General properties of antimicrobial agents

Question 1

Are fungi classified as eukaryotes or prokaryotes and what problems are caused by this

Answer 1

Classified as Eukaryotes so there is no specific toxicity

Attacking common targets can cause side effects.

Question 2

List classes of anti-fungal drugs

Answer 2

Polyenes
Azoles
Echinocandins
Amorolfine

Question 3

List examples of drugs in the azole categories

Answer 3

Imidazole
Triazole
Clotrimazole
Miconazole
Ketoconazole,
fluconazole
Itraconazole

Question 4

MOA of azoles

Answer 4

Inhibit the production of sterols in cell membrane

Question 5

What are the best Azoles to use and why?

Answer 5

Fluconazole and itraconazole
Less toxic than ketoconazole and has good activity again fungi

Safe to use systemically

Used widely for fungal infection and oral/vaginal infcetions

Question 6

Examples of Echinocandins

Answer 6

Caspofungin

Micafungin

Question 7

MOA of echinocandins

Answer 7

Inhibit the enzyme beta-glucan synthase which produced cross link constituent of fungal cell wall

Question 8

MOA of Amorolfine

Answer 8

Affects sterol production: reduced sterols causes accumulation of related compounds

Question 9

Used of amorolfine

Answer 9

Fungal nail infections only- topically

Question 10

MOA of polyenes

Answer 10

Interact with sterols and increase the permeability of fungal membrane.

Question 11

Where are polyenes produced

Answer 11

in the soil

Question 12

Examples of polyenes and their properties

Answer 12

Amphotericin B: High renal toxicity, Liposomal formulation reduces but is more expensive
Nystain: topical only

Question 13

why is there a lack of development of antiparasitic drugs

Answer 13

Infections were rare

There was no money in it.

Question 14

List some antimalarial drugs

Answer 14

Quinines: Chloroquine, mefloquine, Halofantrine

Artemisinin

Question 15

List some conversional anti-bacterial drugs used as antiparasitic and how they work

Answer 15

• doxycycline: Malaria prophylaxis (“anti-protein” NB up to 15% photosensitisation)
• metronidazole : amoebae, giardia, trichomonas (reduced, then nucleic-acid disruption)
• co-trimoxazole: toxoplasma (and PCP) prophylaxis
• clindamycin: toxoplasma (and PCP) treatment (50s “anti-protein”)
• pyrimethamine toxoplasma (and PCP) treatment (DHFR, similar to trimethoprim)

*Toxoplasma gondii and Pneumocystis carinii Pneumonia (PCP)

Question 16

What are helminths

Answer 16

Worms or flukes

Question 17

causes of worms (parasitic infections)

Answer 17

Increased world travel has also increased helminth infections (or detection at least)
Hygiene / sewage management
Sushi/sashimi and poorly managed meat but water supplies and raw unwashed veg/fruit are the major contributor in many countries

Question 18

List some anti-Helminths against Threadworm/pinworms/Ascaris/Roundworm and how they work

Answer 18

-albendazole / mebendazole
Disrupt microtubule formation and glucose uptake which affects the motility and attachment of the worm

-nitazoxanide or ivermectin are alternatives
nitazoxanide disrupts energy transfer processes
ivermectin disrupts the nervous system

Question 19

Anti-Helminths against taenia/Tapeworm

Answer 19

-niclosamide: Inhibits ATP production
-praziquantel (broad-spectrum anti-helminthic)
>Increases the Ca permeability of plasma membranes
>Induces muscle spasms, affects retention, motility and exposes antigenic sites to immune system

Question 20

Anti-helminth treatment against Toxocara/ Roundworm

Answer 20

Albendazole: For parasitic worms of cats and dogs

Question 21

What is Aciclovir used to treat

Answer 21

Effective against both genital, oral and more serious herpes simplex (HSV) infections
Also used with some success in treatment of varicella virus (chickenpox and shingles)
It can be given intravenously or orally or used topically

Question 22

Lists some new variations of Aciclovir

Answer 22

valaciclovir,
famciclovir,
penciclovir

Question 23

How does Aciclovir work

Answer 23

-Nucleoside analogue produced as a prodrug (acycloguanosine)
>Phosphorylated once in the patient’s cells *IF virally coded thymidine kinase is present
>Affects DNA polymerases encoded by viral genes, so effective “only” in infected cells:
>Blockade and termination of viral DNA replication

Question 24

steps of Aciclovir mechanisms

Answer 24

1: Aciclovir + ATP to create aciclovir phosphate using HSV and Thymidine kinase
2: aciclovir phosphate with human enzymes creates Aciclovir triphosphate
3: Aciclovir triphosphate with HSV and DNA polymerase which causes it to be incorporated into viral DNA
4: Viral DNA synthesis inhibited

Question 25

What are the uses of Aciclovir derivatives (different from the)

Answer 25

Ganciclovir: treat cytomegalovirus (CMV) infections - Used effectively for cytomegalovirus in immunocompromised patients - More toxic, particularly to bone marrow (classified teratogen, mutagen, carcinogen) valganciclovir is more well absorbed prodrug of Ganciclovir

Question 26

Mechanism of Foscarnet and what does it treat

Answer 26

acts against DNA replication by inhibiting pyrophosphate binding to DNA polymerases Treats herpes/CMV when aciclovir/ganciclovir is unsuitable

Question 27

Side effects/ caution of Foscarnet

Answer 27

Toxic to kidneys, principally (approx 40% pts)

Question 28

Anti-viral drugs that aren't ciclovir

Answer 28

Oseltamivir Zanamivir

Question 29

Mechanism of oseltamivir, zanamivir

Answer 29

Selective ininhibitor of viral neuraminidase (NA)

Question 30

Use of oseltamivir, zanamivir

Answer 30

Used to prevent infection after exposure, or treat Glycoproteins on the virion surface, important for entry into cells and for the release of recently formed virus particles from cells, allowing spread within the body. In uncomplicated influenza, slightly shorter duration of symptoms but may be significant in patients at risk of severe complications

Question 31

Mechanism of viruses

Answer 31

- They are obligate intracellular parasites - Because they “hijack” many host cellular processes, selective toxicity is more difficult - Many viruses difficult to culture - more difficult to test potential antiviral drugs - The lack of easy, rapid tests means it is difficult to differentiate between various viral infections - Many viruses have multiple strains and also will readily mutate

Question 32

What are the types of HIV antiretrovirals

Answer 32

Entry/fusion inhibitors Nucleoside Reverse Transcriptase Inhibitors (RTIs Integrase Inhibitors (INIs) Protease inhibitors (PIs)

Question 33

How do RTIs work

Answer 33

This is a viral enzyme, so useful target. HIV nucleic acid is RNA, so must be “translated” into DNA. In slightly different ways, these drugs all inhibit the process The “base mimics” are included in the DNA chain but can’t be added to (no 3’OH), so formation is stoppedNon-base inhibitors bind directly to the enzyme

Question 34

Which type of antiviral mechanism is rarely longer used and why

Answer 34

Entry/ fusion inhibitors Not used due to resistance

Question 35

How do Integrase inhibitors work

Answer 35

Integrase is a viral enzyme that “integrates” the newly transcripted DNA into host DNA. The current drugs interact with two Mg2+ ions in the enzyme’s active site structure

Question 36

How to protease inhibitors work

Answer 36

Protease is a viral enzyme that is involved in building new virus particles from the various parts that the host cell has manufactured. These drugs tend not to stop the assembly but the resulting virus particles (virions) are defective