Download 20111215_yunbi_chemotherapeutic_Drugs_III

Section 6
Synthetic antimicrobial agents
Yun-Bi Lu, PhD
卢韵碧
Dept. of Pharmacology,
School of Medicine, Zhejiang University
[email protected]
Contents
• Quinolones ( 喹诺酮类)
• Sulfonamides ( 磺胺类)
• Other Synthetic antimicrobial
Trimethoprim (甲氧苄啶)
Nitrofurans (硝基呋喃类)
Contents
• Quinolones ( 喹诺酮类)
• Sulfonamides ( 磺胺类)
• Other Synthetic antimicrobial
Trimethoprim (甲氧苄啶)
Nitrofurans (硝基呋喃类)
From chloroquine to nalidixic acid
喹诺酮类 (Quinolones)
Generation
1
2
3
4
Example
Nalidixic acid
Pipemidic acid
Norfloxacin
Clinfloxacin
time
萘啶酸
1962
吡哌酸
1973
诺氟沙星
克林沙星 1990’s
First generation fluoroquinolones
From ofloxacin to levofloxacin
Fluoroquinolones
Fluoroquinolones
• broad antimicrobial activity
• effective after oral administration
• relatively few side effects
• resistance to their action does not
develop rapidly.
General properties of Quinolones
1. Antimicrobial activity & spectrum:
(1) bactericidal and have significant PAE.
(2) aerobic G- bacteria, Pesudomonas,
aerobic G+ bacteria, Chlamydia spp.（衣
原体）, Legionella pneumophila(军团菌) ,
anaerobic bacteria, mycobacteria(分枝杆
菌), multiple-resistance strains.
Mechanism of action
DNA gyrase
Topoisomerase
Key enzymes in DNA replication: bacterial DNA is supercoiled.
Mechanism of action
porin
DNA gyrase
Gram (-)
Topo
isomerase
Gram (+)
Mechanism of action
DNA gyrase
Catalytic subunite
Fluoroquinolones:
4 stacked molecules
DNA gyrase
ATP binding subunite
Mechanism of resistance
decreased
permeability
active efflux
system
porin
DNA gyrase
Gram (-)
Topo
isomerase
mutation of
the enzymes
Gram (+)
ADME of fluoroquinolones
• Absorption: well absorbed; bound by divalent
cations
– Do not administer with iron, magnesium, calcium
• Distribution: all distribute widely (even in CSF),
and most concentrate in urine
• Metabolism:
– hepatic metabolism diminishes the activity of
norfloxacin and ciprofloxacin
– Several have predominately hepatic clearance
(Grepafloxacin, Sparfloxacin, Trovafloxacin)
• Excretion: urinary excretion predominates for the
first generation fluoroquinolones
ADME of fluoroquinolones
Clinical Uses
•
•
•
•
Urinary tract infections.
GI and abdominal infections.
Respiratory tract infections.
Bone, joint and soft tissues infections,
Osteomyelitis.
• Meningitis
• STD: Neisseria gonorrhea (奈瑟氏淋球
菌)and Chlamydia (衣原体，Quinolone
resistance in gonorrhea increasing)
Adverse reactions
•Gastrointestinal effects.
•CNS side effects.
•Allergic reaction.
•Hepatotoxicity, nephrotoxicity.
•Joint/cartilage toxicity, Tendinopathy
–Achilles tendon rupture
–Limited FDA approval for children
Fluoroquinolones agents
•
•
•
•
•
•
•
•
•
Norfloxacin
(诺氟沙星)
Ciprofloxacin (环丙沙星)
Ofloxacin (氧氟沙星)
Levofloxacin (左氧氟沙星)
Lomefloxacin (洛美沙星)
Fleroxacin (氟罗沙星)
Sparfloxacin (司帕沙星)
Clinafloxacin
(克林沙星)
Gatifloxacin
(加替沙星)
Contents
• Quinolones ( 喹诺酮类)
• Sulfonamides ( 磺胺类)
• Other Synthetic antimicrobial
Trimethoprim (甲氧苄啶)
Nitrofurans (硝基呋喃类)
Inhibitors of Folate Synthesis
2,4-Diaminoazobenzen-4’-sulfonamide
Prontosil
Gerhard Domagk
Nobel Laureate 1939
First Aid Packet carried by U.S. Soldiers in World War II
http://home.att.net/~steinert/wwii.htm
Sulfonamides
Antimicrobial activity:
• A wide antimicrobial spectrum.
• Exerting only bacteriostatic effect.
