viral Uncoating (Adamantane Inhibitors of Viral Uncoating (Adamantane

derivatives)derivatives)

• Active against Influenza A onlyActive against Influenza A only• Prophylaxis and Treatment of Influenza AProphylaxis and Treatment of Influenza A• CNS excitation (Dizziness, insomnia, CNS excitation (Dizziness, insomnia,

anxiety); mild GI side effectsanxiety); mild GI side effects

Idoxuridine (Idoxuridine ( 碘苷，碘苷， IDUR)IDUR)

• Nucleotide analogues （ thymidine ）

• Topical use for Ophthalmological infections caused by Herpes Simplex viruses (HSV, 单纯疱疹病毒 ) or Varicella Zoster Virus (VZV ，水痘病毒 )

• Severe toxic effects caused by systemisystemic usec use

Vidarabine (Vidarabine ( 阿糖腺苷，阿糖腺苷， Ara-A)Ara-A)

• Nucleotide analoguesNucleotide analogues ( (purine purine nucleosidenucleoside))

• HSV HSV neonatal infection, CNS neonatal infection, CNS infection in adultsinfection in adults and VZV and VZV infectioninfection in AIDS in AIDS

• AcyclovirAcyclovir has replaced Ara-A in tr has replaced Ara-A in treatment of HSV and VZV infection.eatment of HSV and VZV infection.

Structure of acyclovir and related nucleoside analogues

Source: Balfour, HH Jr. Antiviral Drugs NEJM 340 (16):1255

For comparison only; not related to acyclovir

Mechanism of Action of Acyclovir in Cells Infected by Herpes Simplex Virus

Source: Balfour, HH Jr. Antiviral Drugs NEJM 340 (16):1255

AcyclovirAcyclovir

• Used in high dose IV formulation in Used in high dose IV formulation in HSV HSV neonatal infection, CNS infection in adultsneonatal infection, CNS infection in adults

• Used in lower dose for Used in lower dose for HSVHSV or VZV or VZV mucocutaneous disease treatment and mucocutaneous disease treatment and prophylaxisprophylaxis

• Frequent oral dosing necessaryFrequent oral dosing necessary• Toxicities more likely with high doseToxicities more likely with high dose

– Nausea, headache, crystal formation in renal Nausea, headache, crystal formation in renal tubulestubules

GanciclovirGanciclovir

• Approved for treatment, prevention of Approved for treatment, prevention of CMV diseaseCMV disease

• Toxicities mostly related to bone Toxicities mostly related to bone marrow suppressionmarrow suppression– Anemia, neutropenia, thrombocytopeniaAnemia, neutropenia, thrombocytopenia– CNS effectsCNS effects

Ribavirin• Synthetic guanosine analog Synthetic guanosine analog

• Once phosphorylated, interferes with Once phosphorylated, interferes with transcription of viral mRNA and synthesis of transcription of viral mRNA and synthesis of viral ribonucleoprotein complexesviral ribonucleoprotein complexes

• Available as aerosol for treatment of Available as aerosol for treatment of respiratory syncitial virus (RSV), oral tablet respiratory syncitial virus (RSV), oral tablet for Hepatitis for Hepatitis AA

• ToxicityToxicity– Bronchospasm (when used in inhaled Bronchospasm (when used in inhaled

formulation)formulation)– AAnemianemia– TeratogenicityTeratogenicity

Foscarnet

•Organic analogue of pyrophosphosphateOrganic analogue of pyrophosphosphate ((Trisodium phosphonoformate Trisodium phosphonoformate ))•Interferes with viral DNA synthesis: Blocks cleavage of Interferes with viral DNA synthesis: Blocks cleavage of pyrophosphatespyrophosphates•UseUse for treatment of CMV disease for treatment of CMV disease•Active against acyclovirActive against acyclovir--resistant HSV and resistant HSV and ganciclovir-resistant CMVganciclovir-resistant CMV•ToxicityToxicity

Renal toxicityRenal toxicity (dose-dependent) (dose-dependent) Electrolyte abnormalities Electrolyte abnormalities (drug chelates divalent cations)(drug chelates divalent cations): e.g. hypocalcemia: e.g. hypocalcemia

Antiretroviral therapy

for HIV Infection: principles

•In the absence of treatment, HIV replication is a continuous

process

•Plasma HIV RNA concentrations are prognostic and

represent a useful marker of clinical efficacy of a treatment

regimen

•Multidrug therapy is essential for maximal suppression

•Stabilization and improvement of immune function is

possible

•Is HIV Infection Curable? Today: No

General Schema of HIV replication

Target cell

Binding to CD4 and chemokine receptors

Fusion and entry

Assembly and Release

Reverse transcription

Nucleus

Viral RNA and Protein synthesis

Integration

Nucleoside Analogue Reverse transcriptase inhibitors ( 核苷反转录酶抑制剂， NRTI)

