WEEK 4: ANTI-FUNGAL AND ANTI-PARASITIC DRUGS Flashcards
State the 2 main classes of drugs used as anti-fungal treatment and examples under each class.
- POLYENES: MOA of polyenes is the formation of pores in the fungal cell membrane, which allows leakage of cellular contents, ultimately leading to cell lysis.
*Amphotericin B
*Nystatin
- MACROLIDES: Macrolides are a class of antibiotics that are primarily used to treat bacterial infections. They work by inhibiting protein synthesis in bacteria.
*Macrolides, such as erythromycin, clarithromycin, and azithromycin
Outline diseases which can be treated using amphotericin B.
Aspergillus
Blastomyces
Cryptococcus
Candida
Coccidioides
Histoplasma
Leishmania
Trypanosome
Describe the MOA of amphotericin B.
How do fungi develop resistance against it?
Work by binding to ergosterol in the fungal cell membrane, causing the cell membrane to become permeable and allowing essential cellular components to leak out.
Resistance
↓ ergosterol content of the fungal membrane.
Efflux Pumps: Fungi can develop efflux pumps that actively pump out Amphotericin B from the fungal cell, preventing it from reaching effective concentrations within the cell.
Cell Wall Modifications: Some fungi may develop changes in their cell wall structure, which can reduce the drug’s ability to access the cell membrane.
Biofilm Formation: In some cases, fungi can form biofilms that act as protective barriers, making it difficult for the drug to penetrate and reach the fungal cells.
Reduction in Uptake: Fungi can downregulate or reduce the expression of proteins responsible for Amphotericin B uptake.
Outline characteristics of amphotericin B.
*Poorly absorbed across the gut
* Oral drug good only for infection within the gut
*Injectable preparations require addition of sodium deoxycholate
soluble colloidal dispersion
Insoluble in water
High Intravenous doses
Poorly crosses the BBB
State the infusion related toxicity of amphotericin B symptoms.
What is infusion rate?
What premedication can be given to prevent the toxic reaction?
Fever, chills, headache, and hypotension.
Infusion rate refers to the rate at which a fluid, medication, or solution is administered intravenously (through an IV or intravenous line) into a patient’s bloodstream.
It is typically measured in units of volume per unit of time, such as milliliters per hour (mL/hr) or drops per minute (gtts/min).
Administer a small test dose to gauge the severity of the reaction.
Slowing the infusion rate
Premedication with antihistamines and steroids
Amphotericin B results in nephrotoxicity.
Outline 3 signs which are related to this.
CUMULATIVE TOXICITY (NEPHROTOXITY)
Azotemia
Azotemia is a medical term that refers to an elevated level of nitrogen-containing compounds, particularly urea and creatinine, in the blood. These compounds are waste products that are normally excreted by the kidneys.
RTA
Renal Tubular Acidosis (RTA): Renal tubular acidosis is a medical condition that involves the kidney’s inability to effectively remove excess acid from the bloodstream and excrete it in the urine.
Potassium & Magnesium wasting.
Potassium wasting, also known as hypokalemia, refers to a condition in which there is a significant depletion of potassium in the body.
Magnesium wasting, also called hypomagnesemia, is a condition characterized by abnormally low levels of magnesium in the blood.
Salt loading may prevent and even reverse amphotericin B-induced azotemia by an unknown
mechanism.
Overall Toxicity:
Liposomal amphotericin B is often considered a less toxic alternative to conventional amphotericin B and is preferred when the risk of kidney toxicity needs to be minimized, especially in patients with underlying kidney disease.
State other polyene macrolides
OTHER POLYENE MACROLIDES
- AMPHOTERICIN A
Not used clinically.
Experimental drug - NYSTATIN
Poorly absorbed across the membranes.
Its mainly used for local candida infection.
Vomiting and local irritation
What are azoles?
State the 2 types of azoles and their examples.