Mechanism of action
Pteridine+PABA
Dihydropteroate
synthase
Blocked by
sulfonamides
Dihydropteroic acid
glutamate
Dihydrofolic acid
Dihydrofolate
reductasease
NADPH
Blocked by trimethoprim
NADPH
Tetrahydrofolic acid
Mechanism of Resistance
• A lower affinity for sulfonamides by the
dihydropteroate synthase
• Decreased cell permeability or active efflux
of the drug
• An alternative pathway to synthesis the
essential metabolites
• An increased production of essential
metabolites
ADME of sulfonamides
• Approximately 70%-100% of an oral
dose is absorbed.
• Distributing throughout all tissues of
the body, even in CSF ( sulfadiazine
and sulfisoxazole, may be effective in
meningeal infections) ;readily passing
though the placenta.
• Metabolized in the liver by acetylation.
ADME of sulfonamides
• Eliminated mainly in the urine as the
unchanged drug and metabolic
product. In acid urine, the eliminated
may precipitate, thus induced renal
disturbance.
Clinical uses
• Systemic infections.
• Intestinal infections.
• Infections of burn and wound.
Adverse reactions
•
•
•
•
•
•
Urinary tract disturbances
Hypersensitivity reaction
Hematopoietic system disturbances
Kernicterus (胆红素脑病)
Hepatitis
GI effects
Drugs interactions
• All sulfonamides are bound in varying
degree to plasma protein.
Classification:
•
•
•
•
•
•
•
Oral absorbable agents
Short-acting agents
Medium-acting agents
Long-acting agents
Oral nonabsorbable agents
Topical agents
Combination agents
Oral absorbable agents
• Short-acting agents
Sulfafurazole (SIZ,菌得清)
• Medium-acting agents
Sulfadiazine (SD,磺胺嘧啶)
Sulfamethoxazole (SMZ,新诺明)
• Long-acting agents
Sulfadoxine (SDM，周效磺胺)
Oral nonabsorbable agents
Sulfasalazine (柳氮磺吡啶 )
Topical agents.
Mafenide (SML, 甲磺灭脓)
Sulfadiazine sliver (磺胺嘧啶银)
Sulfacetamide (SA,磺胺醋酰）
Combination agents
Co-trimoxazole (复方新诺明)
1) Features
• Trimethoprim(甲氧苄啶) in combination
with Sulfamethoxazole(1:5) exerts a
synergistic effects.
• The ADME of the two agents is similar.
• Co-block essential enzymes of folate
metabolism.
Pteridine+PABA
Dihydropteroate
synthase
Blocked by
sulfonamides
Dihydropteroic acid
glutamate
Dihydrofolic acid
Dihydrofolate
reductasease
NADPH
Blocked by trimethoprim
NADPH
Tetrahydrofolic acid
2)Clinical Uses
• Chronic and recurrent infections in the
urinary tract
• Bacterial respiratory infections
• GI infections (e.g. induced by Salmonella)
• pneumocystis carinii pneumonia (肺囊虫性
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
Other Synthetic antimicrobial
• Trimethoprim (甲氧苄啶)
• Nitrofurans (硝基呋喃类)
Nitrofurantoin(呋喃妥因)
Section 7
Antifungal agents
Antifungal agents
Onychomycosis
Antifungal agents
Onychomycosis
（甲癣）
Fungal infections traditionally have
been divided to two distinct classes:
systemic and superficial. So, the major
antifungal agents are described with
“systemic” and “topical”.
Invasive fungal disease
Ubiquitous pathogens act as opportunists
Candida species (念珠菌属)
Aspergillus species (曲霉菌属)
Cryptococcus (隐球菌属)
Endemic mycoses
Histoplasmosis (组织胞浆菌病)
Coccidioidomycosis (球孢子菌病)
Blastomycosis (芽生菌病)
Oral infection with Candida (Thrush 鹅口疮)
http://vasculitis.med.jhu.edu/treatments/cytoxan.html
www.thachers.org/ internal_medicine.htm
Invasive Aspergillosis
AA= aortic arch, a = aneurysm
SC = 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.
Classification of antifungal agents
• 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）
Antifungal Medications
Polyenes
Amphotercin B（两性霉素B）
broad-spectrum
Amphotercin B
1. Mechanism of action
Amphotercin B
2. Clinical Uses:
• Amphotericin B remains the drug of choice
for all life-threatening mycotic infections (It is
often as the initial regimen).
• E.g. Cryptococcal meningitis
Amphotercin B
3. Adverse reactions:
(1) fever, chill, hyperpnea（喘息）,
myalgia（肌痛） and hypotension, etc.
（~75%）
(2) nephrotoxic
(3) renal tubular acidosis（肾小管酸化）
and renal wasting K+ and Mg 2+
(4) hematological Toxicity: hypochromic
（低血红蛋白性）and normocytic（正
常色素性） anemia, etc.
