antituberculosis, antifungal, antiprotozoal and

Antituberculosis, antifungal,

antiprotozoal and

antihelmintic drugs

Erzsébet Kató M.D., Ph.D.

[email protected]

http://semmelweis.hu/pharmacology/

Tuberculosis - deadly as ever

Egyptian mummy in the British Museum- tubercular decay has been found

in the spines of Egyptian mummies dating from 3000–2400 BC

Tuberculosis - deadly as ever

- 460 BC, Hippocrates , widespread and highly fatal disease

- 19th century, “a romantic disease”- novelist Franz Kafka, composer Frederic Chopin, inventor Alexander Graham Bell

In 2018, 10 million people fell ill with TB, and 1.5

million died from the disease (including 0.4 million

among people with HIV)- WHO

“A vaccine that prevented tuberculosis would merit a

Nobel Prize, but it’s just very difficult to develop.” – Tom

Frieden (Director of the Centers for Disease Control and Prevention)

An estimated 53 million lives were saved through TB diagnosis and

treatment between 2000 and 2016.

Mycobacteria

• Species:

– M. tuberculosis – tuberculosis. – M. bovis- bovine tuberculosis

FYI– M. kansasii - resembles tuberculosis

– M. marinum - granulomatous cutaneous disease

– M. avium complex (avium/intracellulare) - pulmonary disease or

disseminated infection in AIDS

– M. scrofulaceum - cervical adenitis in children

– M fortuitum - abscess, sinus tract, ulcer, bone, joint, tendon infection

– M. ulcerans - skin ulcers

– M. chelonae - abscess, sinus tract, ulcer, bone, joint, tendon infection

– M. leprae - leprosy

Mycobacterium Tuberculosis

Robert Koch 1882

Mycobacteria

• Rods that sometimes show branching filamentous forms resembling

fungal mycelium.

• In cultures they form mold like pellicle: mycobacterium=fungus like

bacteria

• aerobic, non motile, rod shaped bacteria

• very slowly growing

• can be dormant

• hydrophobic (lipid-rich) cell wall (difficult to penetrate)

• intracellular pathogen• (not obligate)

• resistancy

• special inflammation

– acidic pH

– low O2

– cavernes

Mycobacteria

Maturation of pulmonary TB lesions

Anti-tuberculosis drugs travel

• from blood vessels enter

• the interstitial space of granulomas

and then

• penetrate and accumulate in immune

cells, including within subcellular

organelles, such as the

phagolysosome, where intracellular

bacilli can reside.

Finally, the drugs

• permeate the pathogen to reach their

molecular target.

In necrotic granulomas and cavities,

drugs must diffuse through

• caseum in the absence of

vascularization and active transport

systems to reach

• extracellular bacilli that are present in

the necrotic centre.

First line drugs:

Isoniazid (INH)

Rifampin (RA)

Pyrazinamide (PZA)

Ethambutol (ETB)

Streptomycine

Second line drugs:

Ethionamide

Cycloserine

Paraaminosalicylic acid (PAS)

Kanamycine, amikacin

Capreomycin

Fluoroquinolons

Rifabutin

Linezolid

Bedaquiline

Delamanid

Antituberculotics

The Lancet - Infectious diseases, Volume 14, No. 4, p327–340, April 2014

Antituberculotics

Therapeutical specificities

• actively growing bacterias: isoniazid (INH)

• dormant bacterias: rifampin (RA), pyrazinamide (PZA), ethambutol (ETB)

• long term treatment (6 months-2 years)

• social problems

• drugs are given always in combination

• the most common therapeutical protocol:

• INH + RA + PZA + ETB – first 2 months

• INH + RA – 4 months afterward

• the drugs are well absorbed after oral administration and have a good

distribution (exceptions: aminogylcosides, Capreomycine)

Antituberculotics

Antituberculotics. First line drugs

Isoniazid

• Bactericide for actively growing bacterias, bacteriostatic for dormant

bacterias

• Mechanism of action: inhibits synthesis of mycolic acid

• Pharmacokinetics:

• pro drug, well absorbed given orally, iv. adm. is possible as well

• excellent tissue distribution

• it is acetylated in the liver (T1/2 =1 h in the case of fast and T1/2 =3 h in

the case of slow acetylators)

• Adverse effects:

• hepatotoxicity, alcohol enhances its prevalence, more common in rapid

acetylators

• Neurologic problems, more common in slow acetylators

• peripheral neuritis, paresthesias (rarely headache, memory loss,

psychosis, seizures)

• due to B6-deficiency (INH binds to pyridoxine and blocks pyridoxal-5-

phosphate formation - coenzyme of various enzymes).

