Treatment of hypertension Flashcards
What is Blood Pressure?
What is it controlled by? (equation)
why is it essential for organs?
what is the short term and long term regulation mechanism?
How can high blood pressure arise?
Blood pressure is pressure exerted by blood on blood vessels.
It is controlled by cardiac output and total peripheral resistance (resistance in the peripheral arteries): BP = CO x TPR
BP is essential for organ perfusion as we know from Darcy’s law: Flow = Art. BP/TPR
Too little BP and you won’t have perfusion, too much and you’ll start damaging things.
Blood pressure has a short-term regulation mechanism and long-term regulation mechanisms.
- Short-term regulation is neural via baroreceptors etc.
- Long-term regulation is hormonal (through Na+ balance, RAAS and ANP) and to do with controlling extracellular fluid volume and the general degree of vasoconstriction
o People with long term hypertension often have more vasoconstriction in their CVS
High blood pressure can arise from:
- An increase in the ECFV
- An increase in vasoconstrictor agents (e.g. endothelin’s, leukotrienes)
- A reduction in vasodilator agents (e.g. ANP).
What is High Blood Pressure or Hypertension?
bp cut off for high blood pressure? how does it change with age?
Why set at this value?
what is hypertension a strong indicator for?
If you measured a group of middle age people’s BP, the results would end up similar to above. Majority will have a normal BP, while some will have very low BP and some very high BP.
There is quite a large distribution, so there are many risk factors involved.
Hypertension is defined according to increased risk and this is accepted as having a BP 140/90 or over if you’re less than 50yrs old or 160/95 for older individuals.
The cutoff point changes depending on how old you are.
Hypertension is set at 140/90 because of studies done which found a very strong relationship between diastolic BP and stroke/CAD.
We set it at this value, because when your BP starts raising above this level, the risk (relative risk) of having stroke, CAD etc. begins to increase significantly.
o Hypertension is a strong risk factor for many things including: stroke, ischemic heart disease, renal failure, retinopathy, left ventricular hypertrophy, cardiac failure.
We also classify BP (other classifications)
what is optimal bp?
what is isolated systolic hypertenison? how does it arrise and who is it common with?
We’d like to get BP below 120/80, which is the optimal BP. This classification system gives us an idea of people’s level of risk (as they are essentially risk categories).
We also have isolated systolic hypertension, when diastolic is normal but systolic is high. This is linked to age, because the aorta has less compliance, so there is this high blood volume pushing against a non-compliant wall leading to high systolic BP.
o Seen commonly in the elderly.
Causes of Hypertension
what 2 groups are the cause split into? How common is each of these and what is the cause?
examples for each category?
Causes of hypertension are split into secondary and essential.
Secondary hypertension
Accounts for about 10% of cases and is when there is an identifiable cause of the BP. Examples include:
o Renal diseases e.g. glomerulonephritis, diabetic nephropathy
o Vascular diseases e.g. renal artery stenosis
o Hormonal abnormalities e.g. Conn’s syndrome, Cushing’ syndrome, pheochromocytoma
o Drugs e.g. contraceptive pill
o Pregnancy – pre-eclampsia
o Monogenic genetic diseases e.g. Liddle’s (increased ENaC activity)
Essential Hypertension
Essential or primary hypertension (over 90% of cases), this is when there is an unknown cause. The prevalence of essential hypertension in urban-based populations is around 20%.
It is a combination of genetic pre-disposition and environmental factors that are proposed to cause essential hypertension. These factors, such as stress, result in various biological processes
o Increased sympathetic nervous system stimulation
o Increased renin-angiotensin-aldosterone system (RAAS)
o Obesity/insulin resistance (Caused through food)
o Endothelial dysfunction (commonly caused by smoking, the balance between vasodilator and vasoconstrictors changes causing increased in TPR)
o A reduction in capillary density (rarefaction) (capillaries reduce resistance because they are arranged in parallel, so the pressure is distributed across them, so if you reduce the number of, then there will be higher BP)
o Defect in smooth muscle contraction
o Defects in renal Na+ handling, increased salt intake
o Age
o Ethnicity e.g. more common in Afro-Caribbean groups
Why Treat Hypertension?
what are the three main treatment pathways?
The reason why we treat hypertension comes back to the evidence-based medicine seen earlier with defining hypertension.
A reduction in blood pressure level reduces the relative risk of consequences, for example a small 5mmHg drop in diastolic BP for 5 years will reduce strokes by 42%, heart attacks by 16% and vascular mortality by 21%!
So, for this reason there is a real drive for a person with high BP to reduce it.
The goals of anti-hypertensive treatment are firstly adequate blood pressure control, getting it below 140/90mmHg to reduce their relative risk of disease.
Hypertension is linked to these conditions because it is a risk factor for them e.g. hypertension causing heart failure.
