Enzymes as drug targets: Organic Nitrates and Phosphodiesterase Inhibitors Flashcards
3 Clinically used nitrates
glycerylyl trinitrate
isosorbide mononitrate
isosorbide dinitrate
PDE3
Acts on what tissue?
Specific/Non specific to what?
Acts on: Cardiac muscle Platelets Airway muscle Vascular muscle
Hydrolyses both cAMP and cGMP
But cAMP more than cGMP
PDE4
Tissues of action?
Specfic/non specific to what?
Acts on:
Airway smooth muscle
Inflammatory cells (mast cells, basophils, eosinophils)
cAMP specific
PDE5
Tissues it is on?
Specific/non specific to what?
Acts on;
Vascular smooth muscle i.e. corpus cavernosum, pulmonary vessels
cGMP specific
What are non-specific PDE Inhibitors called?
Give 2 examples
Alkylxanthines
Caffeine, Theophylline
High doses of Alkylxanthines cause?
What about “increased” doses?
High doses cause:
Nausea, vomiting, convulsions
Increased doses cause,
insomnia, anxiety, tremors
Uses of Caffeine clinically
Used in neonatal intensive care to manage neonatal apnoea
Uses of theophylline clinically
Downsides and how to reduce these
Chronic asthma - if fail to respond well to steroids
Acute severe asthma - IV aminophylline
Downsides:
Low therapeutic index - monitor plasma levels
Absorption varies - monitor plasma levels
Overcome unwanted effects by using slow release preparations
How does theophylline help with asthma?
PDE3 and PDE4 inhibition leads to bronchodilation (relxation of airway smooth muscle)
PDE4 inhibition leads to antiinflammatory effect as this is the only PDE in inflammatory cells
Name 3 isoform selective inhibitors that inhibit PDE3
Enoximone
Milrinone
Cilostazil
Enoximone and Milirone
Use
Downsides
Given IV injection/infusion in severe congestive heart failure that is unresponsive to conventional therapies.
Short term use only
Do not prolong survival
They tend to cause arrhythmias
What is the deal with Cilostazol
It ↑cAMP - relaxes smooth muscle and inhibits platelet aggregation
Given in intermittent claudication orally where:
-there is no pain at rest
-no peripheral tissue necrosis
BUT it is no longer recommended for patients with peripheral arterial disease BUT those on it are given the option to continue using it if they wish
Name 2 isoform selective PDE inhibitors that target PDE4
Roflumilast
Aprenilast
Roflumilast
Treats
When is it used?
Severe COPD with chronic bronchitis and a history of frequent exacerbation, adjunct to bronchodilators
NICE say it should only be used in clinical trials but those patients using it should have the option to continue using it
Roflumilast unwanted effects
Unwanted effects are severe
Headache
Nausea
Abdominal pain
