IIb C In \201 t elderly patients less than 80 years old SBP values <140 mmHg may be considered, whereas in the fragile elderly population SBP goals should be adapted to individual tolera bility. In individuals older than 80 years old with initial SBP \211 160 mmHg, it is recommended t o reduce SBP to between 150 and 140 mmHg provided they are in good physical and mental cond ition. I B A DBP target of <90 mmHg is always recommended, except in patients with diabetes, in whom v alues <85 mmHg are recommended. It should nevertheless be considered that DBP values betwee n 80 and 85 mmHg are safe and well tolerated. I A aClass of recommendation; blevel of evidence CHAPTER 6 Hypertension 468 Joint National Committee (JNC) guideline The latest iteration of this in \202 uential guid eline has been delayed by an unprecedented degree of prerelease stakeholder scrutiny. Howev er, it is expected that JNC 8 (or JNC \200\230late \200\231 as it has been dubbed) may, li ke ESH-ESC, offer a more stringent interpretation of available data \200\224 retaining a go al of 140/90mmHg for the majority, but suggesting higher targets may be acceptable for many patients age >60 (and particularly age >80). JNC 8 may also echo ESH-ESC by offering a mor e circum- spect view of lower treatment targets (<130/80mmHg) in the presence of comorbidit ies such as diabetes and CKD. The current status is available at: M http://www.nhlbi.nih.gov/ guidelines/hypertension/jnc8/ KDIGO \200 Recommend a BP target <140/90mmHg for non-diabetic, non- proteinuric CKD patients Target <130/80mmHg if proteinuria (>30mg/24h) whether diabetic or not. Tailor treatment regimes for individual elderly patients by carefully considering age, co-morbidities and other therapies. Escalate treatment carefully under app ropriate supervision. X The J-curve phenomenon The question \200\230how low to go? \200\231 remains both valid a nd important. It is possible that there may be a threshold below which additional BP reduc- tion is no longer bene \201 cial. This could be explained by the maintenance of physiolog ical autoregulation within organ vascular beds, particularly in the presence of CV disease. The data supporting a \200\230lower the better \200\231 approach have come from meta-analy zes of multiple trials, rather than from studies speci \201 cally designed to scrutinize d ifferent target ranges. Indeed, some trials, such as ACCORD, have shown no consistent reduc tion in CV events, even when lower average SBPs are achieved. Furthermore, it has been in- ferred from some studies; e.g. ONTARGET that lower BP targets may actually be associated wi th additional coronary events. Many interpret the J-curve relationship to mean that BP reduction to lower levels, even if not harmful, is certainly less meaningful than a reduction to more moderate values. These issues are re \202 ected in the latest iterations of the guidelines discussed above, which have become more guarded in their recom- mendation of lower targets, even in high-ri sk groups. Overall, current evidence suggests that, even if escalating therapy to achieve the lowest p ossible BP is not clearly detrimental, neither is it clearly advantageous \200\224it may no t \210 be cost effective, with patients unnecessarily exposed to side effects that in \202 uence their overall compliance. CLASSIFICATION AND TREATMENT THRESHOLDS 469 Suggested indications for specialist referral \200 Urgent (inpatient) treatment needed: Accelerated hypertension (severe i BP, with grades III \200\223 IV retinopathy). Particularly severe hypertension (>220/120mmHg). \200 Hypertensive emergency (e.g. enceph alopathy, eclampsia, aortic dissection). Impending complications (e.g. LVF, TIA). Possible s hypertension. \200 Resistance to treatment ( \211 3 drugs). \200 Multiple drug intolerances. \200 Multiple drug contraindications. \200 Persistent non-adherence or non-compliance. \200 Other situations: Unusual blood pressure variability. \200 Possible white coat hypertension. \200 Hyperte nsion in pregnancy. CHAPTER 6 Hypertension 470 Cardiovascular risk assessment Formal assessment of CV risk is the starting point for treat ment decisions and discussions between clinicians and patients. The ultimate goal of the tr eatment of hypertension is prevention of CV disease. \200 The absolute risk of a CV event varies widely according to age, sex, severity of BP, and presence or absence of additional risk factors. The relative risk reduc tion of interventions is constant. Overprediction l overtreatment, underprediction l missed opportunity. Estimation of risk is straightforward in many patients; e.g. those with established CV dise ase, diabetes, CKD or a signi \201 cantly elevated single risk factor. In these situations CV risk is high and aggressive intervention highly desirable. Many patients, however, do not