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Hypertensive Vascular Disease

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N ot e : Large im ages and t ables on t his page m ay necessit at e print ing in landscape m ode. Copy r igh t Th e M cGr a w - H ill Com pa n ie s. All r igh t s r e se r v e d. H a r r ison ' s On lin e > Chapt er 247. Hy pert ensiv e Vascular Disease >

H YPERTEN SI VE VASCULAR D I SEASE: I N TRODUCTI ON


Hypert ension is one of t he leading causes of t he global burden of disease. Approxim at ely 7.6 m illion deat hs ( 13 15% of t he t ot al) and 92 m illion disabilit y - adj ust ed life years worldw ide were at t ribut able t o high blood pressure in 2001. Hypert ension doubles t he risk of cardiovascular diseases, including coronary heart disease ( CHD) , congest ive heart failure ( CHF) , ischem ic and hem orrhagic st roke, renal failure, and peripheral art erial disease. I t oft en is associat ed wit h addit ional cardiovascular disease risk fact ors, and t he risk of cardiovascular disease increases w it h t he t ot al burden of risk fact ors. Alt hough ant ihypert ensive t herapy clearly reduces t he risks of cardiovascular and renal disease, large segm ent s of t he hypert ensive populat ion are eit her unt reat ed or inadequat ely t reat ed.

EPI D EM I OLOGY
Blood pressure levels, t he rat e of age- relat ed increases in blood pressure, and t he prevalence of hypert ension vary am ong count ries and am ong subpopulat ions w it hin a count ry. Hypert ension is present in all populat ions except for a sm all num ber of individuals living in prim it ive, cult urally isolat ed societ ies. I n indust rialized societ ies, blood pressure increases st eadily during t he first t w o decades of life. I n children and adolescent s, blood pressure is associat ed w it h growt h and m at urat ion. Blood pressure " t racks" over t im e in children and bet ween adolescence and young adult hood. I n t he Unit ed St at es, average syst olic blood pressure is higher for m en t han for wom en during early adult hood, alt hough am ong older individuals t he age- relat ed rat e of rise is st eeper for wom en. Consequent ly, am ong individuals age 60 and older, syst olic blood pressures of wom en are higher t han t hose of m en. Am ong adult s, diast olic blood pressure also increases progressively wit h age unt il ~ 55 years, aft er which it t ends t o decrease. The consequence is a widening of pulse pressure ( t he difference bet ween syst olic and diast olic blood pressure) beyond age 60. The probabilit y t hat a m iddle- aged or elderly individual w ill develop hypert ension in his or her lifet im e is 90% . I n t he Unit ed St at es, based on result s of t he Nat ional Healt h and Nut rit ion Exam inat ion Survey ( NHANES) , approxim at ely 30% ( age- adj ust ed prevalence) of adult s, or at least 65 m illion individuals, have hypert ension ( defined as any one of t he following: syst olic blood pressure 140 m m Hg, diast olic blood pressure 90 m m Hg, t aking ant ihypert ensive m edicat ions) . Hypert ension prevalence is 33.5% in non - Hispanic blacks, 28.9% in nonHispanic whit es, and 20.7% in Mexican Am ericans. The likelihood of hypert ension increases w it h age, and am ong individuals age 60, t he prevalence is 65.4% . Recent evidence suggest s t hat t he prevalence of hypert ension in t he Unit ed St at es m ay be increasing, possibly as a consequence of increasing obesit y. The prevalence of hypert ension and st roke m ort alit y rat es are higher in t he sout heast ern Unit ed St at es t han in ot her regions. I n African Am ericans, hypert ension appears earlier, is generally m ore severe, and result s in higher rat es of m orbidit y and m ort alit y from st roke, left vent ricular hypert rophy, CHF, and end- st age renal disease ( ESRD) t han in whit e Am ericans. Bot h environm ent al and genet ic fact ors m ay cont ribut e t o regional and racial variat ions in blood pressure and hypert ensionprevalence. St udies of societ ies undergoing "accult urat ion" and st udies of m igrant s from a less t o a m ore urbanized set t ing indicat e a profound environm ent al cont ribut ion t o blood pressure. Obesit y and weight gain are st rong, independent risk fact ors for hypert ension. I t has been est im at ed t hat 60% of hypert ensives are > 20% overweight . Am ong populat ions, hypert ension prevalence is relat ed t o diet ary NaCl int ake, and t he age- relat ed increase in blood pressure m ay be augm ent ed by a high NaCl int ake. Low diet ary int akes of calcium and pot assium also m ay cont ribut e t o t he risk of hypert ension. The urine sodium - t o- pot assium rat io is a st ronger correlat e of blood pressure t han is eit her sodium or pot assium alone. Alcohol consum pt ion, psychosocial st ress, and low levels of physical act ivit y also m ay cont ribut e t o hypert ension. Adopt ion, t win, and fam ily st udies docum ent a significant herit able com ponent t o blood pressure levels and hypert ension. Fam ily st udies cont rolling for a com m on environm ent indicat e t hat blood pressure herit abilit ies are in

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t he range 1535% . I n t win st udies, herit abilit y est im at es of blood pressure are ~ 60% for m ales and 30 40% for fem ales. High blood pressure before age 55 occurs 3.8 t im es m ore frequent ly am ong persons wit h a posit ive fam ily hist ory of hypert ension.

Ge n e t ic Conside ra t ions
Alt hough specific genet ic variant s have been ident ified in rare Mendelian form s of hypert ension ( Table 247 - 5) , t hese variant s are not applicable t o t he vast m aj orit y ( > 98% ) of pat ient s wit h essent ial hypert ension. For m ost individuals, it is likely t hat hypert ension represent s a polygenic disorder in which a com binat ion of genes act s in concert w it h environm ent al exposures t o m ake only a m odest cont ribut ion t o blood pressure. Furt her, different subset s of genes m ay lead t o different phenot ypes associat ed wit h hypert ension, e.g., obesit y, dyslipidem ia, insulin resist ance. Several st rat egies are being ut ilized in t he search for specific hypert ension - relat ed genes. Anim al m odels ( including select ively bred rat s and congenic rat st rains) provide a powerful approach for evaluat ing genet ic loci and genes associat ed wit h hypert ension. Com parat ive m apping st rat egies allow for t he ident ificat ion of synt enic genom ic regions bet ween t he rat and hum an genom es t hat m ay be involved in blood pressure regulat ion. I n associat ion st udies, different alleles ( or com binat ions of alleles at different loci) of specific candidat e genes or chrom osom al regions are com pared in hypert ensive pat ient s and norm ot ensive cont rol subj ect s. Current evidence suggest s t hat genes t hat encode com ponent s of t he renin - angiot ensin- aldost erone syst em , along wit h angiot ensinogen and angiot ensin- convert ing enzym e ( ACE) polym orphism s, m ay be relat ed t o hypert ension and t o blood pressure sensit ivit y t o diet ary NaCl. The alpha- adducin gene is t hought t o be associat ed w it h increased renal t ubular absorpt ion of sodium , and variant s of t his gene m ay be associat ed wit h hypert ension and salt sensit ivit y of blood pressure. Ot her genes possibly relat ed t o hypert ension include genes encoding t he AT 1 recept or, aldost erone synt hase, and t he
2

adrenorecept or. Genom ewide associat ion st udies involve rapidly scanning m arkers across t he

ent ire genom e t o ident ify loci ( not specific genes) associat ed wit h an observable t rait ( e.g., blood pressure) or a part icular disease. This st rat egy has been facilit at ed by t he availabilit y of dense genot yping chips and t he I nt ernat ional HapMap. To dat e, t he result s of candidat e gene st udies oft en have not been replicat ed, and in cont rast t o several ot her polygenic disorders, genom ewide associat ion st udies have had lim it ed success in ident ifying genet ic det erm inant s of hypert ension. Prelim inary evidence suggest s t hat t here m ay also be genet ic det erm inant s of t arget organ dam age at t ribut ed t o hypert ension. Fam ily st udies indicat e significant herit abilit y of left vent ricular m ass, and t here is considerable individual variat ion in t he responses of t he heart t o hypert ension. Fam ily st udies and variat ions in candidat e genes associat ed wit h renal dam age suggest t hat genet ic fact ors also m ay cont ribut e t o hypert ensive nephropat hy. Specific genet ic variant s have been linked t o CHD and st roke. I n t he fut ure, it is possible t hat DNA analysis will predict individual risk for hypert ension and t arget organ dam age and will ident ify responders t o specific classes of ant ihypert ensive agent s. However, w it h t he except ion of t he rare, m onogenic hypert ensive diseases, t he genet ic variant s associat ed wit h hypert ension rem ain t o be confirm ed, and t he int erm ediat e st eps by which t hese variant s affect blood pressure rem ain t o be det erm ined.

M ECH AN I SM S OF H YPERTEN SI ON
To provide a fram ework for underst anding t he pat hogenesis of and t reat m ent opt ions for hypert ensive disorders, it is useful t o underst and fact ors involved in t he regulat ion of bot h norm al and elevat ed art erial pressure. Cardiac out put and peripheral resist ance are t he t wo det erm inant s of art erial pressure ( Fig. 2 4 7 - 1 ) . Cardiac out put is det erm ined by st roke volum e and heart rat e; st roke volum e is relat ed t o m yocardial cont ract ilit y and t o t he size of t he vascular com part m ent . Peripheral resist ance is det erm ined by funct ional and anat om ic changes in sm all art eries ( lum en diam et er 100400 m ) and art erioles.

Figur e 2 4 7 - 1

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D e t e r m in a nt s of a r t e r ia l pr e ssur e .

I nt r a va scula r Volum e
Vascular volum e is a prim ary det erm inant of art erial pressure over t he long t erm . Sodium is predom inant ly an ext racellular ion and is a prim ary det erm inant of t he ext racellular fluid volum e. When NaCl int ake exceeds t he capacit y of t he kidney t o excret e sodium , vascular volum e init ially expands and cardiac out put increases. How ever, m any vascular beds ( including kidney and brain) have t he capacit y t o aut oregulat e blood flow, and if const ant blood flow is t o be m aint ained in t he face of increased art erial pressure, resist ance w it hin t hat bed m ust increase, since

The init ial elevat ion of blood pressure in response t o vascular volum e expansion m ay be relat ed t o an increase of cardiac out put ; however, over t im e, peripheral resist ance increases and cardiac out put revert s t oward norm al. The effect of sodium on blood pressure is relat ed t o t he provision of sodium w it h chloride; nonchloride salt s of sodium have lit t le or no effect on blood pressure. As art erial pressure increases in response t o a high NaCl int ake, urinary sodium excret ion increases and sodium balance is m aint ained at t he expense of an increase in art erial pressure. The m echanism for t his " pressure- nat riuresis" phenom enon m ay involve a subt le increase in t he glom erular filt rat ion rat e, decreased absorbing capacit y of t he renal t ubules, and possibly horm onal fact ors such as at rial nat riuret ic fact or. I n individuals wit h an im paired capacit y t o excret e sodium , great er increases in art erial pressure are required t o achieve nat riuresis and sodium balance. NaCl- dependent hypert ension m ay be a consequence of a decreased capacit y of t he kidney t o excret e sodium , due eit her t o int rinsic renal disease or t o increased product ion of a salt - ret aining horm one ( m ineralocort icoid) result ing in increased renal t ubular reabsorpt ion of sodium . Renal t ubular sodium reabsorpt ion also m ay be augm ent ed by increased neural act ivit y t o t he kidney. I n each of t hese sit uat ions, a higher art erial pressure m ay be required t o achieve sodium balance. Conversely, salt - wast ing disorders are associat ed wit h low blood pressure levels. ESRD is an ext rem e exam ple of volum e- dependent hypert ension. I n ~ 80% of t hese pat ient s, vascular volum e and hypert ension can be cont rolled wit h adequat e dialysis; in t he ot her 20% , t he m echanism of hypert ension is relat ed t o increased act ivit y of t he renin - angiot ensin syst em and is likely t o be responsive t o pharm acologic blockade of renin- angiot ensin.

Aut onom ic N e rvous Syst e m


The aut onom ic nervous syst em m aint ains cardiovascular hom eost asis via pressure, volum e, and chem orecept or signals. Adrenergic reflexes m odulat e blood pressure over t he short t erm , and adrenergic funct ion, in concert wit h horm onal and volum e- relat ed fact ors, cont ribut es t o t he long- t erm regulat ion of art erial pressure. The t hree endogenous cat echolam ines are norepinephrine, epinephrine, and dopam ine. All t hree play im port ant roles in t onic and phasic cardiovascular regulat ion. The act ivit ies of t he adrenergic recept ors are m ediat ed by guanosine nucleot ide - binding regulat ory prot eins ( G prot eins) and by int racellular concent rat ions of downst ream second m essengers. I n addit ion t o recept or affinit y and densit y, physiologic responsiveness t o cat echolam ines m ay be alt ered by t he efficiency of recept or - effect or coupling at a sit e " dist al" t o recept or binding. The recept or sit es are relat ively specific bot h for t he t ransm it t er subst ance and

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for t he response t hat occupancy of t he recept or sit e elicit s. Norepinephrine and epinephrine are agonist s for all adrenergic recept or subt ypes, alt hough wit h varying affinit ies. Based on t heir physiology and pharm acology, adrenergic recept ors have been divided int o t wo principal t ypes: and . These t ypes have been different iat ed furt her int o 1 , 2 , 1 , and 2 recept ors. Recent m olecular cloning st udies have ident ified several addit ional subt ypes. Recept ors are occupied and act ivat ed m ore avidly by norepinephrine t han by epinephrine, and t he reverse is t rue for recept ors. 1 Recept ors are locat ed on post synapt ic cells in sm oot h m uscle and elicit vasoconst rict ion. synt hesize norepinephrine. When act ivat ed by cat echolam ines,
2

Recept ors are localized on presynapt ic m em branes of post ganglionic nerve t erm inals t hat
2 1 - adrenergic

recept ors act as negat ive feedback cont rollers, recept ors increases renal t ubular
1

inhibit ing furt her norepinephrine release. I n t he kidney, act ivat ion of

reabsorpt ion of sodium . Different classes of ant ihypert ensive agent s eit her inhibit

recept ors or act as agonist s of

recept ors and reduce syst em ic sym pat het ic out flow. Act ivat ion of m yocardial 1 recept ors st im ulat es t he rat e 2 and st rengt h of cardiac cont ract ion and consequent ly increases cardiac out put . 1 Recept or act ivat ion also st im ulat es renin release from t he kidney. Anot her class of ant ihypert ensive agent s act s by inhibit ing 1 recept ors. Act ivat ion of
2

recept ors by epinephrine relaxes vascular sm oot h m uscle and result s in vasodilat ion.

Circulat ing cat echolam ine concent rat ions m ay affect t he num ber of adrenorecept ors in various t issues. Downregulat ion of recept ors m ay be a consequence of sust ained high levels of cat echolam ines and provides an explanat ion for decreasing responsiveness, or t achyphylaxis, t o cat echolam ines. For exam ple, ort host at ic hypot ension frequent ly is observed in pat ient s wit h pheochrom ocyt om a, possibly due t o t he lack of norepinephrine induced vasoconst rict ion w it h assum pt ion of t he upright post ure. Conversely, wit h chronic reduct ion of neurot ransm it t er subst ances, adrenorecept ors m ay increase in num ber or be upregulat ed, result ing in increased responsiveness t o t he neurot ransm it t er. Chronic adm inist rat ion of agent s t hat block adrenergic recept ors m ay result in upregulat ion, and wit hdrawal of t hose agent s m ay produce a condit ion of t em porary hypersensit ivit y t o sym pat het ic st im uli. For exam ple, clonidine is an ant ihypert ensive agent t hat is a cent rally act ing 2 agonist t hat inhibit s sym pat het ic out flow. Rebound hypert ension m ay occur wit h t he abrupt cessat ion of clonidine t herapy, probably as a consequence of upregulat ion of 1 recept ors. Several reflexes m odulat e blood pressure on a m inut e- t o- m inut e basis. One art erial baroreflex is m ediat ed by st ret ch- sensit ive sensory nerve endings in t he carot id sinuses and t he aort ic arch. The rat e of firing of t hese barorecept ors increases w it h art erial pressure, and t he net effect is a decrease in sym pat het ic out flow, result ing in decreases in art erial pressure and heart rat e. This is a prim ary m echanism for rapid buffering of acut e fluct uat ions of art erial pressure t hat m ay occur during post ural changes, behavioral or physiologic st ress, and changes in blood volum e. However, t he act ivit y of t he baroreflex declines or adapt s t o sust ained increases in art erial pressure such t hat t he barorecept ors are reset t o higher pressures. Pat ient s wit h aut onom ic neuropat hy and im paired baroreflex funct ion m ay have ext rem ely labile blood pressures wit h difficult - t o- cont rol episodic blood pressure spikes associat ed wit h t achycardia. I n bot h norm al- weight and obese individuals, hypert ension oft en is associat ed wit h increased sym pat het ic out flow . Based on recordings of post ganglionic m uscle nerve act ivit y ( det ect ed by a m icroelect rode insert ed in a peroneal nerve in t he leg) , sym pat het ic out flow t ends t o be higher in hypert ensive t han in norm ot ensive individuals. Sym pat het ic out flow is increased in obesit y - relat ed hypert ension and in hypert ension associat ed wit h obst ruct ive sleep apnea. Barorecept or act ivat ion via elect rical st im ulat ion of carot id sinus afferent nerves has been shown t o low er blood pressure in pat ient s wit h "resist ant " hypert ension. Drugs t hat block t he sym pat het ic nervous syst em are pot ent ant ihypert ensive agent s, indicat ing t hat t he sym pat het ic nervous syst em plays a perm issive, alt hough not necessarily a causat ive, role in t he m aint enance of increased art erial pressure. Pheochrom ocyt om a is t he m ost blat ant exam ple of hypert ension relat ed t o increased cat echolam ine product ion, in t his inst ance by a t um or. Blood pressure can be reduced by surgical excision of t he t um or or by pharm acologic t reat m ent wit h an 1 recept or ant agonist or wit h an inhibit or of t yrosine hydroxylase, t he rat e - lim it ing st ep in cat echolam ine biosynt hesis.

