SECTION 9
Hypertension 50.
Perioperative Management of Hypertension Giridhari Kar
273
51.
Pathophysiology of Renin, RAAS and CCB in Management of Hypertension Narsingh Verma, Anuj Maheshwari, Mayank Agrawal
279
52.
Clinical Approch to the Patient of Hypertesion with Diabetes Mallitus Surendra Daga
284
53.
Current Standards of Management of Hypertension in Chronic Kidney Disease Vivekanand Jha
287
54.
DEAN'S ORATION Hypertension in India-The Way Forward A Muruganathan
293
55.
Management of Hypertension in Co-morbid Conditions Ketan K Mehta
299
C H A P T E R
50
Perioperative Management of Hypertension
ABSTRACT
Perioperative hypertension is a largely unnoticed major public health problem frequently encountered in clinical practice. Despite the large number of studies, which have demonstrated an increased perioperative morbidity and mortality in hypertensive patients, there remains a lack of consensus guidelines regarding the perioperative management of hypertension creating a major challenge for the physicians, anesthetists and surgeons. This issue mandates discussion and this paper reviews the accepted ideas in the general practice and the supporting various studies in regard to the preoperative evaluation, risk stratification and therapeutic management of perioperative hypertension.
INTRODUCTION
Hypertension, defined as blood pressure readings greater than 140/90 mmHg is one of the most common chronic medical condition affecting 1billion individuals worldwide with the incidence increasing with age. In 2000, 26.4% of the world adult population had hypertension with 26.6% men and 26.1% women. The projected score of 29.2% in 2025 is probably underestimated considering the rapid change in lifestyle and a concurrent increase in the risk of hypertension.1 Survey over the past one to two decades has found the prevalence in increasing trend in the developing countries. Epidemiological studies from India has shown that hypertension prevalence has stabilized in urban population to about 25-30% but has increased in rural population from 15 to 25%.2 Treatment of hypertension is essential as it is a well known risk factor for chronic adverse debilities such as cardiovascular diseases, renal diseases and stroke. As the duration and severity of hypertension increases there is a proportionate increase in the degree of end-organ damage and morbidity and mortality.
PERIOPERATIVE HYPERTENSION
Hypertension is a major clinical problem in the management of patients undergoing surgery. Frequent cancellation and postponement of planned surgery due to poor control of hypertension is a major public health problem which largely goes unnoticed. Numerous studies have demonstrated an increase in perioperative morbidity and mortality with chronic hypertension but there is a lack of literature and nationally accepted guidelines creating a major challenge for the physicians and anesthetists in the preoperative evaluation and management of patients with hypertension. Perioperative refers to the time of hospitalization
Giridhari Kar
directly related to a surgical procedure and includes the preoperative, intraoperative and postoperative (ie,3 or 4 days post) periods.3 Perioperative rise in blood pressure occurs in 25% of patients undergoing surgery4,5 increasing the complications and mortality following a wide range of surgical procedures. Both normotensive or pre-existing hypertensive patients are likely to develop elevated blood pressure and tachycardia during induction of anesthesia in surgery.7 Hypertension was found to be the second most common risk factor for surgical morbidity by The National Veterans Administration Surgical Risk Study in 83,000 patients8 further confirmed by various other studies. A meta-analysis of 30 observational studies and extensive literature review by Howell et al. reported an odds ratio of 1.35 (95% CI 1.17-1.56) times higher perioperative cardiac complications in hypertensive patients compared to normotensives.9 Prys-Roberts et al. and Goldman and Caldera et al. have demonstrated an increase in arrhythmias and postoperative myocardial ischemia in hypertensive patients in the early 1970s.4,5 Aronson and colleagues have demonstrated a 30% increase in adverse outcome risk in patients with Isolated systolic hypertension undergoing cardiac surgery.10 Fontes et al. demonstrated increased pulse pressure as an independent risk factor associated with increased incidence of postoperative neurological complications and cardiac failure.11 Perioperative hypertension may occur during airway instrumentation and induction of anesthesia, intraoperatively or in the early postoperative period secondary to sympathetic stimulation due to pain, hypothermia, hypoxia, bladder distension and/or volume overload either due to intraoperative excessive fluid therapy or postoperative mobilization of fluid from the extravascular space. The incidence of postoperative hypertension varies from 4% to 30% following cardiac or noncardiac surgery.12 Hypertensive events are common with carotid or abdominal aortic surgery, peripheral vascular surgery and intraperitoneal or intrathoracic surgeries.4 Hypertensive patients are also prone for hypotension resulting in myocardial or cerebral ischemia due to reduced systemic vascular resistance soon after induction of anesthesia or significant fluid depletion during surgery due to their labile hemodynamics.13 This has led the anesthetists to adopt few techniques to achieve a more stable hemodynamics which includes invasive arterial pressure monitoring with titrated or prophylactic vasopressors, monitoring depth of anesthesia and
274
optimisation of stroke volume with intravascular fluid therapy.
MANAGEMENT OF ANESTHESIA FOR HYPERTENSIVE PATIENTS
HYPERTENSION
Preoperative evaluation •
Adequacy of blood pressure control
•
Review of antihypertensive drugs patient is receiving
•
Continuation of the antihypertensive drugs
•
Evidence of end-organ damage
Induction and maintenance of anesthesia •
Anticipation of hypotension to anesthetic drugs
•
Limit duration of direct laryngoscopy
•
Balanced anesthesia responses
•
Invasive hemodynamic monitors
•
Monitoring for myocardial ischemia
to
blunt
hypertensive
Postoperative management •
Anticipation of periods of systemic hypertension
•
Continuous monitoring of end-organ function
PREOPERATIVE HYPERTENSION & EVALUATION
Diastolic blood pressure more than 110 mmHg is suggested as a preoperative marker of perioperative cardiac complications in patients with chronic hypertension.5 Browner et al reported an increased odds ratio for postoperative death to 3.8 times in preoperative hypertensives who underwent noncardiac surgery(14). Forrest et al. showed an association of perioperative bradycardia, tachycardia and hypertension with preoperative hypertension.15 Mangano et al. and Wolfsthal et al. have demonstrated that controlled preoperative hypertension are comparatively associated with lower risk of intraoperative BP elevations.16,17 Following points are to be considered in preoperative evaluation of hypertensive patients 1.
Newly diagnosed or known hypertensive ?
2.
Whether Primary or secondary hypertension ?
3.
White coat hypertension or sustained hypertension?
4.
Severity of hypertension and end organ damage?
5.
What Antihypertensive Drug therapy the patient is on ?
The preoperative assessment provides an opportunity to identify longstanding undiagnosed hypertensive patients as hypertension per se is generally asymptomatic in most patients. Diastolic hypertension <110 mmHg is not considered as a contraindication for postponement of surgery. Observations suggest that stage 1 & 2 hypertension without evidence of end organ damage is not an independent risk factor for perioperative cardiovascular complications, hence patients may go
for surgery without delay. However, surgery may be postponed for patients with stage 3 hypertension (SBP >180 and/or DBP >110 mmHg) until the blood pressure is adequately controlled. Isolated systolic hypertension (SBP>140 mmHg ; DBP< 90 mmHg) common in elderly is an independent risk factor for postoperative Silent myocardial infarction (SMI) as shown by Howell et al.8 With the above-discussed recommendations applicable for elective surgery, if clinical conditions necessitate for emergency surgery, the patient may be taken for surgery with adequately controlled blood pressure using the short-acting parenteral antihypertensive therapy. Patients with secondary hypertension require further diagnostic evaluation by the suggested approach methods prior to elective surgery to rule out renal, endocrine or other causes according to the age. White coat hypertension, defined as an office/preoperative blood pressure >140/90 mmHg with an average daytime reading < 135/85 mmHg is a frequent misconception which occurs due to stress induced sympathetic stimulation.18 Yet treatment is justified since an association with increased incidence of SMI is observed.19 A review of patient’s antihypertensive medications is necessary for specific considerations with each group. Anti-hypertensive therapy is generally continued up until the day of surgery. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARBs) are notable exceptions because they blunt the compensatory activation of renin-angiotensin-aldosterone system during surgery resulting in prolonged hypotension, hence recommended to hold them the day before surgery.20,21 Chronic diuretic therapy requires special attention to arrhythmia because of hypokalemia and intraoperative hypovolemia, hence avoided on the day of surgery. Abrupt withdrawal of beta blockers and clonidine may cause rebound hypertension with adverse perioperative events which may be prevented and continued perioperatively by supplementing with parenteral therapy or clonidine patch. Clonidine reduces the risk of myocardial ischemia by providing hemodynamic stability and reducing sympathoadrenal activity. Patients with hypertension and coronary heart disease should continue with beta blockers as it is associated with favorable outcome in perioperative myocardial ischemia and reduced risk of death after coronary artery bypass surgery.22 β-blockers also provide hemodynamic stability and interactions are well tolerated with both regional and general anesthesia. Goldman cardiac risk index was the first original cardiac risk index developed by Goldman et al. in 1977 for cardiac risk stratification for non-cardiac surgery. Later in 1999, Lee et al. published a revised cardiac risk index (RCRI) using six independent variables which is easier to use and more accurate and extensively validated (Table 1).23
INTRAOPERATIVE HYPERTENSION
Acute intraoperative blood pressure elevations of >20%,
Table 1: Revised Cardiac Risk Index
No. of Variables
Risk of Major Postoperative Cardiac Complication
0
0.4%
1
0.9%
2
7.0%
≥3
11.0% High risk
more likely in chronic hypertensives are considered a hypertensive emergency.24 Intraoperative hypertensive events are more common in vascular surgeries.12 Perioperative hypertension management in patients undergoing cardiac surgery represents a unique pathophysiological situation characterized by peripheral vasoconstriction and reduced baroreceptor sensitivity.25 The presence of pre-existing left ventricular dysfunction or coronary heart disease is a risk factor for myocardial ischemia or heart failure.26
ACUTE POSTOPERATIVE HYPERTENSION(APH)
APH is defined as significant elevation of blood pressure in the immediate postoperative period. Although no standardized definition exists to define APH, an increase of SBP by >20% or DBP >110 mm Hg are considered to be indicative of treatment in non-cardiac surgery and BP >140/90 mmHg or a mean arterial pressure >105 mmHg for treatment with meticulous BP control in cardiac surgery patients.27,28 APH is more commonly encountered with cardiothoracic, vascular, head and neck and neurosurgical procedures.27 APH usually occurs in the initial 20minutes of postoperative period and may last up to 4 hours.29 Untreated postoperative hypertension is associated with an increased risk of cardiovascular, neurologic or surgical site complication.24 The ECLIPSE trial study has demonstrated a significant association of 30-day mortality with SBP variability outside a range of 75 – 135 mmHg intraoperatively and 85 – 145 mmHg pre and postoperatively.30 Rose et al. found that higher risk of APH is associated with patients presenting with intraoperative hypertension, excessive pain or inadequate ventilation.31 Blood pressure in APH should be decreased gradually over 30 – 60 mins by not more than 25% or to a target value <180/110 mmHg.18 Prior to start of treatment, attention should be given to the reversible causes as mentioned earlier, assessment of volume status and appropriate analgesia and sedation. Postoperative rebound
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PHARMACOTHERAPY
A drug which is rapid in action, predictable and easily titrated, convenient, safe and inexpensive forms an ideal agent for treatment of hypertensive emergencies. Varieties of drugs with distinct advantages and disadvantages are available, their selection being dependent on the patient’s clinical picture. The commonly used drugs are listed in Table 2.
