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PHRM30003: Drug Treatment of Disease > Module 3: Therapeutic application of selective toxicity > Flashcards

Module 3: Therapeutic application of selective toxicity Flashcards

1
Q

What are the features of the pathogen-host-drug relationship?

A
  • pathogen invades host or host fights pathogen through defence mechanism (Passive Defence, Innate & Adaptive Immunity)
  • pathogen forms resistance against drug OR drug selectively targets pathogen
  • drug treatment initiated OR drug affects host through PK/PD factors, selective toxicity and alterations in non-pathogenic flora
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2
Q

What are the potential targets for selective antibacterial activity?

A
  • Distinct Cell Wall Structure
  • Folate synthesis: distrupt bacterial folate production & inhibit essential components for DNA & RNA synthesis
  • Bacterial DNA Replication: drug can inhibit and prevent bacteria from multiplying
  • Bacterial Protein Synthesis: 70s ribosome - 30s and 50s subunits
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3
Q

Describe the PD/PK properties of antibacterial drugs

A

1. Concentration- & Time-dependent effects

2. Bactericidal OR Bacteriostatic
* Kill or Inhibit growth

3. Spectrum of Activity
* influence choice, and dosing schedule of drug

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4
Q

Describe the Narrow & Broad Spectrum of Activity

A

Narrow Spectrum
* specific drugs targeting gram + or -
* useful when drug agent is known

Broad Spectrum
* targets both gram + & -
* useful when drug target in unknown

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5
Q

Describe the different mechanisms of development of bacterial antimicrobial resistance

A

Innate Resistance of Bacteria
* Protective mechanism for survival
* Bacteria naturally possess features that hinder drug effectiveness = cell wall, porins, metabolic enzymes, efflux transporters

Acquired Resistance by Bacteria
* Transfer of resistance genes
* Vertical transfer: Resistance genes passed down from parent to offspring

 * **Horizontal transfer:** Resistance genes **shared** directly between bacteria through plasmids or conjugation
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6
Q

What factors promote resistance of bacterial antibiotics?

A
  • Incorrect antibiotic use: promotes survival of resistance bacteria
  • Antibiotics in the environment: creates selection pressure
  • Impact on normal microbiota: Antibiotics disrupt natural gut bacteria = allows resistance pathogens to thrive
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7
Q

What is the mechanism that changes the innate protective mechanisms?

A
  1. Point mutations = reduce uptake (gram -ve bacteria)
  2. Increased production of enzyme that inactivates drug (β-lactamases)
  3. Reduces affinity for target
  4. Produces enzymes that increase efflux of drug (p-glycoprotein)
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8
Q

What causes bacterial antimicrobial resistance?

A
  • Overprescribing & incorrect prescription
  • Not finishing the full treatment course
  • Lack of hygiene and poor sanitation
  • Overuse in livestock and fish farming
  • Lack of new antibiotics being developed
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9
Q

Identify targets for antiviral therapy in the virus life cycle & possible therapies for each.

A

Attachment & Entry
* Fusion Inhibitors
* Ion Channel Blockers

Viral Replication
* Polymerase Inhibitors

Assembly & Packaging
* Protease Inhibitors

Release
* Neuraminidase Inhibitors

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10
Q

What is Cytotoxic Chemotherapy?

A

Non-specific inhibition of DNA replication or Mitosis

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11
Q

Distinguish different mechanisms of cytotoxic cancer chemotherapy

A

DNA damage
* Alkylating agents
* Intercalating agents

Cell Cycle Disruption
* Topoisomerase inhibitors: interfere with enzymes that unwind DNA for replication
* DNA Synthesis inhibitors: block enzymes involved in DNA synthesis
* Mitosis Inhbitors: prevent cell division by targeting microtubules

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12
Q

What is the mechanism of action of Alkylating agents?

A
  • directly damage DNA
  • impact all cell cycle phases
  • crosslink DNA strands by guanine alkylation
  • prevent replication and transcription
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13
Q

What is the mechanism of action of Intercalating agents?