belong to such high-risk groups and estimation of risk requires the use of risk-prediction models. Many computerized models have been developed. None are perfect. They aim to identify patien ts for intervention and calculate potential risk reduction. Many are based on Framingham data*. However, Framingham studied a Caucasian, middle class p opulation on no treatment (i.e. no aspirin, statins etc.) and is several decades old. See w ww. framinghamheartstudy.org/risk Framingham-based scoring tends to overestimate CV risk in low and medium risk groups and underestimate CV risk in renal disease, diabetes, certain ethnic groups, those with LVH and those with FH of premature CHD. It has \210 been suggested th at the risk score should be adjusted by a factor of x 1.5 if there is one relative with pre mature CVD and by x 1.4 if the individual is a male of South Asian origin. \200 Many mode ls refer to 10-year risk of CV mortality. High risk refers to 10-year CV mortality of \211 20%. The Systematic Coronary Risk Evaluation (SCORE) model has been developed from large European cohort studies. It allows calibration for several different c ountries and is recommended by ESH-ESC. An inter- active version of SCORE is available thro ugh www.heartscore.org. \200 ASSIGN (www.assign-score.com) is based on Scottish data and takes FH and social deprivation into account. There is a move toward estimations of lifetime rather than 10-year risk. For example, the QRISK lifetime risk calculator identi \201 es younger patients with high lifetime risk (de \201 ned as >50%) who would not be identi \201 ed using 10-year r isk estimates. (www.qrisk.org). The prediction of lifetime risk is recommended by the Joint British Societies (see http://www.jbs3risk.com). Risk calculators may not be appropriate when individuals are at higher CV risk because of u nderlying medical conditions/treatments (e.g. HIV, autoimmune disease). Clinical judgment is important when making decisions in certain circumstances (e.g. obesity, taking statins, already on BP treatment, recently stopped smok ing). The Framingham Heart Study: a cohort of over 5,000 men and women, aged 30 \200\22362, from Framingham, Massachusetts, followed up from 1971 to assess the determinants of CV disease. CARDIOVASCULAR RISK ASSESSMENT 471 When you don \200\231t need a risk calculator: Assume the following groups of people are at high risk (10-year CVD risk \211 20%), rathe r than use risk calculators: \200 Pre-existing CVD. \200 DM. \200 CKD. \200 Familia l hypercholesterolaemia. CHAPTER 6 Hypertension 472 Lifestyle measures Lifestyle changes can d BP, reduce drug requirements, and improve CV ris k (see Table 6.5). The effects are synergistic. Clear advice, including culturally appropri ate written and audiovisual material, should be provided to all patients as well as to thos e with a high normal (pre-hypertensive) BP or positive family history. Low-sodium diet Reduces BP in normotensive and hypertensive populations. Enhances response to ACE-I/ARB treatment. Usual Na + intake is in the range 150 \200\223 200mmol/day (8 \200\223 12g/day). Reduce by as much as possible; at least < 100mmol/day ( 7 2.3g of Na + o r 6g NaCl). The majority (80%) of salt is \200\230 hidden \200\231 (breads, stock cubes, \200\230 ready meals \200\231 , breakfast cereals, sauces). Avoid salt in cooking and on the table. Cook using natural ingredients. Dietary sodium can be estimated by 24h urine Na (aim <100mmol/24h). If necessary, refer to a dietitian. Note: 1g of Na + contains 44meq, 1g of NaCl contains 17meq of Na + ; 5g of NaCl 7 1 teaspoon. Patients should be advised that, with time, their taste sensitivity to salt will increase if they undertake a restriction. 1 Low Na + salt substitutes often contain K + as KCl and can cause dan- gerous hyperkalaemi a in patients with CKD and those taking K + -sparing diuretics. Weight loss Obesity (BMI \211 30) is fueling the increasing incidence of i BP and T2DM. W eight reduction improves BP, even without dietary Na + restriction, and has bene \201 cial effects on insulin resistance, lipids, LVH, and diabetic control. Healthy eating Advise a diet high in fruit and vegetables ( \201 ve portions/day), low in saturated fats, low in total and saturated fats. The \200\230 Dietary Approach to Hyperten sion Trial \200\231 (DASH) demonstrated impressive reductions in BP. The DASH eating plan can be downloaded at: M http://www.nhlbi.nih. gov/health/public/heart/hbp/dash . K + , Mg 2 + , and Ca 2+ supplementation is not recommended. Exercise Exercise has been shown to reduce the risk of DM and decrease BP by up to 10mmHg. 2 Think \200\230 FITT \200\231 (Frequency (5 x /week), Intensity (moderate, mildly SOB), Time (at least 30min), Type (any aerobic). Isometric and strenuous exer- cise tends to i BP and is best avoided until BP is under