CHAPTER 6 Hypertension 500 Diuretics 2 Loop diuretics Examples Furosemide, bumetanide. Mechanism \200 Block the type 2 Na + K + 2Cl \200\223 (NKCC2) co-transporter in the thic k ascending limb of the loop of Henle (usually responsible for 15 \200\223 20% of \201 lte red Na + reabsorption). Tubuloglomerular feedback would normally act to compensate by a d in GFR, but this is depen dent on an identical ( 6 inhibited) co-transporter in the macula densa. Like thiazide diuretics, may cause hypokalaemic metabolic alkalosis. \200 Initial Na + an d volume loss may be compensated for by Na + retention during the latter part of the dosing interval, with amelioration of BP-lowering ef \201 ca cy. So, more frequent dosing (at least twice daily) is necessary when used for treatment of hypertension. Role More potent natriuretics than thiazide-type diuretics but less effective BP-lowering a gents. Their place in the management of i BP is limited to patients with CCF (with volume o verload), renal impairment (with volume overload), and other oedematous states (e.g. cirrho sis). Sequential nephron blockade This is a strategy to overcome diuretic resistance in oedematou s states that involves combination therapy with loop and thiazide (or thiazide-like) diuret ics. Potassium-sparing diuretics Examples Amiloride, triamterene. Mechanism \200 Block the epithelial Na + channel (ENaC) expressed in the late DCT and collecting duct. \200 ENaC plays a central role in the control of urinary Na + reabsorption, ECF volume homeostasis, and BP regulation. Several hormones, including aldosterone, vasopressin, angiotensin II, insulin, and endothelin, regulate ENaC activity. K + absorption is tightly coupled with ENaC Na + absorption. Drugs blocking ENaC 6 cause K + retention. Also has Mg 2+ -sparing effects. Role Not \201 rst-line. \200 Useful adjuncts to limit d K + and d Mg 2+ with other diur etics. d K + may actually i BP and is associated with insulin resistance, DM, arrhythmias, and sudden death. DIURETICS 2 501 Amiloride may be used to prevent d K + and i BP associated with excess glucocorticoids or mineralocorticoids ( b p. 477) and in Liddle \200\231 s syndrome (caused by activating mutation(s) in ENaC) ( b p. 801). Can be useful in black patients where ENaC may play a more prominent role. Can be useful in patients with suspected hyperaldosteronism who are avoiding spironolactone/eplerenone before ARR testing. Problems 1 Hyperkalaemia! Cautions: renal impairment (especially in DM), com- bination with B -blockers, ACE-I/ARB, or spironolactone. The incidence of i K + when amiloride is co-pre scribed with a thiazide or loop diuretic is very low. Mineralocorticoid antagonists Increasingly recommended as the fourth-line agent for resista nt hyper- tension. Why is this? \200 Aldosterone activates mineralocorticoid receptors in the heart, vasculature, and brain. Adverse consequences of activation include endothelial dysfunction, myocardial \201 brosis, myocyte hypertrophy, vascular injury, and centrally mediated ele vations in BP. RAS activation is associated with worse outcomes in patients with CCF and i BP. Although ACE-I and ARBs d aldosterone production, levels return toward normal with chronic use. Plasma aldosterone levels correlate with LVH in hypertensive patients. \200 Patients with p hyperaldosteronism have worse CV outcomes. \200 Pharmacological blockade of mineraloco rticoid receptors d LVH and microalbuminuria in hypertensive patients. Experience in severe CCF is positive, with a d in mortality (RALES study). Spironolactone has long been used in the treatment of conditions associated with s hyperaldosteronism and volume expansion, such as cirrhotic ascites. Spironolactone and eplerenone are the mineralocorticoid receptor antagonists in clinical us e. \200 Spironolactone is recommended as \201 rst line on ef \201 cacy and cost ground s. Highly effective. It can be used in combination with thiazide-like diuretics. Not actual ly licensed for use in hypertension in the UK (license withdrawn in the 1980s due to concer ns re malignancy in rodents. This has not been borne out in humans, but patients should be informed of the off-license use). Eplerenone is a selective mineralocorticoid receptor with 20 x af \201 nity for mineraloco rticoid receptor but just 75% potency of spironolactone. However, less af \201 nity for an drogen and progesterone receptors l fewer SE. Adverse effects: gynaecomastia (common), GI upset, impotence, i K + ( 1 caution with ACE-I and ARB, especially if renal impairment). CHAPTER 6 Hypertension 502 B -blockers Competitive inhibitors of catecholamines at B -adrenergic receptors. Many are a vailable, with marked interdrug differences in pharmacodynamic and pharmacokinetic properti es. In general, these characteristics in \202 uence clearance and side effect pro \201 le , rather than ef \201 cacy. Examples See Table 6.10. Mechanism Remains a matter of debate. Potentially: \200 d cardiac output. \200 d renin release. \200 d plasma volume. \200 d vasomotor tone. \200 d peripheral vascular resi stance. \200 Improved vascular compliance. \200 Resetting of baroreceptor levels. \200 Effects on prejunctional B receptors: d noradrenaline release. \200 d pressor response to catecholamines with exercise and stress. \200 Direct CNS effect. Role Downgraded in BHS/NICE in the UK and not \201 rst choice in JNC-7 although still use ful if concomitant angina, post-MI ( d mortality risk), arrhythmias, or hyperdynamic circul ation. Consider in younger people and if resist- ant i BP. Carvedilol, metoprolol, and biso prolol have been shown to d morbidity and mortality in patients with stable CCF. Labetalol is useful in pregnancy ( b p. 849) and for parenteral treatment ( b p. 522). Problems \200 Avoid in marked bradycardia, AV node disease. \200 Avoid abrupt withdrawa l, as rebound tachycardia can cause myocardial ischaemia in susceptible individuals. X Many patients with obstructive airways disease have compelling indications for B -blocker therapy (IHD/CCF/arrhythmias). B 1 selective agents (atenolol or metoprolol) appear to be safe and may actually reduce exacerbations and mortality. Can cause lethargy, impaired concentration and memory, vivid dreams, hallucinations, depression (CNS effects may be more prominent with lipid-soluble agents), d eterioration in peripheral vascular disease (nebivolol has some peripheral vasodilating pro perties and may well be tolerated in patients with claudication), and Raynaud \200\231 s s ymptoms. Metabolic effects: d HDL cholesterol and i triglycerides. \200 i likelihood of new-onset DM, particularly wh en combined with a thiazide (combination leads to 7 1 new case of DM for every 250 patients treated/year.) Avoid this combination if high risk: strong FH of T2DM, impaired glucose to lerance (FPG \211 6.5mmol/L), clinically obese (BMI >30), or of South Asian or Afro-Carib bean origin. B-BLOCKERS 503 Worsen glycaemic control and hypoglycaemic awareness in T1DM (worse with non-selective agents). Combined with diltiazem or verapamil, may cause slowing of SA node negative inotropic effect. Table 6.10 Examples of B -blockers B 1 - selectivity a A -blocking activity d Intrinsic sympath- omimetic activity b Membrane- stabilizing activity c Major route of elimination e Acebutolol 1 + + + Renal Atenolol 1 ++ Renal Bisoprolol ++ Both Carvedilol ++ + Hepatic Celiprolol + + Both Labetalol ++ Hepatic Metoprolol 1 ++ Hepatic Nadolol 1 Renal Nebivolol + + Renal Oxprenolol 1 Hepatic Pindolol 1 ++ + Both Propranolol ++ Hepatic Sotalol 2 \200 + Renal Timolol 1 Hepatic 1 Combination tablet with thiazide diuretic available. Atenolol also available combined wit h CCB. 2 1 Sotalol is not licensed for use in hypertension. \200 Sotalol has class III an tiarrhythmic properties and can prolong the QT interval. B -blockers differ in terms of B 1 selectivity, intrinsic sympathomimetic activity (ISA), membrane-stabilizing activity (MSA) , A -adrenergic blocking ability, and pharmacokinetic properties. a B 1 selectivity: these agents have less effect on B 2 receptors and are, therefore, relatively cardioselective. Ap plies at lower doses only. Theoretically, an advantage in patients with obstructive airways disease but should still be regarded as a contraindication. May not block arteriolar B 2 r eceptors, which may be an advantage in T1DM with hypoglycaemia. b Intrinsic sympathomimetic activity (ISA): partial agonist activity at B 1 receptors, B 2 receptors, or both. Identi \201 ed as slight cardiac stimulation, inhibited by propanolol. Cause less bradycardia and AV node slowing, possibly less negatively inotropic, less effect on peripheral vascular re sistance. Apparent better lipid pro \201 le. Unclear if represents an overall advantage (o r disadvantage). c MSA: these agents have a quinidine or local anesthetic-like effect on th e cardiac action potential. Usually seen above therapeutic levels and 6 apparent in overdos e. d A -blocking activity: antagonistic properties at both A - and B -adrenergic receptors. Causes a reduction in peripheral and coronary vascular resistance. The bene \201 t of car vedilol in heart failure is not dependent on this property. e Water-soluble agents are pred ominantly excreted via the kidney and have a longer half-life. 1 Dose reduction is often ne cessary if d GFR. Lipid-soluble agents mainly undergo hepatic excretion. Usually shorter ac ting (requiring bd or tds dosing) and cause more CNS SE (cross the blood \200\223 brain ba rrier). CHAPTER 6 Hypertension 504 A -blockers A adrenoceptors participate in the regulation of vascular tone by the sym- path etic nervous system (SNS) and play a role in