Transcript 汤慧芳_抗疟药

Anti-parasitic drugs
(抗寄生虫药)
Anti-parasitic drugs
1. Anti-malarial drugs(抗疟药)
2. Anti-schistosomiasis and antifilariasis drugs(抗血吸虫病和抗丝虫病
药)
3. Anti-amebiasis and antitrichomoniasis drugs(抗阿米巴病和抗
滴虫病药)
4. Anthelmintic drugs(抗肠蠕虫药)
Part1 1.
Anti-malarial drugs(抗疟药)
Part1
Antimalarial drugs (抗疟药)
•The malarial parasite(Plasmodium)(疟原虫), is
a very small, single-cell blood organism.
•It lives as a parasite in other organisms,
namely man and mosquito.
•The parasite is the cause of the tropical (热
带)disease malaria(疟疾).
Anti-malarial drugs
Anti-malarial drugs (抗疟药)
1. Biology of malarial parasite:
(1)Classification of malaria:
Human malaria is caused by 4 species of malarial
parasite(plasmodium, 疟原虫), include:
P. falciparum(恶性疟原虫),
P. vivax(间日疟原虫),
P. malariae(三日疟原虫),
P. ovale(卵形疟原虫).
Common malaria in our country are subtertian
malaria(恶性疟) and tertian malaria(间日疟).
The conditions of tertian malaria are milder,
therefore, it is called benign malaria(良性疟) too.
Anti-malarial drugs
Parasite Life Cycle
Anti-malarial drugs
(2)Life cycle of malarial parasite:
Although malaria can be transmitted by
transfusion of infected blood, human beings
are infected more commonly by sporozoites(子
孢子) injected by the bite of infected female
mosquitoes.
①Asexual propagated stage in human body;
②Sexual propagated stage in female mosquitoes.
Anti-malarial drugs
①Asexual propagated stage in human
body:
▲Exo-erythrocytic stage:
There are two types of sporozoites of tertian
malaria(间日疟), that is:
Tackysporozoite(速发型子孢子), and
Bradysporozoite(迟发型子孢子).
The tackysporozoites leave the circula-tion
and localized in liver cells, then they rapidly
transform, multiply and develop into
schizonts(裂殖体) and merozoites(裂殖子).
There are no symptoms in this stage.
Anti-malarial drugs
The bradysporozoites enter liver cells,
then go into hypnozoite(休眠期), they
become to dormancytes(休眠子), which is the
source of tertian malaria relapse.
• Pyrimethamine(乙胺嘧啶) can kill tackysporozoites in the exo-erythrocytic stage.
• Primaquine(伯氨喹) can kill bradysporozoites to radically treat tertian malaria (间
日疟), and prevent tertian malaria relapse.
Anti-malarial drugs
▲Erythrocytic stage:
The schizonts(裂殖体) then rupture,
each releasing thousands of merozoites (裂殖
子), then enter the circulation and invade
erythrocytes, initiate the eryth-rocytic stage,
and transform trophozoite (滋养体) and
schizonts, then release many merozoites.
There are a lot of symptoms in this
stage.
Chloroquine(氯喹), Quinine(奎宁), and
Artemisinin(青蒿素) are effective to this stage,
they can control the symptoms, and prevent
attack of malaria.
Anti-malarial drugs
②Sexual propagated stage in female mosquitoes:
Some erythrocytic malarial parasites differentiate
into sexual forms known as gametocytes(配子体).
The ♂ and ♀ gametocytes in the gut of the
mosquito combine to thezygote(合子), which develops in
the gut wall to infective sporozoites(子孢子), which
invades salivary gland, become the source of infection.
Pyrimethamine can inhibit the development of ♂
and ♀ gametocytes in mosquito to control transmission
of malaria.
Primaquine can kill various gametocytes of
subtertian and tertian malaria.
Anti-malarial drugs
Antimalarial drugs - Drug Classification
1. Tissue schizonticides 组织裂殖体杀灭剂
eliminate developing or dormant liver forms(红外期裂殖体);
---For control the prevention(预防) and relapse (复发)
2. Blood schizonticides 血裂殖体杀灭剂
act on erythrocytic parasites(红内期裂殖体);
---For control the symptom (症状)
3. Gametocides杀配子药 kill sexual stages and prevent
transmission to mosquitoes.