A
  • anti-tumour antibiotics derived from bacteria
  • insert between DNA base pairs = strand breaks = inhibits replication

Antibiotics:
* Anthracyclines (doxorubicin, daunorubicin) = all phases
* Bleomycin = G2 phase

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14
Q

What is the mechanism of action of Topoisomerase inhibitors?

A
  • seperate DNA strands in S phase = leads to strand break

Topoisomerase I inhibitor (Irinotecan)
* makes single strand cuts
* Greater efficacy and lower toxicity than natural alkaloid camptothecin

Topoisomerase II inhibitor (Etoposide)
* makes double stranded cuts

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15
Q

What is the mechanism of action of DNA synthesis inhibitors?

A
  • Inhibits enzymes in DNA synthesis pathway = prevents cell division
  • Active during S phase - chromosome copying

Drugs
* Methotrexate: folic acid analogue = inhibits dihydrofolate reductase

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16
Q

What is the mechanism of action of Mitotic inhibitors?

A
  • disrupts microtubule assembly = prevents M phase

Drug
* Paclitaxel: stabalise tubulin polymer & prevent disassembly == arrests cells in M phase == cell death

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17
Q

What is the side effects of each of the cytotoxic cancer drugs?

A

Alkylating agents
* Increased risk of leukemia, pulmonary fibrosis, renal toxicity.

Intercalating agents
* Dose-limiting myelosuppression, cardiotoxicity (heart damage).

Bleomycin
* Skin pigmentation, pulmonary fibrosis.

Topoisomerase inhibitors
* Diarrhea, secondary leukemia.

DNA synthesis inhibitors
* Gastrointestinal and oral ulcers, renal and liver toxicity.

Mitosis inhibitors
* Neurotoxicity, neuropathy (nerve damage).

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18
Q

Describe the mechanism of action of sulfonamides

A
  • Targets Dihydropteroate synthetase
  • Sulfonamides = blocks production of folic acid that is essential for bacterial growth
  1. Sulfonamides compete with PABA for binding to dihydropteroate synthetase
  2. sulfonamide binding prevents PABA == hinders folic acid production
  3. insufficient folic acid = bacteria cannot replicate DNA = die

Human get folic acid from diet and dont rely on same pathway as bacteria

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19
Q

Describe the mechanism of action of β-lactam antibacterial drugs

A
  • mimics the D-Ala-D-Ala end of peptidoglycan
  1. β-lactam binds to active site of PBP due to structural similarity to D-Ala-D-Ala
  2. Covalent bonds form between drug & serine residue in PBP == irreversibly inhibiting enzyme
  3. cell wall weakens = cell death DUE TO lack of transpeptidase = bacteria cant cross-link peptidoglycan strands

Peptidoglycan = essential component of bacterial cell wall
* made of altering sugars (NAM & NAG) w/ attached pentapeptide chains
* D-Ala-D-Ala = terminal end of pentapeptide chain

Transpeptidase (PBP) = enzyme that cross-links peptidoglycan trands using D-Ala-D-Ala as substrate

20
Q

Describe the mechanism of action of protein synthesis inhibitors

A

Bacterial Ribosomes = 70S structures = 30S and 50S subunits

Drug targets of 30S subunit
Tetracyclines
* competitive inhibition of tRNA binding
* halts protein synthesis
* bacteriostatic

Aminoglycosides
* Causes error by inserting incorrect amino acids
* bactericidal

Drug targets of 50S subunit
Macrolides
* Block peptide transferase
* prevents protein chain elongation (translocation)
* bacteriostatic/cidal

Chloramphenicol
* inhibits peptide bond formation
* bactericidal
* crosses BBB

21
Q

What is the mechanism of action of Amantadine used for Influenza?

A
  • Ion channel blockers
  • M2 ion channel = important for acidification & dissociation
    of virus once inside the cells
22
Q

What is the mechanism of action of Zanamivir used for Influenza?

A
  • Neuraminidase inhibitors
  • Neuraminidase = importance for cleaving (HA/ sialic acid bond) from glycoproteins during shedding phase
23
Q

What is the vaccination primary approach for Influenza?

A
  • target the Hemagglutinin of range of seasonally circulating viruses
24
Q

What is the mechanism of action of drugs used for Herpes?

