12 - Drugs and the Vasculature Flashcards
What is the main driver of peripheral resistance?
Arteriolar constriction
What happens to blood flow through arterioles in the cases of arteriolar smooth muscle contraction and relaxation?
Arteriolar S.M. Contraction
- Radius decreases
- Resistance increases
- Flow decreases
- Vasoconstriction
Arteriolar S.M. Relaxation
- Radius increases
- Resistance decreases
- Flow increases
- Vasodilation
What state is arteriolar smooth muscle in without direct contraction or relaxation?
Arteriolar S.M. normally displays a state of partial constriction
- Vascular tone
What are the two determinants of blood pressure?
BP = CO x TPR
How do you define hypertension?
Hypertension is defined as being consistently above 140/90 mmHg
What symptoms are associated with hypertension?
There are no symptoms associated with just hypertension itself, therefore it is a “silent” disease
What can hypertension be a major risk factor for?
- Single most important risk factor for stroke, causing about 50% of ischaemic strokes
- Accounts for ~25% of heart failure (HF) cases, this increases to ~70% in the elderly
- Major risk factor for myocardial infarction (MI) & chronic kidney disease (KD)
- Ultimate goal of hypertension therapy is to reduce mortality from cardiovascular or renal events
What are the steps to treatment of hypertension?
STEP 1
- Angiotensin converting enzyme (ACE) inhibitor OR angiotensin receptor blocker (ARB) for under 55s
- Calcium channel blocker (CCB) or thiazide-like diuretic for over 55s or afro-Caribbean’s
STEP 2
- CCB or thiazide-like diuretic & ACEior 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
What is resistant hypertension?
Hypertension that is not controlled by the first 3 steps of hypertension treatment.
Resistant hypertension is defined as blood pressure that remains above goal despite concurrent use of three antihypertensive agents of different classes, one of which should be a diuretic
How does the Renin-Angiotensin System (RAS) work?
Angiotensinogen produced by liver
Renin from kidney
Converts angiotensinogen to angiotensin I
Angiotensin ! Converted to II by ACE
Ang II carries out powerful vasoconstriction by AT I receptor
Ang II produces Aldosterone which promotes sodium and water reabsorption
Ang II itself also has aldosterone like effects
What are Angiotensin Converting Enzyme Inhibitors (ACEi)?
Inhibit the somatic form of angiotensin converting enzyme (ACE)
Prevent the conversion of angiotensin I to angiotensin II by ACE
Uses:
- hypertension
- heart failure
- post-myocardial infarction
- diabetic nephropathy
- progressive renal insufficiency
- patients at high risk of cardiovascular disease
Example: Enalapril
What suffix typically denotes ACE inhibitors?
- pril
e. g. Enalapril
How can ACE inhibitors be used to treat hypertension or heart failure?
HYPERTENSION
- decreased vasoconstriction
- decreased TPR
- decreased BP
HEART FAILURE
- less sodium and water reabsorption
- decreases blood in venous system
- decreases venous return
- drecreased EDV
- decreased CO
What occurs in heart failure?
Heart failure: Increased vasoconstriction increases the afterload and increases cardiac work. Increased venous return leads to long term fluid retention and congestion, leading to oedema.
What is the mechanism behind hypertension?
Increased TPR directly contributes to increased BP and increased venous return leads to increased cardiac contractility (via Starling’s Law) and thus CO.
What are ARBs?
Angiotensin Receptor Blockers
Example: losartan
Antagonists of type 1 (AT1) receptors for AngII, preventing the renal and vascular actions of AngII.
Uses: hypertension, heart failure
Block ability of AngII to have an effect
Fairly similar effects as ACE inhibitors
What are some of the side effects of ACE Inhibitors and Angiotensin Receptor Blockers?
COUGH
- ACE Inhibitors
- Prevents bradykinin breakdown
- Therefore can initiate cough
HYPOTENSION
- Both drugs
- These drugs can cause loss of effect of calcium entry
- Overly dilated can cause hypotension
HYPERKALAEMIA
- Aldosterone normally promotes Na+ channels and Na-K ATPase embedding in membrane
- When aldosterone is blocked there are fewer channels
- Therefore, less potassium is lost
- Potassium build up on blood side instead of in urine
RENAL FAILURE
- Ang II normally constricts efferent arteriole
- Stenosis decreases GFR
- Not enough pressure to filter blood
- Ang II would increase this pressure normally
- However, on these drugs, this action of AngII is lost
How does smooth muscle contraction occur?
- Membrane depolarisation opens voltage-gated calcium (Ca2+) channels (VGCCs)
- Ca2+ enters & binds to calmodulin (CaM)
- Ca2+-CaM complex binds to & activates myosin light chain kinase (MLCK)
- MLCK mediated phosphorylation ®smooth muscle contraction
As the efficacies of drugs for hypertension are very similar, how do doctors choose which drugs to administer?
They choose them according to their side-effect profiles and indications.
Some drugs also have a higher rate of patient adherence than others
Elderly
- Blood pressure becomes less coupled to renin
- More coupled to atherosclerosis and peripheral artery disease
Afro-Carribbeans
Tend to have non-renin hypertension
Relatively low plasma renin
Therefore ACE Inhibitors have less of an effect on this group