Re nin - Angiot ensin - Aldost e rone


The renin- angiot ensin- aldost erone syst em cont ribut es t o t he regulat ion of art erial pressure prim arily via t he vasoconst rict or propert ies of angiot ensin I I and t he sodium - ret aining propert ies of aldost erone. Renin is an aspart yl

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prot ease t hat is synt hesized as an enzym at ically inact ive precursor, prorenin. Most renin in t he circulat ion is synt hesized in t he renal afferent renal art eriole. Prorenin m ay be secret ed direct ly int o t he circulat ion or m ay be act ivat ed wit hin secret ory cells and released as act ive renin. Alt hough hum an plasm a cont ains t wo t o five t im es m ore prorenin t han renin, t here is no evidence t hat prorenin cont ribut es t o t he physiologic act ivit y of t his syst em . There are t hree prim ary st im uli for renin secret ion: ( 1) decreased NaCl t ransport in t he dist al port ion of t he t hick ascending lim b of t he loop of Henle t hat abut s t he corresponding afferent art eriole ( m acula densa) , ( 2) decreased pressure or st ret ch w it hin t he renal afferent art eriole ( barorecept or m echanism ) , and ( 3) sym pat het ic nervous syst em st im ulat ion of renin- secret ing cells via 1 adrenorecept ors. Conversely, renin secret ion is inhibit ed by increased NaCl t ransport in t he t hick ascending lim b of t he loop of Henle, by increased st ret ch wit hin t he renal afferent art eriole, and by 1 recept or blockade. I n addit ion, angiot ensin I I direct ly inhibit s renin secret ion due t o angiot ensin I I t ype 1 recept ors on j uxt aglom erular cells, and renin secret ion increases in response t o pharm acologic blockade of eit her ACE or angiot ensin I I recept ors. Once released int o t he circulat ion, act ive renin cleaves a subst rat e, angiot ensinogen, t o form an inact ive decapept ide, angiot ensin I ( Fig. 2 4 7 - 2 ) . A convert ing enzym e, locat ed prim arily but not exclusively in t he pulm onary circulat ion, convert s angiot ensin I t o t he act ive oct apept ide, angiot ensin I I , by releasing t he C- t erm inal hist idyl- leucine dipept ide. The sam e convert ing enzym e cleaves a num ber of ot her pept ides, including and t hereby inact ivat ing t he vasodilat or bradykinin. Act ing prim arily t hrough angiot ensin I I t ype 1 ( AT 1 ) recept ors on cell m em branes, angiot ensin I I is a pot ent pressor subst ance, t he prim ary t ropic fact or for t he secret ion of aldost erone by t he adrenal zona glom erulosa, and a pot ent m it ogen t hat st im ulat es vascular sm oot h m uscle cell and m yocyt e growt h. I ndependent of it s hem odynam ic effect s, angiot ensin I I m ay play a role in t he pat hogenesis of at herosclerosis t hrough a direct cellular act ion on t he vessel w all. An angiot ensin I I t ype 2 ( AT 2 ) recept or has been charact erized. I t is widely dist ribut ed in t he kidney and has t he opposit e funct ional effect s of t he AT 1 recept or. The AT2 recept or induces vasodilat ion, sodium excret ion, and inhibit ion of cell growt h and m at rix form at ion.

Experim ent al evidence suggest s t hat t he AT 2 recept or im proves vascular rem odeling by st im ulat ing sm oot h m uscle cell apopt osis and cont ribut es t o t he regulat ion of glom erular filt rat ion rat e. AT 1 recept or blockade induces an increase in AT2 recept or act ivit y.

Figur e 2 4 7 - 2

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Re nin - a ngiot e nsin - a ldost e r one a x is.

Renin- secret ing t um ors are clear exam ples of renin- dependent hypert ension. I n t he kidney, t hese t um ors include benign hem angiopericyt om as of t he j uxt aglom erular apparat us and, infrequent ly, renal carcinom as, including Wilm s' t um ors. Renin- producing carcinom as also have been described in lung, liver, pancreas, colon, and adrenals. I n t hese inst ances, in addit ion t o excision and/ or ablat ion of t he t um or, t reat m ent of hypert ension includes pharm acologic t herapies t arget ed t o inhibit angiot ensin I I product ion or act ion. Renovascular hypert ension is anot her renin m ediat ed form of hypert ension. Obst ruct ion of t he renal art ery leads t o decreased renal perfusion pressure, t hereby st im ulat ing renin secret ion. Over t im e, as a consequence of secondary renal dam age, t his form of hypert ension m ay becom e less renin dependent . Angiot ensinogen, renin, and angiot ensin I I are also synt hesized locally in m any t issues, including t he brain, pit uit ary, aort a, art eries, heart , adrenal glands, kidneys, adipocyt es, leukocyt es, ovaries, t est es, ut erus, spleen, and skin. Angiot ensin I I in t issues m ay be form ed by t he enzym at ic act ivit y of renin or by ot her prot eases, e.g., t onin, chym ase, and cat hepsins. I n addit ion t o regulat ing local blood flow, t issue angiot ensin I I is a m it ogen t hat st im ulat es growt h and cont ribut es t o m odeling and repair. Excess t issue angiot ensin I I m ay cont ribut e t o at herosclerosis, cardiac hypert rophy, and renal failure and consequent ly m ay be a t arget for pharm acologic t herapy t o prevent t arget organ dam age. Angiot ensin I I is t he prim ary t ropic fact or regulat ing t he synt hesis and secret ion of aldost erone by t he zona glom erulosa of t he adrenal cort ex. Aldost erone synt hesis is also dependent on pot assium , and aldost erone secret ion m ay be decreased in pot assium - deplet ed individuals. Alt hough acut e elevat ions of adrenocort icot ropic horm one ( ACTH) levels also increase aldost erone secret ion, ACTH is not an im port ant t ropic fact or for t he chronic regulat ion of aldost erone.

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Aldost erone is a pot ent m ineralocort icoid t hat increases sodium reabsorpt ion by am iloride- sensit ive epit helial sodium channels ( ENaC) on t he apical surface of t he principal cells of t he renal cort ical collect ing duct ( Chap. 277) . Elect ric neut ralit y is m aint ained by exchanging sodium for pot assium and hydrogen ions. Consequent ly, increased aldost erone secret ion m ay result in hypokalem ia and alkalosis. Because pot assium deplet ion m ay inhibit aldost erone synt hesis, clinically, hypokalem ia should be correct ed before a pat ient is evaluat ed for hyperaldost eronism . Mineralocort icoid recept ors also are expressed in t he colon, salivary glands, and sweat glands. Cort isol also binds t o t hese recept ors but norm ally funct ions as a less pot ent m ineralocort icoid t han aldost erone because cort isol is convert ed t o cort isone by t he enzym e 11 - hydroxyst eroid dehydrogenase t ype 2. Cort isone has no affinit y for t he m ineralocort icoid recept or. Prim ary aldost eronism is a com pelling exam ple of m ineralocort icoid - m ediat ed hypert ension. I n t his disorder, adrenal aldost erone synt hesis and release are independent of renin - angiot ensin, and renin release is suppressed by t he result ing volum e expansion. Aldost erone also has effect s on nonepit helial t arget s. Aldost erone and/ or m ineralocort icoid recept or act ivat ion induces st ruct ural and funct ional alt erat ions in t he heart , kidney, and blood vessels, leading t o m yocardial fibrosis, nephrosclerosis, and vascular inflam m at ion and rem odeling, perhaps as a consequence of oxidat ive st ress. These effect s are am plified by a high salt int ake. I n anim al m odels, high circulat ing aldost erone levels st im ulat e cardiac fibrosis and left vent ricular hypert rophy, and spironolact one ( an aldost erone ant agonist ) prevent s aldost erone induced m yocardial fibrosis. Pat hologic pat t erns of left vent ricular geom et ry also have been associat ed wit h elevat ions of plasm a aldost erone concent rat ion in pat ient s wit h essent ial hypert ension as well as in pat ient s w it h prim ary aldost eronism . I n pat ient s wit h CHF, low - dose spironolact one reduces t he risk of progressive heart failure and sudden deat h from cardiac causes by 30% . Owing t o a renal hem odynam ic effect , in pat ient s w it h prim ary aldost eronism , high circulat ing levels of aldost erone also m ay cause glom erular hyperfilt rat ion and album inuria. These renal effect s are reversible aft er rem oval of t he effect s of excess aldost erone by adrenalect om y or spironolact one. I ncreased act ivit y of t he renin- angiot ensin- aldost erone axis is not invariably associat ed wit h hypert ension. I n response t o a low- NaCl diet or t o volum e cont ract ion, art erial pressure and volum e hom eost asis m ay be m aint ained by increased act ivit y of t he renin- angiot ensin- aldost erone axis. Secondary aldost eronism ( i.e., increased aldost erone secondary t o increased renin- angiot ensin) , but not hypert ension, also is observed in edem at ous st at es such as CHF and liver disease.

Va scula r M ech an ism s


Vascular radius and com pliance of resist ance art eries are also im port ant det erm inant s of art erial pressure. Resist ance t o flow varies inversely wit h t he fourt h pow er of t he radius, and consequent ly, sm all decreases in lum en size significant ly increase resist ance. I n hypert ensive pat ient s, st ruct ural, m echanical, or funct ional changes m ay reduce t he lum en diam et er of sm all art eries and art erioles. Rem odeling refers t o geom et ric alt erat ions in t he vessel wall wit hout a change in vessel volum e. Hypert rophic ( increased cell size, and increased deposit ion of int ercellular m at rix) or eut rophic vascular rem odeling result s in decreased lum en size and hence cont ribut es t o increased peripheral resist ance. Apopt osis, low - grade inflam m at ion, and vascular fibrosis also cont ribut e t o rem odeling. Lum en diam et er also is relat ed t o elast icit y of t he vessel. Vessels wit h a high degree of elast icit y can accom m odat e an increase of volum e wit h relat ively lit t le change in pressure, whereas in a sem irigid vascular syst em , a sm all increm ent in volum e induces a relat ively large increm ent of pressure. Hypert ensive pat ient s have st iffer art eries, and art eriosclerot ic pat ient s m ay have part icularly high syst olic blood pressures and wide pulse pressures as a consequence of decreased vascular com pliance due t o st ruct ural changes in t he vascular w all. Recent evidence suggest s t hat art erial st iffness has independent predict ive value for cardiovascular event s. Clinically, a num ber of devices are available t o evaluat e art erial st iffness or com pliance, including ult rasound and m agnet ic resonance im aging ( MRI ) . I on t ransport by vascular sm oot h m uscle cells m ay cont ribut e t o hypert ension - associat ed abnorm alit ies of vascular t one and vascular growt h, bot h of which are m odulat ed by int racellular pH ( pH i ) . Three ion t ransport m echanism s

part icipat e in t he regulat ion of pH i : ( 1) Na + - H+ exchange, ( 2) Na + - dependent HCO3 - Cl exchange, and ( 3) cat ionindependent HCO3 Cl exchange. Based on m easurem ent s in cell t ypes t hat are m ore accessible t han vascular sm oot h m uscle ( e.g., leukocyt es, eryt hrocyt es, plat elet s, skelet al m uscle) , act ivit y of t he Na + - H+ exchanger is

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increased in hypert ension, and t his m ay result in increased vascular t one by t wo m echanism s. First , increased sodium ent ry m ay lead t o increased vascular t one by act ivat ing Na + - Ca + exchange and t hereby increasing int racellular calcium . Second, increased pH i enhances calcium sensit ivit y of t he cont ract ile apparat us, leading t o an increase in cont ract ilit y for a given int racellular calcium concent rat ion. Addit ionally, increased Na + - H+ exchange m ay st im ulat e growt h of vascular sm oot h m uscle cells by enhancing sensit ivit y t o m it ogens.
2

Vascular endot helial funct ion also m odulat es vascular t one. The vascular endot helium synt hesizes and releases a spect rum of vasoact ive subst ances, including nit ric oxide, a pot ent vasodilat or. Endot helium - dependent vasodilat ion is im paired in hypert ensive pat ient s. This im pairm ent oft en is assessed w it h high - resolut ion ult rasonography before and aft er t he hyperem ic phase of reperfusion t hat follows 5 m inut es of forearm ischem ia. Alt ernat ively, endot helium - dependent vasodilat ion m ay be assessed in response t o an int ra- art erially infused endot helium dependent vasodilat or, e.g., acet ylcholine. Endot helin is a vasoconst rict or pept ide produced by t he endot helium , and t hat orally act ive endot helin ant agonist s m ay lower blood pressure in pat ient s wit h resist ant hypert ension. Current ly, it is not known if t he hypert ension - relat ed vascular abnorm alit ies of ion t ransport and endot helial funct ion are prim ary alt erat ions or secondary consequences of elevat ed art erial pressure. Lim it ed evidence suggest s t hat vascular com pliance and endot helium - dependent vasodilat ion m ay be im proved by aerobic exercise, w eight loss, and ant ihypert ensive agent s. I t rem ains t o be det erm ined whet her t hese int ervent ions affect art erial st ruct ure and st iffness via a blood pressureindependent m echanism and whet her different classes of ant ihypert ensive agent s preferent ially affect vascular st ruct ure and funct ion.

PATH OLOGI C CON SEQUEN CES OF H YPERTEN SI ON


Hypert ension is an independent predisposing fact or for heart failure, coronary art ery disease, st roke, renal disease, and peripheral art erial disease ( PAD) .

Heart
Heart disease is t he m ost com m on cause of deat h in hypert ensive pat ient s. Hypert ensive heart disease is t he result of st ruct ural and funct ional adapt at ions leading t o left vent ricular hypert rophy, CHF, abnorm alit ies of blood flow due t o at herosclerot ic coronary art ery disease and m icrovascular disease, and cardiac arrhyt hm ias. Bot h genet ic and hem odynam ic fact ors cont ribut e t o left vent ricular hypert rophy. Clinically, left vent ricular hypert rophy can be diagnosed by elect rocardiography, alt hough echocardiography provides a m ore sensit ive m easure of left vent ricular w all t hickness. I ndividuals w it h left vent ricular hypert rophy are at increased risk for CHD, st roke, CHF, and sudden deat h. Aggressive cont rol of hypert ension can regress or reverse left vent ricular hypert rophy and reduce t he risk of cardiovascular disease. I t is not clear whet her different classes of ant ihypert ensive agent s have an added im pact on reducing left vent ricular m ass, independent of t heir blood pressurelow ering effect . CHF m ay be relat ed t o syst olic dysfunct ion, diast olic dysfunct ion, or a com binat ion of t he t wo. Abnorm alit ies of diast olic funct ion t hat range from asym pt om at ic heart disease t o overt heart failure are com m on in hypert ensive pat ient s. Pat ient s w it h diast olic heart failure have a preserved ej ect ion fract ion, which is a m easure of syst olic funct ion. Approxim at ely one- t hird of pat ient s wit h CHF have norm al syst olic funct ion but abnorm al diast olic funct ion. Diast olic dysfunct ion is an early consequence of hypert ension - relat ed heart disease and is exacerbat ed by left vent ricular hypert rophy and ischem ia. Cardiac cat het erizat ion provides t he m ost accurat e assessm ent of diast olic funct ion. Alt ernat ively, diast olic funct ion can be evaluat ed by several noninvasive m et hods, including echocardiography and radionuclide angiography.

