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Pharm407 > Lecture 10 part 2: Pharmaceutical science and the renal system > Flashcards

Lecture 10 part 2: Pharmaceutical science and the renal system Flashcards

1
Q

What is the kidney?

A
  • major filtration organ
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2
Q

What is the functional unit of the kidney?

A
  • nephron
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3
Q

What do the tubular structures of the kidney contain? (5 points)

A
  • renal corpuscle
  • Proximal convoluted tubule
  • Loop of henle
  • distal convoluted tubule
  • collecting duct
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4
Q

Why must we be aware of drug excipients when dealing with kidney issues? (3 points)

A
  • excipients and kidneys don’t always mix
  • excipients used in the manufacturing of various dosage forms can also be toxic to kidneys
  • drugs can be toxic to the kidneys
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5
Q

What two structures are contained in the renal corpuscle? (2 points)

A

glomerulus and bowman’s capsule

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6
Q

What are 2 examples of drugs that can be toxic to kidneys?

A
  • aminoglycosides

- NSAIDs

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7
Q

How is excipient usage controlled in drug manufacture? (4 points)

A
  • Regulatory agencies such as medsafe and the FDA tightly control excipient use
  • Excipients may be approved for one route of administration, but not the other
  • Cyclodextrin is approved for oral use, but can have harmful consequences parenterally
  • Off license use is a reality
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8
Q

What is the story behind diethylene glycol? (3 points)

A
  • an elixir of sulfanilamide was formulated with DEG 72% v/v to solubilise the drug and improve taste
  • DEG is toxic to the kidneys and more than 100 children died from consumption
  • Following the incident, the US congress passed the federal food, drug and cosmetic act of 1938
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9
Q

What are inclusion complexes? (2 points)

A
  • Involves the entrapment of a single guest molecule in the cavity of one host molecule
  • e.g. cyclodextrin
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10
Q

What is a cyclodextrin? (2 points)

A
  • CDs are modified starches and look like cyclic oligosaccharides
  • large interior hydrophobic cavity that can host guest molecules by binding to the hydrophobic portion
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11
Q

What are the advantages of inclusion complexes? (6 points)

A
  • Enhance bioavailability
  • Reduce irritation
  • Simplify handling
  • Improve patient compliance
  • Stabilise active ingredients
  • prevent ingredient interactions
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12
Q

How to inclusion complexes enhance bioavailability? (3 points)

A
  • increases dissolution rate and solubility
  • avoids organic solvents
  • reduces active recrystallisation.
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13
Q

What are the 3 main irritations that inclusion complexes help to reduce?

A
  • GI
  • dermal
  • ocular
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14
Q

How do inclusion complexes simplify handling? (2 points)

A
  • reduce volatility

- convert oils/liquids to powders

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15
Q

How to inclusion complexes improve patient compliance? (2 points)

A
  • reduce unppleasant odors

- masks unpleasant tastes

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16
Q

How do inclusion complexes stabilise the active ingredient of drugs? (4 points)

A

they prevent the active ingredient from degradation due to

  • light/UV radiation
  • temperature
  • oxidation
  • hydrolysis
17
Q

What drug interactions do inclusion complexes prevent? (2 points)

A
  • drug drug interactions

- drug additive interactions

18
Q

What are beta cyclodextrins? (5 points)

A
  • essentially non-toxic
  • form insoluble complexes with cholesterol –> disrupts kidney function
  • Not used for parenteral admin,
  • oral use is restricted to 5mg/kg
  • toxicity can be reduced by using CD derivatives
19
Q

What is cyclosporine ? (4 points)

A
  • Unique cyclic polypeptide (1.2kDa)
  • Immunosuppressant which prevents organ rejection
  • Reduces activity of immune systemy by interfering with T cell growth and activity
  • Lipophilic compound requiring solubilisation for clinical use
20
Q

What is sandimmune? (3 points)

A
  • oil based formulation of ciclosporine
  • forms crude o/w emulsion in the gut
  • requires further emulsification by bile salts and digestion by pancreatic enzymes prior to absorption
21
Q

What is neoral? (2 points)

A
  • ciclosporine formulation which is a preconcentrate and forms a homogenous microemulsion immediately on contact with GI fluids
  • this ME is less dependent on bile salts for absorption
22
Q

What are the disadvantages of Sandimmune? (3 points)

