Antiprotozoal and antihelminthic drugs (3) Flashcards
important protozoons
- Plasmodium strains → malaria
- Entamoeba hystolitica
- Trichomonas vaginalis
- Giardia lamblia
- Toxoplasma gondii
- Trypanosoma strains
- Leishmania strains
drugs used for malaria
- Chloroquine
- Mefloquine
- (Cinchona alkaloids), quinine!! (and quinidine)
(4. Halofantrine) - Lumefantrine
- Primaquine
(7. Inhibitors of folate synthesis
Sulfadoxine + pyrimethamine ) - Proguanil
- Atovaquone
- Antibiotics
doxycycline, clindamycin, azithromycin - (artemisinin (natural compound- NOBEL prize) and its derivatives:) arthemeter !!!, (artemotil, artesunat, dihydroartemisinin)
malarone
Atovaquone + proguanil
Profilaxis of malaria
- Chloroquine- area without resistant P. falciparum
- Malarone- area with chloroquine-resistant P. falciparum
- Doxycycline- area with multidrug resistant P. falciparum
Tretament of malaria – overview- some therapeutical possibilities
• Chloroquine sensitive plasmodium strains:
– Chloroquine (if there is a P. vivax or P. ovale infection, Primaquine
follows Choloroquine)
• Uncomplicated infections with chloroquine resistant P. falciparum
– Quinine + Doxycycline or Clindamycine
– Artemisinine d.+ Mefloquine or Lumefantrine+Arthemeter
• Severe or complicated infections with P. falciparum:
– Artesunate (1+2 days) or Quinine, afterward Doxycycline or Clindamycine (7 days) or Artesunate + Mefloquine
Chloroquine
- blood schizonticid
– inhibits heme-polymerase, inhibits the inactivation of heme into hemozoin →heme accumulates→toxic for the protozoons - well absorbed orally, accumulates in the tissues, elimination half life - 4 days
Antacids decrease oral
bioavailability - Treatment + prophylaxis in areas without resistant strains of P. falciparum (1st-line agent)
- Treatment of P. vivax and P. ovale
Adverse effects: few – pruritus, GI symptoms, visual disturbances (rare, due to retina- and cornea deposits). Hemolysis in G6PD deficient persons. Auditory damage QT prolongation rash, headaches
Clinical indications: suppressive therapy and prophylaxis
P. falciparum is commonly resistant
Interfere with macrophages lysosomal pH → inhibit antigen catabolism and presentation
- Oral
- Long T1/2 - Vd↑↑
- Autoimmune diseases (RA, SLE)
*Hydroxychloroquine
Less toxic metabolite of chloroquine; in addition to the use as anti-malaria agent, may be used in autoimmune disorders including RA, SLE, and Sjogren syndrome
Mefloquine
- blood schizonticid. Effective for many chloroquine-resistant P. falciparum strains
- administrated only orally, slow absorbtion
Adverse effects:
- neuropsychiatric
- GI distress
- Skin rash
- Conduction abnormalities
- Neurotoxicity (seizures)
Clinical indications: - for profilaxis in the case of known chloroquine resistancy, because of the adverse effects, less and less common
- therapy of uncomplicated malaria in combination with Artesunat
- Treatment + prophylaxis in areas with resistant P. falciparum
(1st-line agent)
quinine
Cinchona alkaloids
- blood schizonticid
Inhibit protozoal DNA
replication
- well absorbed orally, parenteral administration is also possible (slowly i.v. if severe infection)
Adverse effects:
- quinine intoxication (cinchonism)
– vomit, diarrhoeia, visual and hearing disturbances,
- hypersensitive reaction
- overdose – cardiotoxicity
- Cinchonism (GI distress, headache, vertigo, blurred vision, tinnitus)
- Acute hemolysis in G6PD deficient patients
- Conduction abnormalities
- Teratogenic
Clinical indications: - P. falciparum malaria, last therapeutical option
- Not for profilaxis due to its toxicity
- Babesiosis
- Treatment of multidrug- resistant malaria
- May be used in combination with
doxycycline or clindamycin
*Quinidine
Antiarrhythmic agent, isomer of quinine; can be used IV in the treatment of severe complicated P. falciparum malaria Adverse effects include cinchonism, QRS and QT prolongation with risk of syncope
- Muscarinic receptor inhibition – HR and AV conduction ↑
- May cause vasodilation via α inhibition (potential reflex tachycardia)
- Enhanced effects under hyperkalemia
- Displaces digoxin from tissue binding sites (enhancing toxicity)
- Weak base – antacids increase its absorption (increasing toxicity)
- Oral
- Wide clinical use in many arrhythmias
Quinidine is occasionally used as a class Ia antiarrhythmic agent to prevent ventricular arrhythmias, particularly in Brugada Syndrome, although its safety in this indication is uncertain. It reduces the recurrence of atrial fibrillation after patients undergo cardioversion, but it has proarrhythmic effects and trials suggest that it may lead to an overall increased mortality in these patients. Quinidine is also used to treat short QT syndrome
Halofantrine
not on the list
- blood schizonticid for all plasmodium forms. - good oral absorbtion
Adverse effects: GI, rashes, pruritus
arrhythmia, impulse conduction disturbances!