Br a in
St roke is t he second m ost frequent cause of deat h in t he world; it account s for 5 m illion deat hs each year, wit h an addit ional 15 m illion persons having nonfat al st rokes. Elevat ed blood pressure is t he st rongest risk fact or for st roke. Approxim at ely 85% of st rokes are due t o infarct ion, and t he rem ainder are due t o eit her int racerebral or subarachnoid hem orrhage. The incidence of st roke rises progressively w it h increasing blood pressure levels, part icularly syst olic blood pressure in individuals > 65 years. Treat m ent of hypert ension convincingly decreases t he incidence of bot h ischem ic and hem orrhagic st rokes.

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Hypert ension also is associat ed w it h im paired cognit ion in an aging populat ion, and longit udinal st udies support an associat ion bet w een m idlife hypert ension and lat e- life cognit ive decline. Hypert ension- relat ed cognit ive im pairm ent and dem ent ia m ay be a consequence of a single infarct due t o occlusion of a "st rat egic" larger vessel or m ult iple lacunar infarct s due t o occlusive sm all vessel disease result ing in subcort ical w hit e m at t er ischem ia. Several clinical t rials suggest t hat ant ihypert ensive t herapy has a beneficial effect on cognit ive funct ion, alt hough t his rem ains an act ive area of invest igat ion. Cerebral blood flow rem ains unchanged over a w ide range of art erial pressures ( m ean art erial pressure of 50 150 m m Hg) t hrough a process t erm ed aut oregulat ion of blood flow. I n pat ient s wit h t he clinical syndrom e of m alignant hypert ension, encephalopat hy is relat ed t o failure of aut oregulat ion of cerebral blood flow at t he upper pressure lim it , result ing in vasodilat ion and hyperperfusion. Signs and sym pt om s of hypert ensive encephalopat hy m ay include severe headache, nausea and vom it ing ( oft en of a proj ect ile nat ure) , focal neurologic signs, and alt erat ions in m ent al st at us. Unt reat ed, hypert ensive encephalopat hy m ay progress t o st upor, com a, seizures, and deat h wit hin hours. I t is im port ant t o dist inguish hypert ensive encephalopat hy from ot her neurologic syndrom es t hat m ay be associat ed wit h hypert ension, e.g., cerebral ischem ia, hem orrhagic or t hrom bot ic st roke, seizure disorder, m ass lesions, pseudot um or cerebri, delirium t rem ens, m eningit is, acut e int erm it t ent porphyria, t raum at ic or chem ical inj ury t o t he brain, and urem ic encephalopat hy.

Kidne y
The kidney is bot h a t arget and a cause of hypert ension. Prim ary renal disease is t he m ost com m on et iology of secondary hypert ension. Mechanism s of kidney- relat ed hypert ension include a dim inished capacit y t o excret e sodium , excessive renin secret ion in relat ion t o volum e st at us, and sym pat het ic nervous syst em overact ivit y. Conversely, hypert ension is a risk fact or for renal inj ury and end- st age renal disease. The increased risk associat ed wit h high blood pressure is graded, cont inuous, and present t hroughout t he dist ribut ion of blood pressure above opt im al pressure. Renal risk appears t o be m ore closely relat ed t o syst olic t han t o diast olic blood pressure, and black m en are at great er risk t han whit e m en for developing ESRD at every level of blood pressure. Prot einuria is a reliable m arker of t he severit y of chronic kidney disease and is a predict or of it s progression. Pat ient s wit h high urine prot ein excret ion ( > 3 g/ 24 h) have a m ore rapid rat e of progression t han do t hose w it h lower prot ein excret ion rat es. At herosclerot ic, hypert ension- relat ed vascular lesions in t he kidney prim arily affect preglom erular art erioles, result ing in ischem ic changes in t he glom eruli and post glom erular st ruct ures. Glom erular inj ury also m ay be a consequence of direct dam age t o t he glom erular capillaries due t o glom erular hyperperfusion. St udies of hypert ension- relat ed renal dam age, prim arily in experim ent al anim als, suggest t hat loss of aut oregulat ion of renal blood flow at t he afferent art eriole result s in t ransm ission of elevat ed pressures t o an unprot ect ed glom erulus wit h ensuing hyperfilt rat ion, hypert rophy, and event ual focal segm ent al glom erular sclerosis. Wit h progressive renal inj ury t here is a loss of aut oregulat ion of renal blood flow and glom erular filt rat ion rat e, result ing in a lower blood pressure t hreshold for renal dam age and a st eeper slope bet ween blood pressure and renal dam age. The result m ay be a vicious cycle of renal dam age and nephron loss leading t o m ore severe hypert ension, glom erular hyperfilt rat ion, and furt her renal dam age. Glom erular pat hology progresses t o glom erulosclerosis, and event ually t he renal t ubules m ay also becom e ischem ic and gradually at rophic. The renal lesion associat ed wit h m alignant hypert ension consist s of fibrinoid necrosis of t he afferent art erioles, som et im es ext ending int o t he glom erulus, and m ay result in focal necrosis of t he glom erular t uft . Clinically, m acroalbum inuria ( a random urine album in/ creat inine rat io > 300 m g/ g) or m icroalbum inuria ( a random urine album in/ creat inine rat io 30300 m g/ g) are early m arkers of renal inj ury. These are also risk fact ors for renal disease progression and cardiovascular disease.

Pe r iphe r a l Art er ie s
I n addit ion t o cont ribut ing t o t he pat hogenesis of hypert ension, blood vessels m ay be a t arget organ for at herosclerot ic disease secondary t o long- st anding elevat ed blood pressure. Hypert ensive pat ient s wit h art erial disease of t he lower ext rem it ies are at increased risk for fut ure cardiovascular disease. Alt hough pat ient s wit h st enot ic lesions of t he lower ext rem it ies m ay be asym pt om at ic, int erm it t ent claudicat ion is t he classic sym pt om of PAD. This is charact erized by aching pain in t he calves or but t ocks w hile w alking t hat is relieved by rest . The ankle -

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brachial index is a useful approach for evaluat ing PAD and is defined as t he rat io of noninvasively assessed ankle t o brachial ( arm ) syst olic blood pressure. An ankle- brachial index < 0.90 is considered diagnost ic of PAD and is associat ed wit h > 50% st enosis in at least one m aj or lower lim b vessel. Several st udies suggest t hat an ankle brachial index < 0.80 is associat ed wit h elevat ed blood pressure, part icularly syst olic blood pressure.

D EFI N I N G H YPERTEN SI ON
From an epidem iologic perspect ive, t here is no obvious level of blood pressure t hat defines hypert ension. I n adult s, t here is a cont inuous, increm ent al risk of cardiovascular disease, st roke, and renal disease across levels of bot h syst olic and diast olic blood pressure. The Mult iple Risk Fact or I nt ervent ion Trial ( MRFI T) , w hich included > 350,000 m ale part icipant s, dem onst rat ed a cont inuous and graded influence of bot h syst olic and diast olic blood pressure on CHD m ort alit y, ext ending down t o syst olic blood pressures of 120 m m Hg. Sim ilarly, result s of a m et a - analysis involving alm ost 1 m illion part icipant s indicat e t hat ischem ic heart disease m ort alit y, st roke m ort alit y, and m ort alit y from ot her vascular causes are direct ly relat ed t o t he height of t he blood pressure, beginning at 115/ 75 m m Hg, wit hout evidence of a t hreshold. Cardiovascular disease risk doubles for every 20 - m m Hg increase in syst olic and 10m m Hg increase in diast olic pressure. Am ong older individuals, syst olic blood pressure and pulse pressure are m ore powerful predict ors of cardiovascular disease t han is diast olic blood pressure. Clinically, hypert ension m ay be defined as t hat level of blood pressure at which t he inst it ut ion of t herapy reduces blood pressurerelat ed m orbidit y and m ort alit y. Current clinical crit eria for defining hypert ension generally are based on t he average of t w o or m ore seat ed blood pressure readings during each of t wo or m ore out pat ient visit s. A recent classificat ion recom m ends blood pressure crit eria for defining norm al blood pressure, prehypert ension, hypert ension ( st ages I and I I ) , and isolat ed syst olic hypert ension, w hich is a com m on occurrence am ong t he elderly ( Ta ble 2 4 7 - 1 ) . I n children and adolescent s, hypert ension generally is defined as syst olic and/ or diast olic blood pressure consist ent ly > 95t h percent ile for age, sex, and height . Blood pressures bet ween t he 90t h and 95t h percent iles are considered prehypert ensive and are an indicat ion for lifest yle int ervent ions.

Ta ble 2 4 7 1 . Blood Pr e ssur e Cla ssifica t ion


Blood Pre ssur e Cla ssifica t ion Syst olic, m m H g D ia st olic, m m H g Norm al Prehypert ension St age 1 hypert ension St age 2 hypert ension I solat ed syst olic hypert ension < 120 120139 140159 160 140 and < 80 or 8089 or 9099 or 100

and < 90

Source : Adapt ed from Chobanian et al. Hom e blood pressure and average 24 - h am bulat ory blood pressure m easurem ent s are generally lower t han clinic blood pressures. Because am bulat ory blood pressure recordings yield m ult iple readings t hroughout t he day and night , t hey provide a m ore com prehensive assessm ent of t he vascular burden of hypert ension t han do a lim it ed num ber of office readings. I ncreasing evidence suggest s t hat hom e blood pressures, including 24 - h blood pressure recordings, m ore reliably predict t arget organ dam age t han do office blood pressures. Blood pressure t ends t o be higher in t he early m orning hours, soon aft er waking, t han at ot her t im es of day. Myocardial infarct ion and st roke are m ore com m on in t he early m orning hours. Night t im e blood pressures are generally 10 20% lower t han dayt im e blood pressures, and an at t enuat ed night t im e blood pressure "dip" is associat ed w it h increased cardiovascular disease risk. Recom m ended crit eria for a diagnosis of hypert ension are average aw ake blood pressure 135/ 85 m m Hg and asleep blood pressure 120/ 75 m m Hg. These levels approxim at e a clinic blood pressure of 140/ 90 m m Hg. Approxim at ely 1520% of pat ient s wit h st age 1 hypert ension ( as defined in Table 247 - 1) based on office blood pressures have average am bulat ory readings < 135/ 85 m m Hg. This phenom enon, so- called whit e coat hypert ension, also m ay be associat ed w it h an increased risk of t arget organ dam age ( e.g., left vent ricular hypert rophy, carot id at herosclerosis, overall cardiovascular m orbidit y) , alt hough t o a lesser ext ent t han in individuals wit h elevat ed office and am bulat ory readings. I ndividuals w it h whit e coat hypert ension are also at increased risk for developing

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sust ained hypert ension.

CLI N I CAL DI SORD ERS OF H YPERTEN SI ON


Depending on m et hods of pat ient ascert ainm ent , ~ 80 95% of hypert ensive pat ient s are diagnosed as having " essent ial" hypert ension ( also referred t o as prim ary or idiopat hic hypert ension) . I n t he rem aining 5 20% of hypert ensive pat ient s, a specific underlying disorder causing t he elevat ion of blood pressure can be ident ified ( Ta ble s 2 4 7 - 2 and 2 4 7 - 3 ) . I n individuals w it h "secondary" hypert ension, a specific m echanism for t he blood pressure elevat ion is oft en m ore apparent .

Ta ble 2 4 7 2 . Sy st olic H y pe r t e nsion w it h W ide Pulse Pr e ssur e


1. Decreased vascular com pliance ( art eriosclerosis) 2. I ncreased cardiac out put . a. Aort ic regurgit at ion b. Thyrot oxicosis. c. Hyperkinet ic heart syndrom e. d. Fever. e. Art eriovenous fist ula f. Pat ent duct us art eriosus

Ta ble 2 4 7 3 . Se conda r y Ca use s of Syst olic a nd D ia st olic H ype r t e nsion


Renal Renovascular Adrenal Parenchym al diseases, renal cyst s ( including polycyst ic kidney disease) , renal t um ors ( including renin- secret ing t um ors) , obst ruct ive uropat hy Art eriosclerot ic, fibrom uscular dysplasia Prim ary aldost eronism , Cushing's syndrom e, 17 - hydroxylase deficiency, 11 hydroxylase deficiency, 11- hydroxyst eroid dehydrogenase deficiency ( licorice) , pheochrom ocyt om a

Aort ic coarct at ion Obst ruct ive sleep apnea Preeclam psia/ eclam psia Neurogenic Psychogenic, diencephalic syndrom e, fam ilial dysaut onom ia, polyneurit is ( acut e porphyria, lead poisoning) , acut e increased int racranial pressure, acut e spinal cord sect ion Hypot hyroidism , hypert hyroidism , hypercalcem ia, acrom egaly High- dose est rogens, adrenal st eroids, decongest ant s, appet it e suppressant s, cyclosporine, t ricyclic ant idepressant s, m onam ine oxidase inhibit ors, eryt hropoiet in, nonst eroidal ant i- inflam m at ory agent s, cocaine See Table 247- 4

Miscellaneous endocrine Medicat ions

Mendelian form s of hypert ension

Esse nt ia l H ype rt en sion


Essent ial hypert ension t ends t o be fam ilial and is likely t o be t he consequence of an int eract ion bet ween environm ent al and genet ic fact ors. The prevalence of essent ial hypert ension increases wit h age, and individuals wit h relat ively high blood pressures at younger ages are at increased risk for t he subsequent developm ent of hypert ension. I t is likely t hat essent ial hypert ension represent s a spect rum of disorders w it h different underlying pat hophysiologies. I n t he m aj orit y of pat ient s wit h est ablished hypert ension, peripheral resist ance is increased and cardiac out put is norm al or decreased; however, in younger pat ient s wit h m ild or labile hypert ension, cardiac out put m ay be increased and peripheral resist ance m ay be norm al.

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When plasm a renin act ivit y ( PRA) is plot t ed against 24 - h sodium excret ion, ~ 1015% of hypert ensive pat ient s have high PRA and 25% have low PRA. High- renin pat ient s m ay have a vasoconst rict or form of hypert ension, whereas low - renin pat ient s m ay have volum e- dependent hypert ension. I nconsist ent associat ions bet ween plasm a aldost erone and blood pressure have been described in pat ient s wit h essent ial hypert ension. The associat ion bet ween aldost erone and blood pressure is m ore st riking in African Am ericans, and PRA t ends t o be low in hypert ensive African Am ericans. This raises t he possibilit y t hat subt le increases in aldost erone m ay cont ribut e t o hypert ension in at least som e groups of pat ient s who do not have overt prim ary aldost eronism . Furt herm ore, spironolact one, an aldost erone ant agonist , m ay be a part icularly effect ive ant ihypert ensive agent for som e pat ient s wit h essent ial hypert ension, including som e pat ient s wit h "drug - resist ant " hypert ension.