---For control the communication(传播)
氯喹
阿莫地喹
奎宁
奎尼丁
甲氟喹
伯氨喹
磺胺多辛-乙胺嘧啶
氯胍
多西环素
卤泛曲林
苯芴醇
青蒿素
阿托伐醌/氯胍
(马拉隆 )
青蒿素
氯喹
甲氟喹
奎宁
伯氨喹
磺胺多辛
四环素
阿托伐醌
/氯胍(马拉隆 )
氯喹
甲氟喹
奎宁
伯氨喹
磺胺多辛-乙胺嘧啶
阿托伐醌/氯胍(马拉隆 )
青蒿素
Anti-malarial drugs
Chloroquine(氯喹)
•Chloroquine is a synthetic 4-aminoquinoline
derivate
Anti-malarial drugs
Chloroquine
Mechanism of actions
•Accumulation in erythrocyte→PH↑ →
malarial pigment sythesis↓
•Haemoglobin-quinoline喹啉 compound →
haemoglobin accumulate in plasmodium ↑
•Insert in the double stranded DNA helix →
DNA replication and RNA transcription ↓
Anti-malarial drugs
Chloroquine
Pharmacological effects
1. Antimalarial effects:
erythrocytic stage
•Rapid schizonticidal(裂殖体杀灭剂)activity against all infections of
malaria species .
•gametocytocidal(杀配子体)against P. vivax, P. malariae and P. ovale
as well as immature gametocytes (stages 1-3) of P. falciparum.
•The effects are fast and lasting.
•The symptoms will vanish after oral administration of chloroquine in
24~48 h, blood malarial parasites disappear in 48 ~72 h, the
recurrence rate in one month is low.
2. Immune inhibition
•Treatment of rheumatoid arthritis, lupus erythematosus
3. Extraintestinal amebiasis
•Amoeba trophozoite amebic liver abscess
Anti-malarial drugs
Chloroquine
ADME of chloroquine
A: well absorbed after oral administration;
Tmax = 3 ~ 5 hr, t½> 1 week;
D: Widely distributed, the concentration in liver,
lung, and kidney is higher 200 ~ 700 times than
blood;
The concentration in erythrocyte is higher
20 ~ 30 times than plasma; the concentration in
infected erythrocyte by malarial parasite is
higher 25 times than normal erythrocyte.
M: 50% liver
E: principally excreted in the urine with an initial
half-life of 3–5 days but a much longer terminal
elimination half-life of 1–2 months
Anti-malarial drugs
Chloroquine
Clinical uses:
①Malaria:
▲to control the symptoms of benign malaria(良性疟);
▲to cure subtertian malaria(恶性疟);
▲symptomatic prevention in epidemic area(疫区的症
状性预防).
②Amebiasis(阿米巴病):
It can kill amebic trophozoite(滋养体), to treat
systemic amebiasis(肠外阿米巴病), such as amebic
hepatitis(阿米巴肝炎) and amebic hepatic abscess(阿米巴
肝脓肿).
③Immune disease(免疫性疾病).
Anti-malarial drugs
Chloroquine
Adverse reaction
Rare at the usual antimalarial dosage
Pruritus (搔痒症) common among dark-skinned
people.
Transient headaches, nausea, vomiting,
gastrointestinal symptoms and "blurred vision“.
Others: aplastic blood and neurological
disorders, such as polyneuritis多发性神经炎,
ototoxicity, seizures and neuromyopathy.
Anti-malarial drugs
Other angents kill erythrocytic parasites
1.Quinine 奎宁
2.Mefloquine甲氟喹
3.Pyronaridine 咯萘啶
4.Artemisinin青蒿素
5.Artemether and artesunate
蒿甲醚和青蒿琥酯
Anti-malarial drugs
quinine
Quinine(奎宁)
Quinine is the chief alkaloid of cincho-na(金鸡纳), the bark
of the South Ameri-can cinchona tree.
