SBP

The Management of Hypertension (Interventions)

September 17, 2015 Uncategorized No comments , , , , , ,

Overall Goals

The overall goal of treating hypertension is to reduce hypertension-associated morbidity and mortality. This morbidity and mortality is related to hypertension-associated target-organ damage (e.g., ASCVD, retinopathies, cerebrovascular events, heart disease, kidney disease, and PAD etc.). Reducing CV risk is the primary purpose of hypertension therapy and the specific choice of drug therapy should be determined by evidence demonstrating such CV risk reduction.

Above overall target should be interpreted more deeper. According to JNC 7 guideline, hypertension patients can be divided into two groups, one with compelling indications, most of which are CV diseases but not necessarily due to hypertension (e.g., non-hypertension associated CKD, DM), one without compelling indications. For patients without compelling indications (no existed CV diseases or CV diseases non-detectable), the therapy is to reduce the risk of hypertension-associated CV (primary prevention). For patients with compelling indications which are non-hypertension-associated, for example, hypertension plus diabetes or non-hypertension-associated CKD, the therapy is to reduce the risk of hypertension-associated CV (primary prevention) and to reduce the morbidity and mortality of the compelling condition. For patients with compelling indications which are hypertension-associated,  the therapy is to slow the progression of hypertension and existed CV diseases or secondary prevention (e.g., Post-MI).


BP Goals

Because elevated BP level is related to CV risk/risk of hypertension-associated target-organ damage, which whereas involved with morbidity and mortality of hypertension, to achieve a desire target BP value is simply a surrogate goal of therapy. For primary prevention, reducing BP to goal does not guarantee prevention of hypertension-associated target-organ damage, but is associated with a lower risk of hypertension-associated target-organ damage.

The latest JNC 8 hypertension guideline category hypertension patients into four groups, including

  • Patients without diabetes or CKD >=60 years of age
  • Patients without diabetes or CKD <60 years of age
  • Patients with diabetes but no CKD
  • Patients with CKD

Each category has its target BP goal, as shown in the Figure 1 below.

In the general population aged 60 years or older, initiate pharmacologic treatment to lower BP at systolic blood pressure (SBP) of 150 mm Hg or higher or diastolic blood pressure (DBP) of 90 mm Hg or higher and treat to a goal SBP lower than 150 mm Hg and goal DBP lower than 90 mm Hg (Strong recommendation – Grade A). In the general population aged 60 years or older, if pharmacologic treatment for high BP results in lower achieved SBP (for example, <140 mm Hg) and treatments is not associated with adverse effects on health or quality of life, treatment does not need to be adjusted (Expert opinion – Grade E).

In the general population younger than 60 years, initiate pharmacologic treatment to lower BP of 90 mm Hg or higher and treat to to a goal DBP of lower than 90 mm Hg (For ages 30 through 59 years, strong recommendation – Grade A; for ages 18 through 29 years, expert opinion – Grade E).

In the general population younger than 60 years, initiate pharmacologic treatment to lower BP at SBP of 140 mm Hg or higher and treat to a goal SBP of lower than 140 mm Hg (Expert opinion – Grade E).

For more information about the JNC 8’s BP goals please visit the American Medical Association at http://jama.jamanetwork.com/article.aspx?articleid=1791497.


General Approach to Treatment

Most patients should be placed on both lifestyle modifications and drug therapy concurrently after a diagnosis of hypertension is made. Life-style modification alone is appropriate for most patients with prehypertension. However, lifestyle modifications alone may not be adequate for patients with either additional CV risk factors (in so, not adequate to reduced the CV risk) or hypertension-associated target-organ damage (secondary prevention/slow the progression of existed hypertension-associated target-organ damage).