Clinical indications: rarely used because of its toxicity
Lumefantrine
Similar to Halofantrine with less side effects.
Indicated in combination with arthemeter for the treatment of not complicated P. falciparum malaria
Halofantrine:
- blood schizonticid for all plasmodium forms. - good oral absorbtion
Adverse effects: GI, rashes, pruritus
arrhythmia, impulse conduction disturbances!
QT prolongation
Clinical indications: rarely used because of its toxicity
Primaquine
- tissue schizonticid for all types of plasmodium strains. -
- Tissue schizonticide
(kill schizonts in the liver) - Metabolites act as oxidants
- Eradication of liver stages of P. vivax and P. ovale
- Used in combination with chloroquine (or other blood schizonticide)
Adverse effects: - well tolerated; - in higher doses GI side effects, - very rarely leukocytopenia, - methemoglobinaemia, - hypersensitive reaction - GI distress - Rash, headaches - Acute hemolysis in G6PD deficient patients - Teratogenic
only oral administration
Clinical indications: - radical cure of acute Vivax and Ovale malaria - for prophylaxis of all types of malaria strains
- pneumocystis jiroveci infection (in combination with clindamycine)
Sulfadoxine + pyrimethamine
not on the list?
Inhibitors of folate synthesis
Clinical indications:
- In case of Chloroquine resistancy, treatment of uncomplicated malaria - P. falciparum is commonly resistant
Proguanil
- biguanid derivative
- its active metabolite inhibits the bifunctional dihydrofolate reductase thymidylate synthase → inhibits DNA synthesis
- Oral
- Prodrug
- Generally well-tolerated
→ antimetabolite (folate synthesis ↓)
- Malaria prophylaxis (with atovaquone)
Atovaquone/Proguanil (Malarone) - Atovaquone → disrupts mitochondrial metabolism
- Proguanil → antimetabolite (folate synthesis ↓)
- Oral
- Treatment + prophylaxis of multidrug-resistant
P. falciparum malaria - Generally well-tolerated
- GI distress, fever, rash
Atovaquone
- inhibits mitochondrial functions
- tissue and blood schizonticid
Clinical indications:
atovaquone + proguanil → for treatment and prophylaxis in case of known chloroquine resistancy (P. falciparum is usually susceptible)
atovaquon → alternative compound in pneumocystis jiroveci infection
Antibiotics used in malaria
doxycycline, clindamycin, azithromycin
arthemeter
artemisinin (natural compound- NOBEL prize) and its derivatives: arthemeter (artemotil, artesunat, dihydroartemisinin)
- blood schizonticid (fast effect). They might act through production of free radicals.
- Production of free radicals
within the plasmodium food vacuoles - possible ways of administration: orally, i.v., i.m.
T1/2 too short to be used as prophylaxis
Adverse effects: well tolerated (!), most common GI side effects (nausea, diarrhea, vomiting)
Clinical indications:
• often used for the treatment of falciparum malaria
• oral combinations: Artesunate-mefloquine, Artemether-lumefantrine
- Treatment of multidrug- resistant malaria
- Effective against quinine- resistant strains
Antiprotozoal treatment; drugs action ….
