CPT1: Vasodilators 3 Flashcards
Describe the mechanism of action of NO signalling
- M3 agonist e.g. Ach or Bradykinin binds to M3 receptor on endothelium and activates it (Gq linked) or shear stress activates endothelial mechanoreceptors
- Both lead to increased [Ca2+]
- Ca binds to calmodulin to produce Ca-Calmodulin
- Ca-calmodin activates eNOS
- eNOS catalyses molecule O2 and L-arginine to L-citrulline and free NO
- NO activates guanylyl cyclase basal to active form
- Gaunylyl cyclase converts GTP to cGMP
- cGMP activates PKG
- PKG activates MLCP which dephosphorylates MLC = relaxation
What are the physiological effects of NO
- Vascular smooth muscle relaxation
- Prevents platlet and leukocye aggregation and adhesion
- Part of host defence and cytotoxicity
- Exerts effects on CNS
- NO rapidly reacts with superoxidised anions (O2-) to form peroxynitrates (ONOO-). These cause lipid peroxydation and production of biologically activae isoprostaglandins e.g. 8-iso of PGF2a
What is lipid peroxydation?
It is oxidative degradation. The process by which free radicals steal electrons from lipids in the cell membrane resulting in cell damage
What are the 3 starting points for NO effects
- Decreased venopressure
- Large dose
- Dilation of coronary collaterals
Describe what happens during low doses/ venodilation
Describe signalling with large doses
Describe what happens with coronary collatoral dilation
Describe the different types of nitrates
- organic nitrates
- Glyceryltrinitrate, isosorbide mono nitrate, dinitrate, amyl nitrate
- need bioformation by interaction with a tissue thiol group to release NO
- sydonimines
- molsidomine, sodium nitroprusside
- spontaneously release NO from their structure
What are the anti-anginal effects of nitrates?
- REduction of cardiac O2 consumption due to:
- Reduced venous return (preload)
- Decreased arterial pressure (preload)
- Deceased CO
- Redistribution of coronary blood flow to ischaemic areas
- Relief of conary spasm in variatn angina
- What are examples of short acting nitrates?
- Effects?
- Preperations available
- Duration of action?
- Glyceryltrinitrate (GTN) and isosorbide dinitrate (IDN)
- Used to relief anginal pain and as a prophylaxis prior to exertion
- Sublingual absorbed from buccal cavity
- 10-60 mins
- What are examples of long acting nitrates?]
- Effects?
- Preperations avaiable
- Duration of action
- GTN, IDN, IMN
- To prevent angina attack
- available orally as slow release buccal or transdermally and as chewable tablers
- 4- 10 hours
Describe niitrate tolerance:
- What is it dependent upon?
- Granual loss of clinical effectiveness with organic nitrates dependent upon:
- Treatment duration
- Frequency of use (intensity of exposure to nitrate)
How does tolerance arise?
How can this be prevented?
- Depletion of sulphydryl groups required for biotransformation
- Desensitisation of guanyl cyclase
- Nitrate free period in each 24 hour
What are side effects of nirates?
Headache - due to dilation of cerebral blood vessels
Flushing - due to dilation of blood vessels at skin
Trachycardia - due to fall in arterial BP