They work by inhibiting the synthesis of ergosterol, a crucial component of the fungal cell membrane. Azoles are fungistatic, meaning they inhibit the growth and reproduction of fungi rather than killing them directly
Imidazoles
Ketoconazole
Miconazole
Clotrimazole
Triazoles
Itraconazole
Voriconazole
Fluconazole
Describe characteristics of KETOCONAZOLE
Unlike AmphoB: Not active against Aspergillus
Oral & topical formulation
Oral ketoconazole has largely been replaced by triazoles
Topical drug: Dermatophytes
Mucocutaneous candidiasis
Seborrheic dermatitis
Outline side effects of ketoconazole.
Nausea, anorexia, and vomiting
Hepatotoxicity
CP450 Inhibitor
Antiandrogen effects
Teratogenic
Describe characteristics of MICONAZOLE & CLOTRIMAZOLE.
Topical Imidazoles
Poorly absorbed orally
Widely used topically in the treatment of dermatophyte and
Candida infections.
Local irritation (i.e., stinging & burning sensation)
State the 3 triazoles.
Describe them
ITRACONAZOLE
Itraconazole is the drug of choice for the treatment of dimorphic fungi.
Rarely used for treatment of infections due to Candida and Aspergillus species because of the availability of newer and more effective agents.
Poor permeability of the blood–brain
barrier (BBB)
FLUCONAZOLE
High oral bioavailability (nearly 100%)
Very good CSF penetration
Azole of choice for systemic candidiasis & cryptococcal meningitis
No Activity against aspergillus
Nausea, vomiting, and rashes
VORICONAZOLE
* Candida
* Aspergillus
* Crosses the BBB
State 4 examples of dimorphic fungi.
Dimorphic fungi
Blastomycosis, Sporotrichosis, Paracoccidioidomycosis, and Histoplasmosis.
State the 4 other fungal drugs.
Flucytosine
Caspofungin
Griseofulvin
Terbinafine
Pyrimidine antimetabolite
Resistance due to decreased levels of any
of the enzymes
It is effective in combination with
amphotericin B for treating candidiasis or
cryptococcosis.
Bone marrow suppression
What drug is described above?
Flucytosine
β-glucan synthase inhibitor
Poor oral bioavailability (Available only in parenteral form).
Penetrates poorly into CSF
Txcandida and aspergilusinfections
Extremely well tolerated (minor GIT upset)
What drug is described above?
CASPOFUNGIN
Oral formulation
Gets concentrated in keratinized
tissues
Interact with microtubules/ disrupt
mitotic spindles/ Arrest fungal mitosis
Tx of dermatophytes
AE (Headache, GIT upset), CP450
inducer, Teratogenic
What drug is described above?
GRISEOFULVIN
Squalene epoxidase inhibitor
Fungicidal
Oral/ topical
Onychomycosis (fungal infections of
nails or nail beds)
GIT disturbances, rash, headache
What drug is described above?
TERBINAFINE
State the 3 forms of malaria and their causative agents.
FORMS OF MALARIA
1. Benign tertian malaria
Plasmodium vivax
Plasmodium ovale
- Malignant tertian malaria
Plasmodium falciparum
P. falciparum, which constitutes up to 98% of all
malaria cases in Botswana!!! - Quartan malaria
Plasmodium malariae
Which 2 species of malaria can become dormant in the liver (Hypnozoites)?
P. Vivax and P. Ovale can become dormant in the liver (Hypnozoites).
Outline drugs used to treat acute malaria attack.
DRUGS USED TO TREAT THE ACUTE ATTACK
*Quinoline methanol’s
*Artemisinin
*Folate antagonists
State the symptoms of acute malaria attack.
An attack usually starts with shivering and chills,
followed by a high fever, followed by sweating and
a return to normal temperature.
Describe the MOA of chloroquine.
State some of the side effects of chloroquine.
Chloroquine binds to heme, preventing its polymerization to hemozoin.
Unwanted effects include nausea, vomiting, urticaria, headaches, blurring of vision.
Plasmodium falciparum is now resistant to chloroquine in most parts of the world
Describe the following other quinoline methanol’s.
1. Quinine
2. Mefloquine
OTHER QUINOLINE METHANOLS
QUININE
Bitter taste
Hypoglycemia
Cinchonism: Tinnitus, Hearing Impairment, Headache, Nausea and Vomiting, Visual Disturbances, Confusion or Delirium, Cardiac Arrhythmias
Blackwater fever
MEFLOQUINE
Gastrointestinal Upset
Teratogenic: ability of a substance, agent, or factor to cause congenital malformations or birth defects in a developing fetus.
