Week 7 - Organic Nitrates and Phosphodiesterase Inhibitors Flashcards
Why are enzymes are important drug targets
Enzymes are protein catalysts (they catalyse reactions / allow chemical reactions to occur)
- may speed up or inhibit reactions
How does activation of soluble guanylyl cyclase causes vasodilation
- Organic nitrates produce nitric oxide (NO)
- NO activate sGC (soluble guanylyl cyclase)
- sGC makes cGMP (cyclic guanosine-5’-monophosphate), when cGMP is produced in smooth muscle cells = stimulation of cGMP dependant protein kinase G (PKG)
- Activated PKG causes protein phosphorylation
- Results in ↓ in cytoplasmic Ca2+ = relaxation / vasodilation
List the 3 types of angina
- Stable angina
- most common type
- occurs on exertion e.g. when do exercise, stress
- alleviated with rest
- temporary ischaemia caused by partial occlusion of coronary artery - Unstable angina (UA)
- most dangerous type
- occurs at rest
- high risk of myocardial infarction
- due to disruption of atherosclerotic (fatty) plaque = blockage - Variant angina
- rare
- caused by reflex spasm of coronary rteries
What happens during an attack of angina of effort (stable angina)
During rest the demand and supply of O2 are balanced
BUT
During exercise, stress etc. the vessels dilate resulting in O2 supply not being able to meet the O2 demand
- this activates bradykinin system (inflammatory mediator) causing pain in middle of chest
How do organic nitrate drugs alleviate angina
Organic nitrates are enzyme activators
- they are prodrugs which produce nitric oxide (NO)
- Relieve angina pain by relaxing vascular smooth muscle
List 2 nitrovasodilators (organic nitrate) drugs
Organic nitrates are enzyme activators
- Glyceryl trinitrate (nitroglycerin)
- Isosorbide mononitrate
How do nitrovasodilators relieve angina attacks
- They dilate collateral vessels allowing more blood to bypass plaque blockage
- collateral vessels not coronary artery as artery is already maximally dilated - ↓ O2 demand by ↓ cardiac workload
- achieved by ↓ preload (biggest effect) and afterload
↓ Preload:
- dilation / relaxation of veins = ↓ venous pressure + venous return = ↓ cardiac preload
- by reducing SV, stretch of cardiac muscle and contractile force
↓ Afterload:
- relaxation of large arteries = ↓ cardiac afterload
-
How do the 2 types of nitrovasodilators alleviate angina
Causes vasodilation by relaxing vascular smooth muscle (its a nitrovasodilator)
- ↓ preload, ↓ afterload, dilates collateral vessels
- Glyceryl Trinitrate (nitroglycerol)
-Ineffective if given orally- sublingual tablets: act fast (20-30min), rapidly eliminated (= activity short lived)
- transdermal: longer delivery time, need nitrate-free interval (4-12hrs)
- IV: treats UA, acute heart failure, controls post-op hypertension, if unresponsive to conventional angina treatments
- Ointment
- trinitrate as it has 3 nitrate groups
- Isosorbide Mononitrate
- Effective orally
- use immediate release or extended release tablets
- can develop tolerance with extended release (nitrate-free period during night to prevent)
- mononitrate = has 1 nitrate group
How does Riociguat (enzyme activator) work
- Its an sGC activator
- activates sGC via direct activation OR enhancing effects of NO
Avoid in pregnancy
Understand the physiological role of cyclic nucleotide phosphodiesterases (PDE - enzyme inhibitors)
- cGMP and cAMP are broken down by PDE = ↓ amount present in body = vasoconstriction
- inhibition of PDE = cGMP/cAMP is not broken down = accumulates = vasodilation
-cGMP activates protein kinase G (PKG) - cAMP activates protein kinase A (PKA)
- inhibition of PDE = cGMP/cAMP is not broken down = accumulates = vasodilation
PDE3:
- found in cardiac muscle, vascular smooth muscle, airway + platelets
- hydrolyses more cAMP
PDE4:
- cAMP-specific
- found in airway smooth muscle, inflammatory cells
- inhibition causes anti-inflammatory effect
PDE5:
- cGMP-specific
- found in vascular smooth muscle
How do non-selective PDE inhibitors exert their pharmacological effects
Alkylxanthines
- cause smooth muscle relaxation (esp. in airways) due to accumulation of cAMP
- inhibits PDE + antagonism of adenosine receptor
- e.g. caffeine, theophylline and
- caffeine ~ manages neonatal apnoea
- theophylline ~ used if conventional treatment ineffective, used in COPD / asthmatic patients
Theophylinne Mechanism:
- inhibition of PDE3 + PDE4 = bronchodilation
- inhibition of PDE4 = anti-inflammatory effects
- heart effects = ↑ rate + force of cardiac contraction
- kidney effects = have weak diuretic effect
- CNS = effects like insomnia, nausea, decreased reaction time
How do selective PDE inhibitors exert their pharmacological effects
- Selective PDE3 Inhibitors
E.g. Enoximone, Milrinone
- ↑ cAMP = ↑ heart rate + force of cardiac contraction
- short term use only, given IV or infusion
- used in severe cardiac failure unresponsive to conventional treatment
E.g. Cilostazol
- ↑ cAMP = relaxes vascular smooth muscle = dilation
- inhibits platelet aggregation
- given orally (if no pain or tissue necrosis) - Selective PDE4 Inhibitors
E.g. Theophylinne
- treats chronic inflammation
- inhibits inflammatory cells only expressed by PDE4
E.g. Roflumilast
- used in severe COPD accompanied with bronchitis + history of frequent exacerbation
E.g. Apremilast
- treat arthritis if unresponsive to conventional treatment
- treats moderate-severe plaque psoriasis that are unresponsive to other therapies - Selective PDE5 Inhibitors
E.g. Sildenafil (a.k.a. viagra)
- treat / manage erectile dysfunction
- NO activating cGMP = cGMP accumulation = vasodilation = engorgement of penis erectile tissue with blood
- inhibition of PDE5 prevents breakdown of cGMP = have ↑ cGMP levels
- treats pulmonary arterial hypertension (PAH)
- drug causes vasodilation
- treats enlarged prostate (drug = Tadalfil)
PROLEM: selectivity between PDE5 and PDE6 is small
- PDE6 is found in retina, if inhibited can cause visual disturbance (develop more selective inhibitors)
SIDE EFFECTS: headache, dyspepsia, slow onset of action (1 hr), high fat food slows down its absorption
How does Riociguat (enzyme activator) work
- Its an sGC activator
- activates sGC via direct activation OR enhancing effects of NO
Avoid in pregnancy
How to use GTN spray
- Sit down and spray once into air (ensure its working)
- Take a deep breath, lift up tongue and spray directly under tongue (1-2 sprays)
- whilst spraying don’t breath in - Put tongue down, close mouth and only breath out through your nose
- Rest for 5 min
- If after 5 minutes still in pain repeat (another 1-2 sprays)
- If still in pain do a final 3rd dose (of 1-2 sprays) and if still in pain call 999
Takes 1-3 minutes to work
Use before exercise / things which may cause angina attack
Side Effects of GTN
- Headaches
- take paracetamol - Dizziness
- sit down until feel better - Nausea
- goes away on own but can take sip of cold drink to help - Fatigue
- sit down - Red face (flushing)
- avoid coffee, alcohol as it makes this worse
- use fan, spray face with cold water
- if used once will away after few hours, if used multiple times goes away after few days
If using more frequently see GP or pharmacist
Unused medication bring back to pharmacy
GTN is a P medicine = can be dispensed without prescription by a pharmacist (in emergencies)
