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Pharmacology C Topics > 2-4 Anti- mycobacterial, protozoal, helminthic and fungal > Flashcards

2-4 Anti- mycobacterial, protozoal, helminthic and fungal Flashcards

1
Q

What are mycobacteria and their features? Species?

A
  • Mycobacteria are rod-shaped aerobic, non-motile, rods that multiply slowly, every 18-24h
  • They can be dormant, latent
  • They are intracellular (not obligate) pathogens
  • Thy contain mycolic acids: very long, b-hydroxylated fatty acids
  • They produce highly lipophilic cell walls that stain poorly with gram stain
  • They are acid-fast rods: they are not easily decolorized by acidified organic solvents
  • Mycobacterial infections usually result in the formation of slow-growing granulomatous lesions è tissue destruction

Mycobacterial species:

  • M. tuberculosis – tuberculosis
    • M. bovis – bovine tuberculosis
  • 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
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2
Q

What is tuberculosis? What are it’s therapy protocols? Strategies for drug resistance?

A
  • It is slow growing and requires treatment for months to years
  • It is the leading infectious cause of death worldwide with > 2 billion already infected
  • The disease caused by the atypical mycobacteria increase in frequency
  • TB treatment generally includes 1st line drugs, 2nd line drugs.
    • The latter are less effective, more toxic, and less extensively studied. They are used in patients who cannot tolerate the 1st line drugs or when the mycobacterium has gotten resistant.

TB therapy protocols:

  • Drugs are always given in combination
  • Standard initial therapy:
  • 1. Rifampin + Isoniazid + Pyrazinamide + ethambutol/streptomycin for 2 months (RIPE)
  • 2. Isoniazid + rifampin for 4 months
  • Actively growing bacteria:
    • Isoniazid
  • Dormant bacteria:
    • Rifampin + pyrazinamide + ethambutol for 6 months
  • Treatment for multidrug resistant TB typically lasts for about 2 years

Strategies for drug resistance:

  • Inadequate treatment, especially monotherapy, causes an increase in drug-resistant TB organisms
  • Multidrug therapy is therefore recommended to suppress the resistant organisms
  • The 1st line drugs are preferred because of their high efficacy and acceptable incidence of toxicity
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3
Q

List the 1st line antituberculotic drugs!

A
  • Rifampine
  • Isoniazid
  • Pyrazinamide
  • Ethambutol
  • Streptomycin
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4
Q

1st line antituberculotic drug: rifampine!

A
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5
Q

1st line antituberculotic drug: isoniazid!

A
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6
Q

1st line antituberculotic drug: pyrazinamide!

A
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7
Q

1st line antituberculotic drug: ethambutol!

A
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8
Q

1st line antituberculotic drug: streptomycin!

A
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9
Q

Which are the 2nd line antituberculotic drugs?

A
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10
Q

Which are the drugs to treat leprosy?

A
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11
Q

What are protozoa and their infections? Important protozoa?

A
  • Protozoal infections are common among people in underdeveloped tropical and subtropical countries
  • There are usually bad sanitary and hygienic practices and vector control is inadequate
  • Unicellular eukaryotes with metabolic processes closer to those of the human host than to prokaryotic bacterial pathogens
  • Many of the protozoal drugs cause serious toxic effects in the host, particularly on cells showing high metabolic activity
  • Most of the drugs have not proven to be safe to pregnant patients

Important protozoons:

  • Plasmodium strains → malaria
  • Entamoeba hystolitica
  • Trichomonas vaginalis
  • Giardia lamblia
  • Toxoplasma gondii
  • Trypanosoma strains
  • Leishmania strains
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12
Q

What is malaria and the different plasmodia species?

What is the classification of antiprotozoal drugs?

A
  • Malaria is an acute infectious disease caused by Plasodium species
  • Plasmodium falciparum is the most dangerous causing acute, rapidly fulminating disease characterized by persistent fever, orthostatic hypotension, and massive erythrocytosis
  • Plasmodium vivax cause a milder form of the disease
  • Plasmodium ovale is rarely encountered
  • Plasmodium malariae is common in many tropical regions

Life cycle of plasmodium:

  1. Anophele mosquito inoculates plasmodium sporozoites to initiate human infection.
  2. Sporozoites invade liver cells –> start the extraerythrocytic stage (maturation to merozoites) cycle of malaria.
  3. Merozoites are released and invade the red blood cells: inside growing –> more merozoites (rupture of erythrocytes and invading new erythrocytes, some merozoites change into gametocytes which infect mosquito.