(1)Anti-malarial action and clinical uses:
Quinine acts primarily as a blood schi-zontocide(杀裂殖体
药) to control the clini-cal symptoms;
It is a gametocide for gametocytes(配子体) of P.
vivax(间日疟原虫) & P. malariae(三日疟原虫) also, but not
effective for game-tocytes of P. falciparum(恶性疟原虫).
Quinine is more toxic and less effective than chloroquine.
but, it is especially valuable to treat:
①chloroquine-resistant and multidrug-resistant
subtertian malaria(耐氯喹和多药耐受的恶性疟),
②severe cerebral malaria(严重的脑型疟).
Anti-malarial drugs
quinine
(2)Adverse reaction: more.
①Cinchonism(金鸡纳反应):
ringing in the ears(耳鸣), headache, nausea,
disturbed vision, etc.
②Myocardial depression(心肌抑制作用):
to reduce myocardial contractility, and slow down
conduction and prolong refra-ctory period, but weaker
than quinidine (奎尼丁, dextrogyre of quinine).
③Stimulating womb(兴奋子宫):
can induce abortion, not to be take by pregnant
woman.
④Idiosyncrasy(特异质反应):
acute hemolytic reaction.
Anti-malarial drugs
mefloquine
Mefloquine(甲氟喹)
(1)Anti-malarial action:
It is an efficient schizontocide in ery-throcytic
stage, effective to chloroquine-resistant subtertian
malaria.
(2)Clinical uses:
①to treat chloroquine-resistant subter-tian malaria.
②to prevent and control the symptoms of benign
malaria, once/two week.
(3)Adverse reaction:
GI reaction,
nervous and pschic reaction.
Anti-malarial drugs
Artemisinin(Qinghaosu, 青蒿素)
• (1)Anti-malarial
action:
•
It is a highly efficient malariacide of schizonts in
erythrocytic stage.
•
The effects are faster than that of chloroquine,
and effective to chloroquine-resistant subtertian
malaria, especially effective to cerebral malaria.
• (2)Clinical uses:
•
to treat chloroquine-resistant subter-tian malaria,
and to treat benign malaria also. but its recurrence
rate is high.
• (3)Adverse reaction: less,
•
GI reaction, occasionally serum GPT .
蒿甲醚 - 本芴醇
青蒿琥酯，阿莫地喹
双氢青蒿素 - 哌喹
Anti-malarial drugs
primaquine
Primaquine (伯氨喹)
(1)Anti-malarial action:
can kill dormancytes(休眠子) of tertian
malaria and various gametocytes(配子体) of
subtertian malaria. Owing to elimination fast,
the effects are not lasting.
Pharmacological effects
Highly active against the gametocytes配子体
of all malaria species →dissemination ↓
Active against hypnozoites迟发型子孢子of
the relapsing malarial parasites
The only drug currently used for the
treatment of relapsing malaria
Anti-malarial drugs
primaquine
Antimalarial drugs - Primaquine
(2)Mechanism of actions
Inhibition of coenzyme Q
Inhibition of reduction of NADP
(3)Clinical uses:
①use it with chloroquine to radically
treat benign malaria(良性疟);
②to prevent transmission of subtertian malaria(恶性疟).
Anti-malarial drugs
primaquine
(3)Adverse reaction:
Its toxicity is large
nervous system :Transient dizziness ,
nausea, vomiting, gastrointestinal
symptoms
blood system:Acute hemolytic anemia(急性
溶血性贫血), methemoglobinemia高铁血红
蛋白血症
Anti-malarial drugs
primethamine
Pyrimethamine(乙胺嘧啶)
(1)Anti-malarial action:
①It can kill schizonts(裂殖体) of subter-tian malarial
parasites and benign mala-rial parasites in
exoerythrocytic stage;
②It can also kill immature schizonts of erythrocytic
stage;
③It can not kill gametocytes(配子体), but can inhibit
development of sporop-hytes(孢子体) in mosquito.