A
  • unpredictable PK parameters,
  • large patient variation
  • unpredictable bioavailability when taken with food
23
Q

What are the advantages of Neoral? (3 points)

A
  • More consistent and predictable PK behaviour
  • Reduced inter and intra patient variation
  • smaller and more consistent decrease in bioavailability when administered with food.
24
Q

What are the advantages of targeting drugs to kidneys? (4 points)

A
  • drugs to treat kidney disease can have unwanted extra renal effects
  • intra-renal transport may be insufficient for drug to reach particular target cell type in kidney
  • some drugs are inactivated before they reach the kidneys
  • existing renal pathology can affect distribution of drug in kidneys
25
Q

What is Benephit? (2 points )

A
  • system for targeted renal delivery of drug

- novel catheter based medical device

26
Q

How is Benephit placed in the kidney? (3 points)

A
  • surgeon introduces system through femoral artery
  • moves proximally from femoral artery to aorta
  • bifurcates into renal arteries
27
Q

What are the advantages of Benephit ? (3 points)

A
  • exposes kidneys to drugs used to enhance or maintain renal blood flow and GFR
  • minimises systemic exposure to drug
  • through one port two catheter based systems can be introduced I.e. Benephit system and another catheter based system for coronary diagnosis or intervention procedures
28
Q

What was the patient who received the first patented Benephit treatment in 2005? (4 points)

A
  • patient had CHF
  • angiogram and coronary artery scenting procedures were performed
  • procedures require a dye to be used as a radio-contrast
  • dye increases risk of renal failure (radio contrast nephropathy)
29
Q

What is fenoldopam? (4 points)

A
  • selective peripheral dopamine 1A receptor agonist
  • systemic anti hypertensive actions via arteriolar vasodilation
  • acts specifically on dopamine receptors in nephrons to promote sodium excretion
  • delivered directly to kidneys via renal arteries
30
Q

Why should fenoldopam be avoided in CHF patients? (3 points)

A
  • although fenoldopam is beneficial for patients at risk of entering renal failure (due to its local vasodilatory action on renal arteries)
  • the vasodilation maintains and promotes renal perfusion and GFR
  • however, it may potentially cause harmful systematic hypotension effects in CHF patients
31
Q

How can Benephit help with fenoldopam delivery? (2 points)

A
  • targeted drug delivery using Benephit allows for beneficial renal effects while minimising systemic effects
  • systemic effects are minimised due to dilution factors and renal first pass metabolism (fenoldopam is 90% Renault excreted)
32
Q

What are the differences in GFR, renal plasma flow and systolic BP in IV drug delivery and IR drug delivery of fenoldopam?

A

IR:
Increases GFR, renal plasma flow
Reduces systolic blood pressure less than IV fenoldopam (thus reducing systemic effects)

33
Q

What are renal selective drug carriers? (3 points)

A
  • low MW drug carriers used for selective delivery of drugs to the kidneys
  • preparations are typically administered parenterally
  • increases local concentrations of drugs in the kidneys while minimising systemic concentrations
34
Q

What are examples of renal selective drug carriers? (2 points)

A
  • lysozyme

- captopril

35
Q

Why are renal selective drug carriers a potential for renal drug delivery? (3 points)

A
  • they are freely filtered through the glomerulus and undergo receptor mediated re absorption into proximal tubular cells
  • accumulates in the kidney
  • ACEi have been conjugated to a lysozyme loading to increase ACEi concentration in the kidneys
36
Q

What are renal selective pro drugs? (3 points)

A
  • Pro drugs that are activated by enzymes in the kidney
  • selectivity depends on the enzyme targeted
  • rapid cleavage and drug activation may be explained by low renal selectivity of pro drug and activation in non target tissues
37
Q

What do renal selective pro drugs need? (2 points)

A
  • design of kidney selective pro drugs relies on higher concentrations of converting enzymes in proximal tubular cells compared to other cells in the body
  • enzymes usually targeted to cleave drug from amino acid are cytotoxic enzymes
38
Q

What are the differences between pro drugs and LMWP? (4 points)

A
  • pro drugs can be designed for oral administration
  • pro drug renal specificity can be hard to obtain and there is no specific pro drug currently in the market
  • LMWP requires parenteral administration
  • naproxen LMWP and ACEi LMWP conjugated have been shown to target kidneys with high specificity

Pharm407 (5 decks)

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