Classification of antiprotozoal drugs:

  • Tissue schizonticides: act on liver forms (e.g. primaquine)
  • Blood schizonticides (suppressive therapy): act on erythrocyte forms, prevents the clinical symptoms (e.g. chloroquine, quinine)
  • Gametocides: kill gametocytes (e.g. primaquine)
  • Prophylactic therapy
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13
Q

List the antiprotozoal drugs for malaria!

A
  • Chloroquine
  • Quinine, quinidie
  • Mefloquine
  • Primaquine
  • Halofantrine
  • Lumefantrine
  • Proguanil
  • Sulfadoxine + pyrimethamine
  • Atovaquone + proguanol = Malaron
  • Artmisinin
  • Antibiotics
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14
Q

Describe the antiprotozal drugs for malaria (1st half):

Chloroquine

Quinine, quinidine

Mefloquine

Primaquine

Halofantrine

A
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15
Q

Describe the antiprotozal drugs for malaria (2nd half):

Lumefantrine

Proguanil

Sulfadoxine + pyrimethamine

Atovaquone + proguanil = Malaron

Artemisinin

Antibiotics

A
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16
Q

What is amebiasis infection?

A
  • It is an infection of the intestinal tract caused by Entamoeba hystolitica
  • It can range from mild diarrhea to fulminating dysentery
  • A swallowed cyst cause infection by excysting in the GI tract
  • As the name, histolytic (tissue destroying), indicates it is pathogenic
  • The infection may be asymptomatic, or it can lead to amoebic dysentery or amoebic liver abscess
17
Q

Which are the drugs for amebiasis?

A

Idoquinol:

  • Mechanism of action: not fully understood
  • Pharmacokinetics: poor oral absorption
  • Clinical indications:
  • Monotherapy for treatment of intestinal asymptomatic amebiasis
  • Combination therapy for treatment of intestinal or extraintestinal amebiasis
  • Adverse effects: GI disturbances

Diloxanid Furoat:

  • Mechanism of action: unclear
  • Pharmacokinetics: its metabolite, dilocanid, is absorbed
  • Clinical indications: alternative compound in asymptomatic amebiasis
  • Adverse effects: GI disturbances

Nitroimidazoles:

  • Metronidazole, tinidazole
  • Mechanism of action: reactive reduction products have cytotoxic effect
  • Clinical indications: Combination therapy for intestinal and extraintestinal infections

Paromomycin (aminoglycoside):

  • Mechanism of action: Inhibition of protein synthesis
  • Clinical indications: 2nd line drug in intestinal and extraintestinal infections
18
Q

What is giardiasis infection?

A
  • Giardia Lamblia is the most commonly diagnosed intestinal parasite in the USA
  • 2 life cycles:
    • Binucleate trophozoite with 4 flagella
    • Drug-resistant, 4 nucleate cyst
  • Ingestion from contaminated drinking water
  • Some infections are asymptomatic, but severe diarrhea can occur and it can be very serious in immunocompromised patients
19
Q

Which are the drugs for giardiasis?

A

1st line:

  • Nitroimidazoles: Metronidazole, tinidazole
  • Nitazoxanid:
    • Broad spectrum antiprotozoal drug
    • Unclear mechanism of action
    • Few side effects

2nd line:

  • Paromomycin (aminoglycosides): poor oral absorption
  • Furazolidon:
    • Nitrofuran
      • Oral drug
      • GI side effects
  • Quinacrin:
    • Broad spectrum antiprotozoal drug
    • Good oral absorption
    • Long elimination T1/2 (5 days)
    • GI side effects
20
Q

What is trichomoniasis infection?

Which are the drugs to treat it?

A
  • Trichomonas vaginal is a parasite that doesn’t produce any cysts and has adapted to the urogenital epithelium
  • Transmission: STD, thermal baths, dirty WC and vertical transmission (at birth)
  • Clinical features:
    • If symptoms occur they usually occur 5-28 days after exposure
    • Women are frequently symptomless or have profuse flour (vaginal discharge), vaginitis, inflammation, erosion, itching, and burning pain
    • Men are also frequently symptomless or have urethritis or prostatitis
    • If trichomoniasis affect the cervix a typical “strawberry” appearance can be seen

Drugs:

Nitroimidazoles: metronidazole, tinidazole

21
Q

What is toxoplasmosis infection and what are the drugs to treat it?