Tissue schizonticids : act on liver forms, e.g. primaquine
Blood schizonticids
(suppressive therapy) : act on erythrocyte forms, prevents the clinical symptoms e.g. chloroquine, quinine, most of them
both: atovaquone
gametocides : killgametocytes,e.g. primaquine
prophylactic therapy
Amebiasis
Parasitic infection of the intestines is known as Amebiasis
Signs and symptoms:
- Patient has loose Stools
- Stomach pain
- Amebic Dysentery
- Fever and Tenderness
- Abscess
Treatment:
(iodoquinol, Diloxanid furoat, tinidazole, Paromomycin (aminoglycoside),)
Metronidazole
Iodoquinol
Diloxanid furoat
Paromomycin
(not on the list)
Iodoquinol
poor absorbtion given orally, mainly GI adverse effects
Clinical indications:
- in monotherapy for the treatment of intestinal asymptomatic amebiasis
- in combination for the treatment of intestinal or extraintestinal amebiasis
Diloxanid furoat
Adverse effects: GI
Clinical indications: alternative compound in asymptomatic amebiasis
Paromomycin (aminoglycoside)
Mechanism of action: inhibits protein synthesis
Clinical indications: second line drug in intestinal and extraintestinal infections
TREATMENT OF AMEBIASIS
Metronidazole
Nitroimidazoles
Metronidazole, tinidazole
*Tinidazole share many common properties and indications as metronidazole; provides longer serum T1/2 (allows once daily dosing)
Treatment of amebiasis
Mechanism of action:
reactive reduction products have cytotoxic effect
Clinical indications:
in combination for intestinal and extraintestinal infections
- The drug undergoes a reductive bioactivation of its nitro group by ferredoxin (present in anaerobes) → form reactive cytotoxic products (free radicals) → interfere with nucleic acid synthesis
- Bactericidal effect
spectrum: - Anaerobic gram-negatives - Clostridium species (pseudomembranous colitis) - Gardnerella vaginalis - H. pylori eradication regimen - Intra-abdominal infections - Brain abscesses - Antiprotozoal: Giardia lamblia Trichomonas vaginalis Entamoeba histolytica
*Treatment of amebiasis (Entamoeba histolytica infection) may require co-administration of metronidazole with luminal-active agents (luminal amebicide) → Paromomycin (aminoglycoside antibiotic) or Diloxanide; lumen-active agents which may also be used as the sole treatment of non-invasive, asymptomatic intestinal infection
kinetics: - Oral, parenteral - Achieves high CSF conc. - Hepatic metabolism (dose reduction may be required in liver dysfunction) - Inhibitor of CYP450 enzymes
adverse effects: - GI distress - Leukopenia - CNS effects (neuropathy) - Dark urine discoloration - Metallic taste - Disulfiram-like reaction with ethanol (nausea, vomiting, headache, hypotension)
Treatment of giardiasis
First line drugs
- metronidazole, (tinidazole)
REST IS NOT ON THE LIST
(Nitazoxanid): broad spectrum antiprotozoal drug, not clear mechanism of action, few side effects
Second line drugs
(Paromomycin) (aminoglycoside): poor absorbtion given orally
(Furazolidon: nitrofuran), oral drug with mainly GI adverse effects
(Quinacrin): broad spectrum antiprotozoal drug, well absorbed orally, long elimination half life (5 days), mainly GI adverse effects
Treatment of trichomoniasis
metronidazole, (tinidazole)
Treatment of toxoplasma gondii infection
first choice –
- Spiramycin (in pregnancy),
- Sulfamethoxazole +Trimethoprim
(- Pyrimethamine + Clindamycin + folinic acid)
alternative compounds: - (Pyrimethamine + Sulfadiazine + folinic acid)
Treatment of pneumocystis jiroveci infection
first choice –
1. Sulfamethoxazole +Trimethoprim
alternative compounds: - (Pentamidine) or
- Clindamycin + Primaquine
- Atovaquon
in HIV patient: dapsone
Leishmaniasis
Forms of leishmaniasis
- cutaneous
- mucocutaneous
- visceral (kala azar)
Drugs used for the treatment:
- Amphotericin B – mainly in the visceral leishmaniasis -
only medication listed in the chart!!!