LABETALOL
A combined selective α1 and nonselective β-adrenergic receptor blocker, administered either as IV bolus or continuous infusion has been used for pregnancy-induced hypertension crisis. Labetalol reduces the systemic vascular resistance without compromising the peripheral and visceral blood flow. Heart rate is either maintained or slightly reduced due to its β-blocking effect but the cardiac output is maintained in contrary to the pure β-adrenergic blocking agents which decrease it.31-35 Labetalol is safe and effective for APH following cardiovascular, intracranial and general surgeries with reported 85-100% response rates.36 Labetalol is avoided and caution to be exercised in patients with severe sinus bradycardia, asthma, heart blocks greater than first degree and heart failure.37
ESMOLOL
An ultra-short acting cardioselective β-adrenergic blocker with no vasodilatory action, an ideal agent for hypertensive patients with tachycardia and increased cardiac output is especially useful in severe postoperative hypertension. Because of its RBC dependent metabolism, it has the advantage of safety in renal or hepatic dysfunction but anemia may prolong its half-life and hypotensive action. Esmolol is contraindicated in patients already on β-blockers, with bradycardia and decompensated heart failure according to American College of Cardiology(ACC) /American Heart Association(AHA) guidelines as it may compromise myocardial function and to be used with caution in chronic obstructive pulmonary disease due to bronchospasm.37
ENALAPRILAT
An ACE inhibitor administered as IV bolus with demonstrated efficacy in hypertensive patients with congestive heart failure and prevention of worsening renal function in diabetic and non-diabetic nephropathy. Advantages include lack of reflex tachycardia and effect on intracranial pressure, reported to be effective in patients undergoing craniotomy.38 Difficulties in dose titration due to delayed onset and peak with long duration of action makes enalaprilat a poor choice for use in hypertensive emergency, yet used for management of postoperative hypertension in combination with easily titrable fast acting drugs such as labetalol or nicardipine.36
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Lee Variables 1 High-risk type of surgery 2 Ischemic heart disease (includes any of the following: history of myocardial infarction; history of positive exercise test; current complaint of chest pain that is considered to be secondary to myocardial ischemia; use of nitrate therapy; electrocardiography with pathologic Q waves) 3 Congestive heart failure 4 History of cerebrovascular disease 5 Preoperative treatment with insulin 6 Preoperative serum creatinine > 2.0 mg/dL
hypertension due to the withdrawal of patient’s longterm hypertensive regimen can be prevented by substituting with long-acting preparations on the morning of the day of surgery. Parenteral therapy is advocated for patients unfit for oral intake and/or with end organ damage.
276
Table 2: Summary of Commonly Used Drugs Drug
Class
Dose
Onset & Duration of Action
Labetalol
Combined α+β-blocker
Loading dose-20mg followed by 20-80mg incremental dose every 10mins.
Onset 2-5mins; reaches peak at 5-15mins, lasts up to 4hours; elimination half-life 5.5hours
HYPERTENSION
Alternatively, infusion 1-2mg/ min after initial loading dose until hypotensive effect Esmolol
Β-blocker
Loading dose 500-1000µg/kg in Rapid onset 60secs; short 1min, then infusion starting at duration of action 10-20mins 50µg/kg/min increasing up to 300µg/kg/min as required
Enalaprilat
ACE inhibitor
1.25mg over 5mins every Variable response, slow onset 6hours increased by 1.25mg at & long duration of action, 12-24hours to a maximum 5mg titration difficult every 6hours
Fenoldopam
Peripheral Dopamine-1(DA) receptor agonist
Starting dose 0.1µg/kg/min, increasing by 0.05-0.1µg/kg/ min up to a maximum 1.6µg/ kg/min
Onset within 5mins, maximal response by 15mins, duration of action 30-60mins, elimination half-life 5mins
Hydralazine
Direct-acting arteriolar vasodilator
IV bolus: 10-20mg every 1-4 hours as required
Onset 5-15mins, circulating half-life3hours, fall in BP may last up to 12hours
IV infusion: Loading dose 0.1mg/kg followed by continuous infusion 1.5-5µg/ kg/min Nicardipine
Dihydropyridine CCB – 2nd generation
5mg/hr, incrementing by Onset 5-15mins, duration of 2.5mg/hr every 5-15mins not to action 4-6hours exceed 15mg/hr
Clevidipine
Dihydropyridine CCB – 3rd generation
Starting infusion at 1-2mg/ hr, dose can be doubled every 90secs. As blood pressure approaches goal increase dose by less than doubling and increase time adjustments every 5-10mins
Half-life 2mins, duration of action 5-15mins
Nitroglycerin
Arterial & venous dilator
Starting infusion at 5µg/min, increased by 5µg/min every 3-5mins up to 20µg/min
Onset 2-5mins, duration of action 10-20mins
Nitroprusside
Arterial & venous dilator
Initial infusion 0.25-0.3µg/kg/ min, increase by 0.5µg/kg/ min every 1-2mins to achieve desired results
Rapid onset in seconds, duration of action 1-2mins, plasma half-life 3-4mins
FENOLDOPAM
A unique peripheral vasodilator by its peripheral dopamine-1 receptor agonism is used for management of perioperative hypertension patients with or at risk of renal dysfunction. It causes renal artery vasodilation and activation of dopamine receptors in the proximal and distal tubules thereby promoting natriuresis and diuresis.36 Disadvantages include reflex tachycardia, dose-dependent increase in intraocular and intracranial pressures and rebound hypertension after stopping the infusion.37
HYDRALAZINE
A direct-acting arteriolar vasodilator affecting diastolic more than systolic blood pressure with its advantage and disadvantage profile similar to fenoldopam is often used as a first-line agent in pregnancy-induced hypertension. A recent meta-analysis has suggested the possibility of its association with increased maternofetal complications due to reflex tachycardia and increased myocardial demand in at-risk patients.38 Hydralazine is best avoided for hypertensive crisis management because of its difficulty in titration due to its prolonged and unpredictable antihypertensive effects. Hydralazine is also avoided in patients with dissecting aneurysm.
NICARDIPINE
A short-acting second generation dihydropyridine calcium channel blocker (CCB) produces selective coronary and cerebral vasodilatation, thus reduces the risk of ischemia and beneficial in patients with coronary artery disease and systolic failure.37 The American Heart Association/American Stroke Association guidelines also recommend nicardipine for treatment of ischemic stroke with diastolic pressure >120 mmHg or systolic pressure >220 mmHg.39,40
CLEVIDIPINE
NITROGLYCERIN
A direct vasodilator of peripheral capacitance and resistance vessels, also acts as an antianginal by coronary artery dilatation and increased blood supply to ischemic regions of the myocardium. Disadvantages include reflex tachycardia and hypotension frequently exacerbated with volume depletion and undesirable effects in patients with compromised cerebral and renal perfusion. Nitroglycerin is not considered as primary therapy in hypertension emergencies or urgencies but used as a suitable adjunctive therapy.
SODIUM NITROPRUSSIDE
With similar mechanism of action to nitroglycerin, nitroprusside is often considered a drug of choice in hypertensive emergencies with documented efficacy in perioperative settings.44-48 A significant reduction in coronary perfusion pressure may occur in patients with coronary heart disease.49 Due to its untoward effect of decreased cerebral perfusion and increased intracranial pressure, nitroprusside is avoided in patients with hypertensive encephalopathy or a cerebrovascular accident.50-53 Cyanide accumulation adds to the adversities of nitroprusside.
CONCLUSION
Perioperative management of hypertension in patients undergoing surgery has been a longstanding problem. With wide range of antihypertensives and clinical experiences, there is no unanimity regarding the management of these patients. Therefore, it is essential to develop a consensus guidelines regarding the perioperative management of hypertension. It includes appropriate patient selection, preoperative evaluation of the patient including the assessment of end-organ damage, appropriate therapeutic goals and drug selection
277
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CHAPTER 50
An ultrashort-acting third generation dihydropyridine CCB reduces afterload by selective arterial vasodilation without affecting cardiac filling pressures or causing reflex tachycardia. Clevidipine increases coronary blood flow with consequent increase in stroke volume and cardiac output thus maintaining renal and splanchnic blood flow and protects against ischemia/reperfusion injury in animal model of myocardial ischemia by direct coronary vasodilatory effect.41-43 The ECLIPSE trial has demonstrated significantly lower mortality rate with clevidipine in comparison to nitroprusside group in perioperative treatment of hypertension.
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early management of patients with ischemic stroke: 2005 guidelines update a scientifi c statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke 2005; 36:916–23. 40. Broderick J, Connolly S, Feldmann E, et al. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke 2007; 38:2001–23. 41. Segawa D, Sjoquist PO, Wang QD, et al. Calcium antagonist protects the myocardium from reperfusion injury by interfering with mechanisms directly related to reperfusion: an experimental study with the ultrashort-acting calcium antagonist clevidipine. J Cardiovasc Pharmacol 2000; 36:338– 43. 42. Segawa D, Sjoquist PO, Wang QD, et al. Timedependent cardioprotection with calcium antagonism and experimental studies with clevidipine in ischemicreperfused pig hearts: part II. J Cardiovasc Pharmacol 2002; 40:339–45. 43. Stephens CT, Jandhyala BS. Effects of fenoldopam, a dopamine D-1 agonist, and clevidipine, a calcium channel antagonist, in acute renal failure in anesthetized rats. Clin Exp Hypertens 2002; 24:301–13. 44. Kaplan JA, Jones EL. Vasodilator therapy during coronary artery surgery. Comparison of nitroglycerin and nitroprusside. J Thorac Cardiovasc Surg 1979; 77:301–9. 45. Domenighetti G, Perret C. Variable hemodynamic response to sodium nitroprusside in hypertensive crisis. Intensive Care Med 1982; 8:187–91. 46. van Wezel HB, Koolen JJ, Visser CA, et al. The effi cacy of nicardipine and nitroprusside in preventing poststernotomy hypertension. J Cardiothorac Anesth 1989; 3:700–6. 47. Halpern NA, Goldberg M, Neely C, et al. Postoperative hypertension: a multicenter, prospective, randomized comparison between intravenous nicardipine and sodium nitroprusside. Crit Care Med 1992; 20:1637–43. 48. Leslie J, Brister N, Levy JH, et al. Treatment of postoperative hypertension after coronary artery bypass surgery. Doubleblind comparison of intravenous isradipine and sodium nitroprusside. Circulation 1994; 90:II256–61. 49. Mann T, Cohn PF, Holman LB, et al. Effect of nitroprusside on regional myocardial blood fl ow in coronary artery disease. Results in 25 patients and comparison with nitroglycerin. Circulation 1978; 57:732–8. 50. Anile C, Zanghi F, Bracali A, et al. Sodium nitroprusside and intracranial pressure. Acta Neurochir (Wien) 1981; 58:203–11. 51. Griswold WR, Reznik V, Mendoza SA. Nitroprussideinduced intracranial hypertension. JAMA 1981; 246:2679– 80. 52. Kondo T, Brock M, Bach H.. Effect of intra-arterial sodium nitroprusside on intracranial pressure and cerebral autoregulation. Jpn Heart J 1984; 25:231–7. 53. Hartmann A, Buttinger C, Rommel T, et al. Alteration of intracranial pressure, cerebral blood fl ow, autoregulation and carbondioxide-reactivity by hypotensive agents in baboons with intracranial hypertension. Neurochirurgia (Stuttg), 1989; 32:37–43.