control. Alcohol There is a linear relationship between C 2 H 5 OH consumption and BP, with the inci dence of i BP increasing 7 1.5 \200\223 2.0 x at > 2 drinks/day. It is also asso- ciated w ith drug resistance. Patients will, no doubt, remind you of the apparent paradox that moder ate alcohol intake reduces overall CV risk; LIFESTYLE MEASURES 473 however, recommended daily amounts should not be exceeded ( \231\202 : < 21 units/week; \231\200 : < 14 units/week). The effect of C 2 H 5 OH is reversible; d alcohol intake by 3 units/day l d need for medication (in 7 1 \200\223 6 weeks). Caffeine Caffeine is an adenosine receptor antagonist ( l vasoconstriction). > 5 cups coffe e/day is undesirable. It causes an immediate increase in SBP by 7 10 \200\223 15mmHg for s everal hours. Caffeine is also present in tea and cola drinks, although coffee only has bee n studied. Recommend decaffeinated alternatives. Stress management Modest effect, e.g. meditation, cognitive therapy, biofeedback, muscle re laxation, etc. If patients are keen, cognitive behavioral therapy is most likely to have a signi \201 cant impact. Table 6.5 Lifestyle interventions for BP reduction Intervention Recommendation Expected SBP reduction (range) Weight reduction Maintain ideal BMI (20 \200\223 25kg/m 2 ) 5 \200\223 10mmHg per 10kg weight loss 8 \200\223 14mmHg Diet Consume diet rich in fruit, vegetables, low-fat dairy products with reduced content of satu rated and total fat d dietary sodium intake to < 100mmol/day ( < 2.3g sodium or < 6g sodium chloride) 2 \200\223 8mmHg Dietary sodium restriction 4 \200\223 9mmHg Physical activity Undertake regular aerobic activity, e.g. brisk walking for \211 30min most days \231\202 < 21 units/week \231\200 < 14 units/week Alcohol 2 \200\223 4mmHg Additional lifestyle measures that d CV risk \200 Stop smoking. Does not d BP but will im prove overall CV risk. Quitting before middle age returns life expectancy to near that of lifelong non-smokers. \200 Reduce total fat intake. \200 Replace dietary saturated fats with monounsaturated f ats. \200 Increase consumption of oily \201 sh. CHAPTER 6 Hypertension 474 Secondary hypertension An identi \201 able cause is found in 7 5 \200\223 10% of all case s of i BP, though true prevalence of secondary hypertension remains unknown. It is more com - mon in the subgroup of \200\230 resistant \200\231 hypertension ( b p. 516). History, examination, routine investigation (plus a high index of sus- picion) should ident ify those in need of more specialist assessment. The diagnosis of secondary hypertension is important to make, as curative treatment may be available. Diagnostic clues are shown in Table 6.6. Classi \201 cation \200 Renal disorders (for i BP in CKD, see b p. 203 \200\2234): Virtually any renal parenchymal disease: acute or chronic GN, tubulointerstitial disease, A PKD, obstructive nephropathy. Renovascular disease ( b p. 586). \200 Renin-producing tumors ( b p. 479). \200 Genetic diseases affecting tubular transportation (Liddle \200\231 s syndrome, b p. 800). Very rare. Endocrine disorders: Mineralocorticoid excess ( b p. 476): p aldosteronism, apparent mineralocorticoid excess, c ongenital adrenal hyperplasia, liquorice ingestion, ectopic ACTH secretion, exogenous miner alocorticoids (e.g. \202 udrocortisone), pseudohyperaldosteronism. Others, including phaeochromocytoma, Cushing \200\231 s syndrome, hypothyroidism, hyperthyroidism ( i SBP), hyperparathyroidism, acromegaly, or carcinoid syn drome. Drugs: Prescribed: estrogen-containing contraceptives, sympathomimetic agents (cold cures), glucocorticoids, NSAIDs (and COX-2 inhibitors), ciclosporin, monoamine oxidase inhibitors, sodium bicarbonate. Over the counter: sympathomimetic agents, NSAIDs. \200 Illicit: amphetamines, cocaine. Pregnancy ( b p. 846): Pregnancy-induced hypertension, pre-eclampsia, and eclampsia. Miscellaneous: Obstructive sleep apnoea. \200 Coarctation of the aorta ( d renal perfusion). \200 Incr eased intracranial pressure or spinal cord injury. \200 Acute LVF and intravascular volum e overload (IV \202 uids!). \200 Acute intermittent porphyria. \200 Alcohol withdrawa l. \200 Haemochromatosis. \200 Hyperdynamic circulation (systolic hypertension): anemia , fever, thyrotoxicosis, aortic regurgitation, AV \201 stulae. SECONDARY HYPERTENSION 475 Table 6.6 Diagnosis of secondary hypertension Condition Diagnostic clue Further investigation i SCr Proteinuria haematuria i SCr Acute i SCr post-ACE-I/ARB Renal asymmetry on imaging Flash pulmonary oedema Abdominal bruit (sensitivity: 65%; speci \201 city 90%) Primary renal disease Renal USS (?APKD) Renal biopsy Renovascular hypertension CT angiogram MRA Duplex USS Formal angiography Hypokalaemia (rarely l muscle weakness, polyuria, arrhythmias). May be unmasked following t he introduction of a thiazide