Lecture 4 part 2: Pharmaceutical aspects of CVD1 Flashcards
What are the two types of nitrates available in NZ?
Glyceryl trinitrate
Isosorbide mononitrate
What are the characteristics of GTN? (2 points)
- explosive when pure (also known as nitroglycerin)
- unpredictable and low oral bioavailability
What are the characteristics of isosorbide mononitrate? (1 point)
-good oral bioavailability
What was the mainstay treatment for angina prior to 1857? (1 point)
-patients were bled to relieve angina pain.
How were nitrates discovered? (4 points)
- Prior to 1857, Brunton noticed that administration of inhaled amyl nitrate relieved angina in 30-60 seconds
- in 1846 Sobero noticed a small amount of GTN under the tongue caused a headache
- In the late 1860s, Nobel’s dynamite factories manufactured GTN. Workers developed headaches at the start of the week which were relieved by weekends.
- workers with angina noticed reduction in chest pain on mondays but this returned in the weekend
What are the indications for nitrates that should be considered? (3 points)
- Time till onset of action
- duration of effect
- extended release.
What are the ideal properties of nitrates for symptomatic relief?
-Fast onset to relieve sudden symptoms of angina e.g. GTN spray
What are the ideal properties of nitrates for regular use?
- Long duration of action so that we can use it prophylactically and have effect over a long period of time (e.g. GTN patch)
- A release of drug which is sustained and doesnt fluctuate too much in concentration (e.g. Duride CR tablets)
Why are CR Duride tablets 6 hours long when CR Blood pressure tablets which are CR over 24 hours? (3 points)
- If someone is taking nitrate regularly, they may develop tolerance unless there is a nitrate free period (8-12 hours long)
- If this period is not nitrate free, the patient may not experience relief with the GTN if they get angina due to build up of tolerance
- Duride CR is formulated over a shorter period of time to allow for this nitrate free period.
What are the mechanisms of nitrate tolerance? (5 points)
- Increased reactive oxygen species
- increased plasma volume
- decreased biotransformation of nitrates to NO
- decreased responsiveness to NO
- neurohormonal activation
When is nitrate tolerance lost?
-within 24 hours of discontinued therapy
What are the list of nitrate formulations available in NZ? (7 points)
- SL spray (Nitrolingual)
- SL tablets (Lycinate)
- solution for injection (Nitronal)
- transdermal patch (Nitroderm)
- immediate release tablets (Ismo20)
- modified release tablets (Duride)
- rectal ointment (Rectogesic for anal fissures)
What are the PK properties of the GTN spray? (5 points)
- 0.4mg GTN/spray
- Tmax = 4 minutes
- Half life = 2.5-4.5 minutes
- metabolites less active than parent compound
- Shelf life = a few years.
What are the PK properties of Lycinate tablets? (4 points)
- Releases 0.6mg of GTN/tablet
- Tablet dissolves under the tongue
- Tmax = 4.9 minutes
- Shelf life = 8 weeks from opening (difficult as 1 bottle = 100 tablets)
What are the PK propeties of Nitronal solution for IV administration? (5 points)
- 1mg/mL clear aqueous solution
- Isotonic
- Tmx = immediate
- bioavailability = 100%
- has definied protocols for use
What are the differences between Nitroderm TTS 5 and Nitroderm TTS 10? (2 points)
- Nitroderm TTS 5 delivers 25mg of drug while TTS 10 delivers 50m of drug
- TTS 5 has a smaller drug releasing area of 10 cm^2 while TTS 10 has a bigger drug releasing area of 20 cm^2
What are the PK properties of Nitroderm? (6 points)
- Releases 20-25ug/cm^2/hour
- TTS 5 and 10 numbers denote the amount of active drug released over 24 hours
- can be applied to upper arm, trunk, chest
- Plasma levels plateau after 2 hours
- Plasma levels proportional to area available for drug release to skin
- Patch cannot be halved!
Why is there such a high concentration of drug in a nitroderm TTS if a nitrate free period is needed?
-A high concentration in the patch drives the concentration of the drug into the skin (drug moves from high concentration to low concentration)
What are the PK properties for Ismo 20? (6 points)
- Conventional release tablets which deliver 20mg isosorbide mononitrate
- Release is governed by elements of NW equation
- Bioavailabiltiy ~ 100%
- Onset of action = 20 min
- Tmax = 1 hour
- Half life = 5 hours
- usual dose = 20mg bd/tds
What are the PK properties of duride tablets? (6 points)
- MR tablets which deliver 60mg isosorbide mononitrate
- drug released independent of pH over 10 hours. Produces clinical effect of 12 hours
- Bioavailability = 90%
- T max = 4 hours
- Half life = 5 hours
- Can be divided but not crushed or chewed.
How does the MR formulation of Duride work? (2 points)
- The drug is dispersed in a polymer
- Over time the drug diffuses out, leaving a ghost polymer which is excreted in the faeces.
What is the significance of pH independent release of Duride over 10 hours?
- Duride tablets are exposed to a range of pH as it goes through the GIT
- pH independent release means that it will release the drug over the entire length of the GIT irregardless of environmental pH, thus producing 12 hours of clinical effect
What is the role of a bare metal stent?
-Increase blood flow through an artery by preventing collapse or re-occlusion
What are the disadvantages of bare metal stents? (3 points)
- Risk of immune response and cell proliferation over stent
- Risk of stent thrombosis
- Antiplatelet therapy is required
