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What is metal chelation?

Interaction of a metal ion with a chemical molecule to form a heteroatomic ring


How can metal chelation alter the pharmacokinetics of drugs?

Absorption can be severely reduced
Due to complexes formed from chelation having reduced water solubility
This means they can't cross lipid membranes


When metals chelate with a drug what's the most stable ring size that could form?

6 membered ring
Followed by 5 or 7 membered ring (not aromatic)


When metals chelate with drugs, what's the least stable ring size that may form?

4 membered ring (strained)
Or 8 membered (bond overlap)


Adriamycin, actinomycin, synthetic acridine and quinolone antimalarials are all intercalating cytostatic agents. What do they interfere with?

Bacterial DNA replication
These drugs bind strongly to the DNA of chromatin in the bacterial cell nucleus by slipping between 2 base pairs
Form charge transfer complexes with the nucleotides


What are nitrogen mustard cytostatic agents?

Alkylating agents
They interfere with DNA replication


Which two antibiotics are both aminoglycosides in the group of anthracycline antibiotics produced by some streptomyces species?
Hint: they differ in structure by one hydroxyl group!

Adrimycin and duanomycin


Adriamycin and duanomycin are both anti cancer antibiotics. A big problem is their cardiotoxcity. What can reverse this toxicity?



Quinine is a common antimalarial.
It's more toxic than others.
What's it mainly used in combo with?



Some drugs may be DNA topoisomerase inhibitors. What is topoisomerase?

Topoisomerase I and II
Bacterial DNA must first unwind to be replicated. Unwinding introduces a supertwist. Top I removes this supertwist and produces more relaxed DNA.
Top II further promotes strand separation.
Topoisomerase inhibitors interfere with these enzymes so stop replication.
Used in cancer


Some agents like adriamycin and actinomycin D can stabilise the Topiosomerase enzyme and DNA complexes and therefore make the breaks in the DNA permanent

This way they have made the topoisomerase enzymes (DNA Gyrases) LETHAL enzymes


What other drugs can act by inhibiting DNA Gyrases (topoisomerases)?

Quinolone antibacterial agents but not that active

Ciprofloxacin is highly active


How do tetracyclines exhibit their antibacterial effects?

Interfere with protein synthesis
By inhibiting binding of tRNA to the 30S subunit if ribosomes in bacteria


What two (aminoglycoside antibiotics) antituberucloctics are very important?

Both have a fairly wide antibiotic spectrum
Antituberucloctics: anti TB bacteria


Why do we have to warn people on tetracyclines about dairy products?

Several chances for the antibiotics to chelAte with the calcium ions
6 places where tertacyclines can chelate


How do streptomycin and kanamycin work?

Decrease translation in the bacteria by binding to the 30S subunit of the bacterial ribosome. Therefore stops any more addition of amino acids to the growing peptides


Streptomycin is more ______ than kanamycin, what does this mean?

More ototoxic
Damaging to auditory nerve in the ear so patient goes deaf
(Same with gentamicin)


What is the drug of choice in tuberculosis and leprosy?


Much safer than others as it inhibits only bacterial RNA polymerase, not mammalian.


Chloramphenicol is the drug of choice against ______
By inhibiting the enzyme __________

Against typhoid
Inhibits peptidyl transferase

Chloramphenicol is Another product of the streptomyces species


What antibiotic can compete with chloramphenicol for the same binding site?

Acts in same way as chloramphenicol by inhibiting peptidyl transferase
It is the drug of choice to cure Legionnaires disease


Are fungi more likely to be opportunistic or obligate?



Certain people are way more likely to suffer from Fungal infections. Can you think of the list of 5 patients more likely?

HIV / AIDS patients
Transplant patients (immunosupressed)
Those having radio and chemotherapy
Patients treated with powerful antibiotics
Those with indwelling catheters


One class of fungal infections is superficial

These are caused by the true dermatophytes.
What are these?

Trichophyton species
Epidermophyton species
Microsporum species


What do the true dermatophytes give rise to?

