Transcript Anti-malarial drugs

Anti-parasitic drugs
(抗寄生虫药)
huifang Tang
[email protected]
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 antitricho-moniasis drugs(抗阿米巴
病和抗滴虫病药)
4. Anthelmintic drugs(抗肠蠕虫药)
Part1 1.
疟药)
Anti-malarial drugs(抗
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
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)
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 rel-apse.

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 in-fective
sporozoites(子孢子), which invad-es salivary
gland, become the source of infection.
Pyrimethamine can inhibit the deve-lopment
of ♂ and ♀ gametocytes in mos-quito to control
transmission of malaria.
Primaquine can kill various gameto-cytes of
subtertian and tertian malaria.
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 )
Anti-malarial drugs
Chloroquine(氯喹)
•Chloroquine is a synthetic 4-aminoquinoline
derivate
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.
Anti-malarial drugs
Chloroquine
Pharmacological effects
2. Immune inhibition
•Treatment of rheumatoid arthritis,
lupus erythematosus
3. Extraintestinal amebiasis
•Amoeba trophozoite amebic liver
abscess
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
ADME of chloroquine:
well absorbed after oral administration;
Tmax = 3 ~ 5 hr, t½> 1 week;
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.
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
Quinine(奎宁)
Anti-malarial drugs
quinine
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 schizontocide(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).
Anti-malarial drugs
quinine
Quinine is more toxic and less effective than
chloroquine.
but, it is especially valuable to treat:
①chloroquine-resistant and multidrugresistant subtertian malaria(耐氯喹和多药耐受的恶
性疟),
②severe cerebral malaria(严重的脑型疟).
(2)Adverse reaction: more.
①Cinchonism(金鸡纳反应):
ringing in the ears(耳鸣), headache, nausea,
disturbed vision, etc.
Anti-malarial drugs
quinine
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 erythrocytic stage, effective to chloroquineresistant 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 chloroquineresistant 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 .

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
Antimalarial drugs - Pyrimethamine
Pharmacological effects
•Inhibition of proliferation of sporozoite子孢子
to schizont 裂殖体
•Prophylaxis of infections
Mechanism of actions
•Dihydrofolate reductase inhibitor
Adverse effects
•Folate metabolism disturbtance
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 exo-erythrocytic
stage;
②It can also kill immature schizonts of
erythrocytic stage;
③It can not kill gametocytes(配子体),
but can inhibit development of sporophytes(孢子体) in mosquito.
Anti-malarial drugs
primethamine
(2)Clinical uses:
It is mainly used to prevent malaria, the first
chosen drug for malarial prev-ention.
(3)Adverse reaction:
Its toxicity is less.
But long-term and larger dose administration, 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;
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).
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 treatment 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 spec-trum
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 perme-ability
to certain monovalent and dival-ent cation,
particularly Ca2+, 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
anti-mony tartrate, 酒石酸锑钾).
After oral administration, it can
cause abdominal pain, nausea,
dizziness, and headache in shortterm.
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.
Anti-filariasis drugs
Diethylcarbamazine
Adverse effects
Generally mild and transient
Include headache, malaise, anorexia,
weakness, nausea, vomiting, and dizziness.