Obe sit y a nd t he M et a bolic Syndrom e


( See also Chap. 242) There is a well- docum ent ed associat ion bet w een obesit y ( body m ass index > 30 kg/ m 2 ) and hypert ension. Furt her, cross- sect ional st udies indicat e a direct linear correlat ion bet ween body weight ( or body m ass index) and blood pressure. Cent rally locat ed body fat is a m ore im port ant det erm inant of blood pressure elevat ion t han is peripheral body fat . I n longit udinal st udies, a direct correlat ion exist s bet ween change in weight and change in blood pressure over t im e. Sixt y percent of hypert ensive adult s are m ore t han 20% overweight . I t has been est ablished t hat 6070% of hypert ension in adult s m ay be direct ly at t ribut able t o adiposit y. Hypert ension and dyslipidem ia frequent ly occur t oget her and in associat ion wit h resist ance t o insulin - st im ulat ed glucose upt ake. This clust ering of risk fact ors is oft en, but not invariably, associat ed wit h obesit y, part icularly abdom inal obesit y. I nsulin resist ance also is associat ed w it h an unfavorable im balance in t he endot helial product ion of m ediat ors t hat regulat e plat elet aggregat ion, coagulat ion, fibrinolysis, and vessel t one. When t hese risk fact ors clust er, t he risks for CHD, st roke, diabet es, and cardiovascular disease m ort alit y are increased furt her. Depending on t he populat ions st udied and t he m et hodologies for defining insulin resist ance, ~ 25 50% of nonobese, nondiabet ic hypert ensive persons are insulin resist ant . The const ellat ion of insulin resist ance, abdom inal obesit y, hypert ension, and dyslipidem ia has been designat ed as t he m et abolic syndrom e. As a group, first - degree relat ives of pat ient s wit h essent ial hypert ension are also insulin resist ant , and hyperinsulinem ia ( a surrogat e m arker of insulin resist ance) m ay predict t he event ual developm ent of hypert ension and cardiovascular disease. Alt hough t he m et abolic syndrom e m ay in part be herit able as a polygenic condit ion, t he expression of t he syndrom e is m odified by environm ent al fact ors, such as degree of physical act ivit y and diet . I nsulin sensit ivit y increases and blood pressure decreases in response t o w eight loss. The recognit ion t hat cardiovascular disease risk fact ors t end t o clust er wit hin individuals has im port ant im plicat ions for t he evaluat ion and t reat m ent of hypert ension. Evaluat ion of bot h hypert ensive pat ient s and individuals at risk for developing hypert ension should include assessm ent of overall cardiovascular disease risk. Sim ilarly, int roduct ion of lifest yle m odificat ion st rat egies and drug t herapies should address overall risk and not sim ply focus on hypert ension.

Re na l Pa re nchym a l D isea ses


Virt ually all disorders of t he kidney m ay cause hypert ension ( Table 247 - 3) , and renal disease is t he m ost com m on cause of secondary hypert ension. Hypert ension is present in > 80% of pat ient s w it h chronic renal failure. I n general, hypert ension is m ore severe in glom erular diseases t han in int erst it ial diseases such as chronic pyelonephrit is. Conversely, hypert ension m ay cause nephrosclerosis, and in som e inst ances it m ay be difficult t o det erm ine whet her hypert ension or renal disease was t he init ial disorder. Prot einuria > 1000 m g/ d and an act ive urine sedim ent are indicat ive of prim ary renal disease. I n eit her inst ance, t he goals are t o cont rol blood pressure and ret ard t he rat e of progression of renal dysfunct ion.

REN OVASCU LAR H YPERTEN SI ON


Hypert ension due t o an occlusive lesion of a renal art ery, renovascular hypert ension, is a pot ent ially curable form of hypert ension. I n t he init ial st ages, t he m echanism of hypert ension generally is relat ed t o act ivat ion of t he renin angiot ensin syst em . However, renin act ivit y and ot her com ponent s of t he renin - angiot ensin syst em m ay be elevat ed only t ransient ly; over t im e, sodium ret ent ion and recruit m ent of ot her pressure m echanism s m ay cont ribut e t o elevat ed art erial pressure. Tw o groups of pat ient s are at risk for t his disorder: older art eriosclerot ic pat ient s w ho have a plaque obst ruct ing t he renal art ery, frequent ly at it s origin, and pat ient s w it h fibrom uscular dysplasia.

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At herosclerosis account s for t he large m aj orit y of pat ient s wit h renovascular hypert ension. Alt hough fibrom uscular dysplasia m ay occur at any age, it has a st rong predilect ion for young w hit e w om en. The prevalence in fem ales is eight fold t hat in m ales. There are several hist ologic variant s of fibrom uscular dysplasia, including m edial fibroplasia, perim edial fibroplasia, m edial hyperplasia, and int im al fibroplasia. Medial fibroplasia is t he m ost com m on variant and account s for approxim at ely t wo- t hirds of pat ient s. The lesions of fibrom uscular dysplasia are frequent ly bilat eral and, in cont rast t o at herosclerot ic renovascular disease, t end t o affect m ore dist al port ions of t he renal art ery. I n addit ion t o t he age and sex of t he pat ient , several clues from t he hist ory and physical exam inat ion suggest a diagnosis of renovascularhypert ension. The diagnosis should be considered in pat ient s wit h ot her evidence of at herosclerot ic vascular disease. Alt hough response t o ant ihypert ensive t herapy does not exclude t he diagnosis, severe or refract ory hypert ension, recent loss of hypert ension cont rol or recent onset of m oderat ely severe hypert ension, and unexplained det eriorat ion of renal funct ion or det eriorat ion of renal funct ion associat ed wit h an ACE inhibit or should raise t he possibilit y of renovascular hypert ension. Approxim at ely 50% of pat ient s w it h renovascular hypert ension have an abdom inal or flank bruit , and t he bruit is m ore likely t o be hem odynam ically significant if it lat eralizes or ext ends t hroughout syst ole int o diast ole. I f blood pressure is adequat ely cont rolled wit h a sim ple ant ihypert ensive regim en and renal funct ion rem ains st able, t here m ay be lit t le im pet us t o pursue an evaluat ion for renal art ery st enosis, part icularly in an older pat ient wit h at herosclerot ic disease and com orbid condit ions. Pat ient s wit h long - st anding hypert ension, advanced renal insufficiency, or diabet es m ellit us are less likely t o benefit from renal vascular repair. The m ost effect ive m edical t herapies include an ACE inhibit or or an angiot ensin I I recept or blocker; however, t hese agent s decrease glom erular filt rat ion rat e in a st enot ic kidney owing t o efferent renal art eriolar dilat ion. I n t he presence of bilat eral renal art ery st enosis or renal art ery st enosis t o a solit ary kidney, progressive renal insufficiency m ay result from t he use of t hese agent s. I m port ant ly, t he renal insufficiency is generally reversible aft er discont inuat ion of t he offending drug. I f renal art ery st enosis is suspect ed and if t he clinical condit ion w arrant s an int ervent ion such as percut aneous t ranslum inal renal angioplast y ( PTRA) , placem ent of a vascular endoprost hesis ( st ent ) , or surgical renal revascularizat ion, im aging st udies should be t he next st ep in t he evaluat ion. As a screening t est , renal blood flow m ay be evaluat ed wit h a radionuclide [ 131 I ] - ort hoiodohippurat e ( OI H) scan or glom erular filt rat ion rat e m ay be evaluat ed wit h a [ 99 m Tc] - diet hylenet riam ine pent aacet ic acid ( DTPA) scan before and aft er a single dose of capt opril ( or anot her ACE inhibit or) . The follow ing are consist ent w it h a posit ive st udy: ( 1) decreased relat ive upt ake by t he involved kidney, which cont ribut es < 40% of t ot al renal funct ion, ( 2) delayed upt ake on t he affect ed side, and ( 3) delayed w ashout on t he affect ed side. I n pat ient s wit h norm al, or nearly norm al, renal funct ion, a norm al capt opril renogram essent ially excludes funct ionally significant renal art ery st enosis; however, it s usefulness is lim it ed in pat ient s w it h renal insufficiency ( creat inine clearance < 20 m L/ m in) or bilat eral renal art ery st enosis. Addit ional im aging st udies are indicat ed if t he scan is posit ive. Doppler ult rasound of t he renal art eries produces reliable est im at es of renal blood flow velocit y and offers t he opport unit y t o t rack a lesion over t im e. Posit ive st udies usually are confirm ed at angiography, whereas false- negat ive result s occur frequent ly, part icularly in obese pat ient s. Gadolinium - cont rast m agnet ic resonance angiography offers clear im ages of t he proxim al renal art ery but m ay m iss dist al lesions. An advant age is t he opport unit y t o im age t he renal art eries wit h an agent t hat is not nephrot oxic. Cont rast art eriography rem ains t he "gold st andard" for evaluat ion and ident ificat ion of renal art ery lesions. Pot ent ial risks include nephrot oxicit y, part icularly in pat ient s wit h diabet es m ellit us or preexist ing renal insufficiency. Som e degree of renal art ery obst ruct ion m ay be observed in alm ost 50% of pat ient s w it h at herosclerot ic disease, and t here are several approaches for evaluat ing t he funct ional significance of such a lesion t o predict t he effect of vascular repair on blood pressure cont rol and renal funct ion. Each approach has varying degrees of sensit ivit y and specificit y, and no single t est is sufficient ly reliable t o det erm ine a causal relat ionship bet ween a renal art ery lesion and hypert ension. Funct ionally significant lesions generally occlude m ore t han 70% of t he lum en of t he affect ed renal art ery. On angiography, t he presence of collat eral vessels t o t he ischem ic kidney suggest s a funct ionally significant lesion. A lat eralizing renal vein renin rat io ( rat io > 1.5 of affect ed side/ cont ralat eral side) has a 90% predict ive value for a lesion t hat would respond t o vascular repair; how ever, t he false- negat ive rat e for blood pressure cont rol is 5060% . Measurem ent of t he pressure gradient across a renal art ery lesion does not reliably predict t he response t o vascular repair.

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I n t he final analysis, a decision concerning vascular repair vs. m edical t herapy and t he t ype of repair procedure should be individualized for each pat ient . Pat ient s wit h fibrom uscular disease have m ore favorable out com es t han do pat ient s wit h at herosclerot ic lesions, presum ably ow ing t o t heir younger age, short er durat ion of hypert ension, and less syst em ic disease. Because of it s low risk - versus- benefit rat io and high success rat e ( im provem ent or cure of hypert ension in 90% of pat ient s and rest enosis rat e of 10% ) , PTRA is t he init ial t reat m ent of choice for t hese pat ient s. Surgical revascularizat ion m ay be undert aken if PTRA is unsuccessful or if a branch lesion is present . I n at herosclerot ic pat ient s, vascular repair should be considered if blood pressure cannot be cont rolled adequat ely despit e opt im al m edical t herapy or if renal funct ion det eriorat es. Surgery m ay be t he preferred init ial approach for younger at herosclerot ic pat ient s wit hout com orbid condit ions; how ever, for m ost at herosclerot ic pat ient s, depending on t he locat ion of t he lesion, t he init ial approach m ay be PTRA and/ or st ent ing. Surgical revascularizat ion m ay be indicat ed if t hese approaches are unsuccessful, t he vascular lesion is not am enable t o PTRA or st ent ing, or concom it ant aort ic surgery is required, e.g., t o repair an aneurysm . A Nat ional I nst it ut es of Healt h sponsored prospect ive, random ized clinical t rial is in progress com paring m edical t herapy alone wit h m edical t herapy plus renal revascularizat ion regarding Cardiovascular Out com es for Renal At herosclerot ic Lesions ( CORAL) .

Pr im a r y Aldost er onism
Excess aldost erone product ion due t o prim ary aldost eronism is a pot ent ially curable form of hypert ension. I n pat ient s wit h prim ary aldost eronism , increased aldost erone product ion is independent of t he renin - angiot ensin syst em , and t he consequences are sodium ret ent ion, hypert ension, hypokalem ia, and low PRA. The report ed prevalence of t his disorder varies from < 2% t o ~ 15% of hypert ensive individuals. I n part , t his variat ion is relat ed t o t he int ensit y of screening and t he crit eria for est ablishing t he diagnosis. Hist ory and physical exam inat ion provide lit t le inform at ion about t he diagnosis. The age at t he t im e of diagnosis is generally t he t hird t hrough fift h decade. Hypert ension is usually m ild t o m oderat e but occasionally m ay be severe; prim ary aldost eronism should be considered in all pat ient s wit h refract ory hypert ension. Hypert ension in t hese pat ient s m ay be associat ed wit h glucose int olerance. Most pat ient s are asym pt om at ic, alt hough, infrequent ly, polyuria, polydipsia, parest hesias, or m uscle weakness m ay be present as a consequence of hypokalem ic alkalosis. I n a hypert ensive pat ient wit h unprovoked hypokalem ia ( i.e., unrelat ed t o diuret ics, vom it ing, or diarrhea) , t he prevalence of prim ary aldost eronism approaches 40 50% . I n pat ient s on diuret ics, serum pot assium < 3.1 m m ol/ L ( < 3.1 m eq/ L) also raises t he possibilit y of prim ary aldost eronism ; however, serum pot assium is an insensit ive and nonspecific screening t est . How ever, serum pot assium is norm al in ~ 25% of pat ient s subsequent ly found t o have an aldost erone- producing adenom a, and higher percent ages of pat ient s wit h ot her et iologies of prim ary aldost eronism are not hypokalem ic. Addit ionally, hypokalem ic hypert ension m ay be a consequence of secondary aldost eronism , ot her m ineralocort icoid- and glucocort icoid- induced hypert ensive disorders, and pheochrom ocyt om a. The rat io of plasm a aldost erone t o plasm a renin act ivit y ( PA/ PRA) is a useful screening t est . These m easurem ent s preferably are obt ained in am bulat ory pat ient s in t he m orning. A rat io > 30: 1 in conj unct ion wit h a plasm a aldost erone concent rat ion > 555 pm ol/ L ( > 20 ng/ dL) report edly has a sensit ivit y of 90% and a specificit y of 91% for an aldost erone- producing adenom a. I n a Mayo Clinic series, an aldost erone- producing adenom a subsequent ly w as confirm ed surgically in > 90% of hypert ensive pat ient s wit h a PA/ PRA rat io 20 and a plasm a aldost erone concent rat ion 415 pm ol/ L ( 15 ng/ dL) . There are, however, several caveat s t o int erpret ing t he rat io. The cut off for a " high" rat io is laborat ory - and assay- dependent . Som e ant ihypert ensive agent s m ay affect t he rat io ( e.g., aldost erone ant agonist s, angiot ensin recept or ant agonist s, and ACE inhibit ors m ay increase renin; aldost erone ant agonist s m ay increase aldost erone) . Current recom m endat ions are t o wit hdraw aldost erone ant agonist s for at least 4 w eeks before obt aining t hese m easurem ent s, wit h t his caveat . The rat io has been report ed t o be useful as a screening t est in m easurem ent s obt ained w it h pat ient s t aking t heir usual ant ihypert ensive m edicat ions. A high rat io in t he absence of an elevat ed plasm a aldost erone level is considerably less specific for prim ary aldost eronism since m any pat ient s wit h essent ial hypert ension have low renin levels in t his set t ing, part icularly African Am ericans and elderly pat ient s. I n pat ient s wit h renal insufficiency, t he rat io m ay also be elevat ed because of decreased aldost erone clearance. I n pat ient s wit h an elevat ed PA/ PRA rat io, t he diagnosis of prim ary aldost eronism can be confirm ed by dem onst rat ing failure t o suppress plasm a aldost erone t o < 277 pm ol/ L ( < 10 ng/ dL) aft er I V infusion of 2 L of isot onic saline over 4 h; post - saline infusion plasm a aldost erone values bet ween 138 and 277 pm ol/ L ( 5 10 ng/ dL) are not det erm inant . Alt ernat ive confirm at ory t est s include failure t o suppress aldost erone ( based on t est specific crit eria) in response t o an oral NaCl load, fludrocort isone, or capt opril.

