Resistant Hypertension

(1)

Resistant

Hypertension

and

Malignant

Hypertension

Rebecca Sentman, MD

Nephrology and Hypertension Medical Associates

(2)

(3)

What is Resistant

HTN?

✴ BP above goal (usually 140/90) despite concurrent use of 3 antihypertensive agents of different

classes, one of which should be a diuretic (if

tolerated), at maximally recommended/tolerated doses (AHA, ACC, ISH)

✴ Pts with controlled HTN with 4+ meds

Variable prevalence depending on population studied (8-40%), higher in pts with CKD and

(4)

And why do we care?

rHTN: increases risk of:

Coronary heart disease Stroke

All-cause mortality Heart failure

Peripheral arterial disease ESRD

(5)

First things first:

proper technique for BP measurement

Relaxed, sitting in supportive chair, feet on floor, empty bladder, no clothing under cuff, arm supported

Proper cuff size

Both arms first visit. Avg of ≥ 2 readings obtained on ≥ 2 occasions

Palpated estimate of radial pulse obliteration first, then inflate 20-30 mm Hg above for auscultatory determination. Deflate 2 mm Hg/sec (I was taught 3 sec per 10 mm Hg)

Confirm with out-of-office measurements (ABPM, home BP monitoring

(6)

Always consider:

Poor adherence with medications

✴

$$$$$

✴

understanding

✴

side effects

(7)

Risk Factors for rHTN

• Older age, men, Black race, DM • Suboptimal therapy/adherence

• Lifestyle and dietary (obese, high salt, physical inactivity, heavy EtOH intake) • Medications

(8)

• OCPs/HRT, steroids, NSAIDS • Amphet/cocaine/EtOH

• SSRIs/TCAs/MAOIs

• EPO/calcineurin inhibitors • Decongestants

• Ephedra/ma huang/blue cohos, bitter orange

• Chemotherapeutic agents (esp VEGF inhibitors, tyrosine kinase inhibitors)

(9)

Secondary HTN

• vs primary / “idiopathic” / “essential” • potentially reversible

• RENAL/ADRENAL causes vs EVERYTHING

ELSE (I’m a nephrologist, whaddaya want from me)

(10)

When should you

consider

secondary HTN

?

Age of onset: < 30 with negative family history and no other risk factors

Proven age of onset before puberty

Acute rise or increasing lability in previously stable pt Severe, end-organ damage, flash pulm edema

Hypokalemia/metabolic alkalosis

(11)

Renal/Adrenal Causes

of Secondary HTN:

-RAS

-AKI/CKD

-Vasculitis/Renal infarct/Page kidney -Liddle’s syndrome

-Gordon’s syndrome (type 2 pseudohypoaldosteronism) -Renin-secreting tumor -Primary hyperaldosteronism -Pheochromocytoma -Cushings -GRA -SAME -17-α-OHase deficiency -11-β-OHase deficiency

(12)

Secondary HTN causes:

“other”

Thyroid disease,

hyperparathyroidism

Aortic coarctation

OSA, obesity

Meds/drugs

(13)

(14)

ANGIOTENSINOGEN

(mainly LIVER)

ANGIOTENSIN I

RENAL NaCl REABSORPTION K EXCRETION cardiac fibrosis ?insulin resistance ARTERIOLAR VC ADH secretion ↑SYMPATHETIC ACTIVITY INFLAMMATORY MEDIATOR VASC SM MUSC CELL PROLIF

ALDOSTERONE

(ADRENAL GLAND) RENIN

ANGIOTENSIN II

ACE (mainly LUNGS, KIDNEY)

{

--Juxtaglom cells aff arteriole -low Na intake,↓ECF vol

-cardiac and arterial

baroreceptors, B1 adrenergic receptors

Presenting: the RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM!

(15)

How to use renin and aldosterone levels:

ARR > 20?

Not necessarily

.

Plasma renin activity (PRA; conventional immunoassay) vs direct/ active renin concentration (DRC/ARC; chemiluminescent

immunoassay or mass spectrometry)

Renin can be very low with a low-normal aldosterone, makes ratio ; renin often suppressed if pt is sodium/volume overloaded

Caveat: certain meds can alter levels

Beta blockers and direct renin inhibitors can LOWER renin MCR blockers will RAISE aldosterone

OK to continue ACEI/ARB/CCB when screening (Seifarth et al, Clin Endocrinol, 2002:57(4)457-65.)