So, another goal is to prevent target organ damage, as well as control other CVS risk factors.
There are three main treatment pathways
A. Non-pharmacological e.g. life-style modifications
B. Pharmacologically
C. Surgically (if secondary, e.g. Conn’s syndrome)
What we are interested in this lecture is essential hypertension, so we are going to try treat it non-pharmacologically and pharmacologically.
Non-Pharmacological Treatment – Lifestyle Changes
There are quite a few important life-style changes we can make to really help with hypertension, this is because you are removing/reducing these risk factors.
o Quit smoking – What help is there for someone who wants to quit?
o Weight control – Can you tell the patient what are high/low fat foods?
o Eat less salt – Can you tell the patient the high/low salt foods?
o Regular exercise – How much is enough for me?
o Reduce alcohol intake – What are the recommended levels
o Behavioural therapies – What is CBT?
It is very easy to read off lifestyle changes, so these questions posed are for helping a patient more in actually making them.
Pharmacological Treatment
what are the 5 major classes of anti-hypertensive drugs?
If someone came into the clinic you would first recommend the life-style changes, but if this isn’t really working/non-compliance, we may have to think of pharmacological intervention.
There are five major classes of Anti-Hypertensive Drugs
- ACE inhibitors
- Angiotensin II receptor blockers
- Diuretics
- Drugs acting on sympathetic nervous system
- Vasodilators
ACE Inhibitors and Ang II Receptor Blockers
How do these drugs work? what are theor effects?
How can this drug lead to hyperkalemia?
What is bradykinin? What effect do ace inhibitors have on this? How can angiodema come about?
When are these drugs contraindications?
What do you use if ace inhibitors dont work?
ACE inhibitors (such as enalapril and ramipril) and Ang II receptor (AT1) blockers (e.g. losartan, valsartan) are very useful drugs in treating/managing hypertension.
With an ACE inhibitor we are preventing the conversion of Ang I to Ang II, therefore Ang II means less binding of Ang II to the AT1 receptor, so you will get less vasoconstriction and less aldosterone secretion.
- A decrease in vasoconstriction means a decrease in TPR, while a decrease in aldosterone means a decrease in blood volume and hence CO. Together they link to form a drop in BP.
You could get the same end-result by using the AT1 blocker, by using the antagonistic drug.
There are side effects however of these drugs, especially as they will be given for life, these are important to be aware of.
o So ACE produces Ang II, without Ang II we don’t get aldosterone. Decreased aldosterone means decreased Na+ reabsorption via Na+/K+ ATPase pump, reduced ENaC (hence reduced electrical gradient favouring K+ secretion) and reduced permeability of the luminal membrane to K+, as a result we do not excrete as much K+ so we may get hyperkalemia, this can have dangerous effects on the heart, arrhythmias.
o ACE is also important for bradykinin breakdown, normally it breaks it down. Bradykinin is an inflammatory agent and one of the things it does is stimulate nerve fibres, so if you use an ACE inhibitor you will have less bradykinin breakdown and bradykinin levels will rise.
o More bradykinin means it can stimulate a cough reflex through stimulating the nerve fibres, a dry cough (side effects for ACE inhibitors are rare, but dry cough is common in the proportion of people who experience side effects).
o ACE inhibitors may also cause angioedema, as bradykinin levels go too high causing a lot of vasodilation and swelling.
Contraindications
ACE inhibitors are contraindicated in pregnancy because they cause fetal problems. They are also contraindicated in renal stenosis, this is because Ang II constricts the efferent arteriole which increases back pressure and increases GFR.
- So, if you block this effect in someone whose kidney has stenosis (and therefore low Pc) it prevents Ang II increasing/maintaining the GFR. This can lead to kidney failure.
Hence if ACE inhibitors can’t be used, we can move on to Ang II receptor blockers as these come with fewer side effects.
Diuretics
How do these reduce bp?
side effects? (3)
Diuretics such as loop diuretics, thiazides, K+-sparing etc. will all increase sodium and water excretion and hence reduce blood volume, reduce CVP, reduce CO and reduce BP.
The diuretics can also produce a vasodilation, which can reduce TPR and also reduce BP.
Major side effects however of diuretics include
o Hypokalemia (Loop and thiazide, but not K+ sparing)
o Lipid abnormalities
o Glucose intolerance/hyperglycemia, due to decreased insulin release (this is thought to be due to low K+ levels that change insulin secretion).
Therefore, there are issues with the long-term use of diuretics to control BP
Sympathetic Nerve Stimulation of CVS
what 2 primary things will sympathetic innervation result in? (2 key receptors)
to reduce bP we need to reduce sympathetic activity - how?
6 different drugs and names
We could also target the sympathetic nervous system. The sympathetic nerve activity will result in two primary things on the cardiovascular side.
