Drugs and the cardiovascular system- the vasculature Flashcards
What produces a raft of substances that can impact on smooth muscle tone?
Endothelial cells
What effect does the renin-angiotensin system have on CVS function?
Negative- Ang II promotes vasoconstriction and salt and water retention mainly via the stimulation of aldosterone secretion
What is the mechanism of action of aldosterone?
It passes through the cell membrane and binds to a mineralocorticoid receptor, it then upregulates production of sodium channels and production of Na+/K+ ATPase which means that you get more sodium reabsorption
What do ACE inhibitors inhibit?
Inhibit ACE which inhibits conversion of angiotensin I to angiotensin II
What are ACE inhibitors commonly used to treat?
Hypertension Heart failure Post-MI Diabetic nephropathy Progressive renal insufficiency Patients at high risk of cerebrovascular disease
How do ACE inhibitors reduce hypertension?
They reduce the AT1 dependent vasoconstriction which leads to a fall in TPR and a fall in blood pressure
It also reduces production of aldosterone which means you get a decrease in blood volume and decrease in venous return which is linked by starling’s law to contractility and cardiac output
What causes diabetic nephropathy?
Significant damage to the kidney glomerulus because of toxic products
In terms of diabetic nephropathy, what does high blood glucose lead to?
Production of oxygen free radicals
Why do you not want too much pressure in the glomerulus?
Allows toxic products to accumulate
What effect does ang II have around the glomerulus?
It constricts the efferent arteriole
What is the normal response at the glomerulus when your blood pressure falls?
The RAS will be stimulated and produce more Ang II which will constrict efferent arteriole and allow blood to flow more effectively and a cetain amount of pressure os maintained so the glomerulus can work
Why are ACE inhibitors used in diabetic nephropathy?
You don’t want the glomerular pressure to increase too much because of the toxic products, hence you don’t want Ang II mediated vasoconstriction of the efferent arteriole
What is the main unwanted effect of ACE inhibitors (and angiotensin receptor blockers)?
Cough (hyperkalaemia is also common)
Describe the process of smooth muscle contraction (4 steps)
- Membrane depolarisation opens voltage-gated calcium channels
- Ca2+ enters and binds to calmodulin (CaM)
- Ca2+-CaM complex binds to and activates myosin light chain kinase (MLCK)
- MLCK mediated phosphorylation -> smooth muscle contraction
What are dihydropyridines more selective for?
Blood vessels
Why don’t calcium channel blockers penetrate the plasma membrane to any great degree compared to the drugs that impact the heart?
They aren’t particularly liposoluble
How do dihydropyridines have an effect?
They bind on the extracellular surface of the calcium channel and inhibit calcium entry into vascular smooth muscle
What CCBs are most used in treating hypertension and why?
DHPs because they have a more powerful effect on vascular smooth muscle so a greater effect in reducing TPR
What does the reduction in TPR by CCBs lead to?
Reflex tachycardia but massive reduction in TPR outweighs heart rate increase so bp decreases
What is the most common cause of hypertension in younger patients?
Increased sympathetic drive
How does increased sympathetic drive lead to hypertension?
Noradrenaline binds to B1 receptors and causes increased heart rate and force of contraction, it also binds to B1 receptors in kidneys increasing renin release
What are beta blockers used to treat?
Angina Post MI Cardiac dysrhythmias Chronic heart failure Hypertension
Why have beta blockers been removed as first line treatment for hypertension?
They aren’t particularly effective on blood vessels- reduced TPR has the most profound effect on BP and beta blockers have their main effect on the heart
What is now the first line treatment for hypertension?
CCBs and ARBs
Why are mixed beta-alpha blockers now used?
Blockage of alpha 1 receptors allow the drugs to cause vasodilation
What is the problem with alpha blockers?
You need one that is selective for alpha 1 because the alpha 2 receptor is the negative feedback receptor for SNS which needs to be stimulated to depress sympathetic function
How does sumitriptan work?
It is a triptan which is an agonist at 5HT1D receptors which causes vasoconstriction of some large arteries and inhibits trigeminal nerve transmission
What is sumitriptan used for?
Migraine attacks- painful stimuli is transferred by trigeminal and profound vasodilation is associated with migraine
When is sumitriptan use contraindicated?
Patients with coronary disease
Look at NICE treatment guidelines for hypertension in notes
Will do
What is the first step in hypertension treatment in someone under 55 years?
ACE inhibitor or angiotensin receptor blocker
What race is particularly at risk for hypertension?
Afro Caribbean
What is the first step in hypertension treatment in someone over 55 years or Afro Caribbean of any age?
CCBs or thiazide-like diuretics
What is spironolactone?
Aldosterone antagonist
How does spironolactone work?
It blocks mineralocorticoid effects
What is the definition of chronic heart failure?
Impaired cardiac function due to ischaemic heart disease, hypertension or cardiomyopathy that results in fluid retention, oedema and fatigue (serious condition with high mortality)
What are the three main treatments for cardiac failure?
ACE inhibitors
Beta blockers
Angiotensin receptor blockers
