11. Drugs and the vasculature Flashcards
Where is ACE found?
- Mainly in the capillaries of the lungs
* Can also be found in endothelial and kidney epithelial cells
How does sympathetic discharge effect the arterioles and arterial pressure?
- Increased arteriolar constriction
- Increased peripheral resistance
- Increased arterial pressure
Which vessels are the ‘major resistance vessels’?
- Arterioles
* Biggest drop in BP takes place from one end of an arteriole to another
The BP of which vessels determines the blood flow everywhere else?
Arterial BP
How do you calculate blood pressure?
BP = CO * TPR
What is the definition of hypertension?
BP consistently over 140/90mmHg
What is the single most important risk factor for stroke?
Hypertension
What are the 4 steps of hypertension treatment?
(Lifestyle modifications before thinking about pharmacology)
1) ACE inhibitor or angiotensin receptor blocker (for under 55s)
2) CCB or thiazide-like diuretic (for over 55s or afro-Caribbeans of any age)
3) Combination of ACEi/ARB with CCB and thiazide-like diuretic
4) Consider low-dose spironolactone, beta blocker (used to be first line), or alpha blocker
Why are you less likely to prescribe ACE inhibitors or angiotensin receptor blockers (ARBs) to patients over 55?
- Over 55 - tend to have low renin/renin sensitivity
- Therefore, the RAS is probably not causing the high BP
- Less responsive to ACEi or ARBs
How are thiazides thought to have an antihypertensive effect?
- via diuresis
* However, evidence suggests it is a vasodilation effect
What is the suffix for ACE inhibitors?
-pril
What are the 3 major stimuli for renin production?
- Decreased renal Na reabsorption
- Decreased renal perfusion pressure
- Increased sympathetic activity
Describe how the sympathetic NS affect renin production
- Sympathetic nerves innervate the juxtaglomerular cells, beta receptors
- Renin production stimulated
Which cells respond to renal [Na], and how do they respond when [Na] is low?
Macula densa cells
• Decreased resistance in afferent arterioles
• Increased renin release from juxtaglomerular cells
What does angiotensin II do?
- Powerful vasoconstrictor => increased TPR
- Directly affects kidney to promote salt and water retention => increased blood volume
- Indirectly affects kidney to promote sodium retention and potassium excretion, by stimulating aldosterone production
- Sympathetic activation
- Thirst activation
Which type of nerves release the following:
• noradrenaline
• neuropeptide Y
• ATP
Sympathetic nerves
What role does renin play in the RAS?
Converts angiotensinogen to angiotensin I
What are the uses of ACE inhibitors?
- Hypertension and HF
- Post-MI
- Diabetic nephropathy
- Progressive renal insufficiency
- Patients at high risk of CVD
How do ACE inhibitors treat heart failure?
- Angiotensin II increases salt and water retention => increased blood volume
- Increase in venous return
- ACEi decrease venous return in HF patients => reduced work, reduced congestion in system, reduced preload
- Stress on heart alleviated
How do ACE inhibitors cause a cough?
- Inhibit bradykinin breakdown
- More bradykinin
- Cough reflex hypersensitivity
What are angiotensin II blockers used for and given an example?
• Prevent renal and vascular actions of ATII
• Used in hypertension and HF
e.g. losartan
What are the side effects of both ACEi and ARBs?
- Hypotension
- Hyperkalaemia (less ATII effects, less aldosterone, less K excretion)
- Foetal injury
- Renal failure in patients with renal artery stenosis
What supplements/medication do you need to be careful with when taking ACEi or ARBs?
K supplements or K sparing diuretics
How can ACEi and ARBs cause renal failure in patients with renal artery stenosis?
- Removal of ATII as a major determinant of efferent vasoconstriction
- GFR can’t be maintained when renal perfusion is low
- GFR drops
- Acute renal failure
Describe how depolarisation of smooth muscles lead to contraction?
- Opening of VGCCs
- Ca2+ enters and binds to calmodulin (CaM)
- Ca2+-CaM complex binds to + activates myosin light chain kinase (MLCK)
- MLCK phosphorylates the myosin light chain
- Cross-bridges can form - smooth muscle contraction
Outline the selectivity of dihydropyridines (CCB)
- Affects smooth muscle only
- More selective for blood vessels
- e.g. amlodipine - doesn’t cause negative inotropy
- Licensed for prophylaxis of angina
Outline the selectivity of non-dihydropyridines
- Rate-limiting
- Affects the heart and smooth muscle
- e.g. verapamil - large negative inotropic effect
How does decreased VSMC Ca2+ entry lead to decreased BP?
- Less contraction
- Lower TPR
- Lower BP
Which antihypertensive drugs have better adherence?
- ACEi
- ARBs
Primary reason why we use them - patients more likely to stay on them
What does elderly hypertension tend to be more based on?
Atherosclerosis rather than renin
Compare the overall effects of RAS inhibitors with CCBs
- CCBs decrease SBP and stroke risk more
- RASi decrease HF risk more
• No difference for all-cause death
Compare the overall effects of RAS inhibitors with thiazides
- Thiazides decrease SBP more
- Thiazides decrease HF and stroke risk more
• No difference for all-cause death
Compare the overall effects of RAS inhibitors with beta-blockers
- No difference in SBP reduction
- RASi decrease CV events and stroke more
• No difference for all-cause death
When are alpha 1 adrenoreceptor antagonists used and how do they work?
- Last resort
- Alpha 1 is the predominant vasoconstricting receptor in the vasculature
- Blocking it reduces vasoconstriction => reduced TPR => decreased BP