Pathophysiology of Renin, RAAS and CCB in Management of Hypertension
C H A P T E R
51
Narsingh Verma, Anuj Maheshwari, Mayank Agrawal
ABSTRACT
The renin-angiotensin-aldosterone system (RAAS) is a hormonal cascade that functions in the homeostatic control of arterial pressure, tissue perfusion, and extracellular volume. The classical RAAS cascade begins with the production of renin. Renin converts angiotensinogen to Angiotensin-I (Ang-I). Ang-I requires further activation by angiotensin-converting enzyme (ACE), to form the Angiotensin-II (Ang-II). Ang-II acts by binding to two G-protein coupled receptors, AT1 and AT2; it also acts on the adrenal cortex and causes the release of aldosterone. The current view of the RAAS also includes a local (tissue) RAAS, alternative pathways for Ang-II synthesis (ACE independent), the formation of other biologically active angiotensin peptides (Ang-III, Ang-IV, Ang[1–7]), and additional angiotensin binding receptors (AT4, Mas) that participate in cell growth differentiation, hypertrophy, inflammation, fibrosis, and apoptosis. Activation of local RAAS and local Ang-II production requires the binding of renin or prorenin to the specific (pro) renin receptor (PRR), located on cell surfaces. Angiotensin-converting enzyme inhibitors (ACEIs) and Ang-II receptor blockers (ARBs) are used to block the RAAS. Apart from potent antihypertensives, ACEIs (-)
Hypotension or hypovolemia
Renal hypoperfusion
Low afferent arteriole pressure
Activation of aortic/carotid baroreceptors Increased sympathetic tone
Decreased NaCl delivery to macula densa
Angiotensin
Renin release
produced in the liver
From juxtaglomerular cells of nephrons
Converted by renin
Angiotensin I Converted by angiotensin converting enzyme (ACE) on vascular endothelium
(-)
Site of action of ACE inhibitors
Angiotensin II Binds angiotensin receptors Increased blood pressure Increased blood volume
(-)
Site of action of ARBs
and ARBs have significant cardiovascular and renal therapeutic benefits. Several types of calcium channels occur (P/Q, N, R, L and T type), with a number of classes of blockers, but almost all of them preferentially or exclusively block the L-type voltage-gated calcium channel. In coronary and peripheral arterial smooth muscle and the heart, inhibition of Ca2+ entry blunts the ability of Ca2+ to serve as an intracellular messenger. Thus, CCBs are smooth-muscle dilators and have a negative inotropic and negative chronotropic effect on the working myocardial cells of the atria and ventricles. In 1898, Tiegerstedt and Bergman found a pressor substance from crude saline extracts of the kidney and named it renin. In1940, Braun-Menéndez et al. from Argentina and Page and Helmer from U.S. reported that renin was an enzyme. Renin acted on a plasma protein substrate to catalyse the formation of the actual pressor peptide; that was named hypertension by the old group and angiotonin by the latter. The protein substrate was later renamed as angiotensinogen (Skeggs et al, 1956), and the peptide as angiotensin (Braun-Menendez and Page, 1958). Skeggs et al. demonstrated two distinct forms of angiotensin: angiotensin I (Ang-I, a decapeptide) and angiotensin II (Ang-II, an octapeptide). The relationship between Ang-II and aldosterone was hypothesised by Gross (1958) and subsequently confirmed by Davis (1959). The classical RAAS hormonal cascade begins with the production of renin. Renin, an aspartyl protease produced by the juxtaglomerular cells of the kidney, regulates the initial and rate-limiting step of the RAAS. Renin converts angiotensinogen (an alpha-2-globulin mainly synthesised by the liver) to Ang-I (inactive). Ang-I requires further activation by angiotensin-converting enzyme (ACE, a membrane-bound zinc metalloprotease, synthesised in pulmonary endothelium), a dipeptidyl carboxypeptidase, to form the Ang-II (biologically active). AngII acts by binding to two heptahelical GPCRs, AT1 and AT2. AngII acts on the adrenal cortex and causes the release of aldosterone. Renin secretion from juxtaglomerular cells is controlled predominantly by three pathways:
Vasoconstriction Increased sympathetic NS activity
i.
Macula densa pathway
Aldosterone release (from adrenal cortex) Increased Na absorption (in proximal tubule)
ii.
Intra renal baroreceptor pathway
Endothelial dysfunction Promthrombotic effects (increases PAI-1)
iii.
β1 adrenergic receptor pathway
Fig. 1: RAAS
An increased perfusion of the juxtaglomerular apparatus
beta (TGF- β), which contributes to ventricular remodelling and ventricular
ventricular hypertrophy of the heart through fibrogenesis and apoptosis (programmed cell death).
280
HYPERTENSION
The understanding of the RAS has expanded over the past few years. The current view of the RAS also includes a local (tissue) RAS, alternative pathways for Ang-II synthesis (ACE independent), the formation of other biologically active angiotensin peptides (Ang-III, Ang-IV, Ang[1–7]), and additional angiotensin binding receptors (angiotensin subtypes 1, 2, and 4 [AT1, AT2, AT4]; Mas) that participate in cell growth differentiation, hypertrophy, inflammation, fibrosis, and apoptosis.
COMPONENTS OF THE RAAS
The heavy arrows show the classical pathway, and the light arrows indicate alternative pathways. ACE, angiotensin- converting enzyme; Ang, angiotensin; AP, aminopeptidase; E, endopeptidases; IRAP, insulinregulated aminopeptidases; PCP, prolylcarboxylpeptidase; PRR, (pro)renin receptor. Receptors involved: AT1, AT2, Mas, AT4, and PRR.
Fig. 2: Effects of Angiotensin II inhibits the renin release, through a negative feedback mechanism.
ACTIONS OF ANG-II
Under normal conditions, angiotensin II has following effects: •
Vasoconstriction via GCPR AT1 and vascular smooth muscle hypertrophy through protein kinase C. Constriction of the efferent arterioles in kidney leads to increased perfusion pressure in the glomeruli.
•
Ang-II has a direct effect on the proximal tubules to increase Na+ reabsorption.
•
It stimulates the adrenal cortex to release aldosterone,which acts on kidney tubules, leading tosodium and chloride retention and potassium excretion.
• Stimulation of the posterior pituitary to release vasopressin (antidiuretic hormone, ADH) and secretion of ACTH from the anterior pituitary. It also potentiates the release of norepinephrine by direct action on postganglionic sympathetic fibres. •
Ang-II increases thirst sensation (dipsogen) through the subfornical organ of the brain, decreases the response of the baroreceptor reflex, and enhances the desire for salt.
•
Angiotensin II has prothrombotic potential through adhesion and aggregation of platelets and stimulation of PAI-1 and PAI-2.
•
It stimulates the proto-oncogenes c-fos, c-jun, c-myc, transforming growth factor beta (TGF- β), which contributes to ventricular remodelling and
Source: Brunton L, Chabner B, Knollman B. Goodman and Gilman’s the pharmacological basis of therapeutics. 12ed. McGraw Hill Medical; 2011. ACE-related Carboxypeptidase, now termed ACE2 converts Ang-I to Ang(1–9) and Ang-II to Ang(1–7). The physiological significance of ACE2 is still uncertain; it may serve as a counter- regulatory mechanism to oppose the effects of ACE. ACE2 is not inhibited by the standard ACE inhibitors and has no effect on bradykinin. In animals, reduced expression of ACE2 is associated with hypertension, defects in cardiac contractility, and elevated levels of AngII. Angiotensin III (Ang-III), also called Ang(2–8) is only 25% and 10% as potent as Ang-II in elevating blood pressure and stimulating the adrenal medulla,respectively. Angiotensin IV (Ang-IV), also called Ang(3–8)has potent effects on memory and cognition. Other actions include renal vasodilation, natriuresis, neuronal differentiation, hypertrophy, inflammation, and extracellular matrix remodelling. In animal models, Ang(1–7) induces vasodilation, promotes NO production, potentiates the vasodilatory effects of bradykinin; it has anti- angiogenic, anti- proliferative, and anti- thrombotic effects; and is cardioprotective in cardiac ischemia and heart failure. The modern view of the RAS also includes the local (tissue) RAS, which is an Ang-II producing system that causes hypertrophy, inflammation, remodelling, and apoptosis. Activation of local RAS and local Ang-II production require the binding of renin or prorenin to the specific (pro)renin receptor (PRR), located on cell surfaces. Prorenin is no longer considered the inactive precursor of renin. Prorenin is capable of activating local (tissue) RAS and Ang-II dependent and independent events that may contribute to organ damage. Angiotensinogen may be converted to Ang-I or directly to Ang-II by cathepsin G and tonin. Other enzymes that
281
CHAPTER 51
convert Ang-I to Ang-II include cathepsin G, chymostatinsensitive Ang-II generating enzyme, and heart chymase. Chymase contributes to the local tissue conversion of Ang-I to Ang-II, particularly in the heart and kidneys.
of body fluids contracts, which reduces venous return to the right side of the heart. A further reduction results from venodilation and an increased capacity of the venous bed.
RAAS IN HYPERTENSION
After AMI, RAAS activation occurs as a compensatory and adaptive response to maintain blood pressure and systemic perfusion. Ang-II, being positively inotropic, increases myocardial oxygen demand, but causes vasoconstriction of the coronary vasculatures at the same time, thereby exacerbating myocardial ischaemia (after myocardial infarction), and may result in irreversible myocardial damage. Ang-II also has a direct toxic effect on myocytes and stimulates myocyte hypertrophy, the growth of vascular smooth muscle cells and fibroblasts. Moreover, loss of myocytes triggers abnormal deposition of fibrillar collagen in the heart. All these factors lead to progressive ventricular dysfunction after myocardial infarction.Unless contraindicated (e.g., cardiogenic shock or severe hypotension), RAASinhibitors should be started immediately during the acute phase of myocardial infarction and can be administered along with thrombolytics, aspirin, and β adrenergic receptor antagonists. In high- risk patients (e.g., large infarct, ventricular systolic dysfunction), RAAS inhibition should be continued long term.
Inhibition of RAAS lowers systemic vascular resistance and mean, diastolic, and systolic blood pressures in various hypertensive states except when high blood pressure is due to primary aldosteronism. RAAS blockers cause systemic arteriolar dilation and increase the compliance of large arteries, which contributes to a reduction of systolic pressure. The renal vessels are extremely sensitive to the vasoconstrictor actions of Ang-II;RAAS inhibition increases renal blood flow via vasodilation of the afferent and efferent arterioles. Cardiac function in patients with uncomplicated hypertension islittle changed, although stroke volume and cardiac output may increase slightly with sustained treatment. Baroreceptor function and cardiovascular reflexes are not compromised, and responses to postural changes and exercise are little impaired. Aldosterone secretion is reduced, but not seriously impaired, by ACE inhibitors.
RAAS IN LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
Ang-II is an important mediator of cardiac remodelling; it stimulates fibroblasts to produce collagen, causes hypertrophy of cardiac myocytes and promotes cardiac fibrosis.Unless contraindicated, RAAS inhibitors should be given to all patients with impaired left ventricular systolic function whether or not they have symptoms of overt heart failure. Inhibition of RAAS commonly reduces heart rate, afterload, systolic wall stress, cardiac output, cardiac index increase, stroke work and stroke volume. Renovascular resistance falls sharply, and renal blood flow increases. Natriuresis occurs as a result of the improved renal hemodynamics, the reduced stimulus to the secretion of aldosterone by Ang-II, and the diminished direct effects of Ang-II on the kidney. The excess volume
RAAS IN ACUTE MYOCARDIAL INFARCTION
RAAS IN ATHEROSCLEROSIS
Ang-II promotes the generation of oxidative stress in the vasculatures, which appears to be a key mediator of endothelial dysfunction, endothelial cell apoptosis and lipoprotein peroxidation. Ang-II also induces cellular adhesion molecules, and chemotactic and proinflammatory cytokines, all of which participate in the induction of an inflammatory response in the vessel wall. Ang-II triggers responses in vascular smooth muscle cells that lead to proliferation, migration and a phenotypic modulation, resulting in the production of growth factors and extracellular matrix. While all these effects
282
contribute to neointima formation and development of atherosclerotic lesions, Ang-II may also be involved in acute complications of atherosclerosis by promoting plaque rupture and a hyper thrombotic state.
HYPERTENSION
RAAS IN DIABETIC NEPHROPATHY
Hyperglycaemia is associated with increased production of Ang-II in glomerular mesangial cells. Ang-II increases the expression of transforming growth factor, which stimulates the mesangial matrix synthesis. It also decreases mesangial matrix degradation through promoting synthesis of type 1 plasminogen activator inhibitor (PAI1) and inhibiting activity of mesangial cell collagenase. Other mechanisms of renal injury include the production of reactive oxygen species (ROS) and renal fibrosis by upregulating the expression of Rho A and activating Rho/ Rho kinase pathway. These structural changes lead to microalbuminuria, followed by macroalbuminuria and finally chronic renal failure.
CALCIUM CHANNEL BLOCKERS
Several types of calcium channels occur (as shown in the table given below), with a number of classes of blockers, but almost all of them preferentially or exclusively block the L-type voltage-gated calcium channel.
MECHANISMS OF ACTION
Voltage-sensitive Ca2+ channels (L-type or slow channels) mediate the entry of extracellular Ca2+ into smooth muscle and cardiac myocytes and sinoatrial (SA) and atrioventricular (AV) nodal cells in response to electrical depolarization. In both smooth muscle and cardiac myocytes, Ca2+ is a trigger for contraction, albeit by different mechanisms.The entry of extracellular Ca2+ is necessaryfor initiating the contraction of cardiac myocytes (Ca2+-induced Ca2+ release). The release of Ca2+ from intracellular storage sites also contributes to contraction of the vascular smooth muscle, particularly in some vascular beds. Ca2+ channel antagonists, also called Ca2+ entry blockers, inhibit Ca2+ channel function. In vascular smooth muscle, this leads to relaxation, especially in arterial beds. These drugs alsoproduce negative inotropic and chronotropic effects in the heart. They directly reduce aldosterone production by blocking the calcium signal on adrenal cortex cells, which corroborates to lower blood pressure. The vascular and cardiac effects of some CCBs are summarised in the next Table.