Rifampin

• Bactericide, inhibits RNA polimerase

• Spectrum: M. tuberculosis, M. leprae, Neisseria meningitidis, Haemophilus

influenzae, pox viruses

• Pharmacokinetics:

• well absorbed orally, good distribution (including phagocytic cells,

abscesses, lung cavities), metabolized in the liver (accelerates its own

metabolism)



- hepatotoxicity (enzyme elevation, rarely hepatitis)

- orange discoloration of urine, tears, sweat

- rarely neurologic problems

Rifampin

• Clinical indications:

- mainly in combination! (resistancy)

- the most effective antituberculotic

- leprosy (in combination with dapsone or clofazimine)

- in monotherapy for the profilaxis of contacts in Meningococci, H.

influenzae infections

- highly resistant staphylococcal infections (endocarditis,

osteomyelitis - in combination with ciprofloxacine)


• Interactions

-strong enzyme inducer

- CYP3A4, CYP1A2, CYP2C9, CYP2C19, CYP2D6

- accelerates its own metabolism

Pyrazinamide

• Bactericide, pyrazinoic acid is formed and inhibits cell membrane functions,

dysrupts energy metabolism



- hepatotoxicity

- hyperuricaemia


- in combination for the short term regimen (synergic effect with INH

and rifampin. Thanks to Pyrazinamide it was possible to reduce the original 1

year long therapy to 6 months

- as a substitute of INH in case of INH resistancy

Ethambutol

• Bacteriostatic, inhibits mycobacterial arabinosyl transferases → inhibited

bacterial cell wall synthesis

• Pharmacokinetics

- well absorbed orally (alcohol decreases)



-retrobulbar neuritis (loss of visual activity, red-green

color blindness, scotomas) - periodic visual control

(every month!)

- other rare side effects: nausea, joint pain, headache,

allergy


- early intensive therapy, in combination

Streptomycin

• Bactericide

• Mechanism of action: protein synthesis inhibitor

• Spectrum: M. tuberculosis, not effective against intracellularly residing

bacterias, acts only against mycobacterias in open caverns or bronchi

M. kansasii and M. avium are resistant

• Pharmacokinetics

- only parenteral administration (2-3*/week i.m.)

- does not enter CNS

• Adverse effects

- nephro- and ototoxic


• resistance to first-line agents

• failure of clinical response to conventional

therapy

• treatment limiting adverse drug reactions

Clinical indications

Antituberculotics. Second line drugs

Ethionamide

Cycloserine


Kanamycine, amikacin

Capreomycin

Fluoroquinolons

Rifabutin

Linezolid

Bedaquiline

Delamanid

Ethionamide (related to isoniazide)

• inhibits mycolic acid synthesis

• Adverse effects

- hepatotoxicity

- gastrointestinal side effects

- allergy


Cycloserine

• inhibits alanine racemase and cell wall synthesis

• Adverse effects

- severe central nervous system side effects: tremor, acute

psychosis, seizures; peripheral neuropathy.


• Bacteriostatic, inhibits folate synthesis (structural analog of PABA)

• Adverse effects

- gastrointestinal (ulcer, nausea, diarrhea)

- central nervous system

- hypersensitivity reactions


Kanamycin

• Aminoglycoside

• used rarely, mainly in case of streptomycin resistancy

Amikacin

• Aminoglycoside

• active mainly against M. tuberculosis (poor effect against M. kansasii), used

in the case of multiresistancy

Capreomycin

• protein synthesis inhibitor

• used against multiresistant M. tuberculosis strains

• nephro- and ototoxic

• administrated parenterally

Fluoroquinolons

• Ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin

• in combination against M. tuberculosis


Rifabutin

• similar to Rifampin, less potent enzyme inducer

• indicated in place of rifampin for treatment of tuberculosis in patients with

HIV infection (less interactions)