(16)

Renin and aldosterone levels MAY help you:

*Renovascular HTN

*Aortic coarctation *Renin-secreting

tumor, renal infarct, vasculitis *Primary aldosteronism *GRA *17-α-OHase deficiency *Volume overload *SAME *Cushing’s syndrome *Liddle’s syndrome *11-β-OHase deficiency

{

SUPPRESSED RENIN AND ALDO SUPPRESSED RENIN / HIGH ALDO

(17)

Renovascular HTN

•

Prevalence increases with age and in pts with known CV risk factors or atherosclerosis

•

10-45% Caucasian pts with severe/refractory HTN have RAS; less common in Black pts

•

Can be from atheromatous disease (RAS), fibromuscular dysplasia, or atheroembolic disease

•

FMD: usually affects women < 50, distal main renal artery or infrarenal branches

(18)

UpToDate

(19)

RAS

Clues

‣

Acute rise in BP after previously stable value

‣

Acute rise in creatinine after ACEI or ARB (some bilateral RAS)

‣

Diffuse atherosclerosis or small kidney

‣

Systolic/diastolic bruit (sens 40%, spec 99%)

(20)

To angioplasty, or not to angioplasty?

•

CORAL trial (NEJM 2014) : renal artery stenting did not confer significant benefit when added to medical management

•

Medical tx with RAS inhibitor in everyone with unilateral RAS (and cautiously in bilat RAS) is recommended

•

Selection bias complicates trial interpretation

•

Recommend: only revascularize those with high likelihood of benefit: short duration of HTN, failure of medical tx,

intolerance to optimal tx, recurrent flash pulm edema, bilateral RAS or unilateral RAS in solitary kidney

(21)

(22)

Quiros-Lopez R and Garcia-Alegria J. N Engl J Med 2007;356:2630

A healthy 28-year-old woman presented with a 1-year history of high blood pressure, which

had been diagnosed during her first pregnancy and treated

with amiloride and hydrochlorothiazide Another cause of secondary HTN: what’s your diagnosis?

(23)

Aortic Coarctation

Major cause in young children (esp. males), can occur in adults

HTN in arms with diminished femoral pulses, low or unobtainable BP in legs

Untreated = poor prognosis.

90% cured if corrected in childhood (earlier=better)--surgery or balloon angio

(24)

Quiros-Lopez R and Garcia-Alegria J. N Engl J Med 2007;357:717-718

Coarctation of the Aorta in a Young Woman

•

Diaphragm-like ridge into aortic lumen, usually just distal to L SC artery.

•

CXR: notching of posterior ribs 3-8, “3 sign”: proximal aorta, coarcted segment, post-stenotic dilatation

(25)

High Aldo, Low Renin

1. Primary aldosteronism

2. Glucocorticoid-remediable aldosteronism 3. 17-α-hydroxylase deficiency

(26)

Aldosterone actions on the kidney

•

Binds to mineralocorticoid receptor at cortical collecting duct cells

•

increases # of basolateral Na/K ATPase pumps (resorb sodium, excrete potassium) and luminal sodium

channels

(27)

Primary aldosteronism

(Conn’s syndrome = adenoma)

Most common cause of secHTN, prevalence of approximately 20% among pts with rHTN

Increased Na reabsorption/volume retention, vascular remodeling, fibrosis of heart, adrenal galnds, pancreas, lungs Broadly: unilateral vs bilateral

Spectrum: bilateral adenomas, unilateral hyperplasia, micronodules, microscopic aldosterone producing cell clusters, in variable combinations (Circulation. 2018 138(8):823-835)

3 familial types (including GRA). Rarely carcinoma (> 6 cm)

(28)

•

Renal K wasting (only 9-37% actually hypoK) > 30 mEq/day in presence of hypoK

•

24 hr urinary aldosterone > 12 mcg on high-salt diet

•

Aldo:PRA > 20:1 suggestive.

•

Oral sodium loading (5g/d); saline

suppression test

•

CT/MRI; adrenal vein sampling

J Clin Endocrinol Metab. 2004;89(3):1045.