Besides hypertension, other major and additional CV risk factors should be avoided if possible (e.g., smoking). Major and additional risk factors can be found at http://www.tomhsiung.com/wordpress/2014/07/the-management-of-dyslipidemia/

Choice of Initial Drug Therapy

The choice of initial drug therapy depends on the degree of BP elevation and presence of compelling indications (HFrEF, Post-MI, CAD, DM, CKD, and Recurrent Stroke Prevention). Most patients with stage 1 hypertension should be initially treat with a first-line antihypertensive drug or the combination of two agents. Combination drug therapy is recommended for patients with more severe BP elevation (stage 2 hypertension), using preferably two first-line antihypertensive drug.

It is important to remember that the general goal to treat hypertension patients without compelling is to reduce the risk or slow the progress of hypertension-associated target organ damage.


Treatment

Nonpharmacologic Therapy

All patients with prehypertension and hypertension should be prescribed lifestyle modifications. Recommended modifications that have been shown to lower BP are list in Table 3-4. They can provide small to moderate reductions in SBP. Aside from lowering BP in patients with known hypertension, lifestyle modification can decrease the progression to hypertension in patients with prehypertension BP values.

Table 3-4 Lifestyle Modifications to Prevent and Manage Hypertension

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Pharmacotherapy – No Compelling Indications

First line antihypertensive agents include thiazide, ACEI, ARB, and CCB. They should be used to treat the majority of patients with hypertension because evidence from outcome data have demonstrated CV risk reduction benefits with these classes. As we discussed earlier, the overall goal of management of hypertension is to reduce hypertension-associated morbidity and mortality. This morbidity and mortality is related to hypertension-associated target-organ damage (e.g., CV events, retinopathies, cerebrovascular events, heart failure, kidney disease, and PAD etc.) and therefore reducing CV risk is the primary purpose of hypertension therapy and the specific choice of drug therapy should be determined by evidence demonstrating such CV risk reduction. So the efficacy (clinical outcome) of antihypertensive agents could be measured by comparing the reduction of the CV risk of each drug.

Evidence from ALLHAT trial showed that therapeutic arm of chlorthalidone, compared with lisinopril or amlodipine, respectively, are of no significant differences in the primary end point (fatal CHD and nonfatal MI). However, chlorthalidone had statistically fewer secondary end points than amlodipine (heart failure) and lisinopril (combined CV disease, heart failure, and stroke).

Figure 1 Patient Criteria for ALLHAT Trial 

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PS: Detail information for ALLHAT trail could be found at https://clinicaltrials.gov/ct2/show/study/NCT00000542?term=allhat&rank=3. Note that 36 percent of all patients enrolled were diabetics.

Clinical trial data cumulatively demonstrate that ACEI-, CCB-, or ARB-based antihypertensive therapy reduces CV events. These agents may be used for patients without compelling indications as a first-line therapy.

Clinical trial data cumulatively suggest that beta-blockers may not reduce CV events to the extent that ACEIs, ARBs, or thiazide diuretics do. Available data from meta-analyses demonstrated fewer reductions in CV events with beta-blocker-based antihypertensive therapy compared mostly with ACEI-, and CCB-based therapy. However, it is important for clinicians to remember that beta-blocker-based antihypertensive therapy does not increase risk of CV events; beta-blocker-based therapy reduces risk of CV event compared with no antihypertensive therapy. Using a beta-blocker as a primary antihypertensive agent is optimal when an ACEI, ARB, or thiazide diuretic cannot be used as the primary agent. Besides, beta-blocker still have an important add-on role after first-line agents to reduce BP in patients with hypertension but without compelling indications.

Pharmacotherapy – With Compelling Indications

The JNC 7 report identifies six compelling indications. Compelling indications represent specific comorbid conditions where evidence from clinical trials supports using specific antihypertensive classes to treat both the compelling indiction and hypertension. Drug therapy recommendations typically consist of combination drug therapies. Data from these clinical trials have demonstrated reduction in CV morbidity and/or mortality that justify use for patients with hypertension and with such a compelling indication.

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  • HFrEF (ACEI or ARB + Diuretic, then add Beta-Blocker. Aldosterone receptor antagonist is add-on therapy).