diuretic Plasma aldosterone/ renin ratio Urinary aldosterone excretion (post-salt load) Primary aldosteronism Mainly children i BP, d K + , d renin Aldosterone not i i ratio of THF to THE in urine (see Other \200\230hyperaldosteronism \200\231 syndrome; Bo x 6.4) Apparent mineralocorticoid excess Urinary catecholamines Phaeochromocytoma Paroxysmal symptoms (headache, palpitations sweating) Thyroid disease Both hypo- and hyper- are associated Thyroid function i serum Ca 2+ Hyperparathyroidism Serum PTH Urinary cortisol excretion Dexamethasone suppression tests Cushing \200\231 s syndrome Corticosteroid therapy Cushingoid appearance (central obesity, striae bruising, etc.), musc le weakness, hyperglycaemia, oligomenorrhoea Coarctation of the aorta Midsystolic murmur (precordium l back) Weak femoral pulses Radiofemoral delay BP in arms i , BP in legs d CT or MRA Aortography Sleep observation with pulse oximetry Formal polysomnography Obstructive sleep apnoea Snoring, daytime somnolence, morning headache, obesity (large collar size) i IGF-1 Failure to suppress GH to < 2mU/L post-75g oral glucose load i sweating, headaches, fatigue, arthralgia, change in shoe/ring size, change in appearance, hyperglycaemia Acromegaly CHAPTER 6 Hypertension 476 Primary hyperaldosteronism Introduction Aldosterone acts on the distal tubule to i renal Na + retention (with i urinary K + and H + loss), i total body Na + content ( l i BP). Disord ers of autonomous aldosterone secretion with suppressed renin account for 7 0.1% of the hyp ertensive population (possibly an underestimate, some say 1 \200\223 5%) and is the most c ommon endocrine disorder leading to s hyper- tension. It is also associated with i CV risk beyond that expected by the level of BP alone. Clinical and biochemical \201 ndings vary widely. Often asymptomatic but may present with d K + , metabolic alkalosis, and mild i Na + (helps distin- guish from essential BP treate d with diuretics where Na + is usually low normal). However, d d K + with diuretics (<3.0mm ol/L) remains suspicious. Severe d K + l tetany, myopathy, and nephrogenic diabetes insipid us (polyuria and nocturia). Causes \200 Conn \200\231 s syndrome (aldosterone-producing adrenal adenoma) 7 70%. \200 Bilateral adrenal hyperplasia 7 30%. \200 Aldosterone-producing adrenal carcinoma ( i i aldosterone and d d K + \200\224 may also produce cortisol and sex steroids). Primary (unilateral) adrenal hyperplasia. \200 Glucocorticoid-remediable aldosteronism. Diagnosis \200 d K + is only present in 50 \200\223 80% early on (leading to underdiagno sis). \200 Renal K + wasting (urinary K + > 30mmol/day). \200 Aldosterone \200\223 ren in ratio (ARR): Commonly used diagnostic test (see Box 6.2). \200 Unregulated aldosterone secretion l sup pressed renin production and i ARR. Note i BP in the malignant phase often has electrolyte abnormalities similar to primary hyp eraldosteronism, i.e. d K + , i HCO 3 \200\223 . ARR is not interpretable at this stage so should not be done in this acute setting. There is no gold standard test for p hyperaldost eronism. Con \201 rmatory tests include: \200 Oral or IV salt loading: High Na + diet for 3 days (200mmol/day \200\224 ask your dietitian) or IV normal saline (2L over 4h). Verify with urinary Na + > 250mmol/24h. \200 Measure 24h urinary aldosterone. Normal resp onse: suppressed aldosterone secretion ( l lack of suppression con \201 rms diagnosis). 1 May precipitate d K + ; supplement with slow-release KCl. Fludrocortisone suppression test: 4-day administration of \202 udrocortisone further suppresses plasma renin activity without suppressing plasma al dosterone below a threshold value. PRIMARY HYPERALDOSTERONISM 477 A captopril challenge test fails to suppress aldosterone >30% in primary hyperaldosteronism. Adrenal CT and MRI are used to localize tumors ( > 1.5cm). \200 1 Never order imaging bef ore con \201 rming secretion. \200 Never assume a radiologically apparent adrenal adenom a con \201 rms the laterality of secretions if planning adrenalectomy. Adrenal venous sampling is occasionally necessary \200\224 the distinction between a discr ete adenoma and diffuse hyperplasia is important because of the potential role of surgery i n the former. General principles of treatment Spironolactone (a competitive antagonist of the mineralocor ticoid receptor, b p. 501), initially 50 \200\223 100mg (SE: gynaecomastia, impotence, men strual irregularities, GI upset). Eplerenone is an alternative but less effective. Add amil oride 5 \200\223 20mg if d K + persists or gynaecomastia. Other antihypertensive agents ma y also be required. Surgical resection if ade- noma: 70% normotensive at 1 year ( X results less good in some series \200\224 esp. if BP long-standing). Some argue for a trial of sp ironolactone in all cases of resistant hypertension ( b p. 516). Box 6.2 ARR: the nuts and bolts \200 Correct hypokalaemia ( d K + suppresses aldosterone) . Encourage liberal sodium intake. Tubes: liaise with your biochemistry lab \200\224 usually one plain tube or lithium tube for aldosterone and one EDTA tube for renin. They will de \201 nitely want to know that the samples are coming. Now generally NOT placed on ice (promotes conversion of inactive l active renin). Withdraw agents that markedly affect ARR for at least 4 weeks (spironolactone, eplerenone, amiloride, triamterene, potassium-wasting diuretics). Th is can be dif \201 cult. If it is possible to control BP with other medications, withdraw drugs that may affect the ARR for at least 2 weeks ( B -blockers, ACE-I, ARB, diuretics). This can also be dif \201 cult. The \200\230 cleanest \200\231 drugs are A -blockers, e.g. doxazosin. Hydralazine and verapamil also have minimal effects of ARR. \200 Establish oral contraceptive and HRT sta tus. \200 Conditions for collection blood: Time: 07.00 \200\223 09.00. \200 Posture: upright (for at least 2h). \200 Maintain sam ple at room temperature. \200 Result: aldosterone (pmol/L)/plasma renin activity (ng/mL/h ) > 750 or aldosterone (ng/dL)/plasma renin activity (ng/mL/h) > 30 \200\223 50. The highe r the ratio, the more likely the diagnosis. Refer equivocal cases to a specialist center. CHAPTER 6 Hypertension 478 Speci \201 c causes of hyperaldosteronism Primary hyperaldosteronism Glucocorticoid-remediable aldosteronism (GRA) Very rare. Autosomal dominant. A chimeric ald osterone synthase/ 11 B -hydroxylase is ectopically expressed in the adrenal fasciculata. A CTH l stimulates enzyme activity l normal cortisol production + aldoster- one excess ( l vo lume expansion and i BP). Presents with i BP at a young age, with a family history (early h aemorrhagic stroke in some pedigrees). Diagnosis (see Fig. 6.5) now con \201 rmed with gen etic testing. Dexamethasone l suppresses ACTH secretion l d enzyme activity l d aldosterone production. Congenital adrenal hyperplasia (CAH) Inherited enzymatic defects (autosomal recessive) in c ortisol production. Clinical features depend on the enzyme affected but result from: (i) d cor- tisol synthesis, (ii) i ACTH-driven steroid production. Two forms (of six) are associa ted with mineralocorticoid excess and 6 i BP: \200 11 B -hydroxylase (CYP11B1) de \201 c iency, presenting in childhood; \231\200 are virilized, and \231\202 are sexually precocious. 17 A -hydroxylase (CYP17) de \201 ciency. Extremely rare. Presents with i BP, d K + , and hypogonadism \200\224 often at puberty. Secondary hyperaldosteronism \200 Occurs when aldosterone hypersecretion results from i c irculating renin levels \200\224 often in response to renal hypoperfusion. i renin l i circulating A2, i peripheral resistance, and i BP (often severe). Associated s hyperaldosteronism l i tubular Na + reabsorption ( 6 d K + ). Causes include: Renal artery stenosis. \200 Renal infarction, e.g. atheroemboli. \200 Cirrhosis (vasodi latation l d effective circulating volume). \200 CCF (falling CO l d effective circulatin g volume). \200 Nephrotic syndrome. \200 Renal trauma (so-called \200\230 Page kidney \200\231 ) ( b p. 84). \200 Renin-secreting tumors (see Box 6.3). SPECIFIC CAUSES OF HYPERALDOSTERONISM 479 Box 6.3 Renin-secreting tumors \200 Very rare. \200 Renin-secreting tumor of the juxtag lomerular cells l angiotensin-induced i BP. Presents with severe i BP, d K + ( i urinary K + excretion), i renin, i angiotensin II, and i aldosterone. Diagnosis: MRA, angiography (tumor blush). \200 Treatment: ACE-I and ARBs effectively d B P. \200 Surgery may be curative. Hypertension and hypokalaemia Measure plasma renin activity (PRA) and plasma aldosterone concentration (PAC) iPRA and iPAC nordPRA and iPAC dPRA and dPAC Renovascular - Renal infarct - Acute GN - Diuretics - Coarctation - Renin-secreting tumor Primary aldosteronism - Conn \200\231s syndrome (aldosterone-producing adrenal adenoma) - B ilateral adrenal hyperplasia - Glucocorticoid suppressible hyperaldosteronism - Aldosterone -producing adrenal carcinoma Apparent mineralocorticoid excess - Liquorice - Liddle s syndrome - Congenital adrenal hype rplasia - Exogenous mineralocorticoid - Cushing s syndrome Fig. 6.5 Diagnostic algorithm for hyperaldosteronism. CHAPTER 6 Hypertension 480 Other \200\230hyperaldosteronism \200\231 syndromes Other mineralocorticoids can cause a c linical syndrome very similar to that seen with i aldosterone \200\224 with i BP, d K + , and alkalosis. Crucially, both renin and aldosterone are suppressed. \200 Causes include: Apparent mineralocorticoid excess. \200 Congenital adrenal hyperplasia. \200 Liquorice ingestion. \200 Ectopic ACTH secretion. \200 Exogenous mineralocorticoids, e.g. \202 udrocortisone. Apparent mineralocorticoid excess < 1% hypertensives . Autosomal recessive, presenting in c hildhood. in 11 B -hydroxysteroid dehydrogenase 2 Inactivating mutation (11 B HSD2). The mi neralocorticoid receptor (which has an equal af \201 nity for cortisol and aldosterone) is protected from ongoing cortisol stimula- tion by 11 B HSD2, which metabolizes cortisol l c ortisone (relatively inactive). As cortisol is present at 100-fold concentrations, compared to aldosterone, absence/inhibition of this enzyme allows cortisol to \202 ood the recept or l chronic activation. Diagnosis i ratio of urinary tetrahydrocortisol (THF + 5 A THF) (metabolite of cor- tisol) to tetrahydrocortisone (THE) (metabolite of cortisone). Management Block the mineralocorticoid receptor (spironolactone) or suppress ACTH secretion (dexamethasone suppresses endogenous cortisol syn- thesis but does not activate the minera locorticoid receptor). Liquorice contains glycyrrhizinic acid, which can bind the 11 B HSD2 enzyme, creating a sta te of apparent mineralocorticoid excess. Most com- mercial liquorice preparations in the UK do not contain large amounts, but continental or \200\230 traditional \200\231 preparati ons are stronger (and often are combined with salt!). Also look out for it in herbal prepar ations. \200\230Pseudoaldosteronism \200\231 Caused by abnormalities of renal tubular transportati on, rather than elevated renin or aldosterone. The electrolyte abnormalities mimic those se en with i aldosterone, hence the name ( b p. 800). Causes include: \200 Liddle \200\231 s syndrome. \200 Bartter \200\231 s syndrome (normotensive). \200 Gitelman \200\231 s syndrome (normotensive). OTHER \200\230HYPERALDOSTERONISM \200\231 SYNDROMES 481 CHAPTER 6 Hypertension 482 Other causes of secondary hypertension Cushing s syndrome Prevalence in hypertensive popula tions estimated at 0.5 \200\223 1%. i BP is very common, affecting 7 80%. Look for typical phenotype, and exclude exog- enous glucocorticoids. 24h urinary cortisol excretion is a re liable diagnos- tic test ( > 110nmol/day is highly suggestive). Diagnosis con \201 rmed by a 2-day low-dose dexamethasone suppression test (0.5mg every 6h for eight doses; a cortiso l drawn 4 \200\223 6h after the last dose should be <140nmol/L) or an over- night suppress ion test (1mg at 23.00; cortisol should suppress to <50mmol/L). Measurement of serum ACTH c oncentrations, a long dexamethasone sup- pression test corticotrophin-releasing hormone (CRH) stimulation test and adrenal/pituitary imaging will help to distinguish different for ms of the syn- drome (Cushing \200\231 s disease most common: pituitary overproduction of ACTH). Phaeochromocytoma Adenoma (rarely carcinoma) of adrenal medulla l oversecretion of cat- ech olamines (adrenaline l i HR and contractility; noradrenaline l i SVR). Can also arise in ex tra-adrenal chromaf \201 n tissue (e.g. para-aortic ganglia). Very rare ( < 0.1% hypertens ives). Consider if: \200 Severe sustained and/or paroxysmal i BP refractory to therapy. \200 Large postural drop. \200 i BP + symptoms of catecholamine excess (headache, palpit ations, sweating, angina, anxiety, etc.) i BP triggered by B -blockade ( s to unopposed A stimulation. Avoid if suspected). Previous phaeochromocytoma (risk of recurrence). Associated with multiple endocrine neoplasia (MEN) 2A or 2B, von Hippel \200\223 Lindau di sease, von Recklinghausen \200\231 s neuro \201 bromatosis. Best tested during, or immediately after, episodes. The sensitivity and speci \201 city of various screening tests are shown in Table 6.7. Con \201 rm bio- chemically before imagin g, usually 24h urine catecholamines x 3 (acidi- \201 ed container). CT/MRI identi \201 e s most tumors. MIBG scanning localizes tumors or multiple tumors/metastases ( 7 10% maligna nt). Treatment: A - and B -blockade prior to surgery. Table 6.7 Sensitivity and speci \201 city of screening tests for phaeochromocytoma Sensitivity (%) Speci \201 city (%) Plasma metanephrines 99 89 Plasma catecholamines 85 80 Urinary catecholamines 83 88 Urinary metanephrines 76 94 Urinary vanillymandelic acid 63 94 Reproduced with permission from Pacak K (2001). Recent advances in genetics, diagnosis, loc alization and treatment of phaeochromocytoma. Ann Internal Medicine , 134 , 315 \200\223 2 9. OTHER CAUSES OF SECONDARY HYPERTENSION 483 Coarctation of the aorta A rare cause of s i BP in children and young adults. \231\202 > \231\200 . Represents < 1% of congenital heart disease. Medial and neointimal thickening ca uses a shelf-like structure to extend into the aortic lumen just distal to the left subclav ian artery. Often asymptomatic, may be diagnosed after CV examination; midsystolic murmur, radiofemoral delay, i BP (arms > legs), or CXR (aortic \200\230 3 sign \200\231 from pre- and post-stenotic dilatation and poste- rior rib notching). If undetected