the genesis of i BP and other CV disorders. Examples \200 Selective A 1 antagonists: doxazosin, prazosin, terazosin, indoramin. \200 The bioavailability of modi \201 ed-release (MR) formulations of doxazosin is 7 50% of standard release, so doses need to be adjusted when moving between pr eparations. Unselective A 1 and A 2 antagonists: phentolamine, phenoxybenzamine. Mechanism \200 A 1 r eceptors are post-synaptic. Noradrenaline (norepinephrine) l i intracellular Ca 2+ \202 u x l i smooth muscle contraction l vasoconstriction. Selective A 1 blockade causes d SVR and BP, with little or no effect on heart rate or cardiac output. A -blockers are essentially vasodilators. A 2 receptors are presynaptic. Stimulation l d noradrenaline release. \200 Non- A 1 and A 2 selective agents were developed \201 rst. \200 In normotensive patients with normal sympathetic tone and vascular resistance, A -blockers have minimal BP-lowering effect. Role \200 Antihypertensive effect only modest when used as single agents. Effects are additive with other antihypertensive classes. ALLHAT (see Box 6.5 and b p. 494) provided bad press for A -blockers. In light of this, not considered \201 rst (or even second) line. \200 Favorable lipid e ffects ( d total cholesterol, LDL, triglycerides; i HDL). Safe and effective in renal insuf \201 ciency. \200 BP-lowering effect, independent of a ge race and gender. \200 Non-selective A -blockers are useful in the management of phaeochromocytoma ( b p. 482). Problems Prazosin has a short half-life, causing \201 rst dose (and postural) d BP \200 \224 generally less of a problem with longer-acting agents. Dizziness can persist (even wit hout demonstrable postural d BP). Caution with sildena \201 l, tada- la \201 l, and varde na \201 l ( l rapid d BP). Stress incontinence aggravated in \231\200 . Can cause \202 uid retention ( 6 good combined with a diuretic). A-BLOCKERS 505 Box 6.5 -blockers and ALLHAT ( b p. 494) The doxazosin limb was stopped early (3.3 years \200\231 follow-up, 7 9,000 patients) because of a 25% i incidence of CV disease (mainly CCF; no difference in p endpoints \200\224 fatal and non-fatal MI), compared to the thiazi de group, As a result, A -blockers have fallen in popularity with guideline authors and pre scribers alike. However, (i) SBP was higher in the doxazosin arm; (ii) randomization depriv ed many patients with CCF of diuretics, B -blockers, or ACE-I, creating a disadvantage for the A -blocker group. A -blockers remain a good component of multiple drug regimens for moderate to severe i BP a nd are particularly useful in \231\202 with concomi- tant prostatic disease. Avoid if coex isting CCF. -blockers and bladder out \202 ow symptoms ( b p. 761) \200 Lower urinary tract sympt oms (LUTS) associated with BPH and obstruction are common in \231\202 aged >60. Bladder emptying involves relaxation of A 1 receptor-mediated smooth muscle contraction in the bladder neck and prostate. \200 A 1 receptors are integral to the bulbospinal pathway s from brainstem \200 A -blockers relieve the symptoms of out \202 ow obstruction and re duce l lumbosacral cord, which inhibit re \202 ex urination. the need for surgery. Newer A -blockers, e.g. tamsulosin, are \200\230 uroselective \200\231 , acting on the A receptor subtypes A 1a and A 1b , within the bladder neck and prostate, with limited effect on systemic BP. \200 A -blockers are effective, with > 60% reporting improvement. Medica l therapy is now common, and TURP rates have fallen. A -blockers are the best monotherapy for symptom relief of LUTS. \200 In those with moder ate to severe symptoms and demonstrable prostatic enlargement, combination therapy of an A -blocker and 5 A -reductase inhibitor (block conversion of testosterone l dihydrotestostero ne), e.g. \201 nasteride, provides effective symptom relief and retards disease progressi on. CHAPTER 6 Hypertension 506 Calcium channel blockers Examples \200 Dihydropyridine (vasodilating) CCBs: nifedipine, a mlodipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nisoldipine. Non-dihydropyridine (cardiac active) CCBs: diltiazem, verapamil. Mechanism \200 Block voltage-dependent L-type Ca 2+ channels l d calcium entry into smoot h muscle cells l d smooth muscle contraction l d vascular resistance l arterial vasodilatat ion. \200 Dihydropyridines: more selective at Ca 2+ channels in vascular smooth muscle cells 6 more powerful vasodilators. Non-dihydropyridines: block Ca 2+ channels in cardiac myocytes and d cardiac output. Antiar rhythmic properties via AV node (verapamil > negative inotrope and chronotrope effect than diltiazem). \200 Other CCB effects: d aldosterone release, d growth and proliferation of vascular smooth muscle cells, anti-atherogenic in animal models. Moderately i Na + excretion via natriuresis. d BP effect is not