A
  • Toxoplasma gondii is one of the most common human infections
  • Transmission: raw or inadequately cooked infected meat, or vertical transmission. Cats can shed oocysts, which can infect other animals and humans

Drugs:

1st choice:

  • Spiramycin (in pregnancy)
  • Sulfamethoxazole +Trimethoprim
  • Pyrimethamine + Clindamycin + folinic acid

Alternative compounds:

  • Pyrimethamine + Sulfadiazine + folinic acid
22
Q

What is pneumocystis injection and what are the drugs to treat it?

A
  • It is an opportunistic infection in immunocompromised patients with AIDS

Drugs:

1st choice:

  • Sulfamethoxazole + Trimethoprim

Alternative compounds:

  • Pentamidine or clindamycin + Primaquine or Atovaquone
23
Q

What is leishmaniasis infection?

A
  • Leishmaniae causes the disease Leishmaniasis, which is endemic in tropical and subtropical regions
  • There are 3 types, cutaneous, visceral and mucocutaneous
    • Visceral leishmaniasis:
      • L. donovani is responsible for visceral leishmaniasis or kala-azar (dum-dum fever), the most severe form for leishmaniasis
      • Incubation time is 2-20 months and it will present as mild symptoms; fever, diarrhea, weakness and anemia
      • It infects the mononuclear phagocyte system including the spleen, liver and bone marrow
      • If the disease persists, post-kala-azar dermal leishmaniasis occur presenting as deeply pigmented, granulomatous areas of the skin
    • Cutaneous leishmaniasis:
      • Caused by Leishmania tropica
      • Incubation: 2 weeks – month
      • A red papule will appear at the site of the bite, it becomes itchy and starts to ulcerate, the ulcer becomes hard and exudates a thin serous membrane
    • Mucocutaneous leishmaniasis:
      • Caused by Leishmania Braziliensis
      • Incubation: weeks to months
      • Mucus membrane destruction occurs in addition to the ulcer, and combined with edema and secondary bacterial infection
24
Q

What are the drugs for leismaniasis infection?

A

Visceral leishmaniasis:

  • Amphotericin B: For visceral leishmaniasis
  • Miltefosine: Given orally
  • Pentamidine:
    • Unclear mechanism of action (inhibition of protein synthesis?)
    • Parenteral administration
    • Reserve compound in resistant cases
    • Severe adverse effects: arrhythmias, Hepatonephrotoxicity, Stevens-Johnson syndrome

Cutaneous leishmaniasis:

  • Pentamidine
  • Ketoconazole

Mucocutaneous leishmaniasis - pentavalent antimonials:

  • Sodium stibogluconate:
    • IV or IM administration
    • Unknown mechanism of action
    • Adverse effects: GI, myalgias, arthralgia, headache, QT-prolongation, rarely, hepatonephrotoxic
  • Meglumin antimoniat: IV administration
25
Q

What is trypanosomiasis infection?

A

Trypanosomiasis:

  • There are three main pathogenic species leading to different diseases o
    • T. brucei:
      • T. brucei parasites live and grow in the blood before they invade tissues and the CNS, causing inflammation of the brain and spinal cord that produce the characteristic lethargy and eventually continuous sleep
  • Clinical: Sleeping sickness
    • Symptoms manifest after 1 week
    • Stage:
  • Primer chancre
  • Lymphadenopathy
  • Encephalopathy
    • T. brucei gambiens is prevalent in West-Africa causing sleeping sickness (African trypanosomiasis)
      • Slow onset chronic trypanosomiasis
        • It often ends fatally, with CNS involvement
    • T. brucei rhodesiense is prevalent in East-Africa and causes more virulent sleeping sickness (African trypanosomiasis)
      • Causes fast onset acute trypanosomiasis
  • T. cruzi is prevalent in South-America and leads to Chagas-disease (American trypanosomiasis)
    • Chagas disease has two forms, a trypomastigote found in human blood and an amastigote found in tissue
    • The acute form usually goes unnoticed and may manifest itself as a localized swelling at the site of entry, a chagoma – Romaña’s sign
      • Fever, myalgia and edema may also occur
26
Q

What are the drugs for African trypanosomiasis?

A
27
Q

What are the drugs for American trypanosomiasis?

A
28
Q

What are helminths and the possible drug targets?

A

Helminths:

  • Worms:
    • Nematodes – roundworms
    • Trematodes - flukes
    • Cestodes – tapeworms
  • They usually enter the human body through the mouth, bite of insect vector or penetration
  • They are localized in the internal organs, dermal and lymphatic tissues and blood vessels
  • Characteristic laboratory findings: eosinophilia and elevated IgE titer

Possible drug targets of helminths:

  • Neuromuscular coordination
  • Carbohydrate metabolism
  • Microtubule integration (lie eggs, shooting, larval development, glucose transport, enzyme function)
29
Q

Which are the antihelminthic drugs?

