PCL

                                             QUESTION1—; Discuss with named examples
the clinical pharmacology of Azole antifungi agent and potential threat to its
usage ?

Answer —- ; Azoles are a class of membered  heterocyclic compounds containing a nitrogen
atom and at least one other non carbon atom as part of the ring.

Azole antifungi agent prevent the synthesis
of ergosterol, a major component of fungal plasma membranes , by inhibiting the
cytochrome P-450 dependent enzyme lanosterol demethylase also referred to as 14
alpha-sterol demethylase. This enzyme also plays an important role in
cholesterol synthesis in mammals when azoles are present in therapeutic
concentrations , their antifungal efficacy is attributed to their greater
affinity for fungal P450dm than for the mammalian enzyme. Exposure of fungi to
an azole causes depletion of ergosterol and accumulation of 14alpha -methylated
sterol. This interferes with the  bulk
function of ergosterol in fungal membranes and distrupts both the structure of
the membrane and several of its  function
such as nutrient, transport and chitin synthesis.

                                  Clinical
importance of Azole Antifungal agents.

The azole antifungal agents in clinical use
contain either two or three nitrogens in the azole ring and are there by
classified as imidazoles and triazoles.

Imidazoles are ;

(1) Ketoconazole

(2) Miconazole

(3) Clotrimazole

Triazoles are ;

Itraconazole

Fluconazole

With the expection of ketoconazole , the use
of the imidazole is limited to the treatment of superficial mycoses , whereas
,the triazoles have a broad range of appilications  in the treatment of both superficial and
systemic fungal infections. Another advantage of the triazole is their greater
affinity for fungal rather than mammalian cytochrome P-450 enzyme , which contributes
to an improved safety profel.

QUES (2)  Mention 3 categories of antineoplasm agent
with named examples , discuss briefly the mechanism of action of one examples
in each category

Answer—- Catogory 1—-; Alkylating
agents which are cell cycle non specific (CCNS)

Nitrogen mustard ; Melphalan ,
cyclophosphamide , ifosfamide

Nitrosoureas

Alkysulfunates

Ethyleneimines

Triazenes

Methylhydrazines

Mechanism of action of
cyclophosphamide–;Is an inactive drug, with the help of cytochrome P-450
oxidase system in the liver ,  the
inactive drug is converted into phosphoramide mustard and aerolein which are
very active compounds. Phosphoramide mustard has an ability to introduces alkyl
radicals into DNA strands with interferes DNA replication by forming DNA cross
linkage. Cross linked cancer cell DNA is unable to complete normal cell
division . Thus , it stops cancer cells from growing , causing them to die.
Cyclophosphamide also produces immunosuppresive effects possible through a
cytotoxic effect on lymphocytes.

Category 2 ——Antimetabolities which are
cell cycle specific (CCS)

Folate antagonism ; methotrexate

Purine antagonist

Pyrimidine antagonist ; 5 -fluorouracil ,
cytarabibe

Mechanism of action of 5-fluorouracil —;
It is an antimetabolite fluoropyrimidine analog of the nucleoside pyramidine
with antineoplastic activity. Fluorouracil 
and its metabolites possess a number of different mechanism of action .
In vivo , fluorouracil is converted to 
the active matabolites 5-fluoroxyuridine monophosphate (F-UMP) ;
replacing uracil, F-UMP incorporates into RNA processing , thereby inhibiting
cell growth. Another active metabolite ,5-5-fluoro-2′-deoxyuridine-5′-O-monophosphate
(F-dUMP) , inhibits thymidylate synthase, resulting in the depletion of
thymidine triophosphates used in the in vivo synthesis of DNA. Other
fluorouracil metabolites incorporate both RNA and DNA ; incorporation into  RNA results in major effects on RNA
processing and functions.

Category 3—–; Natural ptoducts are  divided into two parts which are (1) plant and
(2) micro organism products.

(1)  Plant
products are ;

Vinca Alkaloids ;- Vincristine ,
Vinblastine .

Epipodophyllotoxins ,  Etoposide.

Camptothecins  : Irinotecan

(2) Micro organism Products ;

Antibiotics such as Doxorubicin , Bleomycin

Enzymes ; L-Asparaginase.

Mechanism of action of Vinblastine (plant
product)

It binds to tubulin , leading to disruption
of mitotic spindle apparatus and arrest of cell cycle.

Mechanism of action of Doxorubicin (Micro
organism product)

It intercalates and binds to DNA  disrupting helical structure and DNA template  : inhibits RNA and DNA polymerases ; causes
DNA topoisomerase -ll-mediated chain scission ; generates free radicals that
cause DNA scission and cell membrane damage.

 

Ques 3—–; Which of the classes of anti
fungi agent will you considered to be ideal  and  while

Answer–; ECHINOCANDINS  ——; is a new class of antifungi drugs and
it is cyclic lipo peptide antibiotics that interfere with fungal cell wall
synthesis by inhibition of B(1,3)  D-glucan synthase. E.g Capso fungin ,
micafungi , anidulafungin.

                      Advantages
of Echinocandins over other anti fungi agents

Broad range (especially against all candida)
, thus can be given – emperically in febrile neutropenia and stem cell
transplant.

It can be used in case of azole-resistant
candida or use as a second -line agent for refractory aspergillosis.

Long half-life (polyphasic elimation :
alpha phase 1-2 hours + beta phase 9-11 hours + gamma phase 40-50 hours) low
toxicity : only histamine release (3%) ,fever (2.9%) ,nausea and vomiting (2.9%)
and phlebitis at the site of injection (2.9%) , veryrarely allergy and
anaphylaxis.

Not an inhibitor, inducer or  substrate of the cytochrome P450 system , or
P-glycoprotein , thus minimal drug interactions.

Lack of interference from renal failure and
haemodialysis.

No dose adjustment is necessary based on
age , gender and race.

Better (or no less effective) than Amphotericin
B and fluconazole against yeast infections.

 

Ques 4—-; list the principle of
chemotherapeutic resistance. Write short note on the one you considered most
important?

Answer —–;  (a) Pharmacokinectic or Pharmacodynamic
factors.

Mutations

Gene regulations

Generation or use of alternative
biochemical pathways.

Drug misuse.

(b) MUTATIONS

A drug must interact with its target(s) to
achieve the therapeutic effects.

Mutation in drug target is a critical
machanism that results in drug resistance. There are several scenarios under
which a mutation could lead to drug resistance , it could reduce the binding
affinity of a drug to its target or render the target constitutively active .
Worse yet , mutations could turn a drug from antagonist to agonist. For
example, current therapeutic strategy for advanced prostrate cancer is to
inhibit the androgen receptor (AR) signaling. However, the W741C mutation in
the AR was found to convert bicalutamide from an antagonist of the wild type AR
into an agonist of the W741C AR mutant, which actually promotes tumor growth.

Mutation could cause disruption or aberrant
interaction of a specific protein-protein interaction, resulting in drug
resistance.

In general , resistant mutations in drug
targets are derived from tissue specimen of the patients that are resistant  to the drug. Next , mutation related
resistance is demonstrated in a series of in vitro and in vivo models.