Amphotercin B
3. Adverse reactions:
(5) hepatotoxicity
(6) cardiac toxicity
(7) CNS side effects
(8) hypersensitive reaction
Amphotercin B
4. Prevention of adverse reaction:
(1) Pretreatment with oral
acetaminophen or use of intravenous
hydrocortisone hemisuccinate.
(2) Supplemental K+ is required.
(3) Do physical examination termly.
(4) drug interactions
Amphotercin B
5. New formulations of Amphotercin B :
(脂质复合体)
(胶质分散体)
(脂质体)
Topical antifungal agents
Polyenes :
nystatin（制霉菌素）
griseofulvin（灰黄霉素）
- Nucleoside analogue
Allylamines:
terbinafine（特比萘芬）
- squalene epoxidase inhibitor
(角鲨烯环氧化酶抑制剂)
Azoles 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 agents
Mechanism of action:
• reduce ergosterol synthesis by interfering
with lanosterol （14a）- demethylase
• inhibition of fungal cytochrome P450 enzyme
Antifungal activity :
• Systemically
(ketoconazle,
itraconazole) or topically
clotrimazole).
fluconazole,
(miconazole,
Azoles antifungal agents
Ketoconazle （酮康唑） :
• the first oral azoles introduced into clinical use
(systemically or topically).
• less selective for fungal P450
• clinical use has been limited by endocrine side
effects, liver toxicity and the drug interactions.
• itraconazole （伊曲康唑）or fluconazole （氟康唑）
has replaced ketoconazle for patients who can afford
the more expensive, newer product.
Azoles antifungal agents
Itraconazole （伊曲康唑）
• Its antifungal spectrum is broader than
kotoconazole, and its side effects is less
than kotoconazole.
Azoles antifungal agents
Fluconazole （氟康唑）
• good water solubility and good CSF
penetration
• drug interactions and side effects are also
less because of its least effect on hepatic
enzyme of all the azoles.
• Be used in:
(1) Candidiasis（念珠菌病）,
(2) Cryptococcosis（隐球菌病）,
(3) others.
Flucytosine（氟胞嘧啶）
Flucytosine： Mechanism of action
5-FC
Cytosine permease
5-FC
Cytosine deaminase
5-FC
5-FU
Phosphorylation
Conversion to
deoxynucleosides
FdUMP
dUMP
FdUMP
FUTP
dTMP
Substitution for uracil
Inhibition of Protein Synthesis
Ihibition of thymidylate synthase
Inhibition of DNA synthesis
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
Flucytosine
• a norrow-spectrum antifungal drug.
• drug resistance occurs rapidly
when flucytosine is used alone.
• flucytosine is used predominantly
in combination with amphotericin B
for therapy of crypotococcal
meningitis in AIDS patient, etc.
Flucytosine
Adverse reactions:
• depressing the function of bone
marrow (leading to leukopenia and
thrombocytopenia, etc.).
• Plasma levels of hepatic enzymes
are elevated (reversible).
• rash, nausea, vomiting, diarrhea.
Section 8
Antiviral agents
Essential Characteristics of Viruses
• Genome (RNA or DNA) packaged in a
protein core
• Intracellular parasitism
– No ribosomes or mitochondria
– Utilize cellular machinery for synthesis of
macromolecules
• Antiviral therapies target
– Entry into cells
– Virus utilization of cellular machinery
– Or stimulate immune clearance
Specific Antiviral Therapy for
• Respiratory Viruses
– Influenza, Respiratory Syncitial
Virus
• Herpesviruses
– HSV 1 & 2, VZV, CMV, EBV
• Retroviruses
– HIV-1, HIV-2, HTLV-1
• Chronic Hepatitis
– Hepatitis B and C
• Papillomaviruses (乳头瘤病毒)
General schema of virus replication
Virus particle
Adsorption
Penetration
Uncoating
Target cell
Protein and nucleic acid synthesis
Assembly
Release
Docosonal (H)
Chemokine receptor
blocking agents-(HIV)
Sites of Antiviral Drug Action
Amantidine
Rimantidine (A)
Adsorption
Penetration
Nucleoside analogues
Uncoating
(H, HBV, HIV)
Nucleotide analogues
(CMV, HBV, HIV)
Protein, nucleic acid synthesis,
Non-nucleoside Reverse
transcriptase inhibitors
(HIV)
Antisense oligonucleotides
(CMV)
Assembly
HIV Protease
inhibitors
Release
Oseltamivir
Zanamivir (I)
A
E
I
H
CMV
HBV
HIV
Influenza A
Enteroviruses
Influenza A or B
Herpes viruses
Cytomegalovirus
Hepatitis B virus
HIV
Amantadine (金刚烷胺)
• Inhibitors of Viral Uncoating (Adamantane
derivatives)
• Active against Influenza A only
• Prophylaxis and Treatment of Influenza A
• CNS excitation (Dizziness, insomnia,
anxiety); mild GI side effects
Idoxuridine (碘苷，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
systemic use
Vidarabine (阿糖腺苷，Ara-A)
• Nucleotide analogues (purine
nucleoside)
• HSV neonatal infection, CNS
infection in adults and VZV
infection in AIDS
• Acyclovir has replaced Ara-A in
treatment of HSV and VZV
infection.