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Several adrenal abnorm alit ies m ay culm inat e in t he syndrom e of prim ary aldost eronism , and appropriat e t herapy depends on t he specific et iology. Som e 60 70% of pat ient s have an aldost erone- producing adrenal adenom a. The t um or is alm ost always unilat eral, and m ost oft en m easures < 3 cm in diam et er. Most of t he rem ainder of t hese pat ient s have bilat eral adrenocort ical hyperplasia ( idiopat hic hyperaldost eronism ) . Rarely, prim ary aldost eronism m ay be caused by an adrenal carcinom a or an ect opic m alignancy, e.g., ovarian arrhenoblast om a. Most aldost erone- producing carcinom as, in cont rast t o adrenal adenom as and hyperplasia, produce excessive am ount s of ot her adrenal st eroids in addit ion t o aldost erone. Funct ional differences in horm one secret ion m ay assist in t he different ial diagnosis. Aldost erone biosynt hesis is m ore responsive t o adrenocort icot ropic horm one ( ACTH) in pat ient s wit h adenom a and m ore responsive t o angiot ensin in pat ient s wit h hyperplasia. Consequent ly, pat ient s wit h adenom a t end t o have higher plasm a aldost erone in t he early m orning t hat decreases during t he day, reflect ing t he diurnal rhyt hm of ACTH, whereas plasm a aldost erone t ends t o increase wit h upright post ure in pat ient s wit h hyperplasia, reflect ing t he norm al post ural response of t he renin - angiot ensin- aldost erone axis. However, t here is som e overlap in t he abilit y of t hese m easurem ent s t o discrim inat e bet ween adenom a and hyperplasia. Adrenal com put ed t om ography ( CT) should be carried out in all pat ient s diagnosed wit h prim ary aldost eronism . High- resolut ion CT m ay ident ify t um ors as sm all as 0.3 cm and is posit ive for an adrenal t um or 90% of t he t im e. I f t he CT is not diagnost ic, an adenom a m ay be det ect ed by adrenal scint igraphy wit h 6 - [ I 131 ] iodom et hyl- 19norcholest erol aft er dexam et hasone suppression ( 0.5 m g every 6 h for 7 days) ; however, t his t echnique has decreased sensit ivit y for adenom as < 1.5 cm . When carried out by an experienced radiologist , bilat eral adrenal venous sam pling for m easurem ent of plasm a aldost erone is t he m ost accurat e m eans of different iat ing unilat eral from bilat eral form s of prim ary aldost eronism . The sensit ivit y and specificit y of adrenal venous sam pling ( 95% and 100% , respect ively) for det ect ing unilat eral aldost erone hypersecret ion are superior t o t hose of adrenal CT; success rat es are 90 96% , and com plicat ion rat es are < 2.5% . One frequent ly used prot ocol involves sam pling for aldost erone and cort isol levels in response t o ACTH st im ulat ion. An ipsilat eral/ cont ralat eral aldost erone rat io > 4, wit h sym m et ric ACTH- st im ulat ed cort isol levels, is indicat ive of unilat eral aldost erone product ion. Hypert ension generally is responsive t o surgery in pat ient s w it h adenom a but not in pat ient s wit h bilat eral adrenal hyperplasia. Unilat eral adrenalect om y, oft en done via a laparoscopic approach, is curat ive in 40 70% of pat ient s wit h an adenom a. Surgery should be undert aken aft er blood pressure has been cont rolled and hypokalem ia correct ed. Transient hypoaldost eronism m ay occur up t o 3 m ont hs post operat ively, result ing in hyperkalem ia. Pot assium should be m onit ored during t his t im e, and hyperkalem ia should be t reat ed w it h pot assium - w ast ing diuret ics and w it h fludrocort isone, if needed. Pat ient s wit h bilat eral hyperplasia should be t reat ed m edically. The drug regim en for t hese pat ient s, as well as for pat ient s wit h an adenom a w ho are poor surgical candidat es, should include an aldost erone ant agonist and, if necessary, ot her pot assium - sparing diuret ics. Glucocort icoid- rem ediable hyperaldost eronism is a rare, m onogenic aut osom al dom inant disorder charact erized by m oderat e t o severe hypert ension, oft en occurring at an early age. These pat ient s m ay have a fam ily hist ory of hem orrhagic st roke at a young age. Hypokalem ia is usually m ild or absent . Norm ally, angiot ensin I I st im ulat es aldost erone product ion by t he adrenal zona glom erulosa, whereas ACTH st im ulat es cort isol product ion in t he zona fasciculat a. Owing t o a chim eric gene on chrom osom e 8, ACTH also regulat es aldost erone secret ion by t he zona fasciculat a in pat ient s wit h glucocort icoid- rem ediable hyperaldost eronism . The consequence is overproduct ion in t he zona fasciculat a of bot h aldost erone and hybrid st eroids ( 18 - hydroxycort isol and 18- oxocort isol) due t o oxidat ion of cort isol. The diagnosis m ay be est ablished by urine excret ion rat es of t hese hybrid st eroids t hat are 20 t o 30 t im es norm al or by direct genet ic t est ing. Therapeut ically, suppression of ACTH wit h low - dose glucocort icoids correct s t he hyperaldost eronism , hypert ension, and hypokalem ia. Spironolact one is also a t herapeut ic opt ion.

Cush ing's Syn dr om e


( See also Chap. 342) Cushing's syndrom e is relat ed t o excess cort isol product ion due eit her t o excess ACTH secret ion ( from a pit uit ary t um or or an ect opic t um or) or t o ACTH- independent adrenal product ion of cort isol. Hypert ension occurs in 7580% of pat ient s wit h Cushing's syndrom e. The m echanism of hypert ension m ay be relat ed t o st im ulat ion of m ineralocort icoid recept ors by cort isol and increased secret ion of ot her adrenal st eroids. I f clinically suspect ed based on phenot ypic charact erist ics, in pat ient s not t aking exogenous glucocort icoids, laborat ory

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screening m ay be carried out wit h m easurem ent of 24 - h excret ion rat es of urine free cort isol or an overnight dexam et hasone- suppression t est . Recent evidence suggest s t hat lat e night salivary cort isol is also a sensit ive and convenient screening t est . Furt her evaluat ion is required t o confirm t he diagnosis and ident ify t he specific et iology of Cushing's syndrom e. Appropriat e t herapy depends on t he et iology.

Ph e ochr om ocyt om a
( See also Chap. 343) Cat echolam ine- secret ing t um ors are locat ed in t he adrenal m edulla ( pheochrom ocyt om a) or in ext ra- adrenal paraganglion t issue ( paragangliom a) and account for hypert ension in ~ 0.05% of pat ient s. I f unrecognized, pheochrom ocyt om a m ay result in let hal cardiovascular consequences. Clinical m anifest at ions, including hypert ension, are prim arily relat ed t o increased circulat ing cat echolam ines, alt hough som e of t hese t um ors m ay secret e a num ber of ot her vasoact ive subst ances. I n a sm all percent age of pat ient s, epinephrine is t he predom inant cat echolam ine secret ed by t he t um or, and t hese pat ient s m ay present wit h hypot ension rat her t han hypert ension. The init ial suspicion of t he diagnosis is based on sym pt om s and/ or t he associat ion of pheochrom ocyt om a wit h ot her disorders ( Ta ble 2 4 7 - 4 ) . Approxim at ely 20% of pheochrom ocyt om as are fam ilial wit h aut osom al dom inant inherit ance. I nherit ed pheochrom ocyt om as m ay be associat ed wit h m ult iple endocrine neoplasia ( MEN) t ype 2A and t ype 2B, von Hippel- Lindau disease, and neurofibrom at osis ( Table 247- 4) . Each of t hese syndrom es is relat ed t o specific, ident ifiable germ - line m ut at ions. Addit ionally, m ut at ions of succinat e dehydrogenase genes are associat ed w it h paragangliom a syndrom es, generally charact erized by head and neck paragangliom as. Laborat ory t est ing consist s of m easuring cat echolam ines in eit her urine or plasm a. Genet ic screening is available for evaluat ing pat ient s and relat ives suspect ed of harboring a pheochrom ocyt om a associat ed wit h a fam ilial syndrom e. Surgical excision is t he definit ive t reat m ent of pheochrom ocyt om a and result s in cure in ~ 90% of pat ient s.

Ta ble 2 4 7 4 . Ra r e M e nde lia n For m s of H y pe r t e nsion


D ise a se Glucocort icoid- rem ediable hyperaldost eronism 17 - hydroxylase deficiency Phe not ype Aut osom al dom inant Absent or m ild hypokalem ia Aut osom al recessive Males: pseudoherm aphrodit ism Fem ales: prim ary am enorrhea, absent secondary sexual charact erist ics 11 - hydroxylase deficiency Aut osom al recessive Masculinizat ion 11 - hydroxyst eroid dehydrogenase Aut osom al recessive deficiency ( apparent Hypokalem ia, low renin, low aldost erone m ineralocort icoid excess syndrom e) Liddle's syndrom e Aut osom al dom inant Hypokalem ia, low renin, low aldost erone Pseudohypoaldost eronism t ype I I ( Gordon's syndrom e) Aut osom al dom inant Hyperkalem ia, norm al glom erular filt rat ion rat e Aut osom al dom inant Severe hypert ension in early pregnancy Mut at ions of t he CYP11B1 gene on chrom osom e 8q21- q22 Mut at ions in t he 11 hydroxyst eroid dehydrogenase gene Mut at ion subunit s of t he epit helial sodium channel SCNN1B and SCNN1C genes Linkage t o chrom osom es 1q31q42 and 17p11- q21 Ge ne t ic Ca use Chim eric 11 hydroxylase/ aldsot erone gene on chrom osom e 8 Random m ut at ions of t he CYP17 gene on chrom osom e 10

Hypert ension exacerbat ed in pregnancy

Missense m ut at ion w it h subst it ut ion of leucine for serine at codon 810 ( MRL810 ) Mut at ions in t he PKD1 gene on

Polycyst ic kidney disease

Aut osom al dom inant

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Large cyst ic kidneys, renal failure, liver cyst s, cerebral aneurysm s, valvular heart disease Pheochrom ocyt om a Aut osom al dom inant ( a) Mult iple endocrine neoplasia, t ype 2A Medullary t hyroid carcinom a, hyperparat hyroidism ( b) Mult iple endocrine neoplasia, t ype 2B Medullary t hyroid carcinom a, m ucosal neurom as, t hickened corneal nerves, alim ent ary ganglioneurom at oses, m arfanoid habit us ( c) von Hippel- Lindau disease Ret inal angiom as, hem angioblast om as of t he cerebellum and spinal cord, renal cell carcinom a ( d) Neurofibrom at osis t ype 1 Mult iple neurofibrom as, caf- au- lait spot s

chrom osom e 16 and PKD2 gene on chrom osom e 4

( a) Mut at ions in t he RET prot ooncogene ( b) Mut at ions in t he RET prot ooncogene

( c) Mut at ions in t he VHL t um or suppressor gene

( d) Mut at ions in t he NF1 t um or suppressor gene

M isce lla n eous Ca use s of H yper t e nsion


Hypert ension due t o obst ruct ive sleep apnea is being recognized wit h increasing frequency ( Chap. 265) . I ndependent of obesit y, hypert ension occurs in > 50% of individuals wit h obst ruct ive sleep apnea. The severit y of hypert ension correlat es wit h t he severit y of sleep apnea. Approxim at ely 70% of pat ient s w it h obst ruct ive sleep apnea are obese. Hypert ension relat ed t o obst ruct ive sleep apnea also should be considered in pat ient s wit h drug resist ant hypert ension and pat ient s wit h a hist ory of snoring. The diagnosis can be confirm ed by polysom nography. I n obese pat ient s, weight loss m ay alleviat e or cure sleep apnea and relat ed hypert ension. Cont inuous posit ive airway pressure ( CPAP) adm inist ered during sleep is an effect ive t herapy for obst ruct ive sleep apnea. Wit h CPAP, pat ient s wit h apparent ly drug- resist ant hypert ension m ay be m ore responsive t o ant ihypert ensive agent s. Coarct at ion of t he aort a is t he m ost com m on congenit al cardiovascular cause of hypert ension ( Chap. 236) . The incidence is 18 per 1000 live birt hs. I t is usually sporadic but occurs in 35% of children wit h Turner syndrom e. Even when t he anat om ic lesion is surgically correct ed in infancy, up t o 30% of pat ient s develop subsequent hypert ension and are at risk of accelerat ed coronary art ery disease and cerebrovascular event s. Pat ient s wit h less severe lesions m ay not be diagnosed unt il young adult hood. The physical findings are diagnost ic and include dim inished and delayed fem oral pulses and a syst olic pressure gradient bet ween t he right arm and t he legs and, depending on t he locat ion of t he coarct at ion, bet ween t he right and left arm s. A blowing syst olic m urm ur m ay be heard in t he post erior left int erscapular areas. The diagnosis m ay be confirm ed by chest x - ray and t ransesophageal echocardiography. Therapeut ic opt ions include surgical repair and balloon angioplast y, wit h or wit hout placem ent of an int ravascular st ent . Subsequent ly, m any pat ient s do not have a norm al life expect ancy but m ay have persist ent hypert ension, wit h deat h due t o ischem ic heart disease, cerebral hem orrhage, or aort ic aneurysm . Several addit ional endocrine disorders, including t hyroid diseases and acrom egaly, cause hypert ension. Mild diast olic hypert ension m ay be a consequence of hypot hyroidism , whereas hypert hyroidism m ay result in syst olic hypert ension. Hypercalcem ia of any et iology, t he m ost com m on being prim ary hyperparat hyroidism , m ay result in hypert ension. Hypert ension also m ay be relat ed t o a num ber of prescribed or over - t he- count er m edicat ions.

M ON OGEN I C H YPERTEN SI ON
A num ber of rare form s of m onogenic hypert ension have been ident ified ( Table 247 - 4) . These disorders m ay be recognized by t heir charact erist ic phenot ypes, and in m any inst ances t he diagnosis m ay be confirm ed by genet ic analysis. Several inherit ed defect s in adrenal st eroid biosynt hesis and m et abolism result in m ineralocort icoid induced hypert ension and hypokalem ia. I n pat ient s w it h a 17 - hydroxylase deficiency, synt hesis of sex horm ones and cort isol is decreased ( Fig. 2 4 7 - 3 ) . Consequent ly, t hese individuals do not m at ure sexually; m ales m ay present wit h pseudoherm aphrodit ism and fem ales w it h prim ary am enorrhea and absent secondary sexual charact erist ics.

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Because cort isol- induced negat ive feedback on pit uit ary ACTH product ion is dim inished, ACTH- st im ulat ed adrenal st eroid synt hesis proxim al t o t he enzym at ic block is increased. Hypert ension and hypokalem ia are consequences of increased synt hesis of m ineralocort icoids proxim al t o t he enzym at ic block, part icularly desoxycort icost erone. I ncreased st eroid product ion and, hence, hypert ension m ay be t reat ed wit h low - dose glucocort icoids. An 11 hydroxylase deficiency result s in a salt - ret aining adrenogenit al syndrom e t hat occurs in 1 in 100,000 live birt hs. This enzym at ic defect result s in decreased cort isol synt hesis, increased synt hesis of m ineralocort icoids ( e.g., desoxycort icost erone) , and shunt ing of st eroid biosynt hesis int o t he androgen pat hw ay. I n t he severe form , t he syndrom e m ay present early in life, including t he new born period, wit h virilizat ion and am biguous genit alia in fem ales and penile enlargem ent in m ales, or in older children as precocious pubert y and short st at ure. Acne, hirsut ism , and m enst rual irregularit ies m ay be t he present ing feat ures when t he disorder is first recognized in adolescence or early adult hood. Hypert ension is less com m on in t he lat e- onset form s. Pat ient s w it h an 11 hydroxyst eroid dehydrogenase deficiency have an im paired capacit y t o m et abolize cort isol t o it s inact ive m et abolit e, cort isone, and hypert ension is relat ed t o act ivat ion of m ineralocort icoid recept ors by cort isol. This defect m ay be inherit ed or acquired, due t o licorice- cont aining glycyrrhizin acid. The sam e subst ance is present in t he past e of several brands of chewing t obacco. The defect in Liddle's syndrom e ( Chaps. 45 and 342) result s from const it ut ive act ivat ion of am iloride- sensit ive epit helial sodium channels on t he dist al renal t ubule, result ing in excess sodium reabsorpt ion; t he syndrom e is am eliorat ed by am iloride. Hypert ension exacerbat ed in pregnancy ( Chap. 7) is due t o act ivat ion of t he m ineralocort icoid recept or by progest erone.

Figur e 2 4 7 - 3

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Adre na l e nzy m a t ic de fe ct s.

Appr oa ch t o t he Pa t ie nt : H yper t e nsion


H I STORY
The init ial assessm ent of a hypert ensive pat ient should include a com plet e hist ory and physical exam inat ion t o confirm a diagnosis of hypert ension, screen for ot her cardiovascular disease risk fact ors, screen for secondary causes of hypert ension, ident ify cardiovascular consequences of hypert ension and ot her com orbidit ies, assess blood pressurerelat ed lifest yles, and det erm ine t he pot ent ial for int ervent ion. Most pat ient s w it h hypert ension have no specific sym pt om s referable t o t heir blood pressure elevat ion. Alt hough popularly considered a sym pt om of elevat ed art erial pressure, headache generally occurs only in pat ient s w it h severe hypert ension. Charact erist ically, a " hypert ensive headache" occurs in t he m orning and is localized t o t he occipit al region. Ot her nonspecific sym pt om s t hat m ay be relat ed t o elevat ed blood pressure include dizziness, palpit at ions, easy fat igabilit y, and im pot ence. When sym pt om s are present , t hey are generally relat ed t o hypert ensive cardiovascular disease or t o m anifest at ions of secondary hypert ension. Ta ble 2 4 7 - 5 list s salient feat ures t hat should be addressed in obt aining a hist ory from a hypert ensive pat ient .

