Anti-malarial drugs Flashcards
1
Q
Four species of plasmodium typically cause human malaria
A
Plasmodium falciparum
P vivax
P malariae
P ovale
2
Q
Which specie is responsible for the majority of serious complications and deaths?
A
P falciparum
3
Q
Malaria
-Parasite life cycle
A
- mosquito inoculates sporozoites to initiate human infection
- sporozoites invade liver cells –> exoerythrocytic stage: tissue schinzonts mature in the liver
- from liver –> merozoites. Only erythrocytic parasites cause clinical illness
- Sexual stage gametocytes also develop in erythrocytes before being taken up by mosquitoes, where they develop into –> infective sporozites
- in P falciparum and P malariae infection, treatment that eliminates erythrocytic parasites will cure these infections
- in P vivax and P ovale infections, a dormant hepatic stage, the hypnozoite, is not eradicated by most drugs and relapses can occur
4
Q
- Which stage of infections causes clinical malaria?
2. All effective antimalarial treatment are?
A
- Only the asexual erythrocytic stage
2. Blood schinzonticides that kill this stage
5
Q
Only drug that is able to kill quiescent hypnozoites
A
Primaquine
6
Q
Drugs that act on hepatic schizonts during initial infection
A
Atovaquone-proguanil
7
Q
Drugs that act on blood-stage schinzonticides
A
Atovaquone–proguanil,
Doxycycline,
Mefloquine,
Chloroquine
8
Q
Antimalarial drugs
-treatment
A
- Chloroquine –> most nonfalciparum and falciparum infections from areas without known resistance
- Malarone (atavaquone and proguanil) –> uncomplicated falciparum malaria from most areas
- Mefloquine, quinine, halofantrine –> against resistant falciparum malaria
- Intravenous artesunate, quinidine, quinine –> severe falciparum malaria
- Primaquine –> Vivax and ovale malaria, to eradicate liver forms
9
Q
Chloroquine
- pharmacokinetics
- action
A
-initial 1/2 life of 3-5 days but much longer terminal elimination 1/2 of 1-2 month
- effective against blood and gameto forms
- preventing the biocrystallization of the hemoglobin breakdown product heme into hemozoin –> accumulation of heme is toxic to the parasite
- highly effective blood schonzonticide
- not active against liver stage
10
Q
Chloroquine
- basis of resistance
- clinical uses
A
-mutations in putative transporter
- chemoprophylaxis of malaria, amebic liver abscesses, rheumatological diseases
- treatment of uncomplicated malaria,
- rapidly terminates fever and clears parasitemia,
- does not eliminate dormant liver forms of P vivax and P ovale –> primaquine
11
Q
Chloroquine
-adverse effects
A
- usually well tolerated
- ECG changes, severe hypotension, dermatitis
-safe in pregnancy and for young children
12
Q
Quinine
- pharmacokinetics
- action
A
-effective in blood and gameto forms
- mechanism of action is unknown
- gametocidal against P vivax and P ovale
- not active against liver stage parasites
13
Q
Quinine
-clinical uses
A
- treatment of severe palciparum malaria (i/v)
- treatment of falciparum malaria (oral)
- severe, uncomplicated malaria commonly with second drug (doxycycline, in children with clindamycin)
- generally not used for chemoprophylaxis
14
Q
Quinine
- unwanted effects
- contraindications and drug interactions
A
- cinchonism (visual and hearing disturbances, GI distress, headache, virtigo)
- hypoglycemia
- blackwater fever
- underlying visual and auditory problems
- should not be given together with mefloquine
15
Q
Mefloquine
- pharmacokinetics
- action
A
-elimination 1/2 life is about 20 days
- mechanism of action is unknown
- strong blood schinzonticidal activity against P falciparum and P vivax
- not active against hepatic stages or gametocytes
16
Q
Mefloquine
- clinical uses
- adverse effects
A
- uncomplicated falciparum malaria
- combination of artesunate + mefloquine
- chemoprophylaxis of malaria –> against most strains of P falciparum and probably all other species
-potential neurologic and psychiatric toxicities
17
Q
Mefloquine
-contraindication and drug interactions
A
- history of epilepsy, psychiatric disorders
- should not be combined with quinine and mefloquine
18
Q
Artesunate
- pharmacokinetics
- action
A
- water soluble, oral, i/v, rectal
- not useful for chemoprophylaxis because of their short 1/2 lives
- effective against blood forms
- metabolized in the food vacuole of the parasite and forming toxic free radicals
- rapidly acting on blood schinzonticides against all malaria parasites
- no effect on hepatic stages
19
Q
Artesunate
- clinical uses
- adverse effects
- pregnancy
A
- first line treatment of uncomplicated falciparum malaria
- treatment of complicated falciparum malaria
-very well tolerated
- uncomplicated falciparum malaria: second and third trimester of pregnancy
- severe malaria in first, second and third trimesters
20
Q
Primaquine
-action
A
- mechanism of action is unknown
- active against hepatic stages of malaria parasites
- active against the dormant hypnozoite stages of P vivax and P ovale
- gametocidal against the four malaria species
- weak activity against erythrocytic stage parasites
liver, hypno and gameto stages
21
Q
Primaquine
-clinical uses
A
- chemoprophylaxis of malaria - only when mefloquine, atovaquone and proguanil, doxycycline cannot be used
- treatment of acute vivax and ovale malaria (radical cure)
- terminal prophylaxis vivax and ovale malaria a
- gametocidal action
- Pneumocystis Jiroveci infection
22
Q
Primaquine
- adverse effects
- contraindications and cautions
- pregnancy
A
- generally well tolerated, hemolysis or methemoglobinemia (manifested by cyanosis), especially with G6PD deficiency
- should be tested for G6PD deficiency –> if positive, use chloroquine
- should be avoided!
23
Q
Atovaquone
-action
A
- disrupt mitochondrial electron transport
- active against tissue and erythrocytic schizonts, allowing chemoprophylaxis to be discontinued only 1 week after the end of exposure (compared with 4 weeks for mefloquine or doxycycline, which lack activity against tissue schizonts)
- effective in the blood and liver stages
24
Q
Atovaquone
-clinical uses
A
- acute, uncomplicated P falciparum malaria
- chemoprophylaxis of malaria
- Pneumocystis Jiroveci infection
25
Q
Inhibitors of folate synthesis
- name
- pharmacokinetics
- action
A
- Proguanil (atovaquone and proguanil)
- 1/2 life is about 16h - for chemoprophylaxis daily
- proguanil –> some activity against hepatic forms
26
Q
Inhibitors of folate synthesis
- clinical uses
- adverse effect
A
- treatment of chloroquine- resistant falciparum malaria
- intermittent preventive therapy
- chemoprophylaxis of malaria - not recommended
- toxoplasmosis - first line therapy
- Pneumocystis Jiroveci infection - first line therapy
- generally very well tolerated
- safe to be used in pregnancy
27
Q
Doxycycline
-clinical uses
A
- treatment of falciparum malaria with quinine
- chemoprophylaxis of malaria
- effective in the blood form