Linezolid

• Mechanism of action: protein synthesis inhibitor

• Clinical indications: in case of multiresistant and atypical mycobacterias

• adverse effects at long term therapy: bone marrow suppression, neuropathy


Bedaquiline

• Mechanism of action: blocks the proton pump for ATP synthase of

mycobacteria

• Clinical indications: used only in cases of multidrug-resistant tuberculosis

• adverse effects: arrhytmias (QT prolongation), sudden death

Delamanid

• Mechanism of action: mycolic acid synthesis inhibitor

• Clinical indications: in case of multiresistant mycobacterias

• adverse effects: QT prolongation

• M. kansasii - ciprofloxacin, clarithromycin, ethambutol, INH, rifampin,

cotrimoxazole (trimethoprim-sulfamethoxazole)

• M. marinum - amikacin, clarithromycin, ethambutol, doxycycline,

minocycline, rifampin, cotrimoxazole

• M. scrofulaceum - amikacin, erythromycin (macrolides), rifampin,

streptomycin, surgery

• M. avium complex (avium/intracellulare) - amikacin, azithromycin,

clarithromycin, ciprofloxacin, ethambutol, rifabutin

• M. chelonae - amikacin, doxycycline, imipenem, macrolides, tobramycin

• M fortuitum - amikacin, cefoxitin, ciprofloxacin, doxycycline, ofloxacin,

cotrimoxazole

• M. ulcerans - INH, streptomycin, rifampin, minocycline, surgery

FYI: Treatment options for infections with atypical

mycobacteria

Drugs used in leprosy

Dapsone

• inhibits folate synthesis

• commonly in combination with rifampin

• well tolerated, hemolysis in G6PD

Rifampin

Antifungal drugs

A simplified, schematic classification of the most

relevant pathogenic fungi

The Curse of Tutankhamen’s Tomb: A Scientific Explanation

- 1923, Egyptologists Howard Carter, Lord Carnarvon opened the tomb

- “Death Shall Come on Swift Wings to Him Who Disturbs the Peace of the King.„

- wealth of treasures

- string of deaths, injuries, illnesses and misfortune

- found Staphylococcus and Pseudomonas, moulds: Aspergillus niger and Aspergillus flavus

= allergic reactions ranging from congestion to bleeding in the lungs.

- many excavated tombs carry a fungus that can cause histoplasmosis (influenza-like

respiratory disease).

• Systemic fungal infections: – Systemic candidiasis: RTI

– Cryptococcal meningitis, endocarditis

– Rhinocerebral mucormycosis (rare)

– Pulmonary aspergillosis

– Blastomycosis (pneumonia)

– Histoplasmosis (cough, fever, multiple pneumonic infiltrates)

– Coccidiodomycosis

Azoles inhibit

Polyenes (Disrupt membrane structure &

function)

Flucytosine inhibits DNA synthesis

Echinocandins

Classification based on mechanism of

action

1. Fungal cell wall synthesis inhibition: Echinocandins

2. Bind to fungal cell membrane ergosterol: Amphotercin–B,

Nystatin.

3. Inhibition of ergosterol + lanosterol synthesis: Terbinafine,

Naftifine

4. Inhibition of ergosterol synthesis: Azoles

5. Inhibition of nucleic acid synthesis: 5–Flucytosine.

6. Disruption of mitotic spindle and inhibition of fungal mitosis:

Griseofulvin.

7. Miscellaneous: Ciclopirox

Systemic antifungal drugs for systemic infections

Amphotericin B, liposomal amphotericin B

Polyenes (macrolide antibiotics)

- Differentiates between fungal and mammalian cell membranes so it can

be used systemically (binds with higher affinity to the ergosterol type

membranes)

- fungicid, binds to ergosterol and alters the permeability of the cell by

forming pores in the cell membrane

Antifungal spectrum

- Aspergillus

- Blastomyces dermatitidis

- Candida sp.

- Cryptococcus neoformans

- Coccidioides immitis

- Histoplasma capsulatum

- Mucor spp.

Also active against Leishmania, Acanthamoeba!

No effect against dermatophytones!