Ta ble 2 4 7 5 . Pa t ie nt 's Re le va n t H ist or y


Durat ion of hypert ension

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Previous t herapies: responses and side effect s Fam ily hist ory of hypert ension and cardiovascular disease Diet ary and psychosocial hist ory Ot her risk fact ors: weight change, dyslipidem ia, sm oking, diabet es, physical inact ivit y Evidence of secondary hypert ension: hist ory of renal disease; change in appearance; m uscle weakness; spells of sweat ing, palpit at ions, t rem or; errat ic sleep, snoring, dayt im e som nolence; sym pt om s of hypo - or hypert hyroidism ; use of agent s t hat m ay increase blood pressure Evidence of t arget organ dam age: hist ory of TI A, st roke, t ransient blindness; angina, m yocardial infarct ion, congest ive heart failure; sexual funct ion Ot her com orbidit ies Abbr e via t ion: TI A, t ransient ischem ic at t ack.

M EASUREM EN T OF BLOOD PRESSURE


Reliable m easurem ent s of blood pressure depend on at t ent ion t o t he det ails of t he t echnique and condit ions of t he m easurem ent . Proper t raining of observers, posit ioning of t he pat ient , and select ion of cuff size are essent ial. Owing t o recent regulat ions prevent ing t he use of m ercury because of concerns about it s pot ent ial t oxicit y, m ost office m easurem ent s are m ade wit h aneroid sphygm om anom et ers or w it h oscillom et ric devices. These inst rum ent s should be calibrat ed periodically, and t heir accuracy confirm ed. Before t he blood pressure m easurem ent is t aken, t he individual should be seat ed quiet ly in a chair ( not t he exam t able) wit h feet on t he floor for 5 m in in a privat e, quiet set t ing wit h a com fort able room t em perat ure. At least t wo m easurem ent s should be m ade. The cent er of t he cuff should be at heart level, and t he w idt h of t he bladder cuff should equal at least 40% of t he arm circum ference; t he lengt h of t he cuff bladder should be enough t o encircle at least 80% of t he arm circum ference. I t is im port ant t o pay at t ent ion t o cuff placem ent , st et hoscope placem ent , and t he rat e of deflat ion of t he cuff ( 2 m m Hg/ s) . Syst olic blood pressure is t he first of at least t wo regular " t apping" Korot koff sounds, and diast olic blood pressure is t he point at which t he last regular Korot koff sound is heard. I n current pract ice, a diagnosis of hypert ension generally is based on seat ed, office m easurem ent s. Current ly available am bulat ory m onit ors are fully aut om at ed, use t he oscillom et ric t echnique, and t ypically are program m ed t o t ake readings every 1530 m in. Twent y- four- hour am bulat ory blood pressure m onit oring m ore reliably predict s cardiovascular disease risk t han do office m easurem ent s. However, am bulat ory m onit oring is not used rout inely in clinical pract ice and generally is reserved for pat ient s in whom whit e coat hypert ension is suspect ed. The Sevent h Report of t he Joint Nat ional Com m it t ee on Prevent ion, Det ect ion, Evaluat ion, and Treat m ent of High Blood Pressure ( JNC 7) has also recom m ended am bulat ory m onit oring for t reat m ent resist ance, sym pt om at ic hypot ension, aut onom ic failure, and episodic hypert ension.

PH YSI CAL EXAM I N ATI ON


Body habit us, including weight and height , should be not ed. At t he init ial exam inat ion, blood pressure should be m easured in bot h arm s and preferably in t he supine, sit t ing, and st anding posit ions t o evaluat e for post ural hypot ension. Even if t he fem oral pulse is norm al t o palpat ion, art erial pressure should be m easured at least once in t he lower ext rem it y in pat ient s in whom hypert ension is discovered before age 30. Heart rat e also should be recorded. Hypert ensive individuals have an increased prevalence of at rial fibrillat ion. The neck should be palpat ed for an enlarged t hyroid gland, and pat ient s should be assessed for signs of hypo - and hypert hyroidism . Exam inat ion of blood vessels m ay provide clues about underlying vascular disease and should include funduscopic exam inat ion, auscult at ion for bruit s over t he carot id and fem oral art eries, and palpat ion of fem oral and pedal pulses. The ret ina is t he only t issue in which art eries and art erioles can be exam ined direct ly. Wit h increasing severit y of hypert ension and at herosclerot ic disease, progressive funduscopic changes include increased art eriolar light reflex, art eriovenous crossing defect s, hem orrhages and exudat es, and, in pat ient s wit h m alignant hypert ension, papilledem a. Exam inat ion of t he heart m ay reveal a loud second heart sound due t o closure of t he aort ic valve and an S 4 gallop at t ribut ed t o at rial cont ract ion against a noncom pliant left vent ricle. Left vent ricular hypert rophy m ay be det ect ed by an enlarged, sust ained, and lat erally displaced apical im pulse. An abdom inal bruit , part icularly a bruit t hat lat eralizes and ext ends t hroughout syst ole int o diast ole, raises t he possibilit y of renovascular hypert ension. Kidneys of pat ient s wit h polycyst ic kidney disease m ay be palpable in t he abdom en. The physical exam inat ion also should include evaluat ion for signs of CHF and a neurologic exam inat ion.

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LABORATORY TESTI N G
Ta ble 2 4 7 - 6 list s recom m ended laborat ory t est s in t he init ial evaluat ion of hypert ensive pat ient s. Repeat m easurem ent s of renal funct ion, serum elect rolyt es, fast ing glucose, and lipids m ay be obt ained aft er t he int roduct ion of a new ant ihypert ensive agent and t hen annually or m ore frequent ly if clinically indicat ed. More ext ensive laborat ory t est ing is appropriat e for pat ient s wit h apparent drug - resist ant hypert ension or when t he clinical evaluat ion suggest s a secondary form of hypert ension.

Ta ble 2 4 7 6 . Ba sic La bor a t or y Te st s for I nit ia l Ev a lua t ion


Syst em Renal Endocrine Met abolic Ot her Te st Microscopic urinalysis, album in excret ion, serum BUN and/ or creat inine Serum sodium , pot assium , calcium , ?TSH Fast ing blood glucose, t ot al cholest erol, HDL and LDL ( oft en com put ed) cholest erol, t riglycerides Hem at ocrit , elect rocardiogram

Abbr e via t ions: BUN, blood urea nit rogen; HDL, LDL, high - / low- densit y lipoprot ein; TSH, t hyroid- st im ulat ing horm one.

Tr e a t m e nt H ype rt ension

LI FESTYLE I N TERVEN TI ON S
I m plem ent at ion of lifest yles t hat favorably affect blood pressure has im plicat ions for bot h t he prevent ion and t he t reat m ent of hypert ension. Healt h- prom ot ing lifest yle m odificat ions are recom m ended for individuals wit h prehypert ension and as an adj unct t o drug t herapy in hypert ensive individuals. These int ervent ions should address overall cardiovascular disease risk. Alt hough t he im pact of lifest yle int ervent ions on blood pressure is m ore pronounced in persons wit h hypert ension, in short - t erm t rials, weight loss and reduct ion of diet ary NaCl have been shown t o prevent t he developm ent of hypert ension. I n hypert ensive individuals, even if t hese int ervent ions do not produce a sufficient reduct ion in blood pressure t o avoid drug t herapy, t he num ber of m edicat ions or doses required for blood pressure cont rol m ay be reduced. Diet ary m odificat ions t hat effect ively lower blood pressure are weight loss, reduced NaCl int ake, increased pot assium int ake, m oderat ion of alcohol consum pt ion, and an overall healt hy diet ary pat t ern ( Ta ble 2 4 7 - 7 ) .

Ta ble 2 4 7 7 . Life st yle M odifica t ions t o M a n a ge H y pe r t e nsion


Weight reduct ion Diet ary salt reduct ion At t ain and m aint ain BMI < 25 kg/ m 2 < 6 g NaCl/ d

Adapt DASH- t ype diet ary plan Diet rich in fruit s, veget ables, and low - fat dairy product s wit h reduced cont ent of sat urat ed and t ot al fat Moderat ion of alcohol consum pt ion Physical act ivit y For t hose w ho drink alcohol, consum e wom en 2 drinks/ day in m en and 1 drink/ day in

Regular aerobic act ivit y, e.g., brisk walking for 30 m in/ d

Abbr e via t ions: BMI , body m ass index; DASH, Diet ary Approaches t o St op Hypert ension ( t rial) . Prevent ion and t reat m ent of obesit y are im port ant for reducing blood pressure and cardiovascular disease risk. I n short - t erm t rials, even m odest w eight loss can lead t o a reduct ion of blood pressure and an increase in insulin sensit ivit y. Average blood pressure reduct ions of 6.3/ 3.1 m m Hg have been observed wit h a reduct ion in m ean body weight of 9.2 kg. Regular physical act ivit y facilit at es weight loss, decreases blood pressure, and reduces t he overall risk of cardiovascular disease. Blood pressure m ay be lowered by 30 m in of m oderat ely int ense physical act ivit y, such as brisk walking, 67 days a week, or by m ore int ense, less frequent workout s. There is individual variabilit y in t he sensit ivit y of blood pressure t o NaCl, and t his variabilit y m ay have a genet ic basis. Based on result s of m et a- analyses, lowering of blood pressure by lim it ing daily NaCl int ake t o 4.4 7.4 g ( 75 125 m eq) result s in blood pressure reduct ions of 3.7 4.9/ 0.92.9 m m Hg in hypert ensive individuals and lesser

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reduct ions in norm ot ensive individuals. Diet ary NaCl reduct ion also has been show n t o reduce t he long - t erm risk of cardiovascular event s in adult s wit h " prehypert ension." Pot assium and calcium supplem ent at ion have inconsist ent , m odest ant ihypert ensive effect s, and, independent of blood pressure, pot assium supplem ent at ion m ay be associat ed wit h reduced st roke m ort alit y. Alcohol use in persons consum ing t hree or m ore drinks per day ( a st andard drink cont ains ~ 14 g et hanol) is associat ed w it h higher blood pressures, and a reduct ion of alcohol consum pt ion is associat ed wit h a reduct ion of blood pressure. I n pat ient s wit h advanced renal disease, diet ary prot ein rest rict ion m ay have a m odest effect in m it igat ing renal dam age by reducing t he int rarenal t ransm ission of syst em ic art erial pressure. The DASH ( Diet ary Approaches t o St op Hypert ension) t rial convincingly dem onst rat ed t hat over an 8 - w eek period a diet high in fruit s, veget ables, and low - fat dairy product s lowers blood pressure in individuals wit h high - norm al blood pressures or m ild hypert ension. Reduct ion of daily NaCl int ake t o < 6 g ( 100 m eq) augm ent ed t he effect of t his diet on blood pressure. Fruit s and veget ables are enriched sources of pot assium , m agnesium , and fiber, and dairy product s are an im port ant source of calcium .

PH ARM ACOLOGI C TH ERAPY


Drug t herapy is recom m ended for individuals wit h blood pressures 140/ 90 m m Hg. The degree of benefit derived from ant ihypert ensive agent s is relat ed t o t he m agnit ude of t he blood pressure reduct ion. Lowering syst olic blood pressure by 1012 m m Hg and diast olic blood pressure by 5 6 m m Hg confers relat ive risk reduct ions of 35 40% for st roke and 1216% for CHD wit hin 5 years of t he init iat ion of t reat m ent . Risk of heart failure is reduced by > 50% . Hypert ension cont rol is t he single m ost effect ive int ervent ion for slowing t he rat e of progression of hypert ension relat ed chronic kidney disease. There is considerable variat ion in individual responses t o different classes of ant ihypert ensive agent s, and t he m agnit ude of response t o any single agent m ay be lim it ed by act ivat ion of count erregulat ory m echanism s t hat oppose t he hypot ensive effect of t he agent . Most available agent s reduce syst olic blood pressure by 7 13 m m Hg and diast olic blood pressure by 48 m m Hg when correct ed for placebo effect . More oft en t han not , com binat ions of agent s, wit h com plem ent ary ant ihypert ensive m echanism s, are required t o achieve goal blood pressure reduct ions. Select ion of ant ihypert ensive agent s and com binat ions of agent s should be individualized, t aking int o account age, severit y of hypert ension, ot her cardiovascular disease risk fact ors, com orbid condit ions, and pract ical considerat ions relat ed t o cost , side effect s, and frequency of dosing ( Ta ble 2 4 7 - 8 ) .

Ta ble 2 4 7 8 . Ex a m ple s of Or a l D r ugs Use d in Tr e a t m e nt of H ype r t e nsion


D ru g Cla ss Ex a m ple s Usua l Tot a l D a ily D ose * ( D osing Fre quen cy/ D a y) Ot h er I ndica t ions Cont ra indica t ions/ Ca ut ion s

Diuret ics Thiazides Hydrochlorot hiazide 6.2550 m g ( 12) Chlort halidone Loop diuret ics Furosem ide Et hacrynic acid Aldost erone ant agonist s Spironolact one Eplerenone K+ ret aining Bet a blockers Am iloride Triam t erene 2550 m g ( 1) 4080 m g ( 23) 50100 m g ( 23) 25100 m g ( 12) 50100 m g ( 12) 510 m g ( 12) 50100 m g ( 12) CHF due t o syst olic dys- funct ion, renal failure CHF due t o syst olic dysfunct ion, prim ary aldost eronism Diabet es, dyslipidem ia, hyperuricem ia, gout , hypokalem ia Diabet es, dyslipidem ia, hyperuricem ia, gout , hypokalem ia Renal failure, hyperkalem ia

Renal failure, hyperkalem ia

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Cardioselect ive

At enolol Met oprolol

25100 m g ( 1) 25100 m g ( 12) 40160 m g ( 2) 60180 ( 1) 200800 m g ( 2) 12.550 m g ( 2)

Nonselect ive

Propranolol Propranolol LA

Angina, CHF due t o syst olic dysfunct ion, post MI , sinus t achycardia, vent ricular t achyarrhyt hm ias ?Post - MI , CHF

Ast hm a, COPD, 2nd- or 3rddegree heart block, sick - sinus syndrom e

Com bined alpha/ bet a Alpha ant agonist s Select ive

Labet alol Carvedilol

Prazosin Doxazosin Terazosin

220 m g ( 23) 116 m g ( 1) 110 m g ( 12)

Prost at ism

Nonselect ive Sym pat holyt ics Cent ral

Phenoxybenzam ine 20120 m g ( 23)

Pheochrom ocyt om a

Clonidine Clonidine pat ch Met hyldopa Reserpine Guanfacine

0.10.6 m g ( 2) 0.10.3 m g ( 1/ week) 2501000 m g ( 2) 0.050.25 m g ( 1) 0.52 m g ( 1) 25200 m g ( 2) 1040 m g ( 1) 2.520 m g ( 12) 25100 m g ( 12) 80320 m g ( 1) 232 m g ( 12) 150300 m g ( 1) Post - MI , coronary syndrom es, CHF w it h low ej ect ion fract ion, nephropat hy CHF wit h low ej ect ion fract ion, nephropat hy, ACE inhibit or cough Diabet ic nephropat hy Acut e renal failure, bilat eral renal art ery st enosis, pregnancy, hyperkalem ia

ACE inhibit ors

Capt opril Lisinopril Ram ipril

Angiot ensin I I ant agonist s

Losart an Valsart an Candesart an

Renal failure, bilat eral renal art ery st enosis, pregnancy, hyperkalem ia Pregnancy

Renin inhibit ors Calcium ant agonist s Dihydropyridines

Aliskiren

Nifedipine ( longact ing)

3060 m g ( 1) 120360 m g ( 1 2) 180- 420 m g ( 1) 25100 m g ( 2) 2.580 m g ( 12) Post - MI , supravent ricular t achycardias, angina 2nd- or 3rd- degree heart block

Nondihydropyridines Verapam il ( longact ing) Dilt iazem ( longact ing) Direct vasodilat ors Hydralazine Minoxidil
*

Severe coronary art ery disease

At t he init iat ion of t herapy, lower doses m ay be preferable for elderly pat ient s and for select com binat ions of ant ihypert ensive agent s. Abbr e via t ions: ACE, angiot ensin- convert ing enzym e; CHF, congest ive heart failure; COPD, chronic obst ruct ive pulm onary disease; MI , m yocardial infarct ion.