in childhood, pr esents with cardiac fail- ure in middle age and with a worse prognosis. Diagnosis : CT, MRA , or aortography. Treatment : surgical. BP correction is age-dependent ( > 90% in childhood). Drug-induced hypertension See b p. 474. Obstructive sleep apnoea (OSA) The number of diagnosed and treated patients with OSA is ris ing rapidly. i BP is commonly associated. Often treatment-resistant and associated with a l ack of nocturnal dipping on ABPM. Assess for daytime somnolence (see Box 6.4). Rx : treatment of the OSA improves BP. Weight reduction, alcohol avoidance, correction of a irway obstruction, oral prosthetic devices, over- night non-invasive ventilation, CPAP, uvu lopalatopharyngoplasty. Box 6.4 Epworth sleepiness score How likely are you to fall asleep in the following situati ons, in contrast to just feeling tired? 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing 1 \200\223 6 points: normal; 7 \200\223 8 points: average; 9 \200\223 24 points: abnorma l (? pathological). SITUATION Sitting and reading Watching TV Sitting inactive in public place As a passenger in a car fo r an hour without a break Lying down to rest in the afternoon when circumstances permit Sit ting and talking to someone Sitting quietly after lunch without alcohol In a car while stop ped for a few minutes in traf \201 c Thyroid disease \200 Hypothyroidism leads to i DBP, d cardiac output, d renin levels, and narrow pulse pressure. It is salt-sensitive form of hypertension. Hyperthyroidism leads to i SVR and simulates i renin synthesis and secretion, RAS activation, i blood volume, and i preload with a wide pulse pressure. CHAPTER 6 Hypertension 484 Drug management of hypertension Introduction \200 The p goal of treatment is to achieve a reduction in long-term CV morbidity and mortality risk. There is much debate on which medication to start when initiating therapy. In practice, mos t will require \211 2 drugs to attain target. \200 There is increasing popularity in Eu rope and the USA for using combination therapy ( l synergistic effect + better compliance). UK physicians prescribe fe wer combination pills than anywhere else in Europe. Compliance improved by once-a-day formulations and by clearly explaining the bene \201 ts and potential side effects of drug treatment. Although marked interindividual variation in drug responses re \202 ects the heterogeneity of the pathogenesis of i BP, pro \201 ling patients, accor ding to their hypertensive phenotype with a view to individualizing drug therapy, has prove d dif \201 cult (exceptions: the elderly and ethnic groups). Drug withdrawal might be possible if other lifestyle interventions are undertaken and prove successful. The patient may bene \201 t from joining local or national forums (e.g. M http://www.bpassoc.org.uk ). Once BP is adequately controlled, provide at least an annual review for monitoring. The major drug groups are equally well tolerated. They are prescribed in 7 equal amounts in primary care: \200 Thiazide diuretics ( b p. 498). \200 ACE-I and ARBs ( b p. 508 \200\223511). \200 Calcium channel blockers (CCBs) ( b p. 506). \200 B -blockers ( b p. 502). In the UK, B -blockers have been \200\230 downgraded \200\231 and are not recommended as \201 rst-line therapy. However, it largely depends on which guideline you follow. \200 A -blockers are not recommended a s \201 rst line ( b p. 504). \200 X The optimal cardiovascular outcome is most consiste ntly linked with the level of BP control, rather than the class of drug used to achieve it. In general, the lower the BP, the better. Patients will be accruing bene \201 t, even if they do not achieve target BP. There are now generic versions of key medications, which has reduced the cost of choosing many drugs. It is helpful to consider compelling indications and compelling contraindications (see Table 6.8). There are also other less de \201 nite pros and cons th at will be assigned different importance by different prescribers. Timing of therapy may be important. If more than one agent is used, then having at least on e dose at bedtime may improve circadian BP, CV outcomes, and daytime BP control (this has b een demonstrated for both non-CKD and CKD populations in recent RCTs). DRUG MANAGEMENT OF HYPERTENSION 485 Aspirin and statins Consider prescribing other drugs that modify CV risk. \200 Aspirin 75 mg od: p prevention in hypertensives aged >50 and 10-year CV risk > 20% and BP <150/90mmHg, with no contraindication. s prevention of CV disease. Statin therapy: p prevention in hypertensives with 10-year CV risk > 20%. \200 s prevention in all with o vert CV disease, irrespective of baseline total cholesterol or LDL. Targets: d total choles terol by 25% or LDL cholesterol by 30%, or achieve a total cholesterol of < 4.0mmol/L or LD L cholesterol of < 2.0mmol/L (whichever