augmented by dietary Na + r estriction (unlike other classes). Undergo \201 rst pass metabolism to some degree. Most are short-acting 6 require multiple dosing regimens or a slow-release delivery system. Role \200 Recommended with priority over diuretics in BHS/NICE guidelines. \200 BP-lowe ring effect equivalent to most other drug classes, but variability in BP less so may have an advantage. Among CCBs, antihypertensive properties are 7 equivalent. \200 Can be combined with all o ther classes ( 1 avoid diltiazem or verapamil with B -blockers \200\224 cardiac effects ar e additive). Good choice in patients with concomitant angina. \200 Effective in low renin i BP (i.e. b lack or elderly patients). \200 Non-dihydropyridine CCBs can be effectively combined with dihydropyridine CCBs. This combination can be particularly useful in black patients with di f \201 cult BP. \200 Do not worsen dyslipidaemias. \200 d BP effect not blunted by NSA IDs. \200 Nimodipine is used for the prevention of ischaemic de \201 cits, following subarachnoid hemorrhage \200\224 not licensed for hypertension. Problems \200 Flushing, tachycardia, or headache; especially short-acting agents. \200 Dose-dependent peripheral oedema with dihydropyridine CCBs. This is not due to \202 uid r etention ( 6 diuretic unresponsive) but s to mismatched arteriolar and venous vasodilatatio n. In this situation, consider using a pill-cutter and 2.5mg amlodipine od. \200 Gum hype rtrophy occurs with dihydropyridine CCBs. \200 Avoid in systolic LV impairment (esp. non- dihydropyridine). CALCIUM CHANNEL BLOCKERS 507 CCBs have many drug interactions \200\224 worth checking before prescribing. Grapefruit juice inhibits cytochrome P450 CYP3A and i the bioavailability of several dihydropyridine CCBs. Several trials have suggested that CCBs are not as effective protection against hypertensiv e or diabetic renal disease as ACE-I or ARBs 6 not \201 rst line in this situation. Verapamil use is often accompanied by constipation. 1 Early formulations of some dihydropyridines (e.g. capsular or sub- lingual nifedipine) ha d a rapid onset of action, with an unpredictable BP-lowering effect, accompanied by re \202 ex sympathetic stimulation, tachycardia, and RAS activation. These agents have no plac e in the man- agement of hypertension. CHAPTER 6 Hypertension 508 ACE inhibitors (ACE-I) Examples Most commonly used: captopril, enalapril, fosinopril, lisin opril, perindopril, quinapril, ramipril, trandolapril. Ramipril and trandalopril are the only ACE-I with a half-life long enough to be suitable for once-daily dosing. Mechanism \200 Block conversion of angiotensin I l i angiotensin II (A2) by angiotensin-converting enzyme (ACE). The resulting d in A2 l vasodilatation and d BP. A2 has many actions potentially detrimental to the CV system ( b p. 456). Alternative pathways of A2 production, e.g. chymases and other tissue proteases, are unaffected. In the short term, ACE-I reduce AII levels, but, with chronic treatment, they return to nor mal ( \200\230 A2 escape \200\231 ). Other mechanisms of BP lowering are 6 thought to be active. Possibilities: \200 i bradykinin l i NO 9 i PGI 2 ( l vasodilatation). \200 i a ngiotensin-(1 \200\223 7), a peptide that is antagonistic to A2. \200 d sympathetic nerv ous system activity. \200 Direct effect on endothelial function and vascular remodeling. \200 ACE-I can be subdivided, according to their af \201 nity for tissue ACE. It is poss ible that lipophilic compounds with high tissue af \201 nity (e.g. ramipril, quinapril, pe rindopril) exert greater in \202 uence on endothelial function and provide CV bene \201 t s independent of BP lowering X . \200 Increasing the dose of an ACE-I does not generally alter peak effect but extends duration of response. Many patients bene \201 t from a second daily dose. Role \200 Comparable BP lowering to other classes (but no better). \200 Cardioprotectiv e and renoprotective 6 good choice if: CCF, post-MI, DM, CKD (especially proteinuric), or LVH. Patients at high risk of CV disease may have improved survival when treated with ACE-I (independent of BP reduction X ). \200 Synergistic effects when used i n combination with diuretics (diuretics l Na + depletion l RAS activation l A2-dependent (and 6 ACE-I-responsive) i BP. ACE-I also help to ameliorate diuretic-induced i K + . Also suitable for combination with B -blockers, A -blockers, and CCBs. \200 Routine combi nation with an ARB is not recommended. \200 Relatively ineffective as monotherapy in cert ain groups with low renin i BP, e.g. black patients, although response highly variable ( d Na + diet increases ef \201 cacy). Generally effective in the elderly. Documenting plasma renin activity or ACE gene polymorphisms to \200\230 individualize \200\231 therapy is not useful \200\224 neither predicts response. Lack adverse metabolic effects. ACE INHIBITORS (ACE-I) 509 Problems and practical considerations \200 Decline in renal function . When glomerular \201 ltration pressure is dependent on A2-driven efferent arteriolar tone (e.g. volume depl etion, renal artery stenosis, CCF), then ACE inhibition may cause a precipitous decline in GFR. 1 Precautions: Ensure patient is volume-replete. \200 Check U&E and eGFR before commencing treatment and 5 \200\223 7 days after. Expect (and allow) a rise in SCr. Stop ACE-I if change in Cr \211 30% or d eGFR of \211 25%. Ask those on diuretic therapy to take \201 rst dose before retiring to bed. Seek specialist help if high index of suspicion of renovascular disease ( b p. 586). 