(Miltefosine) – orally given in the visceral form
(- pentavalent antimonials:
- sodium stibogluconate - meglumin antimoniat)
intravenously administrated drugs for different leishmania forms with few side effects. First choice drugs in mucocutaneous form
(- Pentamidine)
- not fully understood mechanism of action (inhibits protein synthesis, inhibits DHFR?)
- parenteral administration
- severe adverse effects: arrhythmias, liver and kidney disturbances,
Stevens-Johnson syndrome
- reserve compound in resistant cases
Chagas disease
pathogen: american (Trypanosoma cruzi, Chagas disease)
Sleeping sickness
pathogen:
african (Trypanosoma brucei, sleeping sickness)
Treatment of trypanosomiasis
Forms of trypanosomiasis -
- african (Trypanosoma brucei, sleeping sickness) -
- american (Trypanosoma cruzi, Chagas disease)
Treatment of african trypanosomiasis:
(- Pentamidine )– effective against several protozoals
- it is used in early phase before the CNS involvement - other indication is the antimonial resistant
leishmaniasis
- it has fungicid effect as well
(- Suramin )– not fully undertsood mechanism of action (inhibits protein synthesis but enzymes as well)
- administered i.v., long half life (40-50 days)
- adverse effects: kidney impairment, dermatitis, neuropathy - indicated in the early phase, before CNS involvement
(- Eflornithin )– inhibits ornithin decarboxylase
- given mainly i.v., orally causes diarrhoea
- severe adverse effects (GI, seizures, bone marrow suppression)
- indicated for advanced (CNS) cases
- Melarsoprol undelined in lecture but don´t find it on the list - arsenic containing compound, enzyme inhibitory effect
- given in slow infusion
- severe adverse effects: GI, hepatotoxicity, arrhythmia, encephalopathy (steroid diminishes)
- indicated in advanced (CNS) cases
Trally
- adverse effects: GI, neuropathy, psychosis
Treatment of american trypanosomiasis (T. cruzi)
(- Nifurtimox )- might act by radical metabolites
- effective mainly in the acute phase
- administrated orally
- adverse effects: GI, neuropathy, seizures
(- Benznidazol )– inhibits protein synthesis and RNA synthesis - administrated orally
- adverse effects: GI, neuropathy, psychosis
Classification of helminths (worms)
- Nematodes – roundworms
- Trematodes - flukes
- Cestodas – tapeworms
Nematodes - roundworms
– Soil-transmitted helminths (STH): ascariasis
(roundworm), trichuriasis (whipworm), hookworm
– pinworm
– Filarial nematodes (filariasis)
• Trematodes - flukes
– Schistosomes
– Fasciola hepatica
• Cestodas - tapeworms
– Taenia saginata
– Taenia solium
– Hymenolepis nana
Possible drug targets in helminths
- neuromuscular coordination
- carbohydrate metabolism
- microtubule integration
mebendazole
Benzimidazoles =
(Albendazole), mebendazole, (triclabendazole)
- inhibit the polymerization of the β-tubulin of microtubules
- good against roundworms and tapeworms
- orally given
- adverse effects: GI, hepatotoxicity, visual disturbances - teratogenic - GI distress - Granulocytopenia, alopecia (only at high doses)
- Inhibits microtubule synthesis
- Inhibits glucose uptake
- Oral
- 90% of the given dose is not-absorbed – luminal-active agent
Nematodes - Ascaris lumbricoides - Enterobius vermicularis (pinworm infection) - Trichuris trichuria (whipworm infection) - Visceral larva migrans
Diethylcarbamazine (DEC)
not on the list
- immobilizes microfilariae and alters its surface structure
- orally given
- adverse effects: mild and transient: headache, anorexia,
nausea, vomiting - drug of choice in the tretament of filariasis, loiasis
Ivermectin
(Avermectin-Nobel prize!)
