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PHRM30003: Drug Treatment of Disease > MST 2 > Flashcards

MST 2 Flashcards

1
Q

What is a NARROW spectrum?

A
  • Specific drugs
  • Targets gram + OR -
  • Useful when drug agent is KNOWN
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2
Q

What is a BROAD spectrum?

A
  • Targets BOTH gram + & -
  • Useful when drug agent is UNKNOWN
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3
Q

Describe & list the mechanism of action of β-lactam antibacterial drugs

A
  1. β-lactam binds to active site of PBP
  2. Covalent bonds form between drug & serine residue in PBP
  3. Irreversibly inhibits PBP
  4. Interrupts cell-wall formation
  5. Cell is compromised to the extracellular matrix
  6. Bacteria cells dies/lysis

PBP= pencillin binding protein

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4
Q

How does β-lactam bind to the active site of PBP?

A

β-lactam mimics the D-Ala-D-Ala end of the transpeptide (PBP)
* binds to the pentaglycyl unit before the transpeptidase

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5
Q

How does β-lactam irreversibly inhibit PBP?

A

prevents the PBP from connecting the pentapeptide chains from one NAG to another (usually forms the cell wall)

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6
Q

What is PBP?

A

Penicillin-Binding Proteins = transpeptidase = enzyme that CROSS-LINKS peptidoglycan strands using D-Ala-D-Ala

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7
Q

What are the use of β-lactam antibacterial drugs?

A

for bacterial infection = causes the bacterial cell to die due to compromising the cell wall
* bacteria is hyperosmotic = contents rush in & kills it

DRUGS
* Penicillins (+)
* Cephalosporins (+/-)
* Carbamenpens (+/-)

(-) = two cell wall

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8
Q

Name the two bacterial antimicrobial resistance

A

Acquired Resistance & Innate Resistance

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9
Q

What is ACQUIRED resistance?

A
  • transfering/sharing of information (plasmid) to other bacteria
    • used to share information of different resistance mechanisms
  • Vertical & Horizontal transfer of resistance genes
    • Vertical = gene passed fown to daughter cells
    • Horizontal = gene shared between bacteria thorugh transformation, transduction or conjugation
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10
Q

List and explain the 4 different INNATE resistance

A

1. Blocking entry
* Porin mutation = reduce uptake (-)

2. Inactivating enzymes
* Increased production of enzyme = inactivate drug (β-lactamase)

3. Efflux of Antibiotic
* Production of enzyme = increase efflux of drug (p-glycoprotein)

4. Alteration of target molecule
* Reduce affinity for target

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11
Q

What are the 4 targets for antiviral therapy in the virus life cycle? Explain/give an example

A

1. Entry = Cell Surface Receptors
* e.g. Fusion inhibitors
* block virus from binding & fusing to host cell membrane

2. Entry, Uncoating, Release
* E.g. Ion Channel blockers
* prevents uncoating & release of genetic material

3. Replication = RNA/DNA Replication, DNA nuclear transcription, RNA translation
* e.g. Polymerase inhibitors & Protease inhibitors
* stop replication

4. Release = prevent release to other cells
* e.g. Neuraminidase inhibitors

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12
Q

How does the overexpression of RTK reveal targeted therapeutic strategies? Use Imatinib as an example

A
  • Overexpression of RTK = disrupts normal cellular signalling & promotes uncontrolled growth

Imatinib
* potent & selective inhibitor for ABL, PDGFR, KIT Tyrosine Kinase (cell surface receptor proteins)
* Imatinib significantly reduces kinases ability to bind ATP = potent inhibition of their signalling activity = cease cancer cell growth & survival
* selectively kills BCR-ABL expressing cells in vitro & in vivo

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13
Q

How does the oncogenic KRAS reveal targeted therapeutic strategies? Use Sotorasib as an example

A
  • since KRAS usually regulates cell growth, differentiation & survival = mutation = always on

Sotorasib
* Small molecule inhibitor = covalently & irreversibly binds to KRAS G12C oncoprotein
* Interacts with cysteine residue (induced by mutation)
* occupies pocket beneath switch II region in inactive (GDP bound) conformation of KRAS G12C
* MECHANISM: Sotorasib = binds covalently to specific pocket in mutated KRAS protein = trap enzyme in INACTIVE state = prevents downstream effector (usually promotes uncontrolled cell growth)

Cysteine = only found in KRAS oncogenetic form = not affect wild type

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14
Q

In a Lollipop Plot, list how cancer gene, tumour supressor & oncogene is distinguished.

A

Cancer gene = highly mutated

Tumour supressor gene = mutation scatters with no clear hotspot
* high truncating percentage

Oncogene = mutation hotspot
* cluster of mutations concentration at particular spot in gene

truncating = creates shorter gene

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15
Q

In an oncoprint, state what Missense mutation, Truncating mutation & Alterations mean
ALSO = state how to detect potential tumour suppressor gene

A
  • Missense mutation = amino acid changes
  • Truncating mutation = protein shortening
  • Alterations = amplifications or deletions of gene segments

Tumour suppressor gene
* high percentage of truncating mutation

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16
Q

What is airway remodelling and what is it affected by?