2 Counsel patients that they should avoid NSAIDs and temporarily stop taking their ACE-I in the event of an intercurrent illness, e.g. febrile illness, diarrhea, vomiting. They shoul d inform their doctor in this circumstance. Hypotension . Acute falls in BP with ACE-I occur when RAS is activated, e.g. overdiuresis, CCF, accelerated hypertension. Rare when therapy initiated in uncomplicated hypertensive pa tients (admission to hospital for ACE-I introduction was commonplace in the 1980s). Postura l hypotension is actually comparatively uncommon. In elderly or frail, consider starting at night. Hyperkalaemia . Most common in those with renal impairment 9 other drugs causing i K + (e.g. amiloride, spironolactone, B -blockers). \200 Patients who deve lop mild i K + should not necessarily have their ACE-I stopped, particularly if there is a compelling indication. Dietary advice is usually suf \201 cient to allow re-introduction. Many specialists will tolerate i K + <6.0mmol/L. Cough . Common (5 \200\223 40%, \231\200 > \231\202 ) and generally resistant to all measures, except drug withdrawal ( i bradykinin 9 other vasoactive peptides, e.g. substance P l cough re \202 ex activation). Angioneurotic oedema . Rare. Black patients > Caucasians; also bradykinin-mediated and potentially fatal. Stop the ACE-I, and avoid for life. d Erythropoietin secretion . May cause or worsen anemia. \200 Pregnancy . Contraindicated . \200 Rash and altered taste . Mainly captopril. CHAPTER 6 Hypertension 510 A2 receptor blockers (ARB) Examples Candesartan, eprosartan, irbesartan, losartan, olmesart an, telmisartan, valsartan. Mechanism \200 There are two A2 receptor subtypes: AT 1 mediates: (i) vasoconstrictor effects of A2 and (ii) A2-induced growth in the myocardium and arterial wall. AT 2 function is less well understood. Expressed at high levels in fetal tissues, with d expression after birth. Probably responsible for many of the prolifer ative effects of A2. ARB l inhibition of AT 1 l inhibition of vasoconstrictive action of A2 on smooth muscle. Two major differences between ACE-I and ARB: ACE-I l d activity of A2 at both AT 1 and AT 2 receptors. ARB only d AT 1 activity, with no effect on AT 2 . ACE is a kininase, so ACE-I lead to i kinins. Kinins are responsible for some ACE-I side ef fects (esp. cough) but may also mediate some of their bene \201 cial effects, including BP lowering and i insulin sensitivity. A2 blockade leads to i renin, i angiotensin I, and i A2, although this accumulation does no t appear to overwhelm receptor blockade. Roles \200 Similar BP-lowering effect to ACE-I and other main classes. \200 As with ACE -I, synergistic with diuretics. \200 ARBs have similar bene \201 ts to ACE-I in conditio ns other than i BP, such as CCF (Val-HeFT and CHARM studies) and post-MI (VALIANT). Several major trials (IDNT, IRMA-2, RENAAL,) have demonstrated renoprotection with ARB in n ephropathy associated with T2DM. Problems \200 Generally well tolerated, similar side effect pro \201 le to ACE-I. \200 Less cough than ACE-I (as kinin-mediated). \200 Angio-oedema has been reported. Cause no t clear. \200 Altered taste. \200 Contraindicated in pregnancy. \200 Concerns regardi ng increased cancer risk led to an FDA analysis, but no overall increase in cancer was found. Practical points \200 Not all ARBs are the same. Losartan and valsartan are relatively short-acting. Give twice daily if BP not controlled. \200 Generic preparations mean that cost has reduced. \200 Check salt intake if resistant to treatment. \200 Some studies s uggest increased insulin sensitivity but not conclusive. \200 Losartan has a mild uricosu ric effect, which may be bene \201 cial in patients with gout. A2 RECEPTOR BLOCKERS (ARB) 511 Combined ACE-I and ARBs (see also b p. 614) Two drugs are not better than one \200 Good theoretical rationale for using in combinatio n: ACE inhibitors do not completely block the formation of A2 (other tissue proteases are involved). ARBs are selective for the AT 1 receptor, leaving AT 2 receptor exposed to i A2. With ACE-I, i A2 l renin release, eventually returning