Azidothymidine (AZT) = Zidovudine Azidothymidine (AZT) = Zidovudine (ZDV)(ZDV)Azidothymidine (AZT) = Zidovudine Azidothymidine (AZT) = Zidovudine (ZDV)(ZDV)

AbacavirAbacavir

Mechanism of ActionMechanism of ActionChain Termination of DNA by Chain Termination of DNA by triphosphorylated formstriphosphorylated forms

Toxicities: NumerousToxicities: NumerousZidovudine (AZT)Zidovudine (AZT) 齐多夫定齐多夫定

AnemiaAnemia （贫血）（贫血）NeutropeniaNeutropenia （中性粒细胞减少）（中性粒细胞减少） ThrombocytopeniaThrombocytopenia （血小板减少）（血小板减少）Asthenia (Asthenia ( 无力无力 ))HeadacheHeadache （头痛）（头痛）GI upsetGI upset （胃肠道反应）（胃肠道反应）

Stavudine (Stavudine (DD4T)4T) 司他夫定司他夫定Peripheral neuropathyPeripheral neuropathy （外周神经（外周神经炎）炎） Lipodystrophy Lipodystrophy （脂肪代谢障碍）（脂肪代谢障碍）Pancreatitis Pancreatitis （胰腺炎）（胰腺炎）Lactic acidosis Lactic acidosis （乳酸性酸中毒）（乳酸性酸中毒） withwith hepatic steatosis (hepatic steatosis ( 肝脂肪变）肝脂肪变） Hyperlipidemia Hyperlipidemia （高脂血症）（高脂血症）

Non-Nucleoside Reverse transcriptase inhibitors

( 非核苷反转录酶抑制剂 NNRTI)

Nevirapine

Delavridine

EfavirenzEfavirenz

Mechanism of action Bind in a pocket approximately

10 Å away from the catalytic site where nucleotides bind.

Non-competitive inhibitors of template and substrate binding.

Adverse effects Rash and hypersensitivity

reactions (NVP>EFV) Liver dysfunction (NVP>EFV)

Mechanism of action Bind in a pocket approximately

10 Å away from the catalytic site where nucleotides bind.

Non-competitive inhibitors of template and substrate binding.

Adverse effects Rash and hypersensitivity

reactions (NVP>EFV) Liver dysfunction (NVP>EFV)

奈韦拉平奈韦拉平

依法韦恩茨依法韦恩茨

地拉韦定地拉韦定

HIV Protease Inhibitors

Polypeptide chainPolypeptide chain

NelfinavirNelfinavir

RitonavirRitonavir

SaquinavirSaquinavir

IndinavirIndinavir

Adverse effects:Adverse effects:

Nelfinavir - diarrheaRitonavir - GI intolerance,

hepatitis Indinavir - nephrolithiasis, GI

intolerance

奈非那韦奈非那韦

利多那韦利多那韦

沙奎那韦沙奎那韦

英地那韦英地那韦

Current Antiretroviral Medications

NRTI( 核苷反转录酶抑制剂 )

• Abacavir ABC• Didanosine DDI• Emtricitabine FTC• Lamivudine 3TC• Stavudine D4T• Zidovudine ZDV• Tenofovir TDF

NNRTI ( 非核苷反转录酶抑制剂 )

• Delavirdine DLV• Efavirenz EFV• Nevirapine NVP

PI( 蛋白酶抑制剂 )• Amprenavir APV• Atazanavir ATV• Darunavir DRV • Fosamprenavir FPV• Indinavir IDV• Lopinavir LPV• Nelfinavir NFV• Ritonavir RTV• Saquinavir SQV

– hard gel HGC– tablet INV

• Tipranavir TPV

Fusion Inhibitor• Enfuvirtide T-20

Initial Treatment: Initial Treatment: Preferred ComponentsPreferred Components

*Avoid in pregnant women and women with significant pregnancy potential.**Emtricitabine can be used in place of lamivudine and vice versa.

•Efavirenz* 依法韦恩茨依法韦恩茨

OR

•Atazanavir + ritonavir

•Fosamprenavir + ritonavir (BID)

•Lopinavir/ritonavir (BID)

NNRTI Option

PI Options

Tenofovir + emtricitabine**

Zidovudine + lamivudine**

+

NRTI Options

Thanks !

synthetic antimicrobial agents section 6 yun-bi lu, phd 卢韵碧 dept. of pharmacology, school of...

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