Drugs Flashcards
Know the Drugs, analogs and functions.
Zidovudine
Azidothymidine, AZT
Anti-viral Nucleoside analogues – Viral reverse transcriptase inhibitors
Deoxythymidine analogue
Utilized by the viral reverse transcriptase
Upon incorporation into the double stranded DNA chain termination occurs due to lack of 3’OH
Zidovudine can:-
• Prolong life in HIV infected individuals
• Reduce mother to baby transmission by more than 20%
Didanosine (ddI)
Anti-viral Nucleoside analogues – Viral reverse transcriptase inhibitors
Deoxyadenosine analogue
Utilised by the viral reverse transcriptase
Upon incorporation into the double stranded DNA, chain termination occurs due to lack of 3’OH.
Specificity for infected cells lies in the fact that these drugs have a 100-300 fold greater affinity for incorporation by reverse transcriptase than eukaryotic DNA polymerase.
Used in the treatment of mainly HIV in combination with other anti-virals
Acyclovir
Anti-viral Nucleoside analogues – Viral DNA polymerase inhibitor
Deoxy(guanosine) analogue
Converted to the mono-phosphate by viral thymidine kinase which is much more effective in catalyzing 1st phosphorylation event than host thymidine kinase
Only infected cells possess the viral kinase
Therefore Acyclovir is only activated in infected cells.
It serves as as substrate for viral DNA polymerase.
It causes chain termination due to lack of 3’OH.
It’s 30 x more potent against viral DNA polymerase than host.
Viral kinase
High specificity for herpes simplex & varicella zoster.
Herpes simplex can causes conjunctivitis and coldsores
Tenofovir
Anti-viral Nucleotide Base analogues
Deoxyadenosine monophosphate analog
Tenofovir diphosphate competes with its natural nucleotide counterpart, deoxyadenosine 5 ́-triphosphate, for incorporation into newly forming HIV DNA.
Once successfully incorporated, termination of the elongating DNA chain ensues, and DNA synthesis is interrupted.
Cytosine Arabinoside
Cytarabine or araC
Cytosine nucleoside analogue
Ribose sugar replaced by arabinose
In cells it is rapidly converted
to cytosine arabinoside triphosphate which
acts as a substrate for several human DNA Polymerization.
AraC has a 3’ OH group to act as an acceptor for further chain elongation. However the OH gp at posn., 2 prevents polymerase adding the next dNTP due to stereo restraints causing chain termination.
Important in the therapy of leukaemias, in particular acute myeloid Leukaemia and Lymphoma (Anti cancer agent)
Adenosine Arabinoside
Vidarabine or araA
Deoxyadenosine analogue
3’OH is present but planar configuration of the arabinoside prevents DNA elongation
Uses:
Anti-neoplastic agent - Relapsed Childhood Acute Lymphoblastic Leukemia Herpes Simplex infections (Anti cancer agent)
Decitabine
(5-aza-2’-deoxycytidine)
and
5-azacytidine
Cytidine Analogues – DNA hypomethylation Agents
Deoxycytidine analogues
Once incorporated into DNA and RNA they cause hypomethylation as a methyl group cannot be added to the Nitrogen at position 5.
Additionally, these drugs are know to bind and inhibit DNA methyltransferase enzymes.
Prevents DNA methylation
In eukaryotes, methylation of cytosine is an important mechanism of transcriptional regulation.
An example of the use of DNA hypomethylating agents in Cancer….(Decitabine)
P15 Tumour suppressor gene –p15INK4b
Decitabine causes Hypomethylation
CDKN2B in a HYPOMETHYLATED promoter regions causes TRANSCRIPTION and p15INK4b prevents malignant transformation (inhibits cyclin dependent kinases)
CDKN2B in a HYPERMETHYLATED promoter regions causes TRANSCRIPTIONAL SILENCING therefore No p15INK4b transcribed= Uncontrolled cell division allowing tumor formation
Hypomethylation of CDKN2B correlates with response to decitabine
Used in Myelodysplastic syndrome & Acute myeloid leukemia
Ciprofloxacin
inhibits bacterial DNA gyrase (topoisomerase II)
quinolone drug
It is used in the treatment of respiratory and urinary tract infections and can be used to treat anthrax.
Camptothecin
Inhibitors of eukaryote replication
an anticancer drug
binds to and inhibits topoisomerase I activity whch result is DNA breakage.
Etoposide
another anticancer drug
inhibits the activity of topisomerase II (DNA Gyrase).
Actinomycin D
Dactinomycin
Inhibitors of replication
Drug- DNA complex….stable
Prevents DNA replication by:
- binds tightly to double stranded DNA preventing the formation of regions of single stranded DNA.
- Inhibits RNA transcription and replication in both prokaryotes and eukaryotes (as it prevents strand separation)
- primarily used as an anti-cancer drug (inhibiting DNA replication and cell division)
- not normally used as an antibiotic
Rifampin
- an antibiotic from a strain of Streptomyces
- inhibits initiation of transcription
- blocks formation of the first phospho- diester bond by binding to prokaryote RNA polymerase and changing its conformation
- RNA polymerase of eukaryotes is not affected
- used in the treatment of tuberculosis
Mutations in the genes encoding the target proteins such as RNA polymerase and topoisomerases can lead to drug resistance.
Alpha-Amanitin
toxin from Amanita phalloides/The Death Cap Mushroom
potent inhibitor of RNA polymerase II….which prevents mRNA transcription
There are four clinical phases of poisoning:
1) Asymptomatic phase
2) Gastrointestinal phase (1-2 days) - severe diarrhea
and vomiting
3) Apparent recovery phase - few symptoms
4) Hepatic phase - renal and liver failure
*** death may occur in 7-10 days
Treatment:
- gastrointestinal decontamination
- high dose penicillin (inhibits amanitin activity in liver)
- liver transplant
Courmarins
including Novobiocin
Inhibits bacterial gyrase (topoisomerases)