Plasma half-life of up to 30 days
Artemether. Artesunate. Dihydroartemesinin.
Interact with heme in the parasitic food vacuole and generates cytotoxic
radical species
First choice for chloroquine resistant malaria in most countries
Often combined with longer acting agents. COARTEM = Artemether +
lumefantrine
Commonly reported adverse effects are gastrointestinal.
Name the type of anti-malarial drug described above.
ARTEMESININS
Describe MOA of anti-folate drugs.
Sulfadoxine: dihydropteroate synthase inhibitor
Pyrimethamine: dihydrofolate reductase inhibitor
FANSIDAR = Pyrimethamine sulfadoxine effective against chloroquine resistant malaria
Folic acid deficiency (Megaloblastic
anemia)
What is radical cure?
Radical cure means complete elimination of malaria parasite from the body.
Name the drug administered as radical cure.
Primaquine
Name the drug that is combined with primaquine to achieve radical cure.
To achieve the radical cure primaquine is combined with a blood schizonticide.
The first line antimalarial drug for the treatment of uncomplicated Falciparum malaria is ____________with a single dose of primaquine.
The first line antimalarial drug for the treatment of
uncomplicated Falciparum malaria is Artemether
Lumefantrine (AL) with a single dose of primaquine.
What is the function of schizonticide?
State the contraindication for primaquine.
Tissue schizonticide (Eradicates the hypnozoites
Gametocidal (Interrupting the transmission of the disease)
Metabolites of primaquine are believed to act as oxidants.
Contraindicated in G6PD deficiency and pregnancy.
OUTLINE DRUGS FOR CHEMO-PROPHYLAXIS OF MALARIA.
Chloroquine
Mefloquine
Doxycycline, Tafenoquine, Atovaquone
proguanil
Describe characteristics of drugs used for chemoprophylaxis of malaria.
Block the link between the exoerythrocytic
stage and the erythrocytic stage and prevents clinical attacks
They are given to individuals who intend
travelling to an area where malaria is
endemic
Most are started a week before entering the
area and should be continued throughout
the stay and for up to a month afterwards
Different agents may be required for different
travel destinations
Albendazoleand mebendazole.
Active against nematodes(roundworms) and cestodes(tapeworms)
Bind to beta tubulin and interferes with microtubule dependent function
(motility and DNA replication)
Irreversibly inhibit glucose uptake leading to glycogen depletion
Contraindicated in pregnancy.
What class of anti-helminthic drugs is described above?
Benzimidazoles
Increases the parasite’s permeability to calcium ions
DOC for all forms of schistosomiasis
It is also used in conjunction with niclosamide for tapeworms.
Common AEs are abdominal pains and cramps.
What class of anti-helminthic drugs is described above?
PRAZIQUANTEL
DOC for onchocerciasis and strongyloidiasis
Activates the glutamate gated chloride ion
channels
Headache, ataxia, seizures
What anti-helminthic drug is described above?
IVERMECTIN
Used for txof filarial infections
Inhibits arachidonic acid metabolisms
Commonly reported AE are headache and
GIT upset.
Mazzotti reaction:
What anti-helminthic drug is described above?
DIETHYLCARBAMAZINE
Name the drug associated with Mazzotti reaction.
Outline symptoms associated with this reaction.
The Mazzotti reaction is characterized by the following symptoms and effects, which typically occur within a few hours to a couple of days after taking ivermectin:
Itching and Rash: Individuals may experience intense itching, which can be accompanied by the development of a rash, typically consisting of papules (small, raised bumps) and sometimes hives.
Fever: A mild to moderate fever is a common symptom of the Mazzotti reaction.
Lymph Node Swelling: Enlargement and tenderness of lymph nodes, particularly in the neck and inguinal (groin) regions, can occur.
Joint Pain and Muscle Aches: Many people report experiencing joint pain and muscle aches during the Mazzotti reaction.
General Malaise: A general feeling of illness, malaise, and discomfort is also common.