A2 towards baseline (termed \200\230 A2 escape \200\231 ). Combination therapy is effective in LV dysfunction (Val-HeFT and CHARM studies). Small studies (e.g. CALM) raised expectation. One key study (COOPERATE) was retracted after publication. ON-TARGET, a large RCT comparing the effects of telmisartan, ramipril, and their combination on CV mortality in high-risk patients found the combination was not associated with an improvement in key outcomes but increased the risk of renal fai lure. Current guidelines do not recommend the use of combination therapy for the treatment of hypertension. Renin inhibitors \200 Direct renin inhibition provides an additional means of antagonizing RAS. Aliskiren was the \201 rst commercially available example. \200 Lowers BP to a similar degree to other agents. \200 Anticipated that it might have a useful synergistic role in combination with ACE-I/ARB (as renin increases with long-term use of these agents). In the ALTITUDE study, 8,600 patients with T2DM and nephropathy were assigned to either ali skiren or placebo to take, in addition to their pre-existing ACE-I/ARB. The trial was stopp ed early, as there were no apparent CV or renal bene \201 ts, but there was a higher adver se event rate ( i K + , d BP, stroke). 1 MHRA/FDA now advise not to use aliskiren in combination with ACE-I and ARBs in patients w ith diabetes or renal impairment. \200 They may still have a role in patients with high r enin i BP that is inadequately treated despite maximum therapy or multiple drug intolerance s. Side effects: i K + , d BP, angio-oedema, GI symptoms, raised uric acid ( l gout, renal calculi). \200 Do not use in pregnancy. \200 Important interaction with ciclosporin ( l i blood levels of aliskiren) 6 avoid this combination. CHAPTER 6 Hypertension 512 Other antihypertensive agents With the exception of methyldopa and moxonidine, these drugs are rarely seen in the routine treatment of i BP in the UK. However, they are still widely used around the world \200\224 and generic formulations mean lower costs in many instances . Centrally acting agents Methyldopa Metabolized to a methyl-noradrenaline, a false neurotran smitter that: (i) displaces noradrenaline from A adrenergic receptors, preventing smooth mu scle contraction and (ii) stimulates adrenergic receptors in the central vasomotor centers, inhibiting sympathetic out \202 ow. Large dose range (250mg \200\223 3g daily) and remai ns widely used to treat i BP in pregnancy ( b p. 849). A concomitant diuretic is desirable in non-pregnant patients. Problems: positive Coombs \200\231 test in 20% (though overt hae molytic anae- mia rare), dry mouth, oedema, drowsiness, febrile illness, and depression. Av oid in liver disease. Clonidine Stimulates adrenergic receptors in the central vasomotor centers, inhibit- ing sy mpathetic out \202 ow. Use now rare. Clonidine suppression test occa- sionally used in the diagnosis of phaeochromocytoma ( b p. 482), and it has also been used off-license to assis t smoking cessation and opiate withdrawal (orally or transdermal release), as it reduces th e physiological manifestations of tobacco withdrawal. Problems: dry mouth, sedation, depression. Associated with severe rebound i BP when stopped abruptly (may require treatment with par- enteral A -blockers). Moxonidine A selective imi dazole agonist that acts on central receptors to decrease sympathetic out \202 ow. Can be a useful add-on therapy when other classes are insuf \201 cient or poorly tolerated. Can b e used with caution and careful titration in renal insuf \201 ciency. Problems: dry mouth, headache, fatigue, dizziness, sleepiness. Avoid abrupt withdrawal (if also on B -blockers, stop them \201 rst). Avoid if AV block, bradycardia, severe CCF (wor se outcomes), and pregnancy. Direct acting vascular smooth muscle relaxants Hydralazine and minoxidil d arteriolar resis tance. The consequent d peripheral resistance and BP causes re \202 ex sympathetic activat ion, with tachycardia and palpitations. This can be offset with a B -blocker. Hydralazine (and nitrate) can be a useful adjunct in NYHA class 3 \200\223 4 systolic heart failure. Problems: \202 ushing, headache, palpitations. Avoid in ischaemic heart dis- ease. Cause Na + and water retention (especially minoxidil) 6 give with a diuretic. Hydralazine can cau se a lupus-like syndrome, particularly in slow acetylators. Minoxidil causes hirsutism. Hyd ralazine metabolites accumu- late in renal impairment 6 avoid (minoxidil is OK). OTHER ANTIHYPERTENSIVE AGENTS 513 Antihypertensives on the horizon Endothelin antagonists The endothelins are a group of potent vasoconstrictor peptides pro- duced in many different tissues. ET-1 is the predominant endothelin secreted by the endothe lium where it acts in a paracrine fashion. Several antagonists are under