Antiprotozoal Drugs Flashcards by Maria Haslacher

General concepts of protozoa

= single cell organism: parasites (req. vector)
Eukaryotic–> harder to selectively target

Most frequent infections
   Malaria
   Amebiasis 
  Toxoplasmosis
   Leishmaniasis

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Malaria
Life Cycle
Strains

Most frequent disease in the world; spread by mosquitos
Mostly imported to Europe

Life Cycle
Malaria: sporozoites–> human. –> liver cell
development of schizont–> rupture and release
merozoites.

   Merozoites enter RBC--> asexual multiplication. Some: 
   sexual multiplication (gametocytes). Rupture of RBS

RBC Cycle continues endlessly producing symptoms
Hepatic Cycle only occurs once/infection

Strains
Plasmodium Malariae
Falciparum: most widepread and resistance. CNS malaria
Vivax: stays in liver; can reactivate post treatment
Ovale: stays in liver; can reactivate post treatment

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Malaria

Symptoms
Drugs

Can be fatal within a couple of days
Intermittant fever: erythrocytic phase
Head and muscle aches
Haemolytic anaemia, splenomegaly, jaundice
Haemoglobinuria if severe enough

Drugs
   Primary tissue schizotocidal effect
   Blood schizotocidal effect
   Gametocidal effect
   Spotontocidal effect: kill sporozoa in mosquito
   Secondary tissue schizotocidal effect

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Plasmodia: Metabolism

Plasmodia can’t synth AA–> degrade Hb for AA (done in RBC vacuoles)

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Malaria: Drug Group Names

Inhibitors of Heme Metabolism
Inhibitors of electron transport chain
Inhibitors of protein synthesis
Inhibitor of Folic Acid synthesis

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Malaria: Inhibitors of Heme Metabolism

Drug Names

Chloroquine
Mefloquine
Quinine
Qiunidine
Artemisinin
Artesunate
Artemether

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Malaria: Inhibitors of Heme Metabolism

Chloroquine: Drug Characteristics

Ineffective against P. falciparum (can’t get into mutated
vacuoles)

MoA: Blood Schizotocidal Effect
Weak base; accumulates im food vacules (acidic)
Bind ferriprotoporphyrin IX and inhibit detoxification

T1/2: 5 Days
Req loading dose
Accumulates in various tissues
Renal excretion

Also suitable for prophylactic th

SE: limited as rel selective for infected RBC
negative cardiac effects, hair loss, neuropathy

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Malaria: Inhibitors of Heme Metabolism

Mefloquine

Unknown MoA; similar to that of chloroquine

T1/2: 30 days
Strong PPB
Accumulates in RBC

Used: chloroquine resistant P. Falciparum and P. Vivax
as well as for prophylaxis

SE: Negative Cardiac

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Malaria: Inhibitors of Heme Metabolism

Quinine and Quinidine

Only difference between the two: hydroxy group

MoA: Blood schizotocidal effect
Inhibition of heme polymerase
Bind to strands of DNA–> possibly inhibit transcription

Uses: acute malaria. Chloroquine resistant P. Falciparum
NOT suitable for prophylaxis

SE
Resp Depression; negative cardiac effects
SM contraction also-> splenic contraction-> fever
vasodilation

REM: Quinidine: Na Channel Inhibitor–> antiarrythmic

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Malaria: Inhibitors of Heme Metabolism

Artemisinin
Artesunate
Artemether

Prodrugs, activated by free or heme bound iron

MoA: Blood schizotocidal effect
Prod of radical–> alkylation of proteins and heme

T1/2: few hours–> combine with example piperaquine

Used as first drug in acute malaria in Africa. Not for
prophylaxis

SE
Neuro and cardiotoxic
Elongation of QT

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Malaria: Inhibitors of Electron Transport Chain

Primaquine

Structurally rel. to chloroquine

Secondary tissue schizotocial effect

MoA
Inhibits ubiquinone–> inhibits electron transp chain

If patient lacks glucose 6 P-> increased hemolysis with
drug

SE
Methemoglobinemia
Hemolysis (life threatening in fetus–> CI in pregnancy)

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Malaria: Inhibitors of Electron Transport Chain

Atovaquone

Analogue of ubiquinone

ALWAYS COMBO: Atovaquone+ proguanil as single mutation leads to resistance
–> synergistic effect

Treatment and prophylaxis
Also effective against Toxoplasma

SE
Headache
Nausea

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Malaria: Inhibitors of Protein Synthesis

Doxycycline

Tetracyclic AB

Delayed effect–> only for prophylaxis; not allowed in all countries

SE
Photosensitivity with dermal eruption

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Malaria: Inhibitors of Protein Synthesis

Clindamycin

Can be used for kiddies and pregnant patients

SE
can bind Ca in developing bone

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Malaria: Inhibitor of Folic Acid Synthesis

Proguanil

Inhibitor of protozoal DHF acid reductase

ALWAYS COMBO
Atovaquone with Proguanil

Only for prophylaxis

SE
   macrocytic anaemia (counteract by combo with folic 
         acid)
   haematuria
   diarrhoea

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Drugs used in the symptomatic treatment of Malaria

Chloroquine
Mefloquine
Quinine
Quinidine
Artemisinin
Artesunate
Artemether

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Drugs used only in prophylaxis of Malaria

Proguanil

Doxycycline

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Amebiasis

General characteristics
Symptom

Caused by entameobia hystolytica
Parasite depends on metabolism gluc–> ethanol

Symptoms occur days/weeks post infection
Patients freq asymptomatic while infectious
Diarrhea/abdominal cramps/dysentry
Hepatic abscesses

Amebiasis

Life Cycle and Infection

Feco-oral transmissionE
Excystation and ripening of trophozoites in interstines–>
colonic phase
Can damage barrier–>blood–>liver–>abscess-> late ph.
Excreted with feces
Trophozoites can move with their pseudopodia
Consume bacteria, other protozoa, intestinal and RBCs

Amebiasis

Drug Names

Metronidazole 
Tinidazole
Emetine
Dehydroemetin
Paramomycin
Diiodohydroxyquinolene

Amebiasis

Metronidazole and Tinidazole
Spectrum
MoA
MoR

Main Drugs used
Spectrum
   Anaerobic bacteria
   Microaerophilic bacteria (H. Pylori)
   Microaerophilic protozoa (Entam. Hyst.)

