Lecture 10 part 2: Pharmaceutical science and the renal system Flashcards
1
Q
What is the kidney?
A
- major filtration organ
2
Q
What is the functional unit of the kidney?
A
- nephron
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
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
5
Q
What two structures are contained in the renal corpuscle? (2 points)
A
glomerulus and bowman’s capsule
6
Q
What are 2 examples of drugs that can be toxic to kidneys?
A
- aminoglycosides
- NSAIDs
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
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
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
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
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
12
Q
How to inclusion complexes enhance bioavailability? (3 points)
A
- increases dissolution rate and solubility
- avoids organic solvents
- reduces active recrystallisation.
13
Q
What are the 3 main irritations that inclusion complexes help to reduce?
A
- GI
- dermal
- ocular
14
Q
How do inclusion complexes simplify handling? (2 points)
A
- reduce volatility
- convert oils/liquids to powders
15
Q
How to inclusion complexes improve patient compliance? (2 points)
A
- reduce unppleasant odors
- masks unpleasant tastes
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
What is Benephit? (2 points )
- system for targeted renal delivery of drug
| - novel catheter based medical device
26
How is Benephit placed in the kidney? (3 points)
- surgeon introduces system through femoral artery
- moves proximally from femoral artery to aorta
- bifurcates into renal arteries
27
What are the advantages of Benephit ? (3 points)
- 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
What was the patient who received the first patented Benephit treatment in 2005? (4 points)
- 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
What is fenoldopam? (4 points)
- 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
Why should fenoldopam be avoided in CHF patients? (3 points)
- 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
How can Benephit help with fenoldopam delivery? (2 points)
- 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
What are the differences in GFR, renal plasma flow and systolic BP in IV drug delivery and IR drug delivery of fenoldopam?
IR:
Increases GFR, renal plasma flow
Reduces systolic blood pressure less than IV fenoldopam (thus reducing systemic effects)
33
What are renal selective drug carriers? (3 points)
- 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
What are examples of renal selective drug carriers? (2 points)
- lysozyme
| - captopril
35
Why are renal selective drug carriers a potential for renal drug delivery? (3 points)
- 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
What are renal selective pro drugs? (3 points)
- 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
What do renal selective pro drugs need? (2 points)
- 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
What are the differences between pro drugs and LMWP? (4 points)
- 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