A
30
Q

Which are the types of fungi and their main systemic infections?

A
  • Yeasts:
    • Candida albicans
    • Cryptococcus neoformans
  • Dimorphic:
    • Histoplasma capsulatum
    • Blastomyces dermatitidis
    • Coccidioides immitis
  • Molds:
    • Aspergillus fumigatus
    • Mucor species
  • Dermatophytes:
    • Trychophytons
    • Epidermophytons
    • Microsporon
    • Malassezia furfur

Systemic fungal infections:

  • Systemic candidiasis: RTI
  • Cryptococcal meningitis, endocarditis
  • Rhinocerebral mucormycosis (rare)
  • Pulmonary aspergillosis
  • Blastomycosis (pneumonia)
  • Histoplasmosis (cough, fever, multiple pneumonic infiltrates)
  • Coccidiodomycosis
  • Pneumocystis carinii pneumonia
31
Q

Which are the different classification of antifungal drugs?

A

Based on mechanism of action:

  • Fungal cell wall synthesis inhibition: Echinocandins
  • Bind to fungal cell membrane ergosterol: Amphotericin–B, Nystatin
  • Inhibition of ergosterol + lanosterol synthesis: Terbinafine, Naftifine
  • Inhibition of ergosterol synthesis: Azoles
  • Inhibition of nucleic acid synthesis: 5–Flucytosine
  • Disruption of mitotic spindle and inhibition of fungal mitosis: Griseofulvin
  • Miscellaneous: Ciclopirox

Based on structure:

Antibiotics:

  • Polyene: amphotericin, nystatin
  • Heterocyclic benzofurane: griseofulvin

Antimetabolites:

  • Flucytosine

Azoles:

  • Imidazoles: ketoconazole, clotrimazole, oxiconazole, miconazole
  • Triazoles: fluconazole, itraconazole, voriconazole, posaconazole

Allylamines:

  • Terbinafine
  • Naftifine

Echinocandins:

  • Caspofungin
  • Anidulafungin
  • Micafungin
32
Q

Describe the polyenes, systemic antifungal drug for systemic infections!

A

Polyenes (macrolide antibiotics):

Drugs:

  • Amphotericin B
  • Liposomal amphotericin B

Mechanism of action:

  • It can differentiate between fungal and mammalian cell membranes so it can be used systemically (binds with higher affinity to the ergosterol type membranes)
  • Binds to ergosterol and alters the permeability of the cell by forming pores in the cell membrane ==> cell content leaks out ==> death
  • Fungicide

Spectrum:

  • Broadest spectrum of action
    • Aspergillus
    • Blastomyces dermatitidis
    • Candida sp.
    • Cryptococcus neoformans
    • Coccidioides immitis
    • Histoplasma capsulatum
    • Mucor spp.
  • Leishmaniae and acanthamoeba
  • No effect on dermatophytes

Pharmacokinetics:

  • Parenteral administration
  • Good distribution, but not CNS entry
  • Long elimination half-life
  • Liposomal form:
    • Better effect
    • Less side effects
  • Slow elimination through kidney
  • No dose adjustment is necessary at hepatic or kidney impairment

Clinical use

  • Useful drug in nearly all life threatening mycotic infections: mycosis of the organs, sepsis
  • Coccidio- or candida meningitis
    • Intrathecal administration
  • Topically applied for ocular or bladder infections
  • Effective in leishmaniasis

Adverse effects:

  • Fever
  • GI disturbances (infusion-related toxicity)
  • Cumulative toxicity:
    • Nephrotoxicity (monitorization)
    • Impaired liver functions
    • Bone marrow suppression
  • Liposomal amphotericin B:
    • Less nephrotoxic and bone marrow suppression
    • Higher doses can be used
33
Q

Describe the antimetabolites, systemic antifungal drug for systemic infections!

A

Drugs:

  • 5-flucytosine

Mechanism of action:

  • 5-FU is formed from it in the fungal cells, incorporates into RNA, inhibits protein synthesis

Pharmacokinetics:

  • Well absorbed orally
  • Good distribution, enters CNS
  • Short half-life
  • Renal elimination

Clinical use

  • Combination with amphotericin B ==> synergistic effect:
    • ­Increased entry of 5-flucytosine
    • Reduced toxicity
    • Reduced duration of therapy
    • Reduced resistance
  • Effective against Cryptococcus neoformans and candida species

Adverse effects:

  • Bone marrow and liver toxicity
  • GI disturbances
  • Toxic enterocolitis (rare, at high serum level)
34
Q

Describe the azoles, systemic antifungal drug for systemic infections!