D iur et ics

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Low - dose t hiazide diuret ics oft en are used as first - line agent s alone or in com binat ion w it h ot her ant ihypert ensive drugs. Thiazides inhibit t he Na + / Cl pum p in t he dist al convolut ed t ubule and hence increase sodium excret ion. I n t he long t erm , t hey also m ay act as vasodilat ors. Thiazides are safe, efficacious, inexpensive, and reduce clinical event s. They provide addit ive blood pressurelowering effect s w hen com bined wit h bet a blockers, angiot ensin convert ing enzym e inhibit ors ( ACEI s) , or angiot ensin recept or blockers ( ARBs) . I n cont rast , addit ion of a diuret ic t o a calcium channel blocker is less effect ive. Usual doses of hydrochlorot hiazide range from 6.25 50 m g/ d. Owing t o an increased incidence of m et abolic side effect s ( hypokalem ia, insulin resist ance, increased cholest erol) , higher doses generally are not recom m ended. Tw o pot assium - sparing diuret ics, am iloride and t riam t erene, act by inhibit ing epit helial sodium channels in t he dist al nephron. These agent s are weak ant ihypert ensive agent s but m ay be used in com binat ion wit h a t hiazide t o prot ect against hypokalem ia. The m ain pharm acologic t arget for loop diuret ics is t he Na + - K+ - 2Cl cot ransport er in t he t hick ascending lim b of t he loop of Henle. Loop diuret ics generally are reserved for hypert ensive pat ient s wit h reduced glom erular filt rat ion rat es [ reflect ed in serum creat inine > 220 m ol/ L ( > 2.5 m g/ dL) ] , CHF, or sodium ret ent ion and edem a for som e ot her reason, such as t reat m ent wit h a pot ent vasodilat or, e.g., m inoxidil.

Block er s of t h e Re n in - An giot e n sin Syst e m


ACEI s decrease t he product ion of angiot ensin I I , increase bradykinin levels, and reduce sym pat het ic nervous syst em act ivit y. ARBs provide select ive blockade of AT1 recept ors, and t he effect of angiot ensin I I on unblocked AT 2 recept ors m ay augm ent t heir hypot ensive effect . Bot h classes of agent s are effect ive ant ihypert ensive agent s t hat m ay be used as m onot herapy or in com binat ion wit h diuret ics, calcium ant agonist s, and alpha blocking agent s. ACEI s and ARBs have been show n t o im prove insulin act ion and am eliorat e t he adverse effect s of diuret ics on glucose m et abolism . Alt hough t he overall im pact on t he incidence of diabet es is m odest , com pared w it h am lodipine ( a calcium ant agonist ) , valsart an ( an ARB) has been shown t o reduce t he risk of developing diabet es in high - risk hypert ensive pat ient s. ACEI / ARB com binat ions are less effect ive in lowering blood pressure t han is t he case when eit her class of t hese agent s is used in com binat ion wit h ot her classes of agent s. I n pat ient s wit h vascular disease or a high risk of diabet es, com binat ion ACEI / ARB t herapy has been associat ed wit h m ore adverse event s ( e.g., cardiovascular deat h, m yocardial infarct ion, st roke, and hospit alizat ion for heart failure) wit hout increases in benefit . However, in hypert ensive pat ient s wit h prot einuria, prelim inary dat a suggest t hat reduct ion of prot einuria wit h ACEI / ARB com binat ion t reat m ent m ay be m ore effect ive t han t reat m ent wit h eit her agent alone. Side effect s of ACEI s and ARBs include funct ional renal insufficiency due t o efferent renal art eriolar dilat ion in a kidney wit h a st enot ic lesion of t he renal art ery. Addit ional predisposing condit ions t o renal insufficiency induced by t hese agent s include dehydrat ion, CHF, and use of nonst eroidal ant i - inflam m at ory drugs. Dry cough occurs in ~ 15% of pat ient s, and angioedem a occurs in < 1% of pat ient s t aking ACEI s. Angioedem a occurs m ost com m only in individuals of Asian origin and m ore com m only in African Am ericans t han in whit es. Hyperkalem ia due t o hypoaldost eronism is an occasional side effect of bot h ACEI s and ARBs. A new approach t o blocking t he renin - angiot ensin syst em has been int roduced int o clinical pract ice for t he t reat m ent of hypert ension: direct renin inhibit ors. Blockade of t he renin - angiot ensin syst em is m ore com plet e wit h renin inhibit ors t han wit h ACEI s or ARBs. Aliskiren is t he first of a class of oral, nonpept ide com pet it ive inhibit ors of t he enzym at ic act ivit y of renin. Monot herapy wit h aliskiren seem s t o be as effect ive as an ACEI or ARB for lowering blood pressure, but not m ore effect ive. Furt her blood reduct ions m ay be achieved when aliskiren is used in com binat ion wit h a t hiazide diuret ic, an ACEI , an ARB, or calcium ant agonist s. Current ly, aliskiren is not considered a first - line ant ihypert ensive agent .

Aldost e r on e An t a gon ist s


Spironolact one is a nonselect ive aldost erone ant agonist t hat m ay be used alone or in com binat ion wit h a t hiazide diuret ic. I t m ay be a part icularly effect ive agent in pat ient s wit h low - renin essent ial hypert ension, resist ant hypert ension, and prim ary aldost eronism . I n pat ient s wit h CHF, low - dose spironolact one reduces m ort alit y and hospit alizat ions for heart failure when given in addit ion t o convent ional t herapy wit h ACEI s, digoxin, and loop diuret ics. Because spironolact one binds t o progest erone and androgen recept ors, side effect s m ay include gynecom ast ia, im pot ence, and m enst rual abnorm alit ies. These side effect s are circum vent ed by a newer agent , eplerenone, which is a select ive aldost erone ant agonist . Eplerenone has recent ly been approved in t he Unit ed St at es for t he t reat m ent of hypert ension.

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Be t a Block e rs
- Adrenergic recept or blockers lower blood pressure by decreasing cardiac out put , due t o a reduct ion of heart rat e and cont ract ilit y. Ot her proposed m echanism s by which bet a blockers low er blood pressure include a cent ral nervous syst em effect and inhibit ion of renin release. Bet a blockers are part icularly effect ive in hypert ensive pat ient s wit h t achycardia, and t heir hypot ensive pot ency is enhanced by coadm inist rat ion wit h a diuret ic. I n lower doses, som e bet a blockers select ively inhibit cardiac 1 recept ors and have less influence on 2 recept ors on bronchial and vascular sm oot h m uscle cells; how ever, t here seem s t o be no difference in t he ant ihypert ensive pot encies of cardioselect ive and nonselect ive bet a blockers. Cert ain bet a blockers have int rinsic sym pat hom im et ic act ivit y, and it is uncert ain whet her t his const it ut es an overall advant age or disadvant age in cardiac t herapy. Bet a blockers wit hout int rinsic sym pat hom im et ic act ivit y decrease t he rat e of sudden deat h, overall m ort alit y, and recurrent m yocardial infarct ion. I n pat ient s wit h CHF, bet a blockers have been shown t o reduce t he risks of hospit alizat ion and m ort alit y. Carvedilol and labet alol block bot h recept ors and peripheral - adrenergic recept ors. The pot ent ial advant ages of com bined - and - adrenergic blockade in t reat ing hypert ension rem ain t o be det erm ined.

- Adr e ne rgic Block e r s


Post synapt ic, select ive - adrenorecept or ant agonist s lower blood pressure by decreasing peripheral vascular resist ance. They are effect ive ant ihypert ensive agent s used eit her as m onot herapy or in com binat ion wit h ot her agent s. However, in clinical t rials of hypert ensive pat ient s, alpha blockade has not been show n t o reduce cardiovascular m orbidit y and m ort alit y or t o provide as m uch prot ect ion against CHF as ot her classes of ant ihypert ensive agent s. These agent s are also effect ive in t reat ing lower urinary t ract sym pt om s in m en w it h prost at ic hypert rophy. Nonselect ive - adrenorecept or ant agonist s bind t o post synapt ic and presynapt ic recept ors and are used prim arily for t he m anagem ent of pat ient s wit h pheochrom ocyt om a.

Sym pa t holyt ic Age n t s


Cent rally act ing
2

sym pat het ic agonist s decrease peripheral resist ance by inhibit ing sym pat het ic out flow. They m ay

be part icularly useful in pat ient s w it h aut onom ic neuropat hy who have w ide variat ions in blood pressure due t o barorecept or denervat ion. Drawbacks include som nolence, dry m out h, and rebound hypert ension on w it hdrawal. Peripheral sym pat holyt ics decrease peripheral resist ance and venous const rict ion by deplet ing nerve t erm inal norepinephrine. Alt hough t hey are pot ent ially effect ive ant ihypert ensive agent s, t heir usefulness is lim it ed by ort host at ic hypot ension, sexual dysfunct ion, and num erous drug - drug int eract ions.

Ca lcium Ch a n n el Block e r s
Calcium ant agonist s reduce vascular resist ance t hrough L- channel blockade, which reduces int racellular calcium and blunt s vasoconst rict ion. This is a het erogeneous group of agent s t hat includes drugs in t he following t hree classes: phenylalkylam ines ( verapam il) , benzot hiazepines ( dilt iazem ) , and 1,4 - dihydropyridines ( nifedipine- like) . Used alone and in com binat ion wit h ot her agent s ( ACEI s, bet a blockers, 1 - adrenergic blockers) , calcium ant agonist s effect ively low er blood pressure; however, it is unclear if adding a diuret ic t o a calcium blocker result s in a furt her lowering of blood pressure. Side effect s of flushing, headache, and edem a wit h dihydropyridine use are relat ed t o t heir pot encies as art eriolar dilat ors; edem a is due t o an increase in t ranscapillary pressure gradient s, not t o net salt and wat er ret ent ion.

D ir ect Va sodila t or s
Direct vasodilat ors decrease peripheral resist ance and concom it ant ly act ivat e m echanism s t hat defend art erial pressure, not ably t he sym pat het ic nervous syst em , t he renin - angiot ensin- aldost erone syst em , and sodium ret ent ion. Usually, t hey are not considered first - line agent s but are m ost effect ive when added t o a com binat ion t hat includes a diuret ic and a bet a blocker. Hydralazine is a pot ent direct vasodilat or t hat has ant ioxidant and nit ric oxideenhancing act ions, and m inoxidil is a part icularly pot ent agent and is used m ost frequent ly in pat ient s wit h renal insufficiency who are refract ory t o all ot her drugs. Hydralazine m ay induce a lupus- like syndrom e, and side effect s of m inoxidil include hypert richosis and pericardial effusion.

COM PARI SON S OF AN TI H YPERTEN SI VES


Based on pooling result s from clinical t rials, m et a- analyses of t he efficacy of different classes of ant ihypert ensive

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agent s suggest essent ially equivalent blood pressurelowering effect s of t he follow ing six m aj or classes of ant ihypert ensive agent s when used as m onot herapy: t hiazide diuret ics, bet a blockers, ACEI s, ARBs, calcium ant agonist s, and 2 blockers. On average, st andard doses of m ost ant ihypert ensive agent s reduce blood pressure by 810/ 47 m m Hg; however, t here m ay be subgroup differences in responsiveness. Younger pat ient s m ay be m ore responsive t o bet a blockers and ACEI s, whereas pat ient s over age 50 m ay be m ore responsive t o diuret ics and calcium ant agonist s. There is a lim it ed relat ionship bet ween plasm a renin and blood pressure response. Pat ient s wit h high- renin hypert ension m ay be m ore responsive t o ACEI s and ARBs t han t o ot her classes of agent s, w hereas pat ient s wit h low - renin hypert ension are m ore responsive t o diuret ics and calcium ant agonist s. Hypert ensive African Am ericans t end t o have low renin and m ay require higher doses of ACEI s and ARBs t han whit es for opt im al blood pressure cont rol, alt hough t his difference is abolished when t hese agent s are com bined wit h a diuret ic. Bet a blockers also appear t o be less effect ive t han t hiazide diuret ics in African Am ericans t han in non - African Am ericans. I dent ificat ion of genet ic variant s t hat influence blood pressure responsiveness would pot ent ially provide a rat ional basis for t he select ion of a specific class of an ant ihypert ensive agent in an individual pat ient . Early pharm acogenet ic st udies, ut ilizing eit her a candidat e gene approach or genom ewide scans, have shown associat ions of gene polym orphism s wit h blood pressure responsiveness t o specific ant ihypert ensive drugs. However, t he report ed effect s have generally been t oo sm all t o affect clinical decisions, and associat ed polym orphism s rem ain t o be confirm ed in subsequent st udies. Current ly, in pract ical t erm s, t he presence of com orbidit ies oft en influences t he select ion of ant ihypert ensive agent s. A recent m et a- analysis of m ore t han 30 random ized t rials of blood pressurelow ering t herapy indicat es t hat for a given reduct ion in blood pressure, t he m aj or drug classes seem t o produce sim ilar overall net effect s on t ot al cardiovascular event s. I n bot h nondiabet ic and diabet ic hypert ensive pat ient s, m ost t rials have failed t o show significant differences in cardiovascular out com es wit h different drug regim ens as long as equivalent decreases in blood pressure were achieved. For exam ple, t he Ant ihypert ensive and Lipid - Lowering Treat m ent t o prevent Heart At t ack Trial ( ALLHAT) dem onst rat ed t hat t he occurrence of coronary heart disease deat h and nonfat al m yocardial infarct ion, as well as overall m ort alit y, w as virt ually ident ical in hypert ensive pat ient s t reat ed wit h eit her an ACEI ( lisinopril) , a diuret ic ( chlort halidone) , or a calcium ant agonist ( am lodipine) . However, in specific pat ient groups, ACEI s m ay have part icular advant ages, beyond t hat of blood pressure cont rol, in reducing cardiovascular and renal out com es. ACEI s and ARBs decrease int raglom erular pressure and prot einuria and m ay ret ard t he rat e of progression of renal insufficiency, not t ot ally account ed for by t heir hypot ensive effect s, in bot h diabet ic and nondiabet ic renal diseases. Am ong African Am ericans w it h hypert ension - relat ed renal disease, ACEI s appear t o be m ore effect ive t han bet a blockers or dihydropyridine calcium channel blockers in slowing, alt hough not prevent ing, t he decline of glom erular filt rat ion rat e. I n experim ent al m odels of hypert ension and diabet es, renal prot ect ion w it h aliskiren ( a renin inhibit or) w as com parable t o t hat wit h ACEI s and ARBs. I ndependent of it s blood pressurelowering effect , aliskiren has renal prot ect ive effect s in pat ient s wit h hypert ension, t ype 2 diabet es, and nephropat hy. The renoprot ect ive effect of t hese renin - angiot ensin blockers, com pared wit h ot her ant ihypert ensive drugs, is less obvious at lower blood pressures. I n m ost pat ient s wit h hypert ension and heart failure due t o syst olic and/ or diast olic dysfunct ion, t he use of diuret ics, ACEI s or ARBs, and bet a blockers is recom m ended t o im prove survival. I ndependent of blood pressure, in bot h hypert ensive and norm ot ensive individuals, ACEI s at t enuat e t he developm ent of left vent ricular hypert rophy, im prove sym pt om at ology and risk of deat h from CHF, and reduce m orbidit y and m ort alit y rat es in post - m yocardial infarct ion pat ient s. Sim ilar benefit s in cardiovascular m orbidit y and m ort alit y rat es in pat ient s wit h CHF have been observed wit h t he use of ARBs. ACEI s provide bet t er coronary prot ect ion t han do calcium channel blockers, w hereas calcium channel blockers provide m ore st roke prot ect ion t han do eit her ACEI s or bet a blockers. Result s of a recent large, double- blind prospect ive clinical t rial [ Rat ionale and Design of t he Avoiding Cardiovascular Event s t hrough Com binat ion Therapy in Pat ient s Living w it h Syst olic Hypert ension ( ACCOMPLI SH Trial) ] indicat ed t hat com binat ion t reat m ent wit h an ACEI ( benazepril) plus a calcium ant agonist ( am lodipine) was superior t o t reat m ent wit h t he ACEI plus a diuret ic ( hydrochlorot hiazide) in reducing t he risk of cardiovascular event s and deat h am ong high - risk pat ient s wit h hypert ension. However, t he com binat ion of an ACEI and a diuret ic has recent ly been shown t o produce m aj or reduct ions in m orbidit y and m ort alit y in t he very elderly. Aft er a st roke, com binat ion t herapy wit h an ACEI and a diuret ic, but not w it h an ARB, reduces t he rat e of recurrent st roke. Som e of t hese apparent differences m ay reflect differences in t rial design and/ or pat ient groups.