Mechanism of actions
Dihydrofolate reductase inhibitor
Anti-malarial drugs
primethamine
(2)Clinical uses:
It is mainly used to prevent malaria, the first
chosen drug for malarial prevention.
(3)Adverse reaction: Folate metabolism disturbtance
Its toxicity is less.
But long-term and larger dose admi-nistration,
it can cause megaloblastic anemia(巨红细胞贫血).
This adverse reaction can be treated by formyl
tetrahydrofolic acid(甲酰四氢叶酸).
In addition, once large dose can cause acute
intoxication.
Anti-malarial drugs
3. Summarization:
(1)Selection of antimalarial drugs:
①Symptom control: Chloroquine;
②Cerebral malaria:
Artemisinin, im.
Quinine dihydrochloride, iv gtt(静脉滴注);
③Chloroquine-resistant subtertian malaria:
Artemisinin, Quinine, Mefloquine;
④Resting stage:
Pyrimethamine + Primaquine;
⑤Prevent transmission: Pyrimethamine.
(2)Combined administration:
Chloroquine + Primaquine;
Pyrimethamine + Primaquine(防止复发).
Atovaquone(阿托伐醌)
• Atovaquone, a hydroxynaphthoquinone , was initially
developed as an antimalarial agent
• Atovaquone has also been approved by the FDA for the
treatment of mild to moderate P jiroveci pneumonia.
• Malarone, a fixed combination of atovaquone (250 mg) and
proguanil (100 mg)
– highly effective for both the treatment and chemoprophylaxis of
falciparum malaria（恶性疟疾）, and it is now approved for both
indications in the USA.
– For chemoprophylaxis, Malarone must be taken daily. It has an
advantage over mefloquine and doxycycline in requiring shorter periods
of treatment before and after the period at risk for malaria
transmission, but it is more expensive than the other agents. It should
be taken with food.
Part2 Anti-schistosomiasis drugs
(抗血吸虫药)
Schistosomiasis(血吸虫病) is caused by
Schistosoma(血吸虫, 裂体吸虫) infection.
•
There are five kinds of Schistosoma caused
Schistosomiasis of human:
•
S. japonia(日本血吸虫), S. heamatobium (埃及血吸
虫), S. mansoni(曼索血吸虫), S. intercalatum(间插血吸
虫) and S. mekongi (湄公血吸虫).
•
In our country, the schistosomiasis is caused
mainly by S. japonia.
•
肝硬化主征
巨
脾
腹
水
门脉高压
Anti-schistosomiasis drugs
•In the past, the drug treated schistosomiasis was PAT(酒石酸锑钾, potassium
antimony tartrate), its course of treat-ment
was longer, the toxicity larger, need iv
administration, and the ADRs were severe.
• Since 1970’, praziquantel(吡喹酮) had be
discovered, because its ADRs is less,
praziquantel became the main drug to treat
schistosomiasis.
Anti-schistosomiasis drugs
praziquantel
Praziquantel(吡喹酮)
(1)Anti-parasite effects:
It is a highly effective and broad
spectrum anti-parasite drug.
It can kill schistosoma(血吸虫) directly;
and it can kill other trematde(吸虫) too, e.g.
clonorchis sinensis(华支睾吸虫, 即“肝吸虫”),
lung fluke(肺吸虫), fasciolopsis(布氏姜片虫, 即
“肠吸虫”); certain intestinal parasites(e.g.
tapeworm(绦虫).
Mechanism of anti-schistosoma effects:
It can increase the membrane permeability
to certain monovalent
and divalent cation,
2+
particularly Ca , to cause schistosoma
muscular contraction and spastic paralysis.
Anti-schistosomiasis drugs
praziquantel
(2)Clinical uses:
①Schistosomiasis(血吸虫病):
It is effective to both acute & chronic
schistosomiasis.
To acute schistosomiasis:
It is to bring down the fever, and
alleviate the systematic symptoms fast,
the late results reach 90%;
To chronic schistosomiasis:
The curative effect is well too, only
1～2 days of course of treatment, the
late results reach 90% too.
To the later period patients with cardiac
and hepatic complication:
can accept the course of treatment
smoothly.