- enhances GABA effect in the worm → paralysis
- Facilitates GABA-mediated transmission in nematodes and causes immobilization of parasites
- orally given, does not cross BBB
- effective against certain roundworms (NEMATODES): filarial Loa loa, Ascaris lumbricoides, Ancylostoma duodenale, Trichuris trichiura Intestinal nematodes: - Strongyloides stercoralis Tissue/blood nematodes: - Cutaneous larva migrans - Oncocerca volvulus
Reaction to the dying worms: Fever, headache Rash, pruritus Joint and muscle pain Hypotension Lymphadenopathy (can be managed with antihistamines and NSAID's) - Teratogenic
Pyrantel pamoate
Praziquantel
(not on the list)
Pyrantel pamoate
- releases acetylcholine in the worm, inhibits acetylcholinesterase → depolarizing blockade → spastic paralysis
- given orally, poor absorbtion
- side effects: GI (middle severe), CNS (mild)
- good againts: Ascaris, Necator, Ancylostoma, Enterobius
Praziquantel
- increases Ca++ permeability → spastic paralysis
- orally given, penetrates BBB
- adverse effects: GI, dizziness (mild)
- indicated mainly againts flukes and tapeworms: Schisostoma, Fasciola hepatica, Taenia
Niclosamide
- inhibits oxidative phosphorilation
- Uncoupling oxidative phosphorylation
- orally given, poor absorbtion
- side effects: GI, dizziness (mild)
- Generally well-tolerated
- GI distress, fever, rash
- effective againts tapeworms CESTADODES: Taenia solium, Taenia saginata Tapeworms: - Taenia saginata (beef tapeworm) - Taenia solium (pork tapeworm) - Diphyllobothrium latum (fish tapeworm)
Trichinella (trichinosis)
Roundworm infections
– eating under- or uncooked venison or wild pig
– invades scheletal muscles and heart
– Treatment:
• Albendazole or Mebendazole!!
Lymphatic Filariasis (Wuchereria bancrofti)
Roundworm infections
– trasmission: bite of mosquitoes (tropical, sub-tropical regions)
– acute dermatolymphangioadenitis, elephantiasis
– WHO: all at-risk individuals should take in different regimens:
Albendazole, Ivermectin!!, diethylcarbamazine (DEC)
- therapy: DEC
Loiasis (Loa Loa)
Roundworm infections
– trasmitted by deerflies
– hot erythematous swellings (5 to 10 cm. or more) called Calabar swellings
– therapy: DEC or Ivermectin!!
Ascariasis
Roundworm infections
– tropical regions (70-90%)
– complications: intestinal obstruction, hepatobiliary ascariasis
– Treatment: - benzimidazoles Mebendazole!!!, (Albendazole)
(- Pyrantel Pamoate), in severe infections -> causes paralysis, worms can not cause complications during their elimination (perforation with peritonitis, intestinal obstruction and so), safe in pregnancy
Toxocariasis
no drug on the list
Roundworm infections
– caused by canine ascarid (common in North America, USA, Europe)
– drug of choice - (Albendazole)
Pinworm (Enterobius, Oxyuriasis)
Roundworm infections
– most common helminth infection in temperate climates (USA, EU)
– not severe, rarely secondary complications (salpingitis, peritonitis)
– easy contamination!
– treatment: Albendazole, Mebendazole!!!, Pyrantel pamoate
Taenia saginata (beef tapeworm)
no drug on the list
Tapeworm infections
– cosmopolitan
– drug of choice: Praziquantel
Taenia solium (pork tapeworm)
no drug on the list
Tapeworm infections
– cosmopolitan
– intestinal infection and Cysticercosis (caused by invasive larval forms)
– drug of choice: Albendazole (Niclosamide!!!! is no longer in use.)
Hymenolepis nana (dwarf tapeworm)
no drug on the list
Tapeworm infections
– cosmopolitanthe most common tapeworm
– drug of choice: Praziquantel or Albendazole
Schisostosomiasis (blood flukes)
no drug on the list
Flukes infections
– 200 million infected people
– heavy infection -> squamous cell carcinoma of the bladder
– drug of choice: (Praziquantel)
Fasciola hepatica (large liver fluke)
no drug on the list
Flukes infections
– infection -> eating freshwater plants such watercress
– drug of choice: (Triclabendazole (older drug-Bithionol))
Hookworm (Necator americanus, Ancylostoma duodenale)
Roundworm infections
– America, Africa, South China, Southeast Asia, Egypt, India
– Skin penetration -> lung -> small intestine -> blood feed
– Treatment:
• 1stchoice –Albendazole
• Alternatives: Mebendazole!!, Ivermectin!!
Whipworm (Trichuris trichura)
Roundworm infections
– more common in children- dysentery, colitis
– treatment: Albendazole or Mebendazole!!!