Five drug classes are list as compelling indications for HFrEF. An evidence-based pharmacotherapy regimen for HFrEF, sometimes called standard pharmacotherapy, consists of three to four drugs: an ACEI or ARB plus diuretic therapy, followed by the addition of an appropriate beta-blocker, and possibly an aldosterone receptor antagonist. Evidence from clinical trials shows that ACEIs significantly modify disease progression by reducing morbidity and mortality. Although HFrEF was the primary disease in these studies, ACEI therapy will also control BP in patient with HFrEF and hypertension. ARBs are acceptable as an alternative therapy for patients who cannot tolerate ACEIs based on data from the CHARM studies (https://clinicaltrials.gov/ct2/show/NCT00634309?term=assessment+of+reduction+in+mortality+and+morbidity&rank=1). An ACEI or ARB should be started with low doses for patients with HFrEF, especially those in acute exacerbation. Heart failure induces a compensatory high-rennin condition, and starting ACEI inhibitors or ARBs under these conditions can cause a pronounced first-dose effect and possible orthostatic hypotension.

Diuretics are also a part standard pharmacotherapy primarily to control symptoms. They provide symptomatic relief of edema by inducing diuresis. Loop diuretics are often needed, especially for patients with more advanced heart failure. However, some patients with well-controlled heart failure and without significant CKD may be managed with a thiazide diuretic.

Beta-blocker therapy is appropriate to further modify disease in HFrEF and is a component of standard therapy for these patients. For patients on an initial regimen of diuretics and ACEIs, beta-blockers have been shown to reduce CV morbidity and mortality. It is of paramount importance that beta-blockers be doses appropriately due to the risk of including an acute exacerbation of heart failure. They must be started in very low doses, does much lower than that used to treat hypertension, and titrated slowly to high doses based on tolerability. Bisoprolol, carvedilol, and sustained-release metoprolol succinate are the only beta-blockers proven to be beneficial in HFrEF.

After implementation of a standard three-drug regimen (diuretic, ACEI or ARB, and beta-blocker), other agents may be added to further reduce CV morbidity and mortality, and reduce BP if needed. The addition of an aldosterone antagonist can reduce CV morbidity and mortality in HFrEF. Spironolactone has been studied in severe HFrEF and has shown benefit in addition to diuretic and ACEI therapy.

  • Post-MI (Beta-Blocker, then add ACEI or ARB)

Beta-blockers (those without intrinsic sympathomimetic activity [ISA]) and ACEI inhibitor or ARB therapy are recommended in the AHA/ACC Foundation and JNC 7 guidelines. Beta-blockers decrease cardiac adrenergic stimulation and have been shown in clinical trials to reduce the risk of a subsequent MI or sudden cardiac death. ACEIs have been shown to improve cardiac remodeling and cardiac function and to reduce CV events post-MI. These two drug classes, with beta-blockers first, are considered the first drugs of choice for patients who have experienced an MI. One study, the VALIANT trial, demonstrated that ARB therapy is similar to ACEI therapy for patients post-MI heart failure and/or left ventricular systolic dysfunction.

  • Coronary Artery Disease (Beta-Blocker, then add ACEI or ARB. CCB or Thiazide Diuretic are add-on agents)

Beta-blocker therapy has been considered a standard of care for treating patients with coronary artery disease and hypertension. Beta-blockers are first-line therapy in chronic stable angina and have the ability to reduce BP and improve ischemic symptoms by decreasing myocardial oxygen consumption and demand. Beta-blockers therapy seems to be most effective in reducing the risk of CV events in patients with recent MI and/or ischemic symptoms. Long-acting CCBs may considered alternatives to beta-blockers (diltiazem and verapamil) or as add-on therapy (dihydropyridine CCBs) in chronic stable angina for patients with ischemic symptoms.

For acute coronary syndromes, first-line therapy should consist of a beta-blocker and ACEI. An ARB is a reasonable alternative to an ACEI.

  • Diabetes Mellitus (ACEI or ARB, CCB, Thiazide Diuretic, or Beta-Blocker might be add-on agents)

All patients with diabetes and hypertension should ideally be treated with an ACEI or an ARB. The reason is that, pharmacologically, both of these agents should provide nephroprotection due to vasodilation in the efferent arteriole of the kidney. CCBs are the most appropriate add-on agents for BP control for patients with diabetes.

  • CKD (ACEI or ARB)

Patients with hypertension may develop damage to either the renal tissue or the renal arteries. The rate of kidney function deterioration is accelerated when both hypertension and diabetes are present. Once patients have an estimated GFR <60 mL/min/1.73 m2 or albuminuria, they have significant CKD and risk of CV disease and progression to severe CKD increases. BP Control can slow the decline in kidney function.

In addition to lowering BP, ACEIs and ARBs reduce intraglomerular pressure, which can theoretically provide additional benefits by further reducing the decline in kidney function. ACEIs and ARBs have been shown to reduce progression of CKD in diabetes and in those without diabetes. However, it is difficult to differentiate whether the kidney protection benefits are from RAAS blockade versus BP lowering.

  • Recurrent Stroke Prevention (Thiazide with/without ACEI)

Ischemic stroke (not hemorrhagic stroke) and transient ischemic attack are considered a form of hypertension-associated target-organ damage. Attaining goal BP values in patients who have experienced an ischemic stroke is considered a primary modality to reduce risk of a second stroke. A thiazide diuretic, either in combination with an ACEI or as monotherapy, is considered an evidence-based antihypertensive regimen for patients with a history of stroke or transient ischemic attack. Antihypertensive drug therapy should only be implemented after patients have stabilized following an acute cerebrovascular event.

Combination Therapy

Initial therapy with a combination of two drugs is highly recommended for patients with stage 2 hypertension and is an option of retreating patients with stage 1 hypertension. Also initial two-drug combination therapy may be appropriate for patients with multiple compelling indications for different antihypertensive agents. Clinicians should anticipate the need for combination drug to control BP in most patients. Besides, using low-dose combinations provides greater reductions in BP compared with high doses of single agents and appropriately increasing the number of antihypertensive medications to attain goal BP values does not increase the risk of adverse effects.

The Management of Hypertension (Pathophysiologic Basises)

September 10, 2015 Cardiology, Pharmacology, Physiology and Pathophysiology No comments , , , , , , , , , , ,

Hypertension is a common diseases and is defined as persistently elevated arterial blood pressure of >= 140/90 mm Hg. Most of patients belong to essential hypertension and a small percentage belong to secondary hypertension for which the most common causes include renal dysfunction resulting from severe chronic kidney disease (CKD) or renovascular disease. Besides, certain drugs or other products (Table 3-1), either directly or indirectly, can cause hypertension or exacerbate hypertension by increase BP.

Table 3-1 Secondary Causes for Hypertesnion

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Classification of Hypertension

  • Normal: Systolic lower than 120 mm Hg, diastolic lower than 80 mm Hg
  • Prehypertension: Systolic 120-139 mm Hg, diastolic 80-89 mm Hg
  • Stage 1: Systolic 140-159 mm Hg, diastolic 90-99 mm Hg
  • Stage 2: Systolic 160 mm Hg or greater, diastolic 100 mm Hg or greater

Hypertension Crisis: These are clinical situations where BP values are very elevated, typically >180/120 mm Hg. They are categorized as either hypertensive emergency or hypertensive urgency. The former are extreme elevations in BP that are accompanied by acute or processing target-organ damage. The latter are high elevations in BP without acute or progressing target-organ injury. Prehypertension is not considered a disease category but identifies patients whose BP is likely to increase into the classification of hypertension in the future.

Cardiovascular Risk and Blood Pressure

Hypertension must be treated and the reason why is that hypertension is a major cardiovascular risk factor and there indeed is a causal relationship between hypertension and cardiovascular diseases. Also, epidemiologic data demonstrate a strong correlation between BP and CV morbidity and mortality. (Starting at a BP of 115/75 mm Hg, risk of CV disease doubles with every 20/10 mm Hg increase.) Even patients with prehypertension have an increased risk of CV disease. Because hypertension and CV morbidity/mortality has a casual relationship, treating patients with hypertension with antihypertensive drug therapy provides significant clinical benefits.


Pathophysiology

To further discuss the pathophysiology, we first need to know the mathematic formula to estimate arterial BP. According to the physic law, steady flow (Q) through a closed hydraulic circuit is directly related to the pressure gradient across the circuit (Pin – Pout), and inversely related to the resistance to flow (R) through the circuit. So Q=(Pin – Pout)/R. In the cardiovascular system, Q is cardiac output (CO), Pin is mean arterial pressure (MAP) and Pout is right atrial pressure (RAP), whereas resistance to flow (R) is total peripheral resistance (TPR). So CO=(MAP – RAP)/TPR. Because in normal conditions RAP approaches zero mm Hg, so CO=MAP/TPR and after we make a rearrange we finally get the formula of MAP=CO * TPR. Note that in some pathophysiology status RAP increases significantly and cannot be removed from the formula above.

After the discuss above, the two determinants for MAP is the cardiac output (CO) and the total peripheral resistance (TPR). If we distinguish MAP to systolic BP (SBP) and diastolic BP (DPB), CO is the major determinant of SBP, whereas TPR largely determines DBP. So factors that elevate CO or TPR can elevate BP. We category these factors into 1.humoral; 2.neuronal; 3.peripheral autoregulation; and 4.disturbances in sodium, calcium, and natriuretic hormone.

Humoral Mechanisms

RAAS

RAAS stands for the rennin-angiotensin-aldosterone system, which is a complex endogenous system that play a range of functions including the regulation of arterial pressure. The RAAS regulars sodium, potassium, blood volume, and most important the vascular tone. Because the total periphery resistance (TPR) is primarily generated by arterioles, so elevated TPR could be a result of activation of RAAS – the angiotensin II (angII). For the detail discussion of TPR please refer to the threads of http://www.tomhsiung.com/wordpress/2015/06/flow-resistance-of-vessels-in-series-and-vessels-in-parallel/ and http://www.tomhsiung.com/wordpress/2015/07/vascular-resistances-and-compliance-map-and-pulse-pressure/, respectively, by Tom Hsiung. First, angII increase the vascular tone, including arterioles. Second, angII induced increased aldosterone synthesis and secretion sodium and water retention, which increase the blood volume. Increased blood volume and TPR eventually result in elevation of BP.

Vasopressin

Vasopressin is a polypeptide hormone, also known as antidiuretic hormone/ADH, which plays an important role in extracellular fluid homeostasis (blood volume/plasma volume). Vasopressin acts on collecting ducts in the kidneys to decrease renal excretion of water. This is the most important and wide-known function of vasopressin. However, vasopressin is also a potent arteriolar vasoconstrictor.

Natriuretic Hormone

Natriuretic hormones inhibits sodium and potassium-ATPase and thus interferes with sodium transport across cell membranes. Natriuretic hormone theoretically could increase urinary exertion of sodium and water. However, this hormone might block the active transport of sodium out of arteriolar smooth muscle cells. The increased intracellular sodium concentration concentration ultimately would increase vascular tone and BP.

Insulin Resistance and Hyperinsulinemia

Hypothetically, increased insulin concentrations may lead to hypertension because of increased renal sodium retention and enhanced sympathetic nervous system activity. Moreover, insulin has growth hormone-like actions that can induce hypertrophy of vascular smooth muscle cells. Insulin also may elevated BP by increasing intracellular calcium, which lead to increased vascular resistance. The exact mechanism by which insulin resistance and hyperinsulinemia occur in hypertension is unknown. However, this association is strong because many of the criteria used to define this population (i.e., elevated BP, abdominal obesity, high, triglycerides, low high-density lipoprotein cholesterol, and elevated fasting glucose) are often present in patients with hypertension.

Circulating Catecholamines

It is easy to understand the causal relationship between elevated levels of circulating catecholamines and the hypertension, from the perspective of MAP = CO * TPR.

Neuronal Regulation

Synaptic receptors, baroreceptor reflex system, and CNS are involved in the regulation of vascular resistances, cardiac outputs.

Central and autonomic nervous system are intricately involved in the regulation of arterial BP. Many receptors that either enhance or inhibit norepinephrine release are located on the presynaptic surface of sympathetic terminals. The alpha and beta presynaptic receptors play a role in negative and positive feedback to the norepinephrine-containing vesicles, respectively. Stimulation presynaptic alpha-receptors (α2) exerted a negative inhibition on norepinephrine release. Stimulation of presynaptic beta-receptors facilitates norepinephrine release.

Sympathetic neuronal fibers located on the surface of effector cells innervate the alpha- and beta-receptors. Stimulation of postsynaptic alpha-receptors (α1) on arterioles and venues results in vasoconstriction. There are two types of postsynaptic beta-receptors, β1 and β2. Both are present in all tissues innervated by the sympathetic nervous system. However, in some tissues β1-receptors predominate (e.g., heart), and in other tissues β2-receptors predominate (e.g., bronchioles). Stimulation of β1-receptors in the heart results in an increase in heart rate, and the force of contraction (so cardiac output is increased), whereas stimulation of β2-receptors in the arterioles and venues causes vasodilation.

So after the discussion of the two paragraph above, we know that the disturbance of the function of presynaptic and/or postsynaptic receptors would result the imbalance of autonomic nervous system.

Same with the autonomic nervous system but from a different aspect (above is output of autonomic nervous system and now it’s the input of nervous system),  the baroreceptor reflex system is the major negative feedback mechanism the controls sympathetic activity. Baroreceptors are nerve endings lying in the walls of large arteries, especially in the carotid arteries and aortic arch. Changes in arterial BP rapid activate baroreceptors that then transmit impulses to the brain stem through the ninth cranial nerve and vagus nerve. In this reflex system, a decrease in arterial BP stimulates baroreceptors, causing reflex vasoconstriction and increased heart rate and force of cardiac contraction. Also the periphery vascular tone increase too (TPR).

Stimulation of certain areas within the central nervous system can either increase or decrease BP. I think this mechanism must be rather complex, which involves with neurology. If we have time in future, I will take a look at the neurology.

OK. The purpose of the neuronal mechanisms is to regulate BP and maintain homeostasis. Pathologic disturbances in neuronal systems could chronically elevate BP. These systems are physiologically interrelated. A defect in one component may alter normal function in another. Therefore, cumulative abnormalities may explain the development of essential hypertension.

Peripheral/Local Mechanisms (including autoregulatory, etc.) 

Abnormalities in renal or tissue autoregulatory systems, which is just one of several local vascular regulatory mechanisms of human, could cause hypertension. Recall the formula that MAP = CO * TPR. Similarly, the disorders of local vascular regulatory .For detail information of local vascular regulatory mechanisms please refer to the thread of http://www.tomhsiung.com/wordpress/2015/07/arteriolar-tone-and-its-regulation-local-mechanisms/ by Tom Hsiung.

Electrolytes

Epidemiologic and clinical data have associated excess sodium intake with hypertension. Population-based studies indicate that high-sodium diets are associated with a high prevalence of stroke and hypertension. Conversely, low-sodium diets are associated with a lower prevalence of hypertension. For the perspective of pathophysiology, more sodium, more water. We will discuss this phenomenon in threads that discuss the kidney.

Altered calcium homeostasis also may play an important role in the pathogenesis of hypertension. A lack of dietary calcium hypothetically can disturb the balance between intracellular and extracellular calcium, resulting in an increased intracellular calcium concentration. This imbalance can alter vascular smooth muscle function by increasing PVR (peripheral vascular resistance). Some studies have shown that dietary calcium supplementation results in a modest BP reduction for patients with hypertension.

The role of potassium fluctuations is also inadequately understood. Potassium depletion may increase PVR, but the clinical significance of small serum potassium concentration changes is unclear. Furthermore, data demonstrating reduced CV risk with dietary potassium supplementation are very limited.