WEEK 4: ANTI-FUNGAL AND ANTI-PARASITIC DRUGS

Question 1

State the 2 main classes of drugs used as anti-fungal treatment and examples under each class.

Answer 1

1. 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

2. 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

Question 2

Outline diseases which can be treated using amphotericin B.

Answer 2

Aspergillus
Blastomyces
Cryptococcus
Candida
Coccidioides
Histoplasma
Leishmania
Trypanosome

Question 3

Describe the MOA of amphotericin B.

How do fungi develop resistance against it?

Answer 3

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.

Question 4

Outline characteristics of amphotericin B.

Answer 4

*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

Question 5

State the infusion related toxicity of amphotericin B symptoms.

What is infusion rate?

What premedication can be given to prevent the toxic reaction?

Answer 5

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

Question 6

Amphotericin B results in nephrotoxicity.

Outline 3 signs which are related to this.

Answer 6

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.

Question 7

State other polyene macrolides

Answer 7

OTHER POLYENE MACROLIDES

1. AMPHOTERICIN A
   Not used clinically.
   Experimental drug
2. NYSTATIN
   Poorly absorbed across the membranes.
    Its mainly used for local candida infection.
   Vomiting and local irritation

Question 8

What are azoles?

State the 2 types of azoles and their examples.

Answer 8

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

Question 9

Describe characteristics of KETOCONAZOLE

Answer 9

 Unlike AmphoB: Not active against Aspergillus
Oral & topical formulation
Oral ketoconazole has largely been replaced by triazoles
 Topical drug: Dermatophytes
Mucocutaneous candidiasis
Seborrheic dermatitis

Question 10

Outline side effects of ketoconazole.

Answer 10

 Nausea, anorexia, and vomiting
 Hepatotoxicity
 CP450 Inhibitor
 Antiandrogen effects
 Teratogenic

Question 11

Describe characteristics of MICONAZOLE & CLOTRIMAZOLE.

Answer 11

Topical Imidazoles
Poorly absorbed orally
Widely used topically in the treatment of dermatophyte and
Candida infections.
Local irritation (i.e., stinging & burning sensation)

Question 12

State the 3 triazoles.
Describe them

Answer 12

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

Question 13

State 4 examples of dimorphic fungi.

Answer 13

Dimorphic fungi
Blastomycosis, Sporotrichosis, Paracoccidioidomycosis, and Histoplasmosis.

Question 13

State the 4 other fungal drugs.

Answer 13

Flucytosine
Caspofungin
Griseofulvin
Terbinafine

Question 14

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?

Answer 14

Flucytosine

Question 15

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?

Answer 15

CASPOFUNGIN

Question 16

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?

Answer 16

GRISEOFULVIN

Question 17

 Squalene epoxidase inhibitor
 Fungicidal
Oral/ topical
Onychomycosis (fungal infections of
nails or nail beds)
GIT disturbances, rash, headache

What drug is described above?

Answer 17

TERBINAFINE

Question 18

State the 3 forms of malaria and their causative agents.

Answer 18

FORMS OF MALARIA
1. Benign tertian malaria
 Plasmodium vivax
 Plasmodium ovale

2. Malignant tertian malaria
    Plasmodium falciparum
    P. falciparum, which constitutes up to 98% of all
   malaria cases in Botswana!!!
3. Quartan malaria
    Plasmodium malariae

Question 19

Which 2 species of malaria can become dormant in the liver (Hypnozoites)?

Answer 19

P. Vivax and P. Ovale can become dormant in the liver (Hypnozoites).

Question 20

Outline drugs used to treat acute malaria attack.

Answer 20

DRUGS USED TO TREAT THE ACUTE ATTACK
*Quinoline methanol’s
*Artemisinin
*Folate antagonists

Question 21

State the symptoms of acute malaria attack.

Answer 21

An attack usually starts with shivering and chills,
followed by a high fever, followed by sweating and
a return to normal temperature.

Question 22

Describe the MOA of chloroquine.

State some of the side effects of chloroquine.

Answer 22

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

Question 23

Describe the following other quinoline methanol’s.
1. Quinine
2. Mefloquine

Answer 23

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

Question 24

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.

Answer 24

ARTEMESININS

Question 25

Describe MOA of anti-folate drugs.

Answer 25

 Sulfadoxine: dihydropteroate synthase inhibitor Pyrimethamine: dihydrofolate reductase inhibitor  FANSIDAR = Pyrimethamine sulfadoxine effective against chloroquine resistant malaria  Folic acid deficiency (Megaloblastic anemia)

Question 26

What is radical cure?

Answer 26

Radical cure means complete elimination of malaria parasite from the body.

Question 27

Name the drug administered as radical cure.

Answer 27

Primaquine

Question 28

Name the drug that is combined with primaquine to achieve radical cure.

Answer 28

 To achieve the radical cure primaquine is combined with a blood schizonticide.

Question 29

The first line antimalarial drug for the treatment of uncomplicated Falciparum malaria is ____________with a single dose of primaquine.

Answer 29

The first line antimalarial drug for the treatment of uncomplicated Falciparum malaria is Artemether Lumefantrine (AL) with a single dose of primaquine.

Question 30

What is the function of schizonticide? State the contraindication for primaquine.

Answer 30

 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.

Question 31

OUTLINE DRUGS FOR CHEMO-PROPHYLAXIS OF MALARIA.

Answer 31

Chloroquine Mefloquine Doxycycline, Tafenoquine, Atovaquone proguanil

Question 32

Describe characteristics of drugs used for chemoprophylaxis of malaria.

Answer 32

 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

Question 33

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?

Answer 33

Benzimidazoles

Question 34

 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?

Answer 34

PRAZIQUANTEL

Question 35

 DOC for onchocerciasis and strongyloidiasis  Activates the glutamate gated chloride ion channels  Headache, ataxia, seizures What anti-helminthic drug is described above?

Answer 35

IVERMECTIN

Question 36

 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?

Answer 36

DIETHYLCARBAMAZINE

Question 37

Name the drug associated with Mazzotti reaction. Outline symptoms associated with this reaction.

Answer 37

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.