MoA
non enzymatic red: ferredoxins–> free radicals and
reactive nitroso derivatives
Metronidazole is a prodrug; req. reductive activation of
nitro group by susceptible organism
Selectively toxic towards anaerobic and microareophilic
pathogens

MoR
Low expression of ferrodoxins
NADPH dep. enzym. reduction of nitro group

Amebiasis

Metronidazole and Tinidazole
Pharmacokinetics
SE

Complete GIT absorption; even distribution
Metabolites mainly excreted renally

SE
   metallic taste 
   disulfiram like effect--> no combo with alcohol 
   headache/ nausea/ dry mouth
   darkens urine

Amebiasis

Emetine
Dehydroemetine

Also used as emetics and expectorants–> given IM or SC
(stim. vagal nerve–> nausea and vomiting)
Active against tissue trophozoites
Only used if metronidazole is CI due to SE

Dehydroemetine is favoured; fewer SE

MoA
Binds 40S ribosome subunit and inhibit eukaryotic
protein synthesis

SE
   May inhibit human protein synthesis in high dose
   CF
   Hepatotoxic
   Myopathy

Amebiasis

Paramomycin

Is an aminoglycoside antibiotic

Only used orally; systemic admin–> severe SE

Amebiasis Diiodohydroxyquinolene

Has luminal effect Complexes with iron; iron req by amoebas Thyroid SE as contains iodine

Trypanosomiasis General Symptoms

Africal Trypanosomiasis= sleeping sickness American= Chagas Disease ``` Generalised lymphadenopathy Fever CNS involvement --> meningoencephalitis and narcoleptic states Primary chancre may occur at bite site ```

Trypanosomiasis Life Cycle

Tsetse flies are vectors--> blood meal and injects trymastigotes--> transform into trypomastigotes in blood stream-->carries to other sites. Trypomastigotes multiply--> Tsetse fly has blood meal

Trypanosomiasis Drug Names

Pentamidine Suramin Melarsoprol

Trypanosomiasis Penamidine

Treatment of early phase (pre crossing BBB) Combo with suramin MoA + charged molecule--> actively transp. into parasites--> binds - charged molecules--> inhibition of DNA/RNA/protein synthesis IV or IM Accumulates in various tissues Slow elimination SE Nephro-, Hepato-, Myelotoxic Histamine releasing Dizzyness, headache, tachycardia

Trypanosomiasis Suramin

Treatment of early phase of African Trypanosomiasis + and - charged Inhibits RNA polymerase Poorly absorbed Strong PPB Nephrotoxic Neuropathy Seizures

Trypanosomiasis Melarsoprol

Contains arsenic For late phase treatment Inhibits protozoal pyruvate kinase and therefore energy production Combo with steroids to decrease occurrence of reactive encepathalopathy (5% fatality of drug)

Toxoplasmosis

Toxoplasma Gondii Animal hosts: mammals and birds Cat is natural/ intermediate host Crosses placenta Lymphadenopathy Intraocular Infection meningitis/encephalitis Congenital: retinopathy/blindness and calcifying scars in brain leading to epilepsy

Toxoplasmosis Drug Names

Pyrimethamine Sulfadiazine Spiramycin

Toxoplasmosis Pyrimethamine + Sulpadiazine

Both of them are sulfonamides CI in pregnancy Synergistic inhibition of folic acid synthesis COADMIN folic acid to prevent myelosuppression

Toxoplasmosis Spiramycin

It is a macrolide AB Can be used for kiddies and pregnant patients with acute infection

Leishmaniasis

Intermediate hosts are sand flies; spread via saliva of insects Live IC in macrophages Diseases visceral cutaneous mucocutaneous

Leishmaniasis Drug Names

Na Stibogluconate Amphotericin B Paramomycin

Leishmaniasis Na Stibogluconate

A heavy metal containing drug; cont. antimony Reacts with -SH groups--> damages enzymes ``` SE Myelosuppression Circulatory shock Hepatotoxic QT elongation ```

Leishmaniasis Amphotericin B Chemistry Pharmacokinetics Preparations

Chemistry Polyene Macrolide; amphoteric Water insoluble -> Preps: complexed with sodium encapsulated with liposomes: less nephrotoxic IV Strong PPB Long T1/2 Broad spectrum, even some protozoa es leishmaniasis Crosses BBB poorly--> intrathecal admin possible Slow renal and biliary excretion

Leishmaniasis Amphotericin B Mechanism of Action Side Effects

Selectively toxic: high affinity to ergosterol Interrupts membrane stability: forms pore in membrane Able to integrate via hydrophobic part Resistance due to low ergosterol content ``` SE Renal toxicity: mainly reversible Hypokalemia Anaemia (decreased EPO) !!Cytokine Storm!! Hepatotoxicity ```

Leishmaniasis Paramomycin

Is an aminoglycoside antibiotic Only used orally; systemic admin--> severe SE

Giardia Th possibilities

Metronidazole Furazolidone is resistant cases

Trichomoniasis Th Possibilities

Local suppositories/ creams may suffice Metronidazole Trinidazole Nifuratel