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Pharm407 > Lecture 13 Part 2: Liver Disease- pharmaceutical perspectives > Flashcards

Lecture 13 Part 2: Liver Disease- pharmaceutical perspectives Flashcards

1
Q

What are interferons? (2 points)

A

Proteins made and released by host cells in response to the presence of pathogens.

They interfere with viral replication within host cells and have a MW >40 kDa

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2
Q

What is interferon therapy? (3 points)

A
  • therapy which has been used for the treatment of chronic hepatitis B for many decades
  • normalises alanine aminotransferase levels
  • suppresses hepatitis b virus
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3
Q

What are the limitations of conventional interferon injections? (3 points)

A
  • short half life
  • high incidence of dose related side effects
  • beneficial only in the short term
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4
Q

What are the advanced interferon injections? (3 points)

A
  • PEGylated interferons approved by FDA for the treatment of hepatitis B and C
  • slows down the rate of viral replication
  • available as α2a (PEGIntron) and α2b (Pegasys)
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5
Q

What are the advantages of PEGylated interferons? (7 points)

A
  • decreased immunogenicity of protein drugs
  • optimised rate of absorption following SC injection
  • reduced renal and cellular clearance –> extended blood circulating life
  • increased AUC
  • reduced injection frequency (3x week –> 1x week)
  • increased solubility
  • enhanced protease resistance
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6
Q

What is PEGylation?

A
  • covalent coupling of a non toxic, hydrophilic polyethylene glycol to pharmaceutical ingredients such as proteins and phospholipids.
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7
Q

What is the history of PEGylation? (3 points)

A
  • first developed from pioneering work carried out in 1970s
  • in 1981: first PEG protein company was formed called Enzon
  • in 1990: the first approved PEG drug conjugate was developed- PEG-adenosine deaminase
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8
Q

What are opsonins?

A

Molecules that act as a binding enhancer for the process of phagocytosis

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9
Q

How can opsonins be used? (3 points)

A
  • can attach it onto a target such as bacteria or other foreign bodies
  • can allow it to be recognised by the receptors on the macrophages
  • makes the invading bacteria/foreign body more susceptible to destruction by phagocytes
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10
Q

What are examples of opsonins? (2 points)

A
  • Antibodies e.g. IgG and IgA

- components of the complement system e.g. C3b

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11
Q

What is the liver designed to maintain?

A

The body’s chemical and metabolic homeostasis

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12
Q

What is opsonisation?

A

When particles or macromolecules are coated with opsonins

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13
Q

What kind of particles/macromolecules are more efficiently opsonised? (3 points)

A
  • Those that have a hydrophobic surface.
  • They are easily recognised by the macrophage and cleared rapidly.
  • particles with a hydrophilic surface resist opsonisation and are cleared more slowly
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14
Q

What is the effect of PEGylation on opsonisation? (4 points)

A
  • PEGylation on the surface of particles sterically inhibit hydrophobic and electrostatic interactions of opsonins and the particles
  • Prevents adsorption of opsonins on the particles
  • Slows recognition by phagocytic cells such as macrophages of the RES
  • reduces immunogenicity to the particles
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15
Q

What is PEGylation also known as?

A

Stealth technology

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16
Q

What is stealth technology in drug delivery?

A

-When the surface of a carrier is coated with hydrophilic polymers

17
Q

What are the different polymers used in stealth technology? (4 points)

A
  • PEG
  • Poloxamer
  • Poloxamine
  • Polysaccharides
18
Q

What is doxil? (3 points)

A
  • PEGylated liposomal doxorubicin
  • consists of single lipid bilayer membrane with HSPC and cholesterol which separates the internal aqueous compartment from the external medium
  • Drug is encapsulated in the aqueous compartment
19
Q

What are the advantages of PEGylated doxil?

A
  • more predictable PK
  • Consistent release within therapeutic levels
  • able to achieve sustained release
  • less frequent administration
20
Q

What are the advantages of PEGylation of nanoparticles/macromolecules? (5 points)

A
  • reduces immunogenicity
  • extends circulating life
  • increases aqueous solubility
  • improves PK profile
  • offers opportunities for new delivery formats and dosing regimens, as well as extending the patent life.
21
Q

What are the limitations of PEGylation? (2 points)

A
  • May interfere with ability of a protein to bind to its receptors and decrease biologic effects
  • high cost in formulation of products
22
Q

What are the three main types of liver cells? (3 points)

A
  • hepatocytes (hepatic parenchymal)
  • Kupffer cells (nonhepatic parenchymal)
  • endothelial cells (nonhepatic parenchymal)
23
Q

What are kupffer cells? (5 points)

A
  • Constitute about 15% of liver cells
  • located along sinusoid
  • accounts for 80-90% of resident macrophages in the body (part of RES)
  • Life span of ~14 months
  • only ~3% is responsible for cell population renewal in vivo
24
Q

What are the two types of hepatocyte-directed delivery? (2 points)

A
  • Passive targeting using colloidal carriers

- Receptor mediated (active) targeting

25
Q

What are the colloidal carriers used in passive hepatocyte targeted delivery? (2 points)

A
  • liposomes

- niosomes (these are vesicles formed by self-assembly of surfactants

26
Q

What is the effect of particle size on hepatic drug uptake? (4 points)

A
  • Increasing particle size will increase the relative distribution into the kupffer cells
  • Thus the larger the drug, the more will be cleared by the kupffer cells
  • To target the drug to the liver, we want a smaller sized drug
  • aim for particle size between 20-100nm
27
Q

What is receptor mediated (active targeting) hepatocyte directed delivery? (2 points)

A
  • Based on drug carriers targeting receptors highly expressed in hepatocytes e.g.
  • asialoglycoprotein. (glycyrrhzin is a novel ligand which has been modified on nanoparticle surfaces for hepatocyte targeting.
28
Q

Why do we want to reduce drug-uptake by kupffer cells? (3 points)

A
  • reduces drug toxicity to kupffer cells
  • targets more drug to liver as kupffer cells clear the drug
  • achieved by the use of stealth colloidal carriers

Pharm407 (5 decks)

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