That is athletes foot and ringworm


Other than dermatophytes what's the other kind of fungus that cause superficial fungal infections?

Candida species
C.albicans gives rise to oral and vaginal thrush


Superficial (localised) fungal infection can establish themselves into systemic infection, more like when the patient is?

More seriously ill


What ointment is commonly used to treat UNcomplicated vulvovaginal candidiasis (thrush)?

Ticonazole 6.5% Vaginal ointment

Uncomplicated means healthy, non pregnant women who have have previously been diagnosed by a doctor.

Other options: clotrimazole, miconazole, terconazole
Oral fluconazole as a single dose also commonly used


Why is identifying candida by culture in the absence of any symptoms NOT an indication that someone needs antifungal treatment?

Because approximately 10-20% of women have candida or other yeasts in their vagina! therefore symptoms have to be present to start treatment


How do we treat complicated thrush?

A longer duration of therapy with a intravaginal ointment or oral azole (fluconazole)


What is complicated vulvovaginal candidiasis ?

Infections that are recurrent or severe
Caused by Candida's OTHER than Candida albicans
Occur in women with underlying medical conditions such as pregnancy, diabetes, immunosuppression


Voriconazole is now the antifungal medicine of choice and is always superior to?

always superior to amphotericin B


What is caspofungin used for?

For systemic fungal infections
Given as an IV infusion for adults for invasive aspergillus or invasive candidiasis that aren't responsive to amphotericin or intraconazole, or for intolerant patients


What does Candida albicans use to aquire resistance to Azole treatments ?

An antifungal Efflux transporter protein
A MFS (major facilitator superfamily)
Transports drug out of fungi so it can't accumulate

MFS multidrug transporter CaMdr1p is relevant to azole resistance in Candida

Other way: alteration to the Azole target protein Erg11p


The multidrug transporter CaMdr1p shows selective substrate selectivity. Therefore what could we do to avoid it ? (And therefore avoid C albicans resistance)

Change a functional group in our drug so that the caMdr1p is no longer specific to our drug


Griseofulvin is a SYSTEMIC antifungal.
What's its mode of action?

Accumulates in keratin cells in host
Prevents transmission of fungi into unexfolidated skin cells

Prevents the correct functioning of micro-tubules assembly.

It stops the GROWTH and MOVEMENT of fungus through the cells


What are two examples of Polyene antifungal agents?

Nystatin and amphotericin B

These are for systemic fungal infections


How do the Polyene antifungals work?

Punch holes in cells
They're pore forming
Which allows lipid permeation

Remember polyENES: fungi
Polymyxins: bacteria
But both work at cell membrane


What are the major targets for Azoles, allyamines and morpholines?

Enzymes in the ergosterol biosynthetic pathway of fungus

Amorolfine clotrimazole fluconazole itraconazole ketoconazole terbinafine and Voriconazole all target these


How does amorolfine (nail lacquer) exert it's anti fungal action?

Results in depletion of ergosterol and accumulation of ignosterol in fungal cytoplasmic membranes


Are fungicides selective?

They have higher affinity for fungal ergosterol than mammalian cholesterol


How do miconzaole and ketoconazole (systemic) have their antifungal effects?

They inhibit synthesis of essential fungal cell membrane components such as ergosterol


How do miconzaole and ketoconazole differ?

Miconzaole can exert direct physicochemical cell membrane damage at relatively high levels
Ketoconazole can't do this


What is the mode of action of Azoles?

They are fungistatics
Inhibit oxidative enzymes in fungus especially P450 14a demthylase and C4-demthylase


Which of the triazoles are topical use only?


Fluconazole and itraconazole can be used systemically


Terbinafine and naftifine are both allylamines
How can they be used?

Topical and systemically

They have low mammal toxicity as allylamines have a far lower affinity for mammalian over fungal squalene epoxidases


What could reduce affinity for allylamine drugs?

Mutations in their target enzyme : fungal squalene epxidase


Why aren't pseudomonas bacteria sensitive to beta lactam antibiotics?

They have inactive porins
So beta lactams can't pass through the outer membrane into the cell wall

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