A

Viral DNA polymerase inhibitor
* target viral genomic replication in host cell
* nucleoside analogue = competitive inhibition = prevents virus’s ability to replicate DNA
* prodrug = activation by viral thymidine kinase

Acyclovir = Viral DNA polymerase inhibitor
* Guanine analogue
* prodrug = converted by viral thymidine kinase TO monophosphate TO host cell conversion TO triphosphate
* Triphospho-acyclovir = competes with native substrate for HSV specified DNA polymerase
* missing 3’-OH = prevents further viral DNA synthesis

25
Q

What is the mechanism of action of Reverse Transcriptase Inhibitors used for HIV?

A

Nucleoside Reverse Transciptase Inhibitors (NRTI)
* Similar MoA as Acyclovir BUT:
* uses cellular kinases for phosphorylation
* activated = viral reverse transcriptase uses its natural nucleosides to make ds DNA copy of viral mRNA

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
* Non-nucleoside compound: doesnt require phosphorylation for activity
* Selective inibition: specifically targets HIV-1 reverse transcriptase
* Non-competitive Inhibition: binds to site on reverse transcriptase enzyme NEAR the active site = not directly competing with natural substrates
* Conformational changes: binding induces change in shape of enzyme
* Enzyme inhibition: conformational changes = disrupts norm. function of reverse transcriptase enzyme = hinders ability to convert viral RNA to DNA

26
Q

What is the mechanism of action of Protease Inhibitors for HIV?

A

HIV protease attractive target
* cleaves synthesised polyproteins into key structural & functional proteins
* essential for replication & reassebly of virus

Ritonavir
* peptidomimetic
* reversible inhibition of active site of HIV aspartyl protease
* results in immature, non-infectious viral particles
* act as late stage of viral cycle = effective in both newly and chronically infected cells

27
Q

What is the desirable PD/PK?

A
  • High affinity & selectivity
  • Bioavailability
28
Q

What is the desirable goal when producing drugs?

A
  • Maximise bacterial killing
  • Minimise resistance development
    …..
  • Monotherapy if target is known
  • Synergistic interactions possible
29
Q

What is the use of MIC in determining dosage?

A
  • samples the amount of agent needed to inhibit growth of microorganism
  • indicate bacterial sensitivity
  • provides target plasma concentration (therapeutic window)
  • varies with organism used = inoculum size, temperature, pH, etc.
30
Q

What factors can impact the dose that can be used?

A
  • ADME principles
  • Administration = topic, oral, iv
  • Absorption = lipid solubility, cross membranes
  • Distrubition = Vd; targeted distribution
  • Metabolism = bioavailability. produg, inactivation
  • Excretion = kidney function, liver function
  • Toxicities = ototoxicity
  • Resistance = biofilms
31
Q

What is biofilm?

A

An assemblage of surface-associated microbial cells enclosed in extracellular polyeric substrate matrix

  • provides survival sites for both beneficial & oppotunistic pathogenic bacteria === by providing protection and increasing potential of bacteria to survice & evolve in plant environment
32
Q

What is the rationale for different approaches to treatment with aminoglycosides?

A
  • Effects and side effects
  • Minimise resistance
  • Risk benefit
  • Therapeutic window
  • Dosage (single dose, multiple dose)
  • Post antibiotic effect
  • Balance of safest highest concentration & maximise time above MIC
    • Left better = safe at high dose, longer time over MIC, long post antibiotic effect
33
Q

WK7-1

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38
Q

What are the environmental factors impacting tumour evolution?

A
  • UV exposure
  • Immune system
  • Smoking, Alcohol, Nutrition etc.
39
Q

Define non-coding somatic mutation, driver & passenger mutations

A
40
Q

Define coding somatic mutation, driver & passenger mutations

A
41
Q

What is a cancer gene?

A
42
Q

What is a tumour supressor gene?

A
43
Q

What is a oncogene?

A
44
Q

Explain the mutual exclusivity concept of two genes

A
45
Q

Identify the hallmarks of cancer & how to explot them for treatments. Give examples of targeted therapies in cancer.

A

PHRM30003: Drug Treatment of Disease (3 decks)

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