Broadest spectrum

of action




Pharmacokinetics:

- only parenterally, - good distribution, except CNS

- liposomal form: better effect, less side effects

- slow elimination through the kidney

Clinical indications:

- useful drug in nearly all life threatening mycotic infections : mycosis of the

organs, sepsis

- coccidio- or candida meningitis – intrathecally

- topically applied for ocular or bladder infections

- effective in leishmaniasis

Adverse effects:

- fever, chills, GI side effects (infusion related

toxicity)

- cumulative toxicity

- nephrotoxicity (monitorization!)

- impaired liver functions

- bone marrow suppression etc.

- liposomal amphotericin B

- less nephrotoxicity and bone marrow suppression

- higher doses can be used

Systemic antifungal drugs for systemic

infections



5- fluorocitozine

(flucytosine)

Antimetabolite:

5-FU is formed from it in the

fungal cells, incorporates

into RNA, inhibits protein

synthesis


Advantages of combination:

– enhanced entry of flucytosine

– reduced toxicity

– reduced duration of therapy

– decreased resistance (!)

Adverse effects: - bone marrow- and hepatotoxicity

- GI, toxic enterocolitis (rare, at high serum level)

Clinical indications: - synergic effect with Amphotericin B, they are

given together

- effective mainly against Cryptococcus

neoformans and Candida species


5- fluorocitozine (flucytosine)

Antimetabolites

Pharmacokinetics: - well absorbed orally

- good distribution, enters CNS

- short half life

- eliminated by the urine, dose adjustment at

impaired kidney functions

(Imidazoles: clotrimazole, ketoconazole- used mainly locally)

Triazoles: Ist. gen. fluconazole, itraconazole

IInd. gen. voriconazole, posaconazole,

isavuconazole

Azoles

- inhibit the ergosterol synthesis by binding to the

cytochrome P-450 enzyme system

- high selectivity, greater affinity for the fungal

enzyme system


Azoles

Pharmacokinetics:

- Well absorbed orally

- itraconazole – poorly enters CNS, eliminated mainly through the GI tract

- fluconazole and voriconazole – enter CNS, excreted mainly by the urine

- itraconazole and fluconazole – accumulate in the nails and skin

Adverse effects: - relatively non toxic

- mainly GI

- liver enzyme elevation

- rarely hepatitis

(- ketoconazole – gynaecomastia, oligospermia,

impotence (inhibits testosterone synthesis))



- broad spectrum, Candida sp., Cryptococcus, blastomycosis,

coccidioidomycosis, histoplasmosis, dermatophytons

- itraconazole and voriconazole – effective in Aspergillus infections too

- itraconazole, fluconazole – in dermato- and onychomycosis

- fluconazole – Cryptococcus meningitis, 1st choice in mucocutan

Candidiosis (gastrointestinal tract, genitorurinary), less effective against

Aspergillus

- fluconazole, voriconazole – often used at ICU for the treatment of sepsis,

ex. Candida sepsis

- posaconazole, isavuconazole- indicated in invasive aspergillosis.

Significant effect in mucormycosis.

- (ketoconazole is used mainly locally)

Azoles


Caspofungin, micafungin, anidulafungin

Echinocandins – newest class of antifungal agents

Mechanism of action:

- inhibit beta- glucan synthesis → disruption of fungal cell wall

- effective: Candida sp, Aspergillus niger

- only i.v.


Adverse effects: - well tolerated

- fever, GI, flush


- micafungin increased the risk of liver tumors, and

supresses bone marrow

Indications: - Candida and Aspergillus infections

- sepsis

- multiresistant infections

Terbinafine


- inhibits the fungal enzyme squalene epoxidase → squalenes accumulate

→ toxic effect and lack of ergosterol

- fungicid, broad spectrum

Pharmacokinetics:

- Good oral absorbtion, accumulates in skin, nails, hair

Systemic antifungal drugs for mucocutaneous infections

Adverse effects:

- GI

- skin reactions (rarely Stevens-Johnson syndrome)


Indications: - local and systemic treatment of onycho- and

dermatomycosis (dermatophytons)

- some Candida infections

Griseofulvin

Mechanism of action: - not clear, inhibits mitosis

- fungistatic, effective mainly against

dermatophytons

Pharmacokinetics: - well absorbed orally

- accumulates in nails, hair and skin

Adverse effects: - GI

- liver enzymes elevation, hepatotoxicity

(toxic reaction)