- Stimulation of beta1 receptors on the heart will increase HR (chronotropic)and contractility (inotropic). This will increase CO and thus increase BP
- Stimulation of alpha1 receptors will vasoconstrict arterioles, which will increase TPR and increase BP (also increased venous return which also increase CO).
We want to reduce BP, so we could reduce sympathetic activity. We can do this by reducing sympathetic drive, how much sympathetic neurotransmission is occurring. We do this by drugs acting on the CNS itself, there are various drugs we can use:
A. CNS: alpha2 adrenoceptor agonists, alpha2 receptors are Gi receptors located on pre-synaptic membrane, binding to it will reduce release of NA (by decreasing Ca2+ influx) this means less binding to their receptors and less of their effects. An example is clonidine
B. Ganglion blockers: These are quite strong, you would use NIC blockers e.g. Trimethaphan (used in hypertensive crisis. If hypertension isn’t responding to other treatment)
C. Synaptic Blockade: Another way of stopping release, can use reserpine (which blocks packaging of NA/A into vesicles) to prevent release of NA/A. It is an old anti-hypertensive drug.
D. We can also use Adrenoceptor blockers
E. Alpha1 blockers: Blocking alpha1 receptors on the vascular smooth muscle, it will be unable to stimulate contraction and will result in relaxation of VSMCs, reduced tone, decreased TPR and decreased BP e.g. prazosin,
F. Beta1 blockers: Will prevent stimulation of beta1 receptors on heart so will result in a reduction in CO and reduce renin release (renin is stimulated by beta1 activity), this will reduce the RAAS system effects (vasoconstriction, increased blood volume). An example of a beta1 selective antagonist is atenolol
Vasodilators
what effect do they have on VSMC?
What causes VSMC contraction?
What effect will hyperpolarising the cell have? How do we do this? durgs?
what is a more common way of doing it? drugs?
what are side effects?
Vasodilators cause VSMCs to relax, VSMCs are in a circular orientation so a relaxation of these will cause an increase in diameter. Vessels have a level of tone, so we can give these drugs to produce vasodilation and reduce this tone.
We know that it is a rise in Ca2+ that causes VSMC contraction, these come in through the VGCCs. The Ca2+ enters and binds to calmodulin to form the Ca2+-CaL complex, this then activates MLCK.
MLCK can then phosphorylate the myosin light chains, enabling them to bind to actin and cause contraction via the cross-bridge cycle (troponin is in cardiac and skeletal muscle).
As said previously, we get this rise in Ca2+ primarily from influx from vgCa2+. These are activated when the cell gets depolarised.
If we hyperpolarise the membrane potential, then these vgCa2+ will not be activated and not open. So, we will not get the influx, lack of MLCK activity and instead MLCP will be the main force removing phosphates from the myosin light chains so we do not get contraction.
The way we can hyperpolarise the membrane is via K+ channel openers e.g. Minoxidil, Diazoxide. This would result in the following events:
- K+ channels open, K+ efflux
- VSMC hyperpolarization
- Reduction in vgCa2+ activity
- Reduction in [Ca2+]I
- Less MLCK activity, increased relaxation (as remember vessels usually sitting at a constant level of tone, so we are reducing this)
We can use these K+ channel openers, but there is a more common way. This is by using VDCa2+ channel blockers e.g. amlodipine.
These are drugs that are pore blockers, in particular we have the dihydropyridines, which block the L-type Ca2+ channels found on vascular smooth muscle.
Here we are not messing with the level of polarisation, it doesn’t matter if the cells are depolarised or not, the channel is blocked so Ca2+ cannot enter.
- This will lead to a reduction in [Ca2+]i¬ and thus decrease MLCK activity and more relaxation.
There can be side effects however such as headaches due to increased level of vasodilatation. Also, can get oedema due to venodilation leading to increased back pressure onto capillaries, increasing Pc. Also, you would get postural hypotension.
So which drugs do we use?
There are key issues we must consider in selecting the appropriate drug therapy for a patient
o Is it essential or secondary hypertension?
o What is the evidence of the efficacy of this/these drug(s)?
o What are the side effects of these drugs?
o Any drug interactions?
o Demographics (race considerations)
o Are there any co-existing diseases
o Quality of life?
o Economic considerations
All of this ultimately leads to a very complex situation, hence there are guidelines produce by NICE
Nice Guidelines
age?
drug?
what if drug doesnt work?
First need to decide if under 55 or over 55. If they are of black person of African or Caribbean origin of any age, they go into the same group as the over 55 category.
- If under 55, they have an ACE inhibitor or AT1 blocker
- If over 55 OR of black of any age, they will take a CCB
- If these don’t work, then they will also take the other one they are not taking
- If this still doesn’t work, then you give them a thiazide diuretic
- If still doesn’t work, the person has resistant hypertension and needs to be sent to a specialist. Could also give sympathetic blockers or further diuretics.