Anti-schistosomiasis drugs
praziquantel
②Clonorchiasis(华枝睾吸虫病):
It is the first-chosen drug.
③Other trematode(其他吸虫):
Used to treat paragonimiasis(肺吸虫病)
and fasciolopsiasis(姜片虫病).
It is the first-chosen drug.
④Taeniasis(绦虫病):
Including imago(成虫) & larva(幼虫) of
various tapeworm(绦虫) infective disease,
such as cysticercisis(囊虫症——猪囊虫尾蚴病)
and hydatidosis(包虫病——由细粒棘球绦虫的幼
虫引起).
It is the first-chosen drug too.
Anti-schistosomiasis drugs
praziquantel
(3)Adverse reaction
less and lighter (than potassium antimony tartrate, 酒石酸锑钾).
After oral administration, it can
cause abdominal pain, nausea, dizziness,
and headache in short-term.
Other drugs that act against termatodes
Bithionol ( 硫双二氯酚 )
1. Clinical use—Bithionol is a codrug of choice (with
triclabendazole(三氯苯达唑) for treatment of fascioliasis(肝吸虫)
(sheep liver fluke) and an alternative agent in paragonimiasis(肺
吸虫).
2. The mechanism of action : unknown.
3. Pharmacokinetic : Bithionol is orally effective and is eliminated in
the urine.
4. Toxicity
• Common adverse effects of bithionol include nausea and vomiting,
diarrhea and abdominal cramps, dizziness, headache, skin rash
(possibly a reaction to dying worms), and phototoxicity.
• Less frequently, pyrexia, tinnitus, proteinuria, and leukopenia
may occur.
Other drugs that act against termatodes
Metrifonate (敌百虫)
• Organophosphate prodrug
• Mechanisms: Converted in the body to the
cholinesterase inhibitor dichlorvos. The active
metabolite acts solely against Schistosoma
haematobium (埃及血吸虫)(the cause of
bilharziasis).
• Toxic effects occur from excess cholinergic
stimulation.
• The drug is contraindicated in pregnancy.
Other drugs that act against termatodes
Oxamniquine(奥沙尼喹)
• Oxamniquine is effective solely in Schistosoma
mansoni (曼氏血吸虫)infections (intestinal
bilharziasis肠裂体吸虫病), acting on male immature
forms and adult schistosomal forms.
• The drug causes paralysis of the worms, but its
precise mechanism is unknown.
• Toxicity: Dizziness is a common adverse effect (no
driving for 24 h); headache, gastrointestinal
irritation, and pruritus may also occur. Reactions to
dying parasites include eosinophilia, urticaria, and
pulmonary infiltrates. It is not advisable to use the
drug in pregnancy or in patients with a history of
seizure disorders.
C. anti-filariasis drugs
(抗丝虫病药)
Anti-filariasis drugs
下肢象皮肿
阴囊象皮肿
Anti-filariasis drugs
Diethylcarbamazine 乙胺嗪
Pharmacology action
Diethylcarbamazine immobilizes microfilariae(微丝
蚴)and alters their surface structure, displacing them
from tissues and making them more susceptible to
destruction by host defense mechanisms.
The mode of action against adult worms is unknown.
Adverse effects
Generally mild and transient
Include headache, malaise, anorexia, weakness,
nausea, vomiting, and dizziness.
Anti-filariasis drugs
Ivermectin( 伊维菌素)
• Mechanisms
– Ivermectin intensifies γ-aminobutyric acid (GABA)-mediated
immobilization
of parasites, facilitating their removal by
the reticuloendothelial system.
– Selective toxicity results because in
humans GABA is a neurotransmitter only in
the CNS, and ivermectin does not cross the
blood-brain barrier.
neurotransmission in nematodes and causes
• Clinical use
ciasis,
cutaneous larva migrans, strongyloidiasis,
and some forms of filariasis.
– Ivermectin is the drug of choice for onchocer
• Toxicity
美拉胂醇
硝呋莫司
锥虫病
T锥虫
戊双脒
锥虫病和肺囊虫感染
弓形虫病
葡萄糖酸锑钠
苏拉明
利什曼病