Indications: - microsporia capitis of the scalp

Interactions: - enzyme inducer

Systemic antifungal drugs for mucocutaneous infections

Local antifungal drugs

Nystatin (polyene macrolide antibiotic)


- it is a compound similar to Amphotericin B

Pharmacokinetics:

- not absorbed orally, local effect in the GI tract

- poor absorbtion from the skin and mucosal membranes

Adverse effects: - nausea, vomit, diarrhoeia

- exanthema

Indications: - candidiasis of oral cavity and of oesophagus

- infections of the gastrointestinal tract

- superficial infections of skin and mucosas

Other local antifungal drugs

Allilamines: - Terbinafine, fungicid cream, spray, gel

- Naftitin, fungicid cream and solution

Amorolphin: fungicid, nail polish

Ciclopirox: broad spectrum antifungal drug, with antibacterial and

antiinflammatory effect

onychomycosis, dermatomycosis

cream, nail polish, solution

Azoles: clotrimazole, bifonazole, econazole, flutrimazole,

ketoconazole, omoconazole

Helminth Regulation of Immunity: A Three-prongedApproach to Treat Colitis

Lopes, Fernando PhD; Matisz, Chelsea MSc; Reyes, José L. PhD; Jijon,

Humberto MD, PhD; Al-Darmaki, Ahmed MD; Kaplan, Gilaad G. MD, PhD;

McKay, Derek M. PhD

Inflamm Bowel Dis. 2016 Oct;22(10):2499-512.

Adv Exp Med Biol. 2014;817:319-56. doi: 10.1007/978-1-4939-0897-4_15.

Microbiota, immunoregulatory old friends and psychiatric disorders.

Rook GA1, Raison CL, Lowry CA. Abstract Regulation of the immune system is an important function of the gut microbiota. Increasing

evidence suggests that modern living conditions cause the gut microbiota to deviate from the

form it took during human evolution. Contributing factors include loss of helminth infections,

encountering less microbial biodiversity, and modulation of the microbiota composition by diet

and antibiotic use. Thus the gut microbiota is a major mediator of the hygiene hypothesis (or as

we prefer, "Old Friends" mechanism), which describes the role of organisms with which we

co-evolved, and that needed to be tolerated, as crucial inducers of immunoregulation. At

least partly as a consequence of reduced exposure to immunoregulatory Old Friends, many but

not all of which resided in the gut, high-income countries are undergoing large increases in a wide

range of chronic inflammatory disorders including allergies, autoimmunity and inflammatory

bowel diseases. Depression, anxiety and reduced stress resilience are comorbid with these

conditions, or can occur in individuals with persistently raised circulating levels of biomarkers of

inflammation in the absence of clinically apparent peripheral inflammatory disease. Moreover

poorly regulated inflammation during pregnancy might contribute to brain developmental

abnormalities that underlie some cases of autism spectrum disorders and schizophrenia.

https://www.ncbi.nlm.nih.gov/pubmed/27575495

Antiprotozoal drugs

Some important protozoons

• Plasmodium strains → malaria

• Entamoeba hystolitica

• Trichomonas vaginalis

• Giardia lamblia

• Toxoplasma gondii

• Trypanosoma strains

• Leishmania strains

schizonts

merozoits

schizonts

merozoits

trophozoits

Clinical symptoms

Life cycle of plasmodium

Countries with ongoing transmission of malaria

Note: a 4 years old girl died in Brescia (North of Italy) in 2017

WHO

„Nearly half of the world's population is at risk of malaria

• In 2018, there were an estimated 228 million malaria cases and some

405 000 malaria deaths.

• More than two thirds (70%) of all malaria deaths occur between

children under 5.”

• Around 15 countries account for 78% of the deaths globally. These

countries are mainly in sub-Saharan Africa.

Classification of drugs used for the treatment of malaria

act on liver forms, e.g. primaquineTissue schizonticids

act on erythrocyte forms, prevents the clinical

symptoms e.g. chloroquine, quinineBlood schizonticids

(suppressive therapy)

kill gametocytes, e.g. primaquinegametocides

prophylactic therapy

Antiprotozoal drugs

Chloroquine

Adverse effects: few – pruritus, GI symptoms, visual disturbances

(rare, due to retina- and cornea deposits). Hemolysis in G6PD deficient

persons.