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BLOOD PRESSURE GOALS OF AN TI H YPERTEN SI VE TH ERAPY


Based on clinical t rial dat a, t he m axim um prot ect ion against com bined cardiovascular endpoint s is achieved wit h pressures < 135140 m m Hg for syst olic blood pressure and < 8085 m m Hg for diast olic blood pressure; how ever, t reat m ent has not reduced cardiovascular disease risk t o t he level in nonhypert ensive individuals. More aggressive blood pressure t arget s for blood pressure cont rol ( e.g., office or clinic blood pressure < 130/ 80 m m Hg) are generally recom m ended for pat ient s wit h diabet es, coronary heart disease, chronic kidney disease, or addit ional cardiovascular disease risk fact ors. An even lower goal blood pressure ( syst olic blood pressure ~ 120 m m Hg) m ay be desirable for pat ient s wit h prot einuria ( > 1 g/ d) since t he decline of glom erular filt rat ion rat e in t hese pat ient s is part icularly blood pressuredependent . I n diabet ic pat ient s, effect ive blood pressure cont rol reduces t he risk of cardiovascular event s and deat h as well as t he risk for m icrovascular disease ( nephropat hy, ret inopat hy) . Risk reduct ion is great er in diabet ic t han in nondiabet ic individuals. Alt hough t he opt im al t arget blood pressure in pat ient s wit h heart failure has not been est ablished, a reasonable goal is t he lowest blood pressure t hat is not associat ed wit h evidence of hypoperfusion. To achieve recom m ended blood pressure goals, t he m aj orit y of individuals wit h hypert ension w ill require t reat m ent wit h m ore t han one drug. Three or m ore drugs frequent ly are needed in pat ient s w it h diabet es and renal insufficiency. For m ost agent s, reduct ion of blood pressure at half - st andard doses is only ~ 20% less t han at st andard doses. Appropriat e com binat ions of agent s at t hese low er doses m ay have addit ive or alm ost addit ive effect s on blood pressure wit h a lower incidence of side effect s. Despit e t heoret ical concerns about decreasing cerebral, coronary, and renal blood flow by overly aggressive ant ihypert ensive t herapy, clinical t rials have found no evidence for a "J- curve" phenom enon; i.e., at blood pressure reduct ions achieved in clinical pract ice, t here does not appear t o be a lower t hreshold for increasing cardiovascular risk. A sm all nonprogressive increase in t he serum creat inine concent rat ion w it h blood pressure reduct ion m ay occur in pat ient s wit h chronic renal insufficiency. This generally reflect s a hem odynam ic response, not st ruct ural renal inj ury, indicat ing t hat int raglom erular pressure has been reduced. Blood pressure cont rol should not be allowed t o det eriorat e in order t o prevent a m odest rise in creat inine. Even am ong older pat ient s wit h isolat ed syst olic hypert ension, furt her lowering of diast olic blood pressure does not result in harm . However, relat ively lit t le inform at ion is available concerning t he risk - versus- benefit rat io of ant ihypert ensive t herapy in individuals > 80 years, and in t his populat ion, gradual blood pressure reduct ion t o less aggressive t arget levels of cont rol m ay be appropriat e. The t erm resist ant hypert ension refers t o pat ient s wit h blood pressures persist ent ly > 140/ 90 m m Hg despit e t aking t hree or m ore ant ihypert ensive agent s, including a diuret ic, in a reasonable com binat ion and at full doses. Resist ant or difficult - t o- cont rol hypert ension is m ore com m on in pat ient s > 60 years t han in younger pat ient s. Resist ant hypert ension m ay be relat ed t o " pseudoresist ance" ( high office blood pressures and low er hom e blood pressures) , nonadherence t o t herapy, ident ifiable causes of hypert ension ( including obesit y and excessive alcohol int ake) , and t he use of any of a num ber of nonprescript ion and prescript ion drugs ( Table 247 - 3) . Rarely, in older pat ient s, pseudohypert ension m ay be relat ed t o t he inabilit y t o m easure blood pressure accurat ely in severely sclerot ic art eries. This condit ion is suggest ed if t he radial pulse rem ains palpable despit e occlusion of t he brachial art ery by t he cuff ( Osler m aneuver) . The act ual blood pressure can be det erm ined by direct int ra- art erial m easurem ent . Evaluat ion of pat ient s wit h resist ant hypert ension m ight include hom e blood pressure m onit oring t o det erm ine if office blood pressures are represent at ive of t he usual blood pressure. A m ore ext ensive evaluat ion for a secondary form of hypert ension should be undert aken if no ot her explanat ion for hypert ension resist ance becom es apparent .

H YPERTEN SI VE EM ERGEN CI ES
Probably due t o t he widespread availabilit y of ant ihypert ensive t herapy, in t he Unit ed St at es t here has been a decline in t he num bers of pat ient s present ing wit h "crisis levels" of blood pressure. Most pat ient s who present wit h severe hypert ension are chronically hypert ensive, and in t he absence of acut e end organ dam age, precipit ous low ering of blood pressure m ay be associat ed wit h significant m orbidit y and should be avoided. The key t o successful m anagem ent of severe hypert ension is t o different iat e hypert ensive crises from hypert ensive urgencies. The degree of t arget organ dam age, rat her t han t he level of blood pressure alone, det erm ines t he rapidit y w it h which blood pressure should be lowered. Ta ble s 2 4 7 - 9 and 2 4 7 - 1 0 list a num ber of hypert ension- relat ed

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em ergencies and recom m ended t herapies.

Ta ble 2 4 7 9 . Pr e fe r r e d Pa r e n t e r a l D r ugs for Se le ct e d H ype r t e nsive Em e r ge ncie s


Hypert ensive encephalopat hy Malignant hypert ension ( when I V t herapy is indicat ed) St roke Myocardial infarct ion/ unst able angina Acut e left vent ricular failure Aort ic dissect ion Adrenergic crisis Post operat ive hypert ension Preeclam psia/ eclam psia of pregnancy Nit roprusside, nicardipine, labet alol Labet alol, nicardipine, nit roprusside, enalaprilat Nicardipine, labet alol, nit roprusside Nit roglycerin, nicardipine, labet alol, esm olol Nit roglycerin, enalaprilat , loop diuret ics Nit roprusside, esm olol, labet alol Phent olam ine, nit roprusside Nit roglycerin, nit roprusside, labet alol, nicardipine Hydralazine, labet alol, nicardipine

Source : Adapt ed from DG Vidt , in S Oparil, MA Weber ( eds) : Hypert ension, 2nd ed. Philadelphia, Elsevier Saunders, 2005.

Ta ble 2 4 7 1 0 . Usua l I nt r a ve nous Dose s of Ant ihype r t e nsive Age n t s Use d in H ype r t e nsiv e Em e r ge ncie s.*
Ant ihype r t e nsive Age nt Nit roprusside Nicardipine Labet alol Labet alol Esm olol Phent olam ine Nit roglycerin Hydralazine I nt ra ve nous D ose I nit ial 0.3 ( g/ kg) / m in; usual 24 ( g/ kg) / m in; m axim um 10 ( g/ kg) / m in for 10 m in I nit ial 5 m g/ h; t it rat e by 2.5 m g/ h at 5 15 m in int ervals; m ax 15 m g/ h 2 m g/ m in up t o 300 m g or 20 m g over 2 m in, t hen 40 80 m g at 10- m in int ervals up t o 300 m g t ot al 2 m g/ m in up t o 300 m g or 20 m g over 2 m in, t hen 40 80 m g at 10- m in int ervals up t o 300 m g t ot al I nit ial 80500 g/ kg over 1 m in, t hen 50300 ( g/ kg) / m in 515 m g bolus I nit ial 5 g/ m in, t hen t it rat e by 5 g/ m in at 35- m in int ervals; if no response is seen at 20 g/ m in, increm ent al increases of 1020 g/ m in m ay be used 1050 m g at 30- m in int ervals

* Const ant blood pressure m onit oring is required. St art w it h t he lowest dose. Subsequent doses and int ervals of adm inist rat ion should be adj ust ed according t o t he blood pressure response and durat ion of act ion of t he specific agent . Malignant hypert ension is a syndrom e associat ed wit h an abrupt increase of blood pressure in a pat ient wit h underlying hypert ension or relat ed t o t he sudden onset of hypert ension in a previously norm ot ensive individual. The absolut e level of blood pressure is not as im port ant as it s rat e of rise. Pat hologically, t he syndrom e is associat ed wit h diffuse necrot izing vasculit is, art eriolar t hrom bi, and fibrin deposit ion in art eriolar walls. Fibrinoid necrosis has been observed in art erioles of kidney, brain, ret ina, and ot her organs. Clinically, t he syndrom e is recognized by progressive ret inopat hy ( art eriolar spasm , hem orrhages, exudat es, and papilledem a) , det eriorat ing renal funct ion wit h prot einuria, m icroangiopat hic hem olyt ic anem ia, and encephalopat hy. I n t hese pat ient s, hist oric inquiry should include quest ions about t he use of m onam ine oxidase inhibit ors and recreat ional drugs ( e.g., cocaine, am phet am ines) . Alt hough blood pressure should be lowered rapidly in pat ient s wit h hypert ensive encephalopat hy, t here are inherent risks of overly aggressive t herapy. I n hypert ensive individuals, t he upper and lower lim it s of aut oregulat ion of cerebral blood flow are shift ed t o higher levels of art erial pressure, and rapid lowering of blood pressure t o below t he lower lim it of aut oregulat ion m ay precipit at e cerebral ischem ia or infarct ion as a consequence of decreased cerebral blood flow. Renal and coronary blood flows also m ay decrease wit h overly aggressive acut e t herapy. The

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init ial goal of t herapy is t o reduce m ean art erial blood pressure by no m ore t han 25% w it hin m inut es t o 2 h or t o a blood pressure in t he range of 160/ 100 110 m m Hg. This m ay be accom plished wit h I V nit roprusside, a short - act ing vasodilat or w it h a rapid onset of act ion t hat allows for m inut e- t o- m inut e cont rol of blood pressure. Parent eral labet alol and nicardipine are also effect ive agent s for t he t reat m ent of hypert ensive encephalopat hy. I n pat ient s wit h m alignant hypert ension wit hout encephalopat hy or anot her cat ast rophic event , it is preferable t o reduce blood pressure over hours or longer rat her t han m inut es. This goal m ay effect ively be achieved init ially wit h frequent dosing of short - act ing oral agent s such as capt opril, clonidine, and labet alol. Acut e, t ransient blood pressure elevat ions t hat last days t o w eeks frequent ly occur aft er t hrom bot ic and hem orrhagic st rokes. Aut oregulat ion of cerebral blood flow is im paired in ischem ic cerebral t issue, and higher art erial pressures m ay be required t o m aint ain cerebral blood flow. Alt hough specific blood pressure t arget s have not been defined for pat ient s w it h acut e cerebrovascular event s, aggressive reduct ions of blood pressure are t o be avoided. Wit h t he increasing availabilit y of im proved m et hods for m easuring cerebral blood flow ( using CT t echnology) , st udies are in progress t o evaluat e t he effect s of different classes of ant ihypert ensive agent s on bot h blood pressure and cerebral blood flow aft er an acut e st roke. Current ly, in t he absence of ot her indicat ions for acut e t herapy, for pat ient s w it h cerebral infarct ion w ho are not candidat es for t hrom bolyt ic t herapy, one recom m ended guideline is t o inst it ut e ant ihypert ensive t herapy only for pat ient s w it h a syst olic blood pressure > 220 m m Hg or a diast olic blood pressure > 130 m m Hg. I f t hrom bolyt ic t herapy is t o be used, t he recom m ended goal blood pressure is < 185 m m Hg syst olic pressure and < 110 m m Hg diast olic pressure. I n pat ient s w it h hem orrhagic st roke, suggest ed guidelines for init iat ing ant ihypert ensive t herapy are syst olic > 180 m m Hg or diast olic pressure > 130 m m Hg. The m anagem ent of hypert ension aft er subarachnoid hem orrhage is cont roversial. Caut ious reduct ion of blood pressure is indicat ed if m ean art erial pressure is > 130 m m Hg. I n addit ion t o pheochrom ocyt om a, an adrenergic crisis due t o cat echolam ine excess m ay be relat ed t o cocaine or am phet am ine overdose, clonidine wit hdraw al, acut e spinal cord inj uries, and an int eract ion of t yram ine - cont aining com pounds wit h m onam ine oxidase inhibit ors. These pat ient s m ay be t reat ed wit h phent olam ine or nit roprusside. Tr ea t m en t of hype r t en sion in pa t ie nt s w it h a cut e a or t ic disse ct ion is discusse d in Cha p. 2 4 8 , a nd t re a t m e nt of hype r t e nsion in pr e gna ncy is discusse d in Ch a p. 7 .

FURTH ER READ I N GS
Accord St udy Group: Effect s of int ensive blood pressure cont rol in t ype 2 diabet es m ellit us. N Engl J Med 362: 1575, 2010 Adrogue JH, Madias NE: Sodium and pot assium in t he pat hogenesis of hypert ension. N Engl J Med 356: 1966, 2007 [ PMI D: 17494929] Allhat Collaborat ive Research Group: Maj or out com es in high- risk hypert ensive pat ient s random ized t o angiot ensin convert ing enzym e inhibit or or calcium channel blocker vs. diuret ic: The Ant ihypert ensive and Lipid - Lowering Treat m ent t o Prevent Heart At t ack Trial ( ALLHAT) . JAMA 288: 2981, 2002 Appel LJ et al: Diet ary approaches t o prevent and t reat hypert ension: A scient ific st at em ent from t he Am erican Heart Associat ion. Hypert ension 47: 296, 2006[ PMI D: 16434724] Blood Pressure Lowering Treat m ent Trialist s' Collaborat ion: Effect s of different blood pressure - lowering regim ens on m aj or cardiovascular event s in individuals wit h and wit hout diabet es m ellit us. Arch I nt ern Med 165: 1410, 2005 Casas JP et al: Effect of inhibit ors of t he renin - angiot ensin syst em and ot her ant ihypert ensive drugs on renal out com es: Syst em at ic review and m et a- analysis. Lancet 366: 2026, 2005[ PMI D: 16338452] Chobanian AV et al: The Sevent h Report of t he Joint Nat ional Com m it t ee on Prevent ion, Det ect ion, Evaluat ion, and Treat m ent of High Blood Pressure: The JNC 7 Report . JAMA 289: 2560, 2003[ PMI D: 12748199] Law MR et al: Value of low dose com binat ion t reat m ent wit h blood pressure lowering drugs: Analysis of 354 random ised t rials. Br Med J 326: 1427, 2003[ PMI D: 12829555] Law es CMM et al: Global burden of blood pressure- relat ed disease, 2001. Lancet 371: 1513, 2008[ PMI D: 18456100]

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AccessMedicine | Print: Chapter 247. Hypertensive Vascular Disease

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Mancia G: Role of out com e t rials in providing inform at ion on ant ihypert ensive t reat m ent : I m port ance and lim it at ions. Am J Hypert ens 19: 1, 2006[ PMI D: 16461181] Moser M, Set ano JF: Resist ant or difficult - t o- cont rol hypert ension. N Engl J Med 355: 385, 2006[ PMI D: 16870917] Ong KL et al; Prevalence, awareness, t reat m ent , and cont rol of hypert ension am ong Unit ed St at es adult s 1999 2004. Hypert ension 49: 69, 2007[ PMI D: 17159087] Pickering TG et al: Recom m endat ions for blood pressure m easurem ent in hum ans and experim ent al anim als. Part 1: Blood pressure m easurem ent in hum ans. A st at em ent for professionals from t he Subcom m it t ee of Professional and Public Educat ion of t he Am erican Heart Associat ion Council on High Blood Pressure Research. Hypert ension 45: 142, 2005[ PMI D: 15611362] : Am bulat ory blood- pressure m onit oring. N Engl J Med 3554: 2368, 2006 Text or SC: Current approaches t o renovascular hypert ension. Med Clin Nort h Am 93: 717, 2009[ PMI D: 19427501] Weber MA, Mat erson BJ: Hypert ension guidelines: A m aj or reappraisal crit ically exam ines t he available evidence. J Clin Hypert ens ( Greenwich) 12: 229, 2010[ PMI D: 20433542]

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