(29)

Treatment

•

Spironolactone (aldactone): MCR antagonist, also binds to

androgen and progesterone receptors causing SE: gynecomastia, impotence, breast pain, menstrual irregularities, hyperkalemia,

NAGMA

✴

Start 12.5-25 and titrate gradually up to 100+ mg/d

•

Eplerenone (Inspra): selective aldo receptor antagonist, with

minimal androgen/progesterone receptor binding

✴

More expensive, give bid at twice spironolactone dosing

(30)

(31)

Glucocorticoid-Remediable

Aldosteronism (GRA)

★ AKA familial hyperaldosteronism type I. Very rare, AD inheritance.

★ Chimeric gene: crossover b/w aldosterone synthase and

11-β-hydroxylase

•

11-β-hydroxylase activity is stimulated by ACTH (z. fasciculata)

•

Now in chimer with aldo synthase, therefore… aldosterone produced in response to ACTH stimulation

•

ACTH production is suppressed by glucocorticoids, therefore…treatment is with glucocorticoids

High Aldo, Low Renin #2

(32)

Cholesterol

Pregnenolone --> 17(OH)pregnenolone --> DHEA

Progesterone --> 17(OH)progesterone --> Androstenedione

DOC 11-deoxycortisol Corticosterone Cortisol Aldosterone Cortisone ↓ ↓ ↓ ↓ ↓ ↕ ↓ ↓ ↓ ↓ ↓ 3-β(OH) steroid DH 21-OHase Aldo synthase 17,20- lyase 17-α-OHase 11-β(OH) steroid DH 17-β-reductase

Z GLOMERULOSA Z FASCICULATA Z RETICULARIS

Estradiol Testosterone aromatase ↓ 11-β-OHase CHIMER

High Aldo, Low Renin

(33)

Cholesterol

DOC 11-deoxycortisol Corticosterone Cortisol Aldosterone Cortisone ↓ ↓ ↓ ↓ ↓ ↕ ↓ ↓ ↓ ↓ ↓ 3-β(OH) steroid DH 21-OHase Aldo synthase 11-β-OHase 17,20- lyase 17-α-OHase 11-β(OH) steroid DH 17-β-reductase

Estradiol

Testosterone

aromatase

↓

X

High Aldo, Low Renin #3

17-α-OHASE DEFICIENCY

(34)

(35)

Low Renin and Aldosterone

1. Syndrome of apparent mineralocorticoid excess

2. Cushing’s syndrome

3. 11-β-OHase deficiency 4. Liddle’s syndrome

(36)

Syndrome of AME

•

AR, usually found in childhood.

•

Mutation in 11-β(OH)steroid dehydrogenase leads to decreased conversion of cortisol to cortisone in the kidney (i.e., a lot of cortisol around)

•

Cortisol becomes primary force at MC receptor by force of sheer concentration

(37)

Cholesterol

Estradiol

Testosterone

aromatase

↓

X

SAME

(38)

Acquired SAME

•

Glycyrrhetinic acid: obtained from herb licorice, flavors chewing

tobacco

•

Can bind to and inactivate 11-β(OH)steroid dehydrogenase, allowing cortisol to be major endogenous mineralocorticoid

(39)

Cushing’s Syndrome

★

Mechanisms of HTN with hypercortisolemia:

•

Increased peripheral vascular sensitivity to adrenergic agonists

•

Increased hepatic production of angiotensinogen

•

Activation of renal mineralocorticoid receptors by cortisol excess

(40)

Think Cushing’s Syndrome:

Progressive central obesity involving face, neck, trunk, abdomen

Moon facies, dorsocervical fat pad

Skin atrophy, striae, hyperpigmentation Proximal muscle wasting/weakness

Osteoporosis

Glucose intolerance

(41)

Cholesterol

Estradiol Testosterone aromatase ↓

X

11-β-OHase deficiency

(42)

Liddle’s Syndrome

•

AD mutation in ENaC in the principal cells of the CCT

•

Leads to increased activity of that channel and

therefore increased Na resorption/K excretion. Any guess as to best treatment?

Low Renin and Aldo #4

(43)

Treatment of Liddle’s

Syndrome

Amiloride or triamterene

• Close the Na channels

(ENaC)

• “Potassium-sparing”

diuretics

(44)

(45)

Even

MORE

Causes of

Secondary HTN!