CCB IN HYPERTENSION
Except for nimodipine (whichwas originally developed for treating hypertension but isapproved for subarachnoid haemorrhage) and the short‐actingnifedipine (i.e., the immediate‐release formulation), all CCBsare approved by the US FDA for lowering blood pressureeither alone or in combination with other antihypertensiveagents. There are certain newer CCB which has been developed in Japan like Cilnidipine and Benidipine which are not yet approved by US FDA but we have data that clinidipine has lower incidence of Pedal oedema in comparison
to Amlodipine. Cilnidipine has been extensively studied by researchers in its preclinical and clinical development phases. Renoprotective, neuroprotective and cardioprotective effects of cilnidipine have been demonstrated in clinical practice or animal examinations. It is noticed that cilnidipine may have pleiotropic effects besides N-type Ca2+ channel-blocking action. Therefore, the inhibition of N-type Ca2+ channels may provide a new strategy for the treatment of cardiovascular diseases. Benidipine is long acting CCB which blocks L, T and N channels and said to be have cardioprotective and renoprotective effects.
CCB IN STABLE ANGINA
The antianginal effects of CCBs result from either dilation of the coronary artery and the subsequent increase of oxygen supply or decreased oxygen demand (secondary to a decrease in arterial blood pressure, myocardial contractility, or heart rate), or both. Owing to their coronary dilating effects, CCBs are also useful for treating variant angina (also known as Prinzmetal angina, which is caused by transient localised coronary artery spasm.
CCB IN ACUTE CORONARY SYNDROMES
Available evidence suggests that CCBs have a limited role in the management of patients with acute coronary syndromes (ACS), which include unstable angina, non‐ ST‐segment elevation myocardial infarction (STEMI), and STEMI. No CCB has been shown to reduce mortality, and in certain patients with ACS, the short‐acting CCBs, may even be harmful.
CCB IN HEART FAILURE
Available evidence points to the lack of benefit of CCBs in patients with systolic heart failure. These agents do not improve exercise tolerance, quality of life, or survival. The negative inotropic effects of CCBs, especially verapamil, may worsen the symptoms in patients with severe left ventricular dysfunction. Based on these observations, the use of CCBs in patients with systolic heart failure was not recommended in the current guidelines.
CCB IN CARDIAC ARRHYTHMIAS
Diltiazem and verapamil are useful antiarrhythmic agents in the management of certain arrhythmias, especially supraventricular tachyarrhythmias. These drugs preferentially affect slow‐response myocardial tissues (i.e., sinoatrial and atrioventricular nodes, which depend on calcium currents to generate slowlypropagating action potentials), in contrast to fast‐response myocardial tissues (i.e., the atria, specialised intranodal conducting system, the ventricles, and accessory pathways), which rely on sodium channels.
REFERENCES
1. Ma TK, Kam KK, Yan BP, Lam YY.Renin-angiotensinaldosterone system blockade for cardiovascular diseases: current status. Br J Pharmacol 2010; 160:1273-92. 2.
Garg M, Angus PW, Burrell LM, Herath C, Gibson PR, Lubel JS. Review article: the pathophysiological roles of
the renin-angiotensin system in the gastrointestinal tract. Aliment Pharmacol Ther 2012; 35:414-28. 3.
Brunton L, Chabner B, Knollman B. Goodman and Gilmanâ&#x20AC;&#x2122;s the pharmacological basis of therapeutics. 12ed. McGrawHill Medical; 2011.
4.
Te Riet L, van Esch JH, Roks AJ, van den Meiracker AH, Danser AH.Hypertension: renin-angiotensin-aldosterone system alterations. Circ Res 2015; 116:960-75.
5.
Snutch TP, Peloquin J, Mathews E, McRory JE. Molecular Properties of Voltage-Gated Calcium Channels. Madame Curie Bioscience Database [Internet]. Available from:
283
http://www.ncbi.nlm.nih.gov/books/NBK6181/
6.
Elliott WJ, Ram CV. Calcium channel blockers. J Clin Hypertens (Greenwich) 2011; 13:687-9.
7. Li YR. Cardiovascular diseases. From Molecular Pharmacology toevidenceâ&#x20AC;?Based Therapeutics.John Wiley & Sons, Inc., Hoboken, New Jersey;2015.
CHAPTER 51
C H A P T E R
52
Clinical Approch to the Patient of Hypertesion with Diabetes Mallitus
INTRODUCTION
Essential hypertension specially isolated systolic hypertension (HTN) is a common clinical condition. As such it is not considered as a disease but a trait which affects the outcome of many co morbid diseases which are responsible for major morbidity and mortality i.e. cardiovascular (CVD), cerebrovascular CV) and kidney diseases. That is why it is called as silent killer. Diabetes mellitus (DM) which is serious public health issue. The HTN and DM together are named as deadly duo. DM is leading cause of new blindness, end stage renal diseases, and non traumatic amputations, never the less the CVD is the major cause of mortality in patients of DM. HTN is also a risk factor of micro vascular complication such as nephropathy and retinopathy. Optimum control of HTN in patient of DM has been proved to be highly beneficial in regard to mortality and morbidity outcome shown in many cohort large trails, studies and has been accepted by majority of guidelines. Hence this important clinical situation is been discussed here. However it is very difficult to achieve target control of HTN in clinical practice.
HTN AND TYPE I & II DM
As such HTN is common problem in patients of type I & II DM. The incidence of HTN increases as age advances in patients of type I diabetes. Interestingly the prevalence is closely related to the degree of protienuria. BP begins to rise when albumin excretion rate enters the microalbuminuria stage (< 30 mg /24 h). Whereas situation is different in type II DM, in a series of about 3500 newly diagnosed DM patient about 40 % are already having HTN and half of them are having albuminuria, further HTN is associated with obesity.
HYPERTENSION AND METABOLIC SYNDROME
HTN is closely related to insulin resistance. There is a suggestion that insulin is an endothelium dependent vasodilator, releasing nitric oxide (NO) from endothelium which relaxes the smooth muscles, the blunting action contributes to increase peripheral vascular resistance, in due course increases HTN in patients of DM. Insulin also retain sodium and water by stimulating distal renal tubules, leads to increase in sodium and water level causing HTN. Stimulation of sympathetic outflow by insulin may induce HTN. Insulin stimulates the proliferation of vascular smooth muscles which leads to medial hypertrophy and increases peripheral vascular resistance.
Surendra Daga
BENEFITS OF EARLY TREATMENT AND GOALS
Early treatment of HTN is particularly important in D M to prevent CVD morbidity and mortality and minimize the progression of renal diseases and diabetic retinopathy. Evidence of benefit from treating HTN in DM has come from multiple trials, including UKPDS, ADVANCE AND HOT, as well as meta- analyses of these and other trials. There is near consensus in various guidelines and hypertensive societies about the definition of HTN. As per European society of hypertension BP exceeding 140/90 should be considered as HTN. Once it was believed that aggressive reduction in BP is highly beneficial and guidelines were favor to intensive lowering of BP to bellow 130/80 in patients of DM, but subsequently a consensus started developing that more aggressive lowering does not change the mortality outcome after THE ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES BLOOD PRESSURE TRIAL (ACCORD BP). in this trial randomly selected DM patients with cardiovascular disease, or more than two risk factor for CVD and HTN were treated in two groups, one arm aggressive BP control bellow120/80, other standard 140/90. It was found that there is no significant difference in the annual rate of composite outcome of non fatal myocardial infarction, nonfatal stoke or death from CVD between the aggressive and standard therapy group. Serious adverse drug events were noted in aggressively treated group.
SCREENING FOR HYPERTENSION IN DIABETES
The HTN and DM are so closely associated. All diabetes patients must be regularly screened for hypertension and vice versa annually. BP should be measured in supine and sitting position, using an accurate sphygmomanometer and a cuff of appropriate size. BP should be checked in standing position to rule out postural hypertension in elderly and diabetes with autonomic neuropathy patients. Many time ambulatory BP checks up is of help in ruling out white coat effect and investigates diurnal variability to titrate the doses and timing of drugs. 24 hours ambulatory BP monitoring may help diagnosing the night dip in few patients. Many recent studies have shown that more than 25% of all diabetes has nocturnal hypertension especially obese and those having obstructive sleep apnea and they are prone have target organ damage in future. In future carotid femoral pulse wave velocity and changes in central hemodynamic as marker of arterial stiffness may became the common than today.
There are following aims to investigate the hypertensive diabetic patient: i.
To exclude the causes of secondary hypertensive.
ii.
To access the extent of damage to end organ because of hypertension and or diabetic.
iii.
The CVD morbidity and is selected to HTN & DM so it is also the aim to detect any other potential risk factor exists which can be add to increase mortality due to vesicular disease.
a.
The HTN and macro vascular diseases are less common in Native Americans (Pima Indians) and Mexican American.
CARDIAC FUNCTION
A standard 12 lead ECG to detect ischemia and arrhythmia or LVF. Echocardiography to detect LVH and ventricular dysfunctions, in few cases holter monitoring or stress test may be of some use to detect ischemia and arrhythmia.
RENAL FUNCTION
A fresh urine sample should be tested RBC and WBC cast, microscopic hematuria and microalbuminuria. serum urea, creatinine and glomerular filtration rate needs to be checked. USG of kidney and urinary fact to exclude any additional pathology in kidney responsible for HTN. Sometimes we may require specialized investigation like isotopes renogram for renal artery stinosis.
BLOOD TEST
Complite hemogram to exclude anemia should be done. High WBC count may be indicator of sum infection of kidney and urinary tract. Fasting blood sugar and lipid profile should be done and if found to be high in repeated time lipoprotein subclass is recommended. Serum electrolyte to find out significant renal disease or monitoring the effect of drugs i.e. diuretics and ACE inhibitors.
MANAGEMENT OF HYPRTENTION IN DIABITISE
The aggressive and early initiations of controlling BP in patients of DM are undoubtly beneficial and helpful in preventing cardiovascular disease and minimizing the progression of CBD and renal disease.
NON PHARMOCOLOGICAL METHODS
The life style modification is hallmark of treatment that includes weight reduction, increase consumption of fresh fruits, vegetables, low fat dairy products, salt restriction and alcohol restriction in diet. Cessation of smoking is highly beneficial, smoking not only accelerate the progression of atherosclerosis, but also impairs in insulin sensitivity. Treatment with nicotine supplement for 4-6 weeks (Patch form) a drug like bupropion varenicline are of some use. Successful life style modification is very useful and
285
PHARMACOLOGIC TREATMENT
The drug therapy in hypertensive diabetic patients is unequivocally protective as HTN places diabetic patient at high risk of cardiovascular complication all patients with persistence BP above 140/ 90 mm hg should be started on drug therapy. One meta- analysis compared effect of one antihypertensive with another and concluded that no group of antihypertensive were superior to the others. There are extra benefits by one over other in special situation. i.e. ACE inhibitors are better in patient when associated with microalbiminuria. Calcium channel blockers reduces the risk of stroke compared to other agents and beta-blockers increases the risk of stroke to other agents. The choice of antihypertensive agents in diabetic patients is based upon their ability to do followings:i.
Prevent mortality
ii.
Prevent adverse cardiovascular events such as myocardial infection, stroke and heart failure.
iii.
Prevent the progression of renal disease if present.
In hypertensive with type I DM ACE inhibitors are drugs of choice with or without alburminuria. Diuretics, calcium antagonist and β-selective blocker can be used as second line drug to achieve goal of BP. In type 2 DM BP control is more important than the choice of drug. ACE inhibitors are drug of choice and other drugs are selected on their additional beneficial effects on co-existing conditions. B- Blockers and calcium channel blocker for angina and arrhythmia, ARB and B blocker for heart failure, spironolactone is useful in elderly obese, female patients with HTN and hypervolemia, alpha blocker in elderly patients with prostate hyperplasia and dyslipidemia ( TG). A combination therapy is needed in majority of patients. It is beneficial to use combination to reduce the need of doses and to minimize adverse effects. In non- Caucasians and African American. B receptor blocker and ACE inhibitors are less effective because of low RAAS activity; diuretics and calcium channel blocker is drug of choice.
CONCLUSION
HTN and DM are very serious public health problems individually. The association together should be double whammy. There is substantial overlap between and diabetics and hypertension, Obesity, inflammation oxidative stress and insulin resistance are thought to be common pathways mechanism of disease. All patients of type 2DM should be treated aggressively for HTN if BP is above 140/ 90 mm of Hg to bring it down less than 140/ 90. Most of the patients need more than one drug to achieve
CHAPTER 52
The detail clinical history and physical examination is hallmark in patients of HTN with DM,
reduces the need of drug doses and number of antihypertension agents.
286
the goal less than 140/ 90 mm Hg in spite of life style modification. ACE inhibitors have shown the effect of cardio protection and ARB has shown nephron-protection but there is no consensus on choice of drug in all patients as most of the studies have shown that it is BP lowering per say is more important than the drug used.
HYPERTENSION
Newer drugs are constantly been introduced and should be tested for both efficacy and tolerability. In future the application of CV genomics may substantially change the approach to treating HTN in DM as the genetic architecture of HTN has now been mapped, with the possibility of tailoring antihypertensive treatment
according to genotype of individual patients. So long as we are ready to use newer technology, we shall be dependant on available armamentarium of drug and life style modification to take care of this challenge of HTN in DM.
REFERENCES
1.
American diabetes association (8) Cardiovascular disease and risk management, Diabetes care2015:38 supple:s 49.
2. High blood pressure in adult;report from the panel members appointed to the eighth joint national committee (JNC8), JAMA 2014; 311; 507. 3.
Edmin CA, Rahimi K. Neal B, et al. Blood pressure lowering in type 2 diabetes; a systematic review and meta-analysis, JAMA 2015; 313-603.
C H A P T E R
53
Current Standards of Management of Hypertension in Chronic Kidney Disease
There is a bidirectional relationship between hypertension and kidney disease, with one exacerbating the effect of the other. Kidney disease is an important end-organ effect of hypertension, and hypertension is a frequent finding and the most common comorbidity in both acute and chronic kidney diseases. Elevated blood pressure is an important modifiable risk factor for cardiovascular disease and progression of kidney disease. The frequency and pathogenesis of hypertension varies with the type of kidney disease (eg, glomerular versus vascular) and with the duration of disease (acute versus chronic). This chapter will briefly discuss the aspects of pathophysiology of hypertension in kidney diseases that have an effect on management, and the current guidelines for management of hypertension amongst patients with kidney diseases.
PATHOPHYSIOLOGY
Acute kidney disease
Acute glomerular diseases are characterized by sodium retention leading to volume expansion. Volume expansion suppresses the renin-angiotensin-aldosterone system and promotes release of atrial natriuretic peptide. The sodium retention is due to increased reabsorption in the collecting tubules secondary to resistance to the action of atrial natriuretic peptide and hyperactive Na-K+-ATPase pump in the cortical collecting tubule. In contrast, acute vascular disease produces renal ischemia, either in the whole kidney or in segments that leads to activation of the renin-angiotensin system which causes renin-mediated hypertension.
Chronic kidney disease
Hypertension is found in about 80-85% of patients with chronic kidney disease (CKD). The prevalence increases as the glomerular filtration rate falls progressively. In the Modification of Diet in Renal Disease (MDRD) study, about 65% patients exhibited raised blood pressure at a glomerular filtration rate (GFR) of 85 mL/min per 1.73 m2. This figure went up to 95% as the GFR fell to 15 mL/min per 1.73 m2. The prevalence is also affected by other patient related factors – such as ethnicity, body weight etc. While sodium retention is of primary importance in the genesis of hypertension in CKD, other factors like enhanced activity of the renin-angiotensin system, sympathetic overactivity, secondary hyperparathyroidism (by raising the intracellular calcium concentration), impaired
Vivekanand Jha
vasodilatation secondary to reduced endothelial nitric oxide synthesis and iatrogenic factors like therapy with erythropoiesis-stimulating agents also contribute. Other features of hypertension in CKD are increase in central pulse pressure and isolated systolic hypertension secondary to increased vascular wall stiffening and absence of normal nocturnal decline in blood pressure. In patients with CKD, hypertension not only hastens progression of kidney disease, it also increases likelihood of developing adverse cardiovascular outcomes such as myocardial infarction, stroke and heart failure. Moreover, a fair degree of interaction is noted between hypertension and proteinuria, so that the same level of blood pressure is associated with greater risk of adverse outcomes in patients with proteinuria compared to those without this abnormality. As a result, hypertension treatment goals are usually aligned with some urine protein reduction targets (typically <1 g/day), and lower targets have been suggested in those with significant persistent proteinuria.
MANAGEMENT OF HYPERTENSION IN KIDNEY DISEASE
The only firm statement that can be made regarding blood pressure management in CKD is that blood pressure lowering is desirable. Kidney Disease: Improving Global Outcomes (KDIGO) Workgroup performed a rigorous review of evidence, and developed guidelines for management of hypertension in CKD in 2012 (Table 1). However, there are no strong recommendations supported by high quality evidence regarding the level of blood pressure reduction, the goal blood pressure or choice of therapy in different situations. Several professional societies have produced commentaries on the KDIGO guidelines to provide practical recommendations on its application. It has been emphasized that guidelines should not be used as a cookbook, and application of recommendations should be tailored to the needs of an individual patient. Recommendations might vary depending on ethnicity or gender. For example, calcium channel blockers might be more effective compared to other drugs in black patients.
Blood pressure measurement
A few words are necessary on describing the techniques of BP measurement on CKD. Most of the data on BP control comes from studies where BP has been measured in physicians’ offices. To minimize the possibility of confounding due to white coat hypertension, blood pressure should be measured more than once during the same visit, with an interval of at least 1– 2 min. BP should
288
Table 1: Summary of KDIGO recommendation statements Chapter
Number
Intervention (threshold)
Target
Grading
(2) Lifestyle and pharmacological treatments
HYPERTENSION
General strategies
Lifestyle Modification
2.1
Individualize of targets and agents according to age, CVD, comorbidities, risk of CKD progression, retinopathy (DM) and tolerance of treatment
Not graded
2.2
Inquire about postural dizziness Check for postural hypotension regularly
Not graded
2.3.1
Achieve/maintain healthy weight
BMI 20-25 kg/m2
ID
2.3.2
Lower salt intake
<90 mmol/day (<2 g/day) of sodium
1C
2.3.3
Exercise Programme
≥30’, 5x/week
ID
2.3.4
Limit alcohol intake
≤2 drinks/day (male); ≤1 drink/ day (female)
2D
(3/4) CKD patients without/with diabetes (DM-/DM+) DM-/DM+
Ualb (Uprot)a
BP thresholdb
BP targetc
DM-/DM+
3.1/4.1
<30(<150)
>140/90
≤ 140/90
1B/1B
≤ 130/80
2D;2C/2D
Agent: no recommendation 3.2; 3.3/4.2
≥30(≥150)
>130/80
3.4; 3.5/4.3; 4.4
Agent: ACE-I or ARB
2D;1B/2D;1B
(5) Kidney transplants 5.1
Any
>130/80
≤ 130/80
2D
5.2
Agent: time after transplantation, use of calcineurin inhibitors, albuminuria, comorbidities
6.1/6.2
Any
6.3
Agent: ACE-I or ARB
7.1
• Tailor, age, co-morbidities, other therapies Not graded • Gradual escalation • Close attention to adverse events: electrolyte disorders, acute deterioration in kidney function, orthostatic hypotension and drug side effects
Not graded
(6) Children >90th percentiled
≤50th percentiled
1C/2D 2D
(7) Elderly
Ulb, albuminuria; Uprot, proteinuria; in g/24 h or g/g urinary creatinine. BP, blood pressure (mmHg); should be consistently above the systolic or diastolic threshold. C BP, blood pressure (mmHg); should be consistently at or below the systolic and diastolic goal. d Thresholds and targets for mean arterial pressure, percentiles for height, age and sex. a
b
be measured in both arms when the patient is seen for the first time, and when possible, measurements should be made on more than one occasion. The utility of home and ambulatory blood pressure monitoring are less clearly established. However, for those who measure BP at home, as a rule of thumb, target values should be 5– 10 mmHg lower. The use of oscillometric devices is increasing. However, they may produce erroneous readings in patients with advanced arteriosclerosis and arterial stiffness, common in patients with advanced kidney disease.
Goal blood pressure
Hypertension in CKD is a chronic condition, and the arterial system adapts to a higher pressure by remodeling. Therefore, rapid lowering of blood pressure should be avoided; the longer hypertension exists, the longer it should take to obtain the desired target. Another point of note is to look for consistency in blood pressure measurements and not to make changes based on a single measurement alone unless the value is clearly abnormal. Finally, the aim of treatment should be to achieve a blood pressure that is below a target in resting conditions most of the time.
Sodium restriction is central to management of hypertension. In addition to a direct salutary effect, this enhances the antihypertensive effect of many drugs, especially angiotensin inhibitors. In a controlled trial, in patients with proteinuric CKD, a low-sodium diet decreased blood pressure to a greater degree than addition of valsartan. It is less clear that salt restriction alone would have a similar effect in patients with CKD as seen in the general population since the primary defect in these subjects is in reduced capability of kidneys to handle a given salt load. The recommended salt intake varies from 4-5 gm/day (corresponsing to 1.5-2 g of sodium).
A major issue which has seen fair amount of controversy in the last two decades is the goal blood pressure in patients with CKD. The most recent evidence has been provided from the Systolic Blood Pressure Intervention Trial (SPRINT). A total of 9361 nondiabetic individuals over 50 years of age with high cardiovascular risk were randomized to a systolic blood pressure target < 140 mm Hg (standard arm) or < 120 mm Hg (intensive arm). The study had targeted to include over 40% patients with CKD, but the final population had only about 28% with CKD. Individuals with eGFR <20 ml/min/1.73 m2, proteinuria ≥1 g/d or equivalent, or polycystic kidney disease were excluded.
Given the primacy of salt and water overload in genesis of hypertension in dialysis patients, the major therapeutic goal in hypertensive dialysis patients is gradual fluid removal to attain dry weight. Daily nocturnal dialysis is superior to standard 3/week dialysis for this purpose.
Individuals assigned to the intensive arm experienced a significant reduction in the primary composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, and cardiovascular death, as well as several secondary outcomes (hazard ratio 0.75, 95% confidence interval [CI] 0.64–0.89). There was also a 27% reduction in all-cause mortality in the intensive arm. For subjects with baseline CKD, there was no significant between-group difference in the composite renal outcome of ESRD or a 50% decline in eGFR. However, participants without CKD at baseline randomized to intensive therapy had a greater likelihood of ≥30% decline in eGFR to < 60 ml/min/1.73 m2 (hazard ratio 3.49, 95% CI 2.44–5.10). In addition, subjects assigned to intensive arm 70% increased risk of developing acute kidney injury (AKI). The study was stopped before reaching full recruitment target in view of the clear benefit in terms of cardiovascular events and all-cause mortality. The number of antihypertensive agents was 1.8 in the standard treatment and 2.8 in the intensive treatment arm. It should be noted that over 50% of the participants in the intensive therapy arm of had systolic blood pressure > 120 mm Hg after 1 year, highlighting the challenges of achieving and maintaining a lower target blood pressure.
General strategies and lifestyle modification
Most of the evidence around the effect of lifestyle changes such as physical exercise and salt restriction comes from general population studies. Several observational studies have demonstrated a salutary effect of physical activity on various end points such as mortality and quality of life, but none have specifically investigated the effect on BP control in the CKD population.
Maintenance of ideal body weight is a common-sense advice based on data from general population. Obesity has been associated with CKD progression. However, there is no data to show that reducing body weight improves kidney disease progression in obese patients. Rather, body weight is positively associated with outcomes amongst patients on dialysis. Finally, weightloss diets are often high in potassium and protein which may be harmful in CKD. Also, in the absence of data from CKD population, recommendation on smoking cessation and limitation of ethanol intake have been derived from general population as common sense recommendations.
Choice of antihypertensive agents
Angiotensin converting enzyme-inhibitors (ACE-I) and angiotensin receptor blockers (ARB): Most guidelines support the primacy of place given to this class of antihypertensive agents in patients with kidney disease, based on evidence from multiple large randomized clinical trials. The effect is particularly evident in patients with proteinuric CKD. Doubts have, however, been raised whether the apparent superiority of these agents is not simply a reflection of better BP control. Although there is a theoretical rationale for combining these two classes of amgiotensin blocking agents, agents, risk of harm in the form of hyperkalemia has led to recommendation against combining these agents. Caution should be also exercised in patients with advanced CKD even on a single agent. In particular, suggestion has been made that these agents should be discontinued in patients with CKD stages 4– 5. Current guidelines do not support discontinuation of these agents, but emphasize the need for close monitoring and careful selection. Availability of new potassium lowering agents, such as patiromer and sodium zirconium cyclosilicate might make these concerns moot. These agents should also be avoided early after kidney transplantation as they may alter renal hemodynamics leading to elevation in serum creatinine that will need to be differentiated from other causes of graft dysfunction, and produce some lowering of hemoglobin.
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Patients with CKD exhibit vascular stiffness related to changes in the blood vessel wall and/or vascular calcification. This leads to a situation where the measured systolic blood pressure stays relatively high whereas the diastolic blood pressure can fall to dangerously low levels. It is therefore important to be on the lookout for warning signs such as postural dizziness. Regular inquiry about symptoms of postural hypotension should be made. Altering antihypertensive therapy to reduce asymptomatic postural hypotension or to achieve a target standing BP has not been recommended since there is no evidence to show benefit from such approach.
No additional benefit on rate of Not powered to detect differences progression to ESRD from further in CV event rates BP reduction by adding felodipine to ACE-inhibitor therapy Mean GFR slope from baseline Not powered to detect differences through 4 y did not differ in CV event rates significantly between lower-BP and usual-BP group; lower BP goal did not significantly reduce rate of clinical composite outcome; follow-up trial; no significant between-group difference in risk for primary outcome, with potential benefit in patients with protein-creatinine ratio > 0.22 Annual percentage increase Not powered to detect differences in total kidney volume was in CV event rates significantly lower in the low-BP than standard-BP group without significant differences between the lisinopril-telmisartan group and lisinopril-placebo group
Intensified control < 130/ 80 mm Hg; conventional control < 90 mm Hg diastolic
African Americans 18-70 y Lower MAP goal ≤ 92 mm Hg; with hypertension, GFR 20-65 usual MAP goal 102-107 mm Hg mL/min/1.73 m2, and no other identified cause of CKD; excluded DM, proteinuria (proteincreatinine ratio > 2.5 g), malignant hypertension, CHF
Low BP target 95/60 to 110/75 mm Hg; standard BP target 120/ 70 to 130/80 mm Hg
Intensive therapy target SBP 120 mm Hg; standard therapy target 140 mm Hg
Pts 15-49 y with ADPKD and eGFR > 60 mL/min/ 1.73 m2
Type 2 DM and either ≥40 y with CV disease or ≥55 y with atherosclerosis, albuminuria, LVH, or 2 additional CV disease risk factors, plus SBP 130-180 mm Hg taking 0-3 agents and <1.0g/d proteinuria
AASK16,17
HALT-PKD18
ACCORD BP2
Only primary outcome benefit was reduced strokes with intensive therapy; kidney end points of eGFR and macroalbuminuria were reduced in the intensive treatment group with no difference in ESRD rates
Excluded patients with Scr > 1.5 mg/ dL or proteinuria >1g/d
There was greater use of ACE inhibitors in the low-BP group; not powered to detect differences in CV event rates
Pts 18-70 y with nondiabetic proteinuric kidney disease (>1 g/24 h) not receiving ACEinhibitor therapy; CLcr < 45 mL/ min/1.73 m2 if 1-3 g proteinuria, or <70 mL/min/1.73 m2 if ≥ 3 g
Low BP goal group had significantly reduced proteinuria and faster GFR decline during the first 4 mo and a slower subsequent decline in GFR
REIN-215
MDRD
Low BP goal MAP< 92 mm Hg for age < 60 y, <98mm Hg for age > 61 y; usual BP goal MAP< 107 mm Hg for age < 60 y, <113mm Hg for age > 61 y
Comments
Pts 18-70 y with Scr 1.2-7.0 mg/ dL (women), 1.4-7.0 mg/dL (men), or CLcr < 70 ml_/min/1.73 m2 and MAP ≤ 125 mm Hg; excluded DM requiring insulin or proteinuria > 10 g/24 h
Kidney Disease Outcomes
BP Targets
Study Population
14
Trial
Table 3: Randomized Controlled Hypertension Treatment Trials for Patients With CKD
HYPERTENSION 290
Excluded pts with stage > 4 CKD or proteinuria > 1 g/d; trial terminated early Primary CV outcomes were reduced with intensive treatment for pts with pre-existing CKD as with the full study population; no difference in rates of 50% reduction of eGFR or ESRD rates; more pts without incident CKD had >30% decline in eGFR with intensive treatment Intensive therapy target SBP 120 mm Hg; standard therapy target 140 mm Hg Pts ≥50 y, SBP 130-180 mm Hg taking 0-4 agents with increased CV risk (prior CV event but not stroke), CKD with eGFR 20-<60 mL/min/ 1.73 m2, age ≥ 75 y, or 10-y risk for CV events ≥ 15% SPRINT
Abbreviations; AASK, African American Study of Kidney Disease and Hypertension; ACCORD BP, Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial; ACE, angiotensin-converting enzyme inhibitor, ADPKD, autosomal dominant polycystic kidney disease; BP, blood pressure; CHF, congestive heart failure; CKD, chronic kidney disease; CLcr, creatinine clearance; CV, cardiovascular, DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; ESRD, end stage renal disease; GFR, glomerular filtration rate; HALT-PKD, Halt Progression of Polycystic Kidney Disease; LVH, left ventricular hypertrophy; MAP, mean arterial pressure; MDRD, Modification of Diet in Renal Disease; pt, patient; REIN-2, Ramipril Efficacy In Nephropathy-2; SBP, systolic blood pressure; Scr, serum creatinine; SPRINT, Systolic Blood Pressure Intervention Trial.
Comments Kidney Disease Outcomes BP Targets Study Population
1
Trial
Table 3: Randomized Controlled Hypertension Treatment Trials for Patients With CKD
Diuretic therapy should be increased until either the BP goal is achieved; or the patient develops symptoms related to volume loss (cramps, fatigue, orthostatic hypotension or unexplained elevation in the serum creatinine). Calcium channel blockers: Dihydropyridine calciumchannel blockers abolish renal autoregulation and can increase proteinuria when used as a single agent and hence should be used only as a second-line therapy after angiotensin-blocking drugs. Non-dihydropyridine agents, however do not have this disadvantage. The use of diltiazem in kidney transplant recipients demands caution because of its effect on cytochrome P-450 system that metabolizes immunosuppressive agents, leading to need to dose reduction. Beta-blockers: Beta-blockers have fallen out of favour as first-line antihypertensive agents because of their short duration of action, heart rate lowering effect, and lack of effect on central blood pressure. They may however provide beneficial effect on patients with CKD at risk of sudden cardiac death by lowering sympathetic overactivity. Finally, newer class of beta blockers such as carvedilol, nebivolol and celiprolol do not share the aforementioned negative properties. Finally, subjects with CKD are likely to require more drugs for BP control, and suffer from resistant hypertension. They are also on multiple drugs, raising the possibility of side effects and drug interactions. It is important to look into these points as they will impact adherence to treatment. Nocturnal therapy: Normally, the blood pressure is approximately 15 percent lower during night. Failure of the blood pressure to fall by at least 10 percent during sleep is called “nondipping”, a common phenomenon amongst CKD subjects and associated with adverse cardiovascular outcomes. Studies have shown that shifting of at least one antihypertensive medication from the morning to the evening can restore the normal nocturnal blood pressure dip.
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Diuretics: The use of diuretic therapy as primary antihypertensive agent for subjects with edema due to salt and water overload, and an add-on therapy to other agents is well-established. Most data is available for thiazide- like diuretics, such as hydrochlorothiazide, chlorthalidone and indapamide. The latter may be preferred in CKD because of its better metabolic sideeffect profile and potassium-depleting effect. Thiazides become less effective as the glomerular filtration rate falls. Loop diuretics need to be used as initial therapy in these patients, with some preference for torsemide, which has a longer duration of action than furosemide. Higher doses are typically required in patients with CKD who are usually volume expanded even in the absence of edema. If edema persists despite loop diuretic therapy, a thiazide can be added. The diuretic efficacy of thiazides is enhanced in those already on a loop diuretic. Diuretics also enhance the BP lowering effect of ACE-I and ARBs.
HYPERTENSION
292
Renal denervation: Renal denervation (RDN) involves introduction of catheter into the renal arteries, and application of radiofrequency energy against the blood vessel wall to damage the nerve fibers (in particular the sympathetic fibres) surrounding the artery. Although the first sham-controlled study did not show a benefit of this approach, recent years have seen a revival with doubts on the technical approach used in the earlier study. Special case has been made for its use in subjects with CKD from a pathophysiological perspective, and selecting CKD patients for RDN have been described. This strategy, however, must be considered experimental at this stage. While there is a general agreement on the KDIGO treatment recommendations and blood pressure targets in most CKD subpopulations (with or without diabetes, proteinuric and non proteinurics, dialysis or nondialysis, and special populations â&#x20AC;&#x201C; children, elderly and kidney transplant recipients), some differences have been expressed by other societies, in particular the Canadian Society of Nephrology suggestion of keeping the BP target <130/80 for all non-dialysis diabetic subjects irrespective of the degree of proteinuria.
CONCLUSIONS
Although there are several clinical trials on management of hypertension in CKD (Table 3), most of them have shortcomings that limit the extraction of high quality evidence that could lead to strong statements. The lack of 1A guideline for such a common clinical problem is disappointing, and imposes a burden of further research on the nephrology community. Also, the presence of guidelines should not detract from the need to exercise clinical judgement in making therapeutic decisions. The key to success of any therapeutic approach for a chronic condition lies in making decisions that have real-world validity, communicating the rationale to the patient and revisiting periodically to ensure long-term compliance.
REFERENCES
1. Chertow GM, Beddhu S, Lewis JB, Toto RD, Cheung AK. Managing Hypertension in Patients with CKD: A Marathon, Not a SPRINT. J Am Soc Nephrol 2016; 27:40-3. 2. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney inter 2012; 2:337â&#x20AC;&#x201C;414. 3. Ruzicka M, Quinn RR, McFarlane P, Hemmelgarn B, Ramesh Prasad GV, Feber J, Nesrallah G, MacKinnon M, Tangri N, McCormick B, Tobe S, Blydt-Hansen TD, Hiremath S. Canadian Society of Nephrology commentary on the 2012 KDIGO clinical practice guideline for the management of blood pressure in CKD. Am J Kidney Dis 2014; 63:869-87. 4. SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, Kimmel PL, Johnson KC, Goff DC Jr, Fine LJ, Cutler JA, Cushman WC, Cheung AK, Ambrosius WT. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med 2015; 373:2103-16. 5. Taler SJ, Agarwal R, Bakris GL, Flynn JT, Nilsson PM, Rahman M, Sanders PW, Textor SC, Weir MR, Townsend RR. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD. Am J Kidney Dis 2013; 62:201-13. 6.
Verbeke F, Lindley E, Van Bortel L, Vanholder R, London G, Cochat P, Wiecek A, Fouque D, Van Biesen W. A European Renal Best Practice (ERBP) position statement on the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for the management of blood pressure in non-dialysis-dependent chronic kidney disease: an endorsement with some caveats for real-life application. Nephrol Dial Transplant 2014; 29:490-6.
C H A P T E R
DEAN'S ORATION
54
Hypertension in IndiaThe Way Forward A Muruganathan
INTRODUCTION
Hypertension is one of the most significant public health problem and a common lifestyle disease today in India. In 90% patients, the cause is idiopathic.1 Around 50% of the population remain undiagnosed. According to experts, Hypertension is likely to end up being an epidemic in the near future and 1/3 of the population would suffer from hypertension by the year to 2020. Increased awareness, treatment, and control of high blood pressure are critical for the reduction of mortality and morbidity. Shifting focus from expensive tertiary care for non-communicable diseases to primary and secondary prevention provided by primary health care and the community would be cost effective and will also save lives. It is suggested that community screening programs combined with simplified diagnostic evaluation and intense patient education and follow-up may greatly increase the success rate. Policy related, health systemrelated, as well as individual factors are the determinants and barriers for the poor-quality of hypertension management.2
INDIAN SCENARIO
In India 100 million patients are with hypertension. Overall estimates for the prevalence of awareness, treatment, and control of blood pressure (BP) are 25.3%, 25.1% and 10.7% for rural Indians and 42.0%, 37.6% and 20.2% for urban Indians respectively. (J Hypertens. Jun 2014; 32(6): 1170– 1177).3 According to CURE study, only15.4% of the total hypertensive group had blood pressure under control.4 Significant differences were noted in the rural and urban Disease burden estimates1990 Injuries 15%
Non-communicable 29%
Disease burden estimates2020
Injuries 19%
Communicable 24%
Communicable 56%
Non-communicable 57%
Source: Nutrition transition in India, 1947-2007, Ministry of women and child welfare
Fig-1 : A big cause of concern for India
areas for awareness and control of hypertension (P = 0.002 and 0.03, respectively). One recent study showed that young people working in IT industry have high BP because of their lifestyle. Youngsters spend more time on smartphones and seem to be living in a virtual world instead of being physically active.
Transition to Non-Communicable Diseases
There is a rapid transition in the disease burden seen over the past couple of decades from communicable to non-communicable disease in India. This is because of India’s economic growth, urbanization over the past decades, changing lifestyles, reduced physical activity, other rapidly evolving socioeconomic determinants, unhygienic and overcrowded living conditions, growing levels of stress, higher exposure to pollution, faulty food habits like increasing intake of saturated fats and tobacco by the people.5 The amount of fat intake increased by more than 25%, both in urban and rural areas,6 the per capita consumption of proteins went down. This, coupled with reduced physical activity, gives rise to intermediate risk factors such as hypertension and metabolic syndrome.20 million Indians are obese today with projected rise to 70 million by 2025[7]. Around 14% of Indians smoke daily and more young people are taking up smoking, levels of drinking and smoking are the highest amongst the lowest income quintile in India[8]. Due to poor access to health care, the high cost of treatment, social stigma, and low awareness they tend to ignore the disease. Seeking treatment would also mean missing wages, reduced productivity, an additional cost of transport to reach the nearest health facility especially for those in rural settings. Improved healthcare in India has increased the average life expectancy from 48.8 years in 1970 to 64.1 years in 2009[9], resulting in a growing aging population which faces an increased risk of hypertension. Between 2011 and 2031, the number of people above 60 years of age is expected to more than double in India. A recent screening drive by the government in Bangalore found 14% and 21% people to be suffering from diabetes and high blood pressure respectively. The government has announced the expansion of the program to screen 15-20 crore people across the country this year.
F -Family
294
R-Relatives I-Institutions, industry, E-Education group, schools, college, polytechnics
Normal
N-Neighborhood, house, village, town camps D-Doctor community, dears, and nears
HYPERTENSION
Prehypertension
Hypertension
Free BP checkup can be done in the following places 1.
Bus stands, railway stations, airports
2.
Shopping malls, supermarkets
3.
Banks, government, and corporate offices
4.
Petrol pumps
5. Theaters 6.
Temples and other religious places
7. Exhibitions
Fig. 2 Economic Burden of Hypertension in India •
The annual income loss from non-communicable disease in India was Rs. 251 billion
•
Hypertension alone has contributed Rs. 43 billion
•
It is a leading cause of hospitalization and outpatient visits
•
It is leading cause of absenteeism at workplace
Why screening for hypertension?
8.
Schools and colleges
In clinics and hospitals 1.
Check BP for all patients, attendees, visitors, and strangers
Through national health programs like noncommunicable disease (NCD) program by government of India in all the centers and also by conducting free health check-up camps by NGOs like Rotary, Lions, IMA, API, professional bodies and through self-help groups screening for hypertension can be done.
Hypertension screening is a strategy used in a population to identify the possible presence of yet to be diagnosed individuals without signs or symptoms.
What we should achieve by screening 1.
Identify people with prehypertension and advise preventive measures and lifestyle modifications.
1.
2.
Early detection of hypertension and management to prevent complications
3.
Treat hypertension and target organ damage aggressively
4.
Detect and treat associated risk factors
5.
Proper follow-up and suitable advice with documentation
2.
3.
4.
5.
Screening adults to detect hypertension early and initiate treatment before the onset of target organ damage occurs is highly cost effective. Major public health problem on cardiovascular health in India and leads annually to 1.1 million deaths. Account for 10.8% of all deaths and 4.6% of all Disability Adjusted Life Years (DALYs) in the country. Hypertension is directly responsible for 57% of all stroke deaths and 24% of all coronary heart disease (CHD) deaths in India. However, World Health Organization (WHO) has said that hypertension is the most easily preventable problem. The WHO report states that a 2 % reduction in diastolic blood pressure could prevent 3,00,000 deaths from cardiovascular disease by 2020.
How to screen for hypertension?
“FRIEND” approach for screenings
After identification, patients have to be referred to hospital for further management.
EVALUATION
Once the diagnosis of hypertension is clearly established by multiple blood pressure readings on different visits including readings in the supine and standing position, the physician must detect; whenever possible; the secondary forms of hypertension with the best cost effect approach. This can be done with the medical history, physical examination and selected clinical and biochemical analysis.
CRITICAL POINTS IN HISTORY TAKING FOR HYPERTENSION
1.
Duration of hypertension and previous therapeutic history.
2.
Personal and family medical history - hypertension, renal disease, diabetes, gout, etc., Habits -smoking and alcohol.
4.
Intake of hypertensinogenic agents- estrogen, sympathomimetics or steroid drugs.
5.
Lifestyle - exercise, stress (both at home and at work).
6.
Sleep history for sleep apnea.
7. Symptoms linked to secondary forms of hypertension- muscle weakness, spells of tachycardia, sweating and tremors and flank pain. 8.
Symptoms of target organ damage- a headache, dizziness, transient weakness, decrease of visual activity, chest pain, dyspnoea, claudication, and nocturia.
CRITICAL POINTS IN PHYSICAL EXAMINATION FOR HYPERTENSION
I.
In measurement of blood pressure-adhere rule of 12345
1.
One limb BP daily (same limb).
2.
Take BP in both limbs and for treatment purpose the limb with higher BP to be taken.
3.
Take BP in all three positions sitting, standing and supine position.
4.
Record all four limb BP when consulting for the first time.
5.
Take BP at least five times a week.
1.
BP should be recorded in all patients with loud- A2.
2.
Record twice, if in doubt,after10-minute interval.
3.
Three-time average BP in irregular pulse, like atrial fibrillation, ectopics.
4.
Four consecutive patients had elevation in diastole check your stethoscope earpiece for block and /or check your ears for wax.
5.
Before starting treatment ask them to check for BP with different times, different equipment/doctor at least five times
II.
General appearance- waist circumference, fitness, blushing and sweating.
III.
Psychologicalgeneral behavior- personality traits.
IV.
Fundus examination
V.
Neck examination – carotid auscultation and thyroid palpation.
VI.
Heart rate, rhythm, and murmur.
VII. Lungs-rhonchi, rales.
IX.
295
Extremities- pulse and edema.
INVESTIGATIONS FOR UNCOMPLICATED HYPERTENSION
1. Hemogram 2.
Analysis of renal functions
a.
Urine analysis and microscopic examination of sediment
b.
Blood urea, nitrogen, and creatinine
3.
Blood biochemistry
4.
Serum sodium, potassium, uric acid and glucose
5.
Lipid profile
6.
Chest x-ray, ECG, and ECHO
MANAGEMENT
In management of hypertension, usually physicians encounter so many pitfalls either directly related to him or through the patient
APPROACHES TO THE PREVENTION OF HYPERTENSION
[10]
The World health organization(WHO) has recommended the following approaches in the prevention of hypertension: 1.
Primary prevention
a.
Population strategy
b.
High-risk strategy
2.
Secondary prevention
PRIMARY PREVENTION
Primary prevention is a measure to reduce the incidence of disease in a population by reducing the risk. The earlier the prevention started the more likely it is to be effective.
POPULATION STRATEGY
The population approach is directed at the whole population, irrespective of individual risk levels. The concept of population approach is based on the fact that even a small reduction in the average blood pressure of a population would produce a large reduction in the incidence of cardiovascular complications such as stroke and CHD. The goal of the population approach is to shift the community distribution of blood pressure towards lower levels or “biological normality”. This involves a multifactorial approach, based on the following nonpharmacotherapeutic interventions
EDUCATION AND LIFESTYLE MODIFICATION
Nutrition 1.
Reducing salt (sodium) intake
•
Aim for less than 3-5 grams per day. However, the daily average salt consumption in Indian scenario is 8-9 grams per day.
Ways to reduce sodium intake
CHAPTER 54
3.
VIII. Abdomen- renal masses, bruit over aorta, renal and femoral arteries.
HYPERTENSION
296
•
Food items without added salts
•
Unsalted nuts, seeds, beans
•
Avoid adding salt and canned vegetables to homemade dishes
•
Unsalted and sodium, fat-free broths and soups
•
Use fresh poultry, lean meat, and fish.
•
Rinse canned foods to reduce sodium.
•
Low-sodium, low-fat cheeses
•
Add spices and herbs to enhance taste
•
Add fresh lemon juice instead of salt to fresh vegetables
Salt restricted food should be made available at hotels, marriage and other functions. This would create awareness among the public.
Know What to Eat: Dietary Approaches to Stop Hypertension (DASH)diet is an eating plan rich in fruits, vegetables, whole grains, fish, poultry, nuts, legumes, and low-fat dairy. These foods are high in key nutrients such as potassium, magnesium, calcium, fiber, and protein. The DASH diet can lower blood pressure because it has less salt and sugar.
Weight Reduction: The prevention and correction of overweight /obesity (BMI > 25) is a prudent way of reducing the risk of hypertension and indirectly Coronary artery disease; it goes with dietary changes. Even small amount of weight loss can make a big difference in helping prevention
Exercise Promotion: Lifestyle Recommendations for Hypertension: Physical activity should be prescribed to reduce blood pressure
F Frequency - Four to seven days per week
I Intensity
- Moderate
T Time
- 30-60 minutes
T- Type
- Cardiorespiratory Activity
- Walking, jogging
- Cycling
- Non-competitive swimming
historian stated that “The people’s health ought to be the concern of the people themselves. They must struggle for it and plan for it, this was against disease and for health cannot be fought by physicians alone. It is a people’s war in which the entire population must be mobilized permanently”.
An important element in community-based health programs is patient participation. The patient is taught about self-care, i.e., Home Blood Pressure Monitoring (HBPM) and keep a log-book of his BP readings.
High-Risk Strategy: The aim of this approach is “to prevent the attainment of levels of blood pressure at which the institution of treatment would be considered”. Detection of high-risk subjects should be encouraged by the optimum use of clinical methods. Since hypertension tends to cluster in families, the family history of hypertension and “tracking” of blood pressure from childhood may be used to identify individuals at risk.
2.
Secondary Prevention
The goal of secondary prevention is to detect and control high blood pressure in affected individuals.
Early Case Detection: Early detection is a major problem. This is because high blood pressure rarely causes symptoms until organic damage has already occurred, and our aim should be to control it before this happens. The only effective method of diagnosis of hypertension is to screen the population.
Treatment: In essential hypertension, we scale down the high BP to acceptable levels by the multi factorial approach.
Patientcompliance: The treatment of high blood pressure must normally is always life-long either through life modification or drugs and this where the problem of patient compliance arises, which is defined as ‘the extent to which patient behavior (in terms of taking medicines, following diets or executing other lifestyle changes) coincides with can be improved through education directed to patients, families and the community. Compliance can only be achieved through adequate patient education and strict follow-up.
Exercise should be prescribed as an adjunctive to pharmacological therapy
Behavioral Changes: Reduction of stress and smoking, moderation of alcohol drinking, modification of personal lifestyle, yoga, and transcendental meditation could be beneficial.