investigation, and it is hoped they will prove reno- and card ioprotective as well as antihypertensive. Darusentan, a marginally selective ET A receptor antagonist, has been shown to reduce BP and proteinuria in early studies (e.g. DORADO). Bos entan is already licensed for use in pulmonary hypertension. Vasopeptidase inhibitors (VPIs) Simultaneously inhibit both ACE (preventing the conversion of AI l A2) and neutral endopeptidase, The latter is a membrane-bound metal- loprotease inv olved in the enzymatic degradation of natriuretic peptides (ANP and BNP) and various other peptides, so inhibition will prolong their duration of action. The combined effect of reduced A2 activity and increased natriu- retic peptide activity is attractive. Early studies with VPIs showed a very favorable therapeutic effect. However, a signi \201 cant incidence of poten- tially life-threatening angio-oedema ultimately led to failed FDA approval and stalled development. Angiotensin receptor blockers with neutral endopeptidase inhibition (ARNi) Currently being evaluated in preclinical and clinical studies. Preliminary results suggest increased BP red uction in comparison to ARB alone \200\224 and with no increase in angio-oedema. CHAPTER 6 Hypertension 514 Non-pharmacological strategies Introduction It is important not to forget (and to often rev isit) dietary salt restriction, reduced alcohol intake, weight loss, and patient education. There has also been growing recent interest in novel, often invasive, thera- pies, particul arly in the management of resistant hypertension. These include: Renal denervation with radiofrequency energy \200 It has been known for years that interr uption of the renal nerves can lead to a reduction in BP. However, surgical intervention to achieve this was associated with appreciable morbidity an d mortality and was not selective for renal sympathetic nerves, resulting in more widesprea d sympathetic denervation. Endovascular (or catheter-based) renal nerve ablation has been studied in patients with resistant hypertension (patients on a mean of \201 ve drugs, inc luding a diuretic) in a series of trials (including Simplicity HTN-1 and 2). Mean reduction in SBP of 28 \200\223 32mmHg, compared to control. \200 An endovascular c atheter is placed in the femoral artery and guided to the kidneys. The sympathetic nerves are closely related to the renal arteries, and radio frequency energy is used to disrupt them at several sites along the vessel. Most patients remain on some therapy, but bene \201 ts are sustained to 3 years. No longer-term outcomes yet available. \200 7 15% treatment failure (possibly higher). \200 Invasive, uncomfortable procedure. Day case or overnight stay. \200 No evidence of new atherosclerotic lesions in the \201 eld of RF energy. \200 Limited data in patients with CKD, but those available (CKD 3 \200\223 4 with resistant i BP) show a bene \201 ci al BP-lowering effect and favorable safety pro \201 le. Simplicity HTN-3 (USA-based) is currently recruiting. It incorporates 24h BP measurements a nd a sham procedure to allow testing for placebo response. Device-guided respiration \200 Portable electronic devices that promote slow and deep bre athing (e.g. RESPeRATE ). Consist of a control box, a respiration sensor, and headphones (which provide feedback to the patient). The device analyzes breathing patterns and creates audibl e tones for the patient to then synchronize their breathing to. The device gradually slows breathing to <10 breaths per minute. Marketed as non-pharmacological treatment for BP reduction but can be used as an adjunct to drug therapy. Published trials show a small, but signi \201 cant, effect ( d SBP 3.67mmHg and d DBP 2.51 mmHg), although they have been of short duration. Evidence of long-term bene \201 t currently lacking. NON-PHARMACOLOGICAL STRATEGIES 515 Baroreceptor activation therapy (BAT) \200 Electrical stimulation of the carotid sinus ba rore \202 ex system, using a surgically implanted device. Appears effective but limited outcome data. \200 Procedure-related adverse events relativ ely common. CHAPTER 6 Hypertension 516 Resistant hypertension Introduction Variably de \201 ned but usually a failure to reach ta rget BP despite multiple antihypertensive agents, including a diuretic. It is most commonly a conse- quence of poorly controlled SBP. Although thought to be relatively common \200\224 up to 20 \200\223 30% of study populati ons in clinical trials \200\224 the experience, when recruiting to these studies, has been that true resistant hypertension is actually less common if drug therapy is optimized and contributing factors are recti \201 ed. In the UK, resistant hypertension is considered to be BP not controlled to target with maxi mal recommended and tolerated doses of an ACE-I/ ARB + CCB + thiazide. The 2011 