A

structure of airway wall changes = cell growth & breakdown is balanced

Affected by:
* growth factors e.g. PDGF, FGF, TGFβ, VEGF
* cytokines e.g. IL-5, GM-CSF
* chemokines e.g. RANTES, eotaxin, CXCL8
* lipid mediators e.g. PGE2
* extracellular matrix components e.g. collagen

17
Q

What is the mechanism of airway CONTRACTION?

A
  1. Increase in intracellular Ca2+ = triggered by signals, hormones, or inflammatory mediators
    Enter cell = voltage gated Ca2+ channels OR released from internal stores = signals = phospholipase C & inositol triphosphate
  2. Ca2+ binds to calmodulin = activates Myosin Light Chain Kinase (MLCK) enzyme
  3. MLC phosphorylated = actomyosin ATPase activated (actual motor for contraction)
    MLCK phosphorylates site on protein MLC
  4. Cell shortening = cross bridges between actin & myosin BREAK & REFORM = sliding past each other
    Shortening of individual muscle cell = shortening of airway smooth muscle layer
18
Q

What are the factors INCREASING Ca2+?

contraction

A
  • Vca2+ channels
  • Phospholipase C
  • Inositol trisphosphate IP3
    * Release from intracellular stores
19
Q

What is the mechanism of airway RELAXATION?

A

1.Decrease influx of Ca2+ entering cell = closure of VCa2+ channels OR reduced release from internal stores
2.Increase Ca2+ Removal

  • Plasma membrane Ca2+ ATPase = pump Ca2+ out of cell
  • Sarcoplasmic reticulum Ca2+ ATPase(SERCA) = pump calcium back into internal stores
20
Q

What are the factors DECREASING Ca2+?

relaxation

A
  • Plasma Ca2+ ATPase (Efflux)
  • Sarcoplasmic reticulum Ca2+ ATPase
  • Uptake into internal stores
21
Q

How is contractile proteins inhibited during airway relaxation?

A

Myosin Light Chain Phosphatase Activation
* MLCP enzyme = removes phosphate added by MLCK during contraction
* Dephosphorylation = deactivates actomyosin complex = prevent cross-bridge formation & actomyosin ATPase activity

22
Q

What are the rationale for drug combinations in asthma?

A

targetting different aspects of asthma

  • As asthma involves both inflammation & airway hyperresponsiveness = increased sensitivity to triggers
    • inhaled steroids = target chronic inflammation in airways, reduce swelling & mucus production
    • LABA = relax smooth muscle surrounding airways causing bronchodilation = provides quick relief from symptoms but dont address underlying inflammation
    • COMBINE BOTH
23
Q

What are the similar characteristics of symptoms between COPD & Asthma?

A
  • Eosinophilic inflammation
  • Recurrent exacerbation
24
Q

What are the general similarities between Asthma and COPD?

A
  • chronic inflammatory disorder
  • obstructive lung disease
  • airway obstruction
  • difficulty breathing
25
Q

What are the roles of inhaled steroids in terms of Asthma drugs?

for COPD

A
  • Reducing airway inflammation
  • Decreasing swelling and mucus production
  • Also reduce frequency and severity of exacerbations
  • Improve overall breathing comfort

HOWEVER
* Limited impact on underlying cause = doesnt address permanent damage
* Lung function improvement is minimal
* Long Term use = side effects

26
Q

List the 3 approaches for treatment of CF

no explanation pls

A
  1. Antibacterial agents
  2. Improving mucociliary clearance
  3. Modulators improving CFTR protein function
27
Q

Explain how Antibacterial Agents are an approach to treatment of CF

A

Antibiotics
* Quinolone antibiotics
* Oral = Ciprofloxacin
* Inhaled = Levofloxacin
* Aminoglycoside antibiotics

Rationale
* CF = chronic build up of thick and highly viscous mucus = creates ideal environment for bacterial growth and proliferation
* High viscosity of mucus = allows prolonged exposure to normally non-harmful bacteria = harmful as they build up

28
Q

Explain how improving mucociliary clearance is an approach to treatment of CF

A
  • DNase alpha inhibition = thins mucus
  • Osmotic agents = Mannitol
    • Chronic secretion of excess mucus = creates environment for bacteria growth = start of CF complications = increasing osmolarity of periciliary fluid layer enhances clearance of mucus = restore mucosal layer thickness & excrete bacterial through coughing
29
Q

Explain how modulators improving CFTR protein function is an approach to treatment of CF

A
  • Directly targets underlying genetic defect of CFTR gene

Correctors & Potentiators
* Correctors
* targets class II mutations
* increase cellular processing & delivery of CFTR protein to cell surface
* Potentiators
* targets class III mutations
* improve Cl- gating/transport/flow through CFTR ion channels

PHRM30003: Drug Treatment of Disease (3 decks)

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