The basis of follow-up lies in the proper maintenance of records either by the physician or by the patient. It can be achieved through
a.
Hospital records or patient follow-up records
b.
Home-based monitoring of records using-
Health Education: The general public requires preventive advice on all risk factors and related health behavior. The whole possibility of primary prevention
Home blood pressure diary by British Hypertension Society[11]
My blood pressure log by American heart association.
Self-Care: Long ago, Henry Sigerist, the medical
Use www.heart360.org, a free online tool to track
and monitor health information including blood pressure.
THE WAY FORWARD[12]
Collaboration between stakeholders Government
•
Salt, sugar, and fat content in processed food to be regulated in collaboration with the food industry.
•
Advertising of unhealthy food to be regulated especially those targeted towards children.
•
Proper labelling of food to be mandated to show its nutritional content and warn about excess levels of salt, sugar or fats.
•
Anti-smoking laws to be implemented.
INDUSTRY
Pharmaceutical and Medical Technology12 •
Given the differences in genetic makeup across Indian population it is mandatory to make India specific clinical trials and sub-group data analysis.
•
Encourage localized price effective innovations like the low cost HBPM, and the polypill.
Insurance Agencies[12] •
Medical Equipment/ Pharma cos
Providers
Employers[12]
Stakeholders
Community/ Employers
Out-patient treatment and annual health checkups, wellness programs to be covered for all through innovative products of insurance scheme which can be incentivized.
Health Insurers
•
Awareness screening, by holding health camps, risk screening camps and other activities at work places.
•
Apart from creating healthy work environments that promote physical activity and healthy eating, conduct periodical health camps for improving awareness screening at work place.
Academia
COMMUNITY
[12] Hypertension control can be achieved by better government Academia
policies, political focus and social determinants of health such as education, development health system, proper health care financing, free or low-cost BP medicines, education for health care providers, free primary care, use of innovation in technology, collaboration with various stakeholders and patient empowerment.Patient empowerment has been said to be the blockbuster drug of 21st century.38 Self-control and behavioral strategies such as self-monitoring of BP, BP diary are important for improving adherence.13
•
Continuing medical education (CMEs) must be made mandatory to update the knowledge of health care professionals.
•
Teaching methods and syllabus to reflect the paradigm shift to prevention rather than intervention in light of increase of lifestyle diseases to be updated along with strengthening medical education and training infrastructure.
•
Study innovative business models like North Karelia Project, Finland The Tianjin Project, China Model and Recommendations of the World Hypertension League.
TACTICAL12
•
Primary and secondary healthcare system to be strengthened by retraining medical staff to focus towards surveillance, prevention and counselling.
•
Community health workers such as ASHAs, to be trained to raise awareness and to flag high risk people to the local health centre for timely intervention.
•
Improve health information systems for surveillance and monitoring of individuals by using ICT.12
Community12 •
All the stakeholders including media jointly create multi-sectoral and integrated programs involving the community and its leaders to raise awareness of the diseases and emphasize on prevention of the diseases.
•
Social marketing campaigns involving celebrities to promote physical activity, reduce smoking and
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CHAPTER 54
India has the intellectual and financial capability to overcome challenges being faced in delivering efficient and cost effective health service. Indian stakeholders need to collaborate and innovate in order to address the challenges of low accessibility, affordability, and awareness and to meet the healthcare needs of the population. Another area for innovation is the use of mobile technology and can give alert messages for proper follow-up. Another possible collaboration can be between the government, academia, and the pharmaceutical industry to conduct India specific trials and upgrading of the teaching manuals to include the latest content[12].
FOOD & AGRICULTURE LAWS12
healthy eating. Similar education programs to be conducted at schools and colleges.
298
CONCLUSION
Hypertension management is everybody’s responsibility. All stakeholders must co-ordinate, co-operate, collaborate and innovate to tackle this serious significant health concern of hypertension.
HYPERTENSION
“Today’s unhealthy behaviors are tomorrow’s risk factors. Today’s risk factors are tomorrow’s disease”
REFERENCES
1.
Strategies for Better Hypertension Control in India and Other Lower Middle Income Countries, Rajeev Gupta1 et al. Journal of the Association of Physicians of India 2016; 64.
2.
Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005; 353:487-497.
3. Hypertension in India: a systematic review and metaanalysis of prevalence, awareness, and control of hypertension - Raghupathy Anchala et al. Journal of Hypertension 2014; 32:1170–1177. 4. Prevalence, Awareness and Control of Hypertension in Chennai - The Chennai Urban Rural Epidemiology Study (CURES – 52) – V. Mohan et. al. JAPI 2007; 55. 5.
Nutrition Transition in India, 1947-2007. Ministry of Women
and Child Development, Government of India. http://wcd. nic.in/research/nti1947/8%20 Health%20transition.pdf 6.
India’s Pace of Urbanization Speeds Up, WSJ, July 2011 http://blogs. wsj.com/indiarealtime/2011/07/18/ Indiaspace-of-urbanization-speeds-up/
7.
Smoking & Heart Disease. Cleveland Clinic. http:// my.clevelandclinic.org/heart/prevention/smoking/ smoking_hrtds.aspx
8.
Xavier D, et.al. Treatment and outcomes of acute coronary syndromes in India (CREATE): a prospective analysis of registry data. The Lancet 2008; 371:1435-1442.
9.
Leeder S, et al. A Race Against Time. The Challenge of Cardiovascular Disease in Developing Countries. Columbia University, 2005.
10. K. Park (2015) Preventive and social medicine, 23 edn., 11. BHS (2016) Home Blood Pressure Diary, Available at: http://www.bhsoc.org/files/8514/1088/8028/Home_blood_ pressure_diary.pdf (Accessed:). 12. Cardiovascular diseases in India Challenges and way ahead - International Heart Protection Summit September 2011 www.deloitte.com/in 13. Chase D. Patient engagement is the block-buster drug of the century. Forbes/ Pharma and Healthcare. 9 Sep 2012. Available at: http://www.forbes.com/ sites/davechase/2012/09/09/ patientengagement-is-the-blockbuster-drug-ofthecentury/. Accessed 3 Jan 2016.
C H A P T E R
55
Management of Hypertension in Co-morbid Conditions Ketan K Mehta
This article will deal with non-cardiac, non-nephro & non-endocrine conditions, which are associated with hypertension. As we all know, hypertension has become the leading cause of death globally (as per WHO report) (Figure 1). The possible combination antihypertensives are discussed in Table 1. There are a large number co-morbidities that coexist along with hypertension. Let us discuss few of them.
TREATMENT OF HYPERTENSION IN ASTHMA & COPD (TABLE 2)
•
The calcium channel blockers (especially those of the dihydropyridine group, such as nifedipine and nicardipine) are excellent agents for the treatment of hypertension in asthma.
•
Diuretics can be effectively used in asthmatics, but may cause serious hypokalemia if used concurrently with inhaled ß2-receptor agonists which drive potassium into the cells and oral corticosteroids which enhance urinary potassium excretion.
•
In addition, diuretic-induced metabolic alkalosis can suppress the ventilatory drive, potentially exacerbating the degree of hypoxemia.
•
It is safest to administer only low thiazide doses (12.5 to 25 mg of hydrochlorothiazide) to nonedematous hypertensive patients with asthma or COPD
•
In addition to effectively lowering the blood
pressure, they also have the theoretical advantages of opposing muscle contraction in tracheobronchial smooth muscle, inhibiting mast cell degranulation, and possibly reinforcing the bronchodilator effect of beta agonists. •
The use of a low-dose thiazide alone or with a calcium channel blocker represents the preferred regimen for the initial management of the hypertensive asthmatic.
•
The management of hypertension in a patient with asthma or chronic obstructive pulmonary disease (COPD) may be made difficult by the asthmaexacerbating effect of some antihypertensive drugs.
•
Beta blockers can cause increased bronchial obstruction and airway reactivity, and resistance to the effects of inhaled or oral beta receptor agonists (such as albuterol or terbutaline) in patients with asthma but not COPD.
•
Even topical ophthalmic administration of nonselective beta blockers for the treatment of glaucoma has led to asthmatic exacerbations.
•
Although the clinical effects of more ß1-selective beta blockers on pulmonary function appear to be less severe, even ß1-selective agents should be used with caution in patients with severe obstruction or markedly reduced baseline pulmonary function.
•
As the duration of Hypertension advances, patient will require combination therapies for control of BP.
Table 1: Possible Combination Drugs for Hypertension Combination type
Examples
ACE inhibitors and calcium channel blockers
Amlodipine-benazepril, enalapril-felodipine
ACE inhibitors and diuretics
Lisinoprilhydrochlorothiazide
Angiotensin II antagonists Losartanand diuretics hydrochlorothiazide
Fig. 1: Death due to leading risk factors
Beta blockers and diuretics
Bisoprololhydrochlorothiazide
Centrally acting drug and diuretic
Methyldopahydrochlorothiazide
Diuretic and diuretic
Triamterenehydrochlorothiazide
HYPERTENSION
300
Table 2: Summary of comments and recommendations regarding use of antihypertensive agents in patents with chronic obstructive pulmonary disease Thiazide diuretics
Low doses are probably effective and safe
Loop diuretics
Should not be used as an antihypertensive except in patients with advanced renal disease who do not respond to thiazide diuretics.
Potassium-sparing diuretics
Not a first-line agent. Limited (Lata but no specific contraindications.
Aldosterone receptor blockers
Not a first-line agent. Limited data but no specific contraindications.
Beta blockers
Some conflicting data, but cumulative evidence supports safety. Historical underutilization probably not justified. Probably not a first-line agent if hypertension is die only indication. Propranolol and atenolol should not be used.
Limited data but probably Beta blockers with intrinsic sympathomimetic similar to beta blockers. activity Combined alpha and beta blockers
Should probably not be used if hypertension is the only indication.
Angiotensin-converting enzyme inhibitors
Should not be used as a first-line agent because of the associated cough.
AngiotensinII antagonists
Limited data but no safety concerns.
Calcium channel blockers: non-dihydropyridines
Can be used safely.
Calcium channel blockers: dihydropyridines
First-line agent.
Alpha-1 blockers
No safety concerns.
Central alpha-2 agonists and other centrally acting drugs
Limited data but there may be some safety concerns.
Direct vasodilators
Limited data but no safety concerns
HYPERTENSION IN LIVER DISEASES
•
A decrease in the arterial blood pressure is seen when the patients develop cirrhosis.
•
The prevalence of fatty liver in non-obese, nondiabetic hypertensive patients is at least twice that of the general population and may be related to increase in insulin resistance and body weight.
•
Most of the drugs can be safely used in chronic liver disease.
TREATMENT OF HYPERTENSION IN BPH
Many of the alpha blockers used to treat BPH also decrease BP, and Terazosin, Doxazosin & Prazosin have been shown to have significant CV side effects, such as asthenia/fatigue, postural hypotension and dizziness when used to treat BPH patients. Furthermore, these drugs are not first line therapies for Hypertension, and majority of hypertensive BPH patients will be receiving other antihypertensive agents. Therefore, it is possible that that introduction of these drugs will affect BP control, at least temporarily, with possible adverse effects. In contrast, the selective alpha1A blocker tamsulosin does not appear to have significant CV side effects and produces minimal BP reductions. Evidence from outcome trial suggest alpha 1 blockers should not be used as first-line antihypertensive therapy. The Hypertension and BPH Intervention Trial (HABIT) is a large, community-based trial in patients with concomitant symptomatic BPH and hypertension. It showed that doxazosin not only provided effective treatment for both BPH symptoms and hypertension, but also was successful as add-on therapy for controlling BP in the majority of patients whose BP had been inadequately controlled with previous antihypertensive therapy. Age did not influence the efficacy and tolerability of Doxazosin, and no detrimental effect on sexual function was noted.
RECOMMENDED READING
1.
Integr Blood Press Control. 2013; 6: 101–109.
2.
World J Gastroenterol 2006; 12:678–685.
3.
J Hypertens 2010; 28:1829-35.
4.
J Clin Hypertens 2005; 7:212-7.
5.
Clinical Therapeutics 2004; 26:11.
6.
ESH Scientific Newsletter: Update on Hypertension Management, 2012; 13: No. 51
7.
Gut 2004; 53:923-924