BHS/NICE gu ideline recommends that such patients are managed with a further diuretic (consider spirono lac- tone), an A -blocker, or a B -blocker (and that a referral for specialist input is con sidered). Although evidence for treatment strategies are generally limited, more robust guidance will hopefully emerge in the next few years; for exam- ple, the BHS PATHWAY 2 study has been de signed to evaluate whether resistant hypertension is due to excess sodium retention and whe ther further diuretic is the most effective treatment. The study also hopes to determine wh ether plasma renin can be a useful guide to further treat- ment in this circumstance. At pr esent, some clinicians measure renin con- centrations in resistant patients, add a B -block er or additional ACE/ARB if high and an A -blocker if normal, and change the diuretic (usua lly to spironolactone) if low. (See Fig. 6.9 for management algorithm.) Characteristics of patients with resistant hypertension \200 Obese. \200 Elderly. \200 Black patients. \200 CKD. \200 DM. \200 High starting BP. Checklist \200 Is it really resistant BP? Does it meet the de \201 nition given earlier? Are you con \201 dent about compliance? Does the patient understand the condition, the be ne \201 ts of treatment. and the role of each tablet? Revisit dietary salt restriction (aim to restrict 24h uNa + to <100meq), alcohol consumption, and weight loss (diet and exercise). Exclude contributory drugs (e.g. NSAIDs, steroids, COC, ciclosporin, decongestants, ESAs). Reconsider secondary causes of i BP, especially renal disease, sleep apnoea, and primary hyperaldosteronism ( b p. 474). RESISTANT HYPERTENSION 517 BP not controlled ( \211 140/90mmHg) despite optimal doses of A + C + D Check 1. Compliance 2. Alcohol 3. Salt intake 4. Contributing medications 5. Obesity Exclude secondary hypertension Confirm with ABPM and ideally with supervised tablet ingestion, although the latter is not practical outside of an inpatient setting Consider specialist referral to hypertension specialist Consider further diuretic or or blocker Fig. 6.9 Algorithm for the management of resistant hypertension. CHAPTER 6 Hypertension 518 Hypertensive urgencies and emergencies De \201 nitions \200 2 Hypertensive crises are cl assi \201 ed as emergencies or urgencies , based on the presence or absence of progressive target organ dysfunction. \200 Emergencies: severe i BP complicated by evidence of acute or progressive organ dysfunction, such as cardiac ischaemia, encephalopathy, stroke, pulmo nary oedema, or renal failure. \200 Urgencies: severe i BP without evidence of acute or p rogressive target organ dysfunction. The term malignant hypertension was coined before antihypertensive therapy improved an appa lling prognosis (1-year mortality 7 90%). It is a syndrome of i BP with progressive target organ damage and papilloedema. Pathologically, arteriolar \201 brinoid necrosis is the ch aracteristic lesion. Accelerated hypertension was applied to the scenario of retinal hemorrhages and exudates without papilloedema. The distinction from malignant hypertension is unhelpful, as both carry an identical prognosis. There is no threshold of BP above which malignant hypertension develops. DBP ranges from 10 0 \200\223 180mmHg, SBP 150 \200\223 290mmHg. \200 2 Severity is not determined by BP a lone \200\224 it is the clinical context and degree of target organ dysfunction. Affects < 1% of the hypertensive population, but the hypertensive population is large. \231\202 > \231\200 . Essential hypertension accounts for 7 2 \200\223 30% of episodes in Caucasians but 7 80% in black patients ( 2 therefore, usually avoidable). Renal disease (intrinsic and renovascular) accounts for the majority of the rest. Other pre viously unrecognized forms of secondary i BP may also be responsible. The duration of hypertension prior to the development of malignant phase may range from days to years. Pathophysiology Vascular autoregulation Autoregulation describes the ability of organs to m aintain their perfusion, regardless of BP. i BP causes distal arteriolar vasoconstriction, protecting end-organs from hypertensive mechanical stress. Hypertensive emergen- cies are a ssociated with a failure of this process, resulting in transmission of i BP to the microvas culature where mechanical trauma l endothelial injury l i vascular permeability l leakage l platelet and \201 brin deposi- tion l \201 brinoid necrosis. Catecholamines and vasopr essin release also contribute. Endocrine and paracrine mediators, including RAS, are activated with i A2, leading to furth er vasoconstriction and ischaemia. Volume depletion due to pressure natriuresis stimulates further renin release and worsens i BP. A vicious cycle of vasoconstriction and worsening i BP ensues. HYPERTENSIVE URGENCIES AND EMERGENCIES 519