A

Drugs:

  • Imidazoles:
    • Clotrimazole
    • Ketoconazole (not used systematically)
  • Triazoles:
    • 1st generation: Fluconazole, itraconazole
    • 2nd generation: voriconazole, posaconazole

Mechanism of action:

  • Inhibit the ergosterol synthesis by binding to the cytochrome P-450 enzyme system
  • High selectivity, greater affinity for the fungal enzyme system

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

Clinical use

  • Broad spectrum:
    • Candida spp
    • Cryptococcus
    • Blastomycosis
    • Coccidioidomycosis
    • Histoplasmosis
    • Dermatophytons
  • Itraconazole and voriconazole: effective in Aspergillus infections too
  • Itraconazole, fluconazole: in dermato- and onychomycosis
  • Fluconazole: Cryptococcus meningitis
  • Fluconazole, voriconazole: often used at ICU for the treatment of sepsis, ex. Candida sepsis
  • Posaconazole: the newest, indicated in invasive aspergillosis. Significant effect in mucormycosis.
  • Ketoconazole is used only locally

Adverse effects:

  • Relatively non-toxic
  • Mainly GI
  • Liver enzyme elevation
  • Rarely hepatitis
  • Ketoconazole – gynaecomastia, oligospermia, impotence (inhibits testosterone synthesis)
35
Q

Describe the echinocandins, systemic antifungal drugs fo systemic infections!

A
  • Newest class of antifungal agents

Drugs:

  • Capsofungin
  • Micafungin
  • Anidulafungin

Mechanism of action:

  • Inhibit b-glucan synthesis ==> disruption of fungal cell wall

Pharmacokinetics:

  • Only IV administration

Clinical use

  • Candida species
  • Aspergillus niger
  • Sepsis
  • Multiresistant infections

Adverse effects:

  • Well tolerated but:
    • Fever
    • GI disturbances
    • Flush
    • Increased­ liver enzymes
    • Micafungin: ­Increased risk of liver tumors and suppresses bone marrow
36
Q

Which are the systemic antifungal drugs for mucocutaneous infections?

A

Terbinafine:

Mechanism of action:

  • Inhibit the fungal enzyme squalene epoxidase ==> accumulation of squalene
    • Toxic effect and lack of ergosterol
  • Fungicide

Pharmacokinetics:

  • Good oral absorption
  • Accumulates in skin, hair and nails

Clinical use

  • Broad spectrum
  • Local and systemic treatment of onicho- and dematomycosis (dermatophytons)
  • Some candida infections

Adverse effects:

  • GI disturbances
  • Skin reactions (rarely, Stevens-Johnson syndrome)
  • Increased­ liver enzymes

Griseofulvin:

Mechanism of action:

  • Unclear
  • Inhibits mitosis
  • Fungistatic
    • Effective mainly against dermatophytons

Pharmacokinetics:

  • Good oral absorption
  • Accumulates in hair, skin and nails
  • Interactions:
    • Enzyme inducer

Clinical use

  • Microsporia capitis of the scalp

Adverse effects:

  • GI disturbances
  • Increased­ liver enzymes, hepatotoxicity
37
Q

Which are the local antifungal drugs?

A

Nystatin (polyene macrolide antibiotic):

Mechanism of action:

  • Compound similar to amphotericin B

Pharmacokinetics:

  • Not absorbable orally as it has local effects in the GIT
  • Poor absorption from the skin and mucosal membranes

Clinical use

  • Candidiasis of oral cavity and of esophagus
  • Infections of the gastrointestinal tract
  • Superficial infections of skin and mucosas

Adverse effects:

  • Nausea, vomiting
  • Diarrhea
  • Exanthema

Others:

Allylamines:

  • Terbinafine:
    • Fungicide cream, spray, gel
  • Naftitin:
    • Fungicide cream and solution

Amorolfine:

  • Fungicide
  • Nail polish

Ciclopirox:

  • Broad spectrum antifungal drug
  • Antibacterial and anti-inflammatory effect
  • Onychomycosis, dermatomycosis
  • Cream, nail polish, solution

Azoles:

  • Clotrimazole
  • Bifonazole
  • Econazole
  • Flutrimazole
  • Ketoconazole
  • Omoconazole

Pharmacology C Topics (12 decks)

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