Drugs and the vasculature Flashcards
What is hypertension defined as?
BP = CO x TPR
Defined as blood pressure being consistently above 140/90mmHg
Hypertension causes:
- 50% of ischaemic stroke
- 25% of HF –> 70% in the elderly
- risk factor for MI and KD
What are the steps to hypertension treatment?
Step 1
- Under 55s - Angiotensin converting enzyme (ACE) inhibitor OR angiotensin receptor blocker (ARB)
- Over 55s or afro-Caribbeans - Calcium channel blocker (CCB) or thiazide-like diuretic
Step 2
CCB or thiazide-like diuretic and ACEi or ARB
ARBs preferred to ACEi for AfroCaribbean’s
Step 3
Combination of ACEi/ ARB with CCB and thiazide-like diuretic is recommended
Step 4 - resistant hypertension
Consider low-dose spironolactone
Consider beta-blocker or alpha blocker
See slides
What stimulates the production of renin?
From the juxtoglomerular cells in the kidneys, renin is produced when there is:
- decreased Na+ reabsorption
- decreased renal perfusion pressure
- increased sympathetic NS stimulation (Beta 1)
What does ACE inhibitors do?
Prevent the conversion of angiotensin I to angiotensin II
Prevent the break down of bradykinin
What does bradykinin do?
Causes vasodilaiton
What does Angiotensin receptor blockers do?
They block AT1 receptors that causes:
- SNS activation –> thirst
- Vasocontriction
- Aldosterone secretion
- Salt and water retention (AGII has aldosterone like effect)
What are the uses of ACE i?
Give an example
Uses: • hypertension • heart failure • post-myocardial infarction • diabetic nephropathy • progressive renal insufficiency • patients at high risk of cardiovascular disease
Enalapril - ends in -pril probably an ACEi
In terms of BP = CO x TPR what causes hypertension? Why use ACEi?
Increased TPR directly contributes to increased BP and increased venous return leads to increased cardiac contractility (via Starling’s Law) and thus CO.
Decreases TPR (reduce vasoconstriction) and decrease salt and water retention (reduced venous return = less fluid in the system)
In terms of BP = CO x TPR what causes heart failure? Why use ACEi?
Increased vasoconstriction increases the afterload and increases cardiac work. Increased venous return leads to long term fluid retention and congestion, leading to oedema.
vasodilation - means the after load decreases
Decreasing venous return - decreases how hard the heart needs to work.
What are the uses of ARB
Give an example?
Uses:
- Hypertension
- Heart failure
Antagonists of type 1 (AT1) receptors for Ang II, preventing the renal and vascular actions of Ang II,
Losartan
What is a problem with ACEi?
Bradykinin - causes cough
Hypotension
Give an example of an ARB?
Losartan - Antagonists of type 1 (AT1) receptors for Ang II, preventing the renal and vascular actions of Ang II.
What is Losartan used for?
Hypertension and Heart failure
Angiotensin Receptor Blocker
Describe normal smooth muscle contraction?
1) Membrane depolarisation opens voltage-gated calcium (Ca2+) channels (VGCCs)
2) Ca2+ enters and binds to calmodulin (CaM)
3) Ca2+-CaM complex binds to and activates myosin light chain kinase (MLCK)
4) MLCK mediated phosphorylation –> smooth muscle contraction
Angiotensin II promotes contraction
What are the two types of calcium channel blockers?
Dihydropyridines (DHPs) Non-rate limiting - Amlodipine (selective for blood vessels and does not cause negative intropy)
Non-DHPs rate limiting - Verapamil (large negative inotropic effect)
Describe the mechanism of action of DHPs?
Hypertension: Go for a calcium channel blocker that target smooth muscle - so the non-rate limiting one.
Dihydropyridines inhibit Ca2+ entry into vascular smooth muscle cells
↓ T.P.R. = ↓ B.P.
N.B. Powerful vasodilation can lead to reflex tachycardia and increased inotropy thus increased myocardial oxygen demand
Compare RASi vs CCBs
CCBs ↓ SBP more than RAS inhibitors
RAS inhibitors ↓ heart failure
RAS inhibitors ↑ stroke
No difference for all-cause death (mortality)
Compare RASi vs thiazides
Thiazides ↓ SBP more than RAS inhibitors
RAS inhibitors ↑ heart failure
RAS inhibitors ↑ stroke
No difference for all-cause death
Compare RASi vs beta-blockers
No difference in SBP reduction
RAS inhibitors ↓ CV events
RAS inhibitors ↓ stroke
No difference for all-cause death
Why are alpha-blockers used as anti-hypertensives
a(1)-receptor blocker- decreases vasoconstriction = promotes vasodilation
[a(2)-receptor - decreased sympathetic simulation]
Used when you have resistant hypertension
a1 = prazosin a1+2 = phentolamine
Why do you get hyperkalaemia with ACEi and ARBs?
Aldosterone causes the insertion of Na+ channels and Na/K+ ATPases into the cells.
These drugs cause fewer channels in the membrane. As a result the potassium can not be excreted in the urine. Sodium cannot be reabsorbed into the cell = K+ build up in the blood as it cannot be exchanged in the ATPase.
See diagram
Why do you get renal failure with ACEi and ARBs?
Renal failure in patients with renal artery stenosis. There is poor flow into the glomerulus = low GFR. Angiotensin II will constrict the efferent artiole to increase the the pressure in the glomerulus = to increase the GFR. If you give ACEi or ARB you remove the mechanism to increase the GFR leading to renal failure.
Describe how treatment changes when dealing with low renin levels?
If plasma renin levels are low relatively to Angiotensin II, ACEi will have less of an effect.
Use other methods.
This affects Afro Caribbean and old people. blood pressure becomes uncoupled –> atheroscleroiss