- well absorbed orally, accumulates in the tissues, elimination

half life 4 days

- blood schizonticid – inhibits heme-polymerase, inhibits the inactivation

of heme into hemozoin → heme accumulates → toxic for the protozoons

Clinical indications: suppressive therapy and prophylaxis

P. falciparum is commonly resistant

Treatment of malaria

Cinchona alkaloids, quinine and quinidine

Adverse effects: quinine intoxication (cinchonism) – vomit,

diarrhoeia, visual and hearing disturbances, hypersensitive reaction

overdose – cardiotoxicity

- well absorbed orally, parenteral administration is also possible

(slowly i.v. )

- blood schizonticid

Clinical indications: - P. falciparum malaria, last therapeutical option

- Not for profilaxis due to its toxicity

- Babesiosis


Mefloquine

Adverse effects: GI, neuropsychiatric

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

- blood schizonticid. Effective for many chloroquine-resistant P.

falciparum strains

- administrated only orally, slow absorbtion


Primaquine

Adverse effects: well tolerated; in higher doses GI side effects, very

rarely leukocytopenia, methemoglobinaemia, hypersensitive

reaction

- tissue schizonticid for all types of plasmodium strains.

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)


- only oral administration

Halofantrine

Adverse effects: GI, rashes, pruritus

arrhythmia, impulse conduction disturbances!

- blood schizonticid for all plasmodium forms.

Clinical indications: rarely used because of its toxicity

- good oral absorbtion

Lumefantrine

Similar to Halofantrine with less side effects.

Indicated in combination with arthemeter for the treatment of not

complicated P. falciparum malaria


Sulfadoxine + pyrimethamine

Inhibitors of folate synthesis


- 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

Atovaquone + proguanil = Malarone


atovaquone + proguanil → for treatment and prophylaxis in case of

known chloroquine resistancy (P.

falciparum is usually susceptible)

atovaquon → alternative compound in pneumocystis jiroveci infection

Atovaquone: - inhibits mitochondrial functions

- tissue and blood schizonticid


Antibiotics

doxycycline, clindamycin, azithromycin

artemisinin (natural compound- NOBEL prize) and its

derivatives: arthemeter, artemotil, artesunat, dihydroartemisinin

- possible ways of administration: orally, i.v., i.m.

- blood schizonticid (fast effect). They might act through production

of free radicals.


• often used for the treatment of falciparum malaria

• oral combinations: Artesunate-mefloquine, Artemether-lumefantrine

Adverse effects: well tolerated (!), most common GI side effects


• Chloroquine- area without resistant P. falciparum

• Malarone- area with chloroquine-resistant P. falciparum

• Doxycycline- area with multidrug resistant P. falciparum

Profilaxis of malaria

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

• Severe or complicated infections with P. falciparum:

– Artesunate (1+2 days) or Quinine, afterward Doxycycline or

Clindamycine (7 days) or Artesunate + Mefloquine

Treatment of amebiasis

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

Nitroimidazoles

Clinical indications: in combination for intestinal and extraintestinal

infections

Metronidazole, tinidazole

Mechanism of action: reactive reduction products have cytotoxic effect

Paromomycin (aminoglycoside)

Mechanism of action: inhibits protein synthesis

Clinical indications: second line drug in intestinal and extraintestinal

infections

Treatment of amebiasis

Treatment of giardiasis

First line drugs

Nitroimidazoles: metronidazole, tinidazole

Paromomycin (aminoglycoside): poor absorbtion given orally

Nitazoxanid: broad spectrum antiprotozoal drug, not clear mechanism of

action, few side effects

Second line drugs

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

Nitroimidazoles: metronidazole, tinidazole

first choice – Sulfamethoxazole +Trimethoprim

alternative compounds: - Pentamidine or Clindamycin + Primaquine

or Atovaquon

Treatment of pneumocystis jiroveci infection

first choice – Spiramycin (in pregnancy), Sulfamethoxazole +Trimethoprim

- Pyrimethamine + Clindamycin + folinic acid

alternative compounds: - Pyrimethamine + Sulfadiazine + folinic acid

Treatment of toxoplasma gondii infection

Leishmaniasis

Forms of leishmaniasis - cutaneous

- mucocutaneous

- visceral (kala azar)

Treatment of leishmaniasis

Drugs used for the treatment:

- Amphotericin B – mainly in the visceral leishmaniasis

- 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

Trypanosoma brucei parasite (light blue) that causes African trypanosomiasis (sleeping

sickness) in humans in the presence of erythrocytes (red) and lymphocytes (yellow). After

infection of the mammalian host by bite of the tsetse fly, the parasite lives the bloodstream

before it invades the central nervous system and the brain.

glimpse.clemson.edu

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


Treatment of african trypanosomiasis

- 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 - arsenic containing compound, enzyme inhibitory effect

- given in slow infusion

- adverse effects: GI, hepatotoxicity, arrhythmia,

encephalopathy (steroid diminishes)

- indicated in advanced (CNS) cases

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


Antihelminthic agents

Classification of helminths

(worms)• Nematodes – roundworms

• Trematodes - flukes

• Cestodas – tapeworms

Classification of helminths

(worms)• 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

- mikrotubule integration

Benzimidazoles

- inhibit the polymerization of the β-tubulin of microtubules

- good against roundworms and tapeworms

- orally given

- adverse effects: GI, hepatotoxicity, visual disturbances

- teratogenic

Albendazole, mebendazole, triclabendazole,

- 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

Diethylcarbamazine (DEC)

- enhances GABA effect in the worm → paralysis

- orally given, does not cross BBB

- adverse effects: mild, due to the disintegration of the worms

(fever, headache, dizziness, itching, joint pain)

- effective against certain roundworms: filarial Loa loa, Ascaris

lumbricoides, Ancylostoma duodenale, Trichuris trichiura

Ivermectin (Avermectin-Nobel prize!)

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

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

- inhibits oxidative phosphorilation

- orally given, poor absorbtion

- side effects: GI, dizziness (mild)

- effective againts tapeworms: Taenia solium, Taenia saginata

Niclosamide

Whipworm

(Trichuris trichura)

– more common in children- dysentery, colitis

– treatment: Albendazole or Mebendazole

Hookworm (Necator americanus, Ancylostoma

duodenale)

– America, Africa, South China, Southeast Asia, Egypt, India

– Skin penetration -> lung -> small intestine -> blood feed

– Treatment:

• 1st choice – Albendazole

• Alternatives: Mebendazole, Ivermectin

Roundworm infections

Lymphatic Filariasis (Wuchereria bancrofti)

– 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

Trichinella (trichinosis)

– eating under- or uncooked venison or wild pig

– invades scheletal muscles and heart

– Treatment:

• Albendazole or Mebendazole

Loiasis (Loa Loa)

– trasmitted by deerflies

– hot erythematous swellings (5 to 10 cm. or more) called Calabar swellings

– therapy: DEC or Ivermectin


Ascariasis

– tropical regions (70-90%)

– complications: intestinal obstruction, hepatobiliary ascariasis

– Treatment: - benzimidazoles (Mebendazole, Albendazole)

- Pyrantel Pamoate, in severe infections -> causesparalysis, worms can not cause complications during their elimination(perforation with peritonitis, intestinal obstruction and so), safe inpregnancy

Toxocariasis

– caused by canine ascarid (common in North America, USA, Europe)

– drug of choice - Albendazole

Pinworm (Enterobius, Oxyuriasis)

– most common helminth infection in temperate climates (USA)

– not severe, rarely secondary complications (salpingitis, peritonitis)

– easy contamination!

– treatment: Albendazole, Mebendazole, Pyrantel pamoate


Taenia saginata (beef tapeworm)

– cosmopolitan

– drug of choice: Praziquantel

Taenia solium (pork tapeworm)

– cosmopolitan

– intestinal infection and Cysticercosis (caused by invasive larval forms)

– drug of choice: Albendazole (Niclosamide is no longer in use.)

Hymenolepis nana (dwarf tapeworm)

– cosmopolitanthe most common tapeworm

– drug of choice: Praziquantel or Albendazole

Tapeworm infections

Schisostosomiasis (blood flukes)

– 200 million infected people

– heavy infection -> squamous cell carcinoma of the bladder

– drug of choice: Praziquantel

Fasciola hepatica (large liver fluke)

– infection -> eating freshwater plants such watercress

– drug of choice: Triclabendazole (older drug-Bithionol)

Flukes infections

antituberculosis, antifungal, antiprotozoal and

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