Structure of acyclovir and related nucleoside analogues
For comparison only; not related to acyclovir
Source: Balfour, HH Jr. Antiviral Drugs NEJM 340 (16):1255
Mechanism of Action of Acyclovir in Cells Infected
by Herpes Simplex Virus
Source: Balfour, HH Jr. Antiviral Drugs NEJM 340 (16):1255
Acyclovir
• Used in high dose IV formulation in HSV
neonatal infection, CNS infection in adults
• Used in lower dose for HSV or VZV
mucocutaneous disease treatment and
prophylaxis
• Frequent oral dosing necessary
• Toxicities more likely with high dose
– Nausea, headache, crystal formation in renal
tubules
Ganciclovir
• Approved for treatment, prevention of
CMV disease
• Toxicities mostly related to bone
marrow suppression
– Anemia, neutropenia, thrombocytopenia
– CNS effects
Ribavirin
• Synthetic guanosine analog
• Once phosphorylated, interferes with
transcription of viral mRNA and synthesis
of viral ribonucleoprotein complexes
• Available as aerosol for treatment of
respiratory syncitial virus (RSV), oral
tablet for Hepatitis A
• Toxicity
– Bronchospasm (when used in inhaled
formulation)
– Anemia
– Teratogenicity
Foscarnet
•Organic analogue of pyrophosphosphate
(Trisodium phosphonoformate )
•Interferes with viral DNA synthesis: Blocks cleavage of
pyrophosphates
•Use for treatment of CMV disease
•Active against acyclovir-resistant HSV and
ganciclovir-resistant CMV
•Toxicity
Renal toxicity (dose-dependent)
Electrolyte abnormalities
(drug chelates divalent cations): 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
Binding to CD4 and chemokine receptors
Target cell
Fusion and entry
Reverse transcription
Integration
Nucleus
Viral RNA and Protein synthesis
Assembly and Release
Nucleoside Analogue Reverse transcriptase
inhibitors (核苷反转录酶抑制剂， NRTI)
Mechanism of Action
Chain Termination of DNA by
triphosphorylated forms
Toxicities: Numerous
Zidovudine (AZT) 齐多夫定
Anemia（贫血）
Neutropenia（中性粒细胞减少）
Thrombocytopenia（血小板减少）
Asthenia (无力)
Headache（头痛）
GI upset（胃肠道反应）
Abacavir
Azidothymidine (AZT) = Zidovudine (ZDV)
Stavudine (D4T) 司他夫定
Peripheral neuropathy（外周神经炎）
Lipodystrophy （脂肪代谢障碍）
Pancreatitis （胰腺炎）
Lactic acidosis （乳酸性酸中毒）
with hepatic steatosis (肝脂肪变）
Hyperlipidemia （高脂血症）
Non-Nucleoside
Reverse transcriptase inhibitors
(非核苷反转录酶抑制剂 NNRTI)
Nevirapine
奈韦拉平
Efavirenz
依法韦恩茨
Delavridine
地拉韦定
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)
HIV Protease Inhibitors
Polypeptide chain
Nelfinavir
奈非那韦
Ritonavir
利多那韦
Saquinavir
沙奎那韦
Indinavir
英地那韦
Adverse effects:
Nelfinavir - diarrhea
Ritonavir - GI intolerance,
hepatitis
Indinavir - nephrolithiasis, GI
intolerance
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
• Atazanavir
• Darunavir
• Fosamprenavir
• Indinavir
• Lopinavir
• Nelfinavir
• Ritonavir
• Saquinavir
– hard gel
– tablet
• Tipranavir
APV
ATV
DRV
FPV
IDV
LPV
NFV
RTV
SQV
HGC
INV
TPV
Fusion Inhibitor
• Enfuvirtide
T-20
Initial Treatment:
Preferred Components
NNRTI Option
NRTI Options
•Efavirenz*依法韦恩茨
OR
PI Options
+
•Atazanavir + ritonavir
•Fosamprenavir + ritonavir (BID)
•Lopinavir/ritonavir (BID)
*Avoid in pregnant women and women with significant
Tenofovir +
emtricitabine**
Zidovudine +
lamivudine**
pregnancy potential.
**Emtricitabine can be used in place of lamivudine and vice versa.
Thanks !