Drugs and the vasculature Flashcards
Summarise the regulation of vascular tone
The contractile state of vascular smooth muscle regulates the diameter of arteries and veins and influences blood flow, blood pressure and venous return. The contractile state of vascular
smooth muscle is controlled by a variety of neural, circulating and local factors
Some agents cause relaxation, some cause contraction.
Describe the influence of the sympathetic nervous system on the vasculature
The sympathetic nerve has varicosities along its length and these primarily release NA to stimulate vasoconstriction.
Can also release ATP and NPY
What mediators can cause vascular smooth muscle contraction
§ VSM mediators that can increase [Ca2+] in the vascular smooth muscle cell and stimulate a VSM contraction include:
o AngII à AT1r
o PGG2, PGH2 à TP (T-prostanoid receptor).
o ET1 à ETA/B (various thrombin, IL-1 and endotoxin can stimulate this receptor)
What mediators can cause vascular smooth muscle relaxation
§ Endothelial cell agonists that can stimulate a relaxation from an increase in [Ca2+] in the endothelial cell include:
o NO. (cGMP)
o CNP – C-Type Naturietic Peptide.cGMP)
o PGI2.
IP (cAMP)
o EDHF – Endothelial Hypopolarising Factor.
What is important to remember about prostaglandins and their influence on the vasculature
Some cause contraction, others cause relaxation.
What is blood pressure mediated by
§ BP is generally mediated by CO and TPR (BP =CO x TPR).
What is the effect of shear stress on the vasculature
Causes VSMC relaxation by inhibiting ET1 whilst increasing the conc of Ca2+ in the endothelial cell.
What happens when our arterial blood pressure falls
The fall in arterial blood pressure is detected by a reduced firing of arterial baroreceptors.
The baroreceptor reflex mediated via medullary centres then takes place:
Increased sympathetic discharge to arterioles (excluding the brain and the heart)- increasing arteriolar constriction and peripheral resistance.
Increased sympathetic discharge to veins- increasing venous tone, venous pressure, venous return, ventricular filling and EDV- increasing SV
Increased sympathetic discharge to heart- increasing HR and contractility- increased Q
Decreased PSNS discharge to heart- increasing heart rate- increased Q
All of these will increase arterial pressure.
What is important to remember about arterioles
§ Arterioles contribute the greatest to blood pressure regulation.
o These vessels exhibit “vascular tone” and so always display a partial state of constriction.
o Hypertensive patients tend to have a raised base vascular tone à more TPR à more BP.
Sum of resistance in arterioles is TPR
More resistance- the harder it is for blood to move from the arteries to the arterioles- thus increasing the pressure of blood in the arteries- hypertension.
Describe the effects of contraction and relaxation of the arteriole
Contraction:
decreased radius, increased resistance, decreased flow
Relaxation:
Increased radius, decreased resistance, increased flow/.
What is the normal blood pressure range
120/80 mmHg
Depends on factors such as size, height and gender
Someone who is tall and skinny may have a lower BP
What is hypertension defined as
Hypertension is defined as being consistently above 140/90 mmHg
Describe the morbidity and mortality associated with hypertension
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 (failing heart has to work harder to pump blood against an increased afterload)
Major risk factor for myocardial infarction (MI) & chronic kidney disease (KD)- blood flow to the kidneys needs to be tightly regulated.
What is the ultimately goal in management of hypertension
Ultimate goal of hypertension therapy reduce mortality from cardiovascular or renal events
However, as anti-hypertensive drugs are often given when the patient isn’t experiencing any symptoms, there is an issue with adherence as if that drug produces a side-effect, the patient will stop taking the drug due to them seeing no percieved benefit
What is step 1 in the treatment for hypertension
o Step 1 – Single Therapy:
§ Under 55 – ACEi or ARB (Angiotensin Receptor Blocker).
§ Over 55, Afro-Caribbean – CCB or Thiazide diuretic.
What is step 2 in the treatment for hypertension
§ ACEi and CCB.
§ ACEi and thiazide diuretic.
What is step 3 in the treatment for hypertension
Step 3 – Triple Therapy:
§ ACEi, CCB and thiazide diuretic
What is step 4 in the treatment for hypertension
Now classified as resistant hypertension.
Symptomatic Relief:
§ Low-dose spironolactone (diuretic therapy).
§ b-blockade or a-blockade.
What is important to remember about RAAS
Not necessarily the cause of hypertension- but it will exacerbate its progression- therefore we want to control it in hypertension.
Name 3 drug classes that can interfere with RAAS
Renin inhibitors
ACE inhibitors
Angiotensin receptor blockers
What is RAAS stimulated by
o LOW renal Na+ reabsorption.
o LOW renal perfusion pressure.
o HIGH SNS activation.
Outline the RAAS
RAAS stimulated (i.e SNS activation) Renin converts angiotensinogen to angiotensin I
ACE then converts angiotensin I — angiotensin II
Ang II (effector hormone)
Ang II exerts various effects (through the AT1 receptor) to increase BP:
Increased SNS activation and thirst – brain
Vasoconstriction
Salt and water retention
Aldosterone secretion.
Describe the effects of aldosterone in the collecting duct tubule cells
Aldosterone passes through the plasma membrane and binds to mineralocorticoid receptors intracellularly and increases the synthesis of Na+ channels and Na+/K+ pumps
This causes an increase in sodium reabsorption
What is important to remember about aldosterone
Aldosterone increases sodium retention by the kidney and may exert pro-fibrotic effects on the heart and vasculature.
Describe the actions of ACEi and their uses
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