is the greatest reduction). CHAPTER 6 Hypertension 486 r a l u c s a v o n e r r a l u c s a v o n e r e c n e n i t n o c n d n a k c o b s n o i t a c i d n i a r t n o c t r a e h y l b i s s o p / a m h t s A l d e h s i l s g u r d t r a e h g n , k c o b , , b a t s e y c n a n g e r P y c n a n g e r P i l l e p m o C i l d e s a e s i d d e s a e s i d y r a n i r U , D P O C e v i s n e t r e p y h i t n a e r u f t u o G t r a e H s i e r e h t l i a f \200\223 . l o n i r u p o n e h w e c v d a t r a e h s e t e b a d c c D V P C V P l l a , n o i s n e t o p y h i i h t i b , t n e m b , t n e m ) , h t i D V P c , e r u w n o i t a n b m o c D H C h t i f t s i l a c e p s o s e s s a l c w n o i t a n b m o C e d a k c o b - a t e b i r i a p m r i a p m i w n o i t u a C l i a f l a r u t s o P d n a t p e c x e ( l a e r u i i i t r a e H l a n e R l a n e R r o a m e h t , n n o i s i v r e p u s l i a f i j \200\223 d e s u . e s a e s i d l a n e r . e s a e s i d . c i t e b a d e s a e s i d e r u y l l a e d . n o i s i v r e p u s e c n a r e o t n l i a f r a l u c s a v o n e r e s o l c c n o r h c r o i i i , s g u r d t r a e h , t u o g r a l u c s a v l a n e r f I I l s n o i t u a c , n o i t u a c e p y t n e s r o w y a m f o y r o t s i h e v i s n e t r e p y h i t n a , c i r u n e t o r p i t s i l a c e p s e s a e s i d , I l a r e h p i r e p b , e s a e s i d M h t i s n o i t a c i d n c e r u i t s o p h t i i w n o i t a c o s s a w d e s u d n a l i a f l a n e r a r e d n u h t i n o i t c n u f s y d V L s r e k c o b - a t e b a n g n a l a n e r t r a e h , i , y h t a p o r h p e n w e p o e p e r u D V P , s n o i t a c d n a r t n o c i c i r u n e t o r p e b i e s a e s i d l l i a f e l b i s s o P l r e h t o c n o r h C y l n o d u o h s , ; , e s a e s i d i n o i s n e t r e p y h y l r e d E f o e s u a c e b i t r a e H n i r a l u c s a v o n e r I l i f M l o , r e v e w o H P B i l o r t n o c o t I t u b M e s a e s i d n o i s n e t r e p y h c i t e b a d c n o i t n e v e r p e k o r t s t s o p c i l e r u I I o t s y s I M . e r u e p y t h t i l i a f , s n o i t a c d n t s o p r a l u c s a v i y h p o r t r e p y h , n o i t c n u f s y d V L y r a s s e c e n l i a f w s t n e i t a p s d e t a l o s i l a n e r I , e c n a r e o t n e p y t , n t r a e h s n o i t a c i d n e r u , s t n e i t a p i e k o r t s e r u c n o r h c , l a r e h p i r e p l i a f y h t a p o r h p e n i i , D H C d e h s i l , e b a t s l i a f H S I e b l l n t r a e h i i c i t a t s o r p s e m t r a e h s d e s u e b i s s o p ; t n a r e o t n i - E C A i e s a e s i d n l ) . n o i s s i i r o t i b h n t a e r t o t i , , y h t a p o r h p e n g n e r u i t e m o s l a c \201 e n e b , H S I H S I n s e m n o i t n e v e r p i i i l l e p m o C , a n g n a l H V L s B R A d n a l i a f i b a t s e m r e p c i t e b a d i y r a n o m u p , , i t e m o s y l r e d E y l r e d E a n g n A n g n e B d e s u i t r a e H y a m d n a E C A i h t i i , I . e b y p a r e h t o n o m r o h t i M i l l w s c i t e r u d y l g n i s a e r c n l e r a y a m w d e s U g n s r o t i b h n . t n e m e v i t c u r t s b o c n o r h c i l l s B R A d n a ) e n d i r y p o r d y h d ( s B R A r o s r o t i b h n i e p m o C i e k e k r i a p m i . s e n ) g n i t i i i E C A h t i i l - e d i z a h t / e d i z a h T i l - e d i z a h t / e d i z a h T e r a s a i l e d u g s r o t i b h n i d e s u s r e k c o b - a h p A m s r o t i b h n s r e k c o b - a t e B g u r d f l a n e r s r e k c o b - a t e B i i i l - e t a r ( 8 6 i i w n o i t u a C . S H B m o r F ( n e h w F H i i i t n a c \201 n g i s i s c i t e r u d l l o s s a l C e l b a T i i l , D P O C E C A E C A i s B C C s B C C s B R A E C A i i i l i d b e c a f DRUG MANAGEMENT OF HYPERTENSION 487 CHAPTER 6 Hypertension 488 Guidelines for drug treatment Algorithms Guidelines have become increasingly didactic, as p revious less speci \201 c rec- ommendations generally proved ineffective. The British Hypertensive Society and NICE Two key UK advisory bodies published updated guid elines in 2011 on the treatment of hypertension (see Fig. 6.6). In the 2006 guidelines, B - blockers were downgraded in response to evidence suggesting they may be less effective at d major CV events (particularly stroke) than other drug classes and that they have a higher diabetes risk than ACE-I or CCBs (particularly in patients also taking a thiazide diuretic ( b p. 502)). In this recent update, there has been a change in the priority of medications in people >55 years, with CCB as the \201 rst-line choice, based on event reduction and cost effectiveness. Thiazide-like diuretics (e.g. indapamide) are suggested in those with h eart failure or very elderly who are intolerant of a CCB.