Case, Hypertension, From Course of Pharmacotherapy

[Janis.Y.Chen]

Mr. Li, 57 years of age, seeded to medical help because of fatigue, diuresis, and thirsty. He has a history of hypertension of 10 years.

Physical exam results:

BP: 154/96 mm Hg
HR: 88 ppm
Temperature: 37.4 C
Respiratory rhythm: 20/minute

Body weight: 90 kg
Height: 173 cm
BMI: 30.1

Lab parameters:

Serum sodium: 140 mmol/L
Serum potassium: 4.5 mmol/L
Serum chloride: 100 mmol/L
Serum HCO3: 30 mmol/L

Blood urine nitrogen: 7.6 mmol/L (21.29 mg/dL)
Serum creatinine: 167 umol/L (1.89 mg/dL)

Fasting plasma glucose: 18.9 mmol/L (340.54 mg/dL)
A1c: 10%

Urinary glucose: (++)
Urinary ketones (-)
Urinary protein (-)

Current Rx:

Hydrochlorothiazide 25 mg Qd
Enalapril 5 mg Bid

[admin]

Question 1 What is the clinical presentation of Mr. Li?

Mr. Li, 57 years of age, seeded to medical help because of fatigue, diuresis, and thirsty. He has a history of hypertension of 10 years.

Physical exam results:

BP: 154/96 mm Hg
HR: 88 ppm
Temperature: 37.4 C
Respiratory rhythm: 20/minute

Body weight: 90 kg
Height: 173 cm
BMI: 30.1

Lab parameters:

Serum sodium: 140 mmol/L
Serum potassium: 4.5 mmol/L
Serum chloride: 100 mmol/L
Serum HCO3: 30 mmol/L

Blood urine nitrogen: 7.6 mmol/L (21.29 mg/dL)
Serum creatinine: 167 umol/L (1.89 mg/dL)

Fasting plasma glucose: 18.9 mmol/L (340.54 mg/dL)
A1c: 10%

Urinary glucose: (++)
Urinary ketones (-)
Urinary protein (-)

Current Rx:

Hydrochlorothiazide 25 mg Qd
Enalapril 5 mg Bid

General Considerations

The major discomfort that this patient face are fatigue and diuresis, and thirst. Fatigue is a non-specific symptom, whereas diuresis maybe due to the diuretics of hydrochlorothiazide and urinary glucose of (++). But more discussion are needed to talk. Because the patient felt thirst, so we need to take a look at the serum osmolality. According to the physiology, serum osmolality could be calculated with the following formula:

Osm = 2*[Na⁺] + [Glucose]/18 + BUN/2.8= 2*140 mEq/L + 340.54 mg/dL /18 + 21.29 mg/dL /2.8 = 280 + 18.92 + 7.60 = 306.52 mOsm/kg. So the reason the patient felt thist is because of the elevated serum osmolality. In additional, patient lost ECF (external cellular fluids) due to diuresis (both hydrochlorothiazide and urinary glucose), so the volume of ECF is compromised (any relative findings of signs via physical examination like, dry lips, etc.) and compromised ECF stimulate the CNS to generate feeling of thirst via RAAS. Despite the ACEI of enalapril, drugs that block the action of angII do not completely block the thirst response to hypovolemia.

PS: Normal range of serum osmolality is between 275 to 290 most/kg.

Mr. Li has a history of hypertension for 10 years, with antihypertension of hydrochlorothiazide 25 mg Qd plus enalapril 5 mg Bid. The control of his BP was not good because the latest BP measured was 154/96 mm Hg. He has stage 1 hypertension.

[admin]

According to Mr. Li's clinical presentation, we cannot exclude secondary hypertension. But it looks that Li's renal function is severely compromised. According to Li's information, Li could be secondary hypertension caused by CKD, or Li could be essential hypertension with hypertension-associated complication (CKD).

Pathophysiological mechanism for hypertension are below (References: Tom "Prophet" Hsiung / The Management of Hypertension (Pathophysiologic Basises)):

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 Tom "Prophet" Hsiung / Flow Resistance of Vessels in Series and Vessels in Parallel and Tom "Prophet" Hsiung / 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 Tom "Prophet" Hsiung / 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.

[admin]

Probable but cannot be assured because clinical presentation are limited. CKD is present but patient history only refer to the history of hypertension, no related information about renal function.

A comprehensive physical examination and regular laboratory tests should be performed to identify or rule out the secondary causes for hypertension.

Common secondary causes for hypertension are shown below.

[admin]

If Li belongs to essential hypertension, he indeed has hypertension-associated complications. Furthermore, A complete physical examination to evaluate hypertension-associated complications includes examination of the optic funds; auscultation for carotid, abdominal, and femoral bruits; palpation of the thyroid gland; heart and lung examination; abdominal examination for enlarged kidney, masses, and abnormal aortic pulsation; lower extremity palpation for edema and pulses; and neurologic assessment. Routine laboratory assessment after diagnosis should include the following: EKG; urinalysis; fasting glucose; hematocrit; serum potassium, creatinine, and calcium; and fasting lipid panel. Optional testing may include measurement of urinary albumin excretion or albumin-to-creatinine ratio, or additional tests specific for secondary causes if suspected.

Li's renal function is compromised, with a estimated GFR of 39 mL/min/1.73 m². So Li's has stage 3 CKD. If Li's has other hypertension-associated complication cannot be certain because the patient history, physical examination, and laboratory tests are limited.

[admin]

Hypertension adversely affects many organ systems, including the heart, brain, kidneys, peripheral circulation, and eyes (Table 14-5). Damage to these systems resulting from hypertension is termed hypertension-associated complications, target-organ damage, or CV disease. There are often misconceptions about the term CV disease and CAD. CV disease encompasses the broad scope of all forms of hypertension-associated complications. CAD is simply a subset of CV disease and refers specifically to disease related to the coronary vasculature, including ischemic heart disease and MI.


Hypertension can affect the heart either indirectly, by promoting atherosclerotic changes, or directly, via pressure-related effects. Hypertension can promote CV disease and increase the risk for ischemic events, such as angina and MI. Antihypertensive therapy has been shown to reduce the risk of these coronary events. Hypertension also promotes the development of LVH, which is a myocardial (cellular) change, not an arterial change. These two conditions often coexist, however. It is commonly believed that LVH is a compensatory mechanism of the heart in response to the increased resistance caused by elevated BP (more accurately, the afterload). Recall the definition of afterload, that is, wall tension=(pressure * radius)/(wall thickness). LVH is a strong and independent risk factor for CAD, left ventricular dysfunction, and arrhythmia. LVH does not indicate the presence of left ventricular dysfunction, but is a risk for progression to left ventricular dysfunction, which is considered a hypertension-associated complication. This may be caused by ischemia, excessive LVH, or pressure overload. Ultimately, left ventricular dysfunction results in a decrease ability to contract (systolic dysfunction).

Hypertension is one of the most frequent causes of cerebrovascular disease. Cerebrovascular signs can manifest as transient ischemic attacks, ischemic strokes, multiple cerebral infarcts, and hemorrhages. Residual functional deficits caused by stroke are among the most devastating forms of hypertension-associated complications. Clinical trials have demonstrated that antihypertensive therapy can significantly reduce the risk of both initial and recurrent stroke. A sudden, prolonged increase in BP also can cause hypertensive encephalopathy, which is classified as a hypertensive emergency.

Peripheral arterial disease, a non coronary form of atherosclerotic vascular disease, is considered a hypertension-associated complication. It is equivalent in CV risk to CHD. Risk factor reduction, BP control, and anti platelet agent(s) are needed to decrease progression. Complications of peripheral arterial disease can include infection and necrosis, which in some cases require revascularization procedures or extremity amputation.

Hypertension causes retinopathies that can progress to blindness. Retinopathy is evaluated according to the Keith, Wagener, and Barker funduscopic classification system. Grade 1 is characterized by narrowing of the arterial diameter, indicating vasoconstriction. Arteriovenous nicking is the hallmark of grade 2, indicating atherosclerosis. Longstanding, untreated hypertension can cause cotton wool exudates and flame hemorrhages (grade 3). In severe cases, papilledema occurs, and this is classified as grade 4.

[admin]

As shown in Table 14-5, major CV risk factors include advanced age (>55 years for men, >65 years for women), cigarette smoking, diabetes mellitus, dyslipidemia, family history of premature atherosclerotic vascular disease (men <55 years or women <65 years) in primary relatives, hypertension, kidney disease (microablubuminuria or estimated GFR <60 mL/min/1.73 m2), obesity (BMI >=30 kg/m2), and physical inactivity.

So Li has:

Advanced age
Diabetes mellitus
Hypertension
Kidney disease
Obesity

If Li has are not known because of limited patient data:

Cigarette smoking?
Dyslipidemia?
Family history of premature atherosclerotic vascular disease in primary relatives?
Physical inactivity?

[admin]

According to the JNC8 Guideline from NIH, Li's BP goal should be 140/90 mm Hg.




For Framingham risk score, there are limited patient information so no risk score could be generated.