Delivery of nitrates by buccal + transdermal route Flashcards
Identify nitrates mechanism of action in vivo and biological target
Nitrovasodilators
They act by relaxing smooth muscle, also relaxing/dilating coronary blood vessels - improving 02 supply to the heart
It reduces preload and afterload to stop angina by dilating peripheral veins (+ higher doses for peripheral arteries) - reducing oxygen consumption of the heart.
Inhibit platelet aggregation
What are the 3 ways nitrates are used to treat angina?
- To relieve an attack that is occurring by using the medicine when the attack begins
- To prevent attacks from occurring by using the medicine just before an attack is expected to occur
- To reduce the number of attacks that occur by using the medicine regularly on a long-term basis
Function of organic nitrates
Name a few examples
Potent vasodilators
Draw the synthesis of organic nitrates
How do organic nitrates form NO?
Organic nitrates require enzymatic processes to form NO
Main mechanism of organic nitrate-induced smooth muscle relaxation is achieved via NO signalling pathways including activation of soluble guanylyl cyclase which leads to an increase in cGMP levels
You need hydrolysis + reduction to form a nitrate
What is the oral bioavailability of organic nitrates + why is this?
How does this affect oral administration?
Oral bioavailability is low because of first-pass metabolism by the liver (isosorbide mononitrate is the exception)
Oral administration therefore requires much higher doses than sublingual/buccal/transdermal administration, which is not subject to first-pass hepatic metabolism
What is the use of short-acting nitrate formulations?
Describe the typical pharmacokinetic profile of the formulations including the formulation type
Why are some nitrate formulations sublingual?
They are used:
- to provide relief from an acute anginal attack
- before physical activities to prevent anginal attacks (typically 5-10 min before)
Sublingual nitroglycerin tablets ( tablet disintegrates + dissolutes beneath the tongue) cause rapid dissolution to give rapid drug effect, avoidance of destructive first passage through the liver by direct access to systemic circulation
Buccal tablets placed on top gum under upper lip
What is the use of long-acting nitrate formulations?
Prophylaxis: to reduce the number of attacks that occur by using the medicine regularly on a long-term basis
Cannot be used to relieve an attack that is occurring by using the medicine when the attack begins
HOWEVER, plasma levels maintained continuously (> 10-12 h) result in a rapid development of nitrate tolerance
What is nitrate tolerance?
How administration regimens are designed to avoid it?
What nitrates cause tolerance?
What has recent data dscovered on how tolerance develops?
Nitrate tolerance is the impaired responsiveness to the organic nitrate, demonstrated by reduced nitrate-induced vasodilation and a blunting of blood pressure lowering effects.
Nitrate-induced tolerance to other endothelium-dependent and independent vasodilators is termed cross-tolerance.
Tolerance development occurs in all nitrates except PETN
It has recently been found that nitrate-induced increases in the formation of ROS may inhibit the nitrate-metabolizing enzyme.
Dose escalation does not overcome this effect.
To avoid tolerance to long term nitrate therapy, regimens should be tailored to provide a 10-12 hour nitrate-free interval when possible.
Why is transdermal nitroglycerin an effective admin. route?
Nitroglycerin is better suited in the form of patches
Nitroglycerine: extensive first-pass effect (patch form bypasses this), rapid disappearance from plasma, large inter-individual variations
Severe headaches if plasma levels too high
Log P = 2.2. Transdermal delivery → prolonged and controlled plasma levels → ideal for prophylaxis of angina
Formulations: ointments, patches