•

Chronic (or acute) kidney disease

•

Sleep apnea

•

Pheochromocytoma

•

Thyroid disease

(46)

Kidney disease

★

Helpful clues!: elevated creatinine, abnormal UA. Why does kidney dz lead to HTN? Well..

•

Volume overload from sodium retention

•

Ischemia-induced activation of RAAS

•

Enhanced SNS activity

(47)

Volume Control

• Essential to optimize volume status (sodium load)! • Everybody needs a diuretic (pretty much)

• Higher doses needed in CKD

• Chlorthalidone more potent/efficacious than HCTZ • Torsemide more bioavailable and longer

acting than furosemide/bumetanide • Consider class combinations

(48)

Sleep Apnea and HTN

•

50-90% patients with SA also have HTN

•

Thought to be causal relationship but the mechanism is not known

•

SNS involved

•

Hypoxic interference with function of vascular endothelium?

(49)

Pheochromocytoma

Med student:

“I got a pheo!”

Dr. Nash:

(50)

Pheochromocytoma

•

Rare: probably occurs < 0.2% of pt with HTN. 50% diagnosed at autopsy in one series. Most common in ages 30s-40s.

•

>50% discovered incidentally, 27% due to syx (Gruber et al 2019)

•

Adenoma of adrenal medulla.

•

Can be extraadrenal (10-15%), then called a catecholamine-secreting paraganglioma

•

Hypersecretion of catecholamines (norepinephrine, epinephrine, and dopamine); also may have increased sympathomimetic activity

•

Classic triad: HA, sweating, tachycardia. Sustained or paroxysmal HTN is most common sign

(51)

Pheochromo-cytoma:

Association with

Familial AD Board Exam Syndromes

MEN 2A

pheochromocytoma medullary thyroid cancer primary hyperparathyroidism

MEN 2B

pheochromocytoma medullary thyroid cancer

mucosal neuromas

intestinal ganglioneuromatosis

VON-HIPPEL LINDAU DISEASE

pheochromocytoma

hemangioblastoma (cerebellar, spinal) retinal angiomas

RCCA

cystadenoma (pancreas, epididymis) pancreatic neuroendocrine tumors

NEUROFIBROMATOSIS TYPE 1

pheochromocytoma café au lait spots

axillary/inguinal freckling iris hamartomas (Lisch nodules)

(52)

Dx: Pheochromocytoma

•

Plasma fractionated metanephrines (metabolites of epi and norepi) have high sensitivity but low specificity

•

24 hr urine catecholamines and fractionated metanephrines have high sensitivity and specificity

•

Biochemical confirmation should be followed by radiographic evaluation

•

with CT or MRI; also123-I-metaiodobenzylguanidine (MIBG) scintigraphy (compound resembling NE taken up by adrenergic tissue)

•

Tx: surgical removal. High risk procedure

•

give phenoxybenzamine or other alpha blockade (and beta blockade) pre- and perioperatively

(53)

Thyroid disease

and HTN

•

HYPOthyroidism: usually diastolic elevation

•

Increased catecholamine levels, increased peripheral vascular resistance; decreased CO/SV/HR

•

HYPERthyroidism: usually systolic elevation

•

Increased CO/SV/HR, RAAS activation; decreased PVR

(54)

Hyperparathyroidism:

mechanisms of HTN

•

May be related in part to actions of PTH itself, but most likely from..

•

Hypercalcemia:

•

causes increase in vascular resistance (renal > peripheral vasculature

direct effect of vascular smooth muscle calcium-induced hypercatecholaminemia

(55)

(56)

Summary: Resistant HTN

•

Go over their meds. Again. And again.

•

Check renin, aldosterone levels.

•

Get a UA.

•

It’s (probably) not a pheo.

•

Why not more diuretic?

(57)

HTN Urgency vs

Emergency

•

Both: severe elevation in BP, generally systolic > 180 and/or diastolic >120

•

URGENCY: generally asymptomatic, not

associated with end-organ damage. Urgency

does not require urgent treatment!

•

EMERGENCY: Always associated with

(58)

Hypertensive emergency

pathophysiology

•

Acute arteriolar/endothelial injury

‣

abrupt rise in vascular resistance

‣

proinflammatory cytokines

‣

overwhelming endothelial vasodilator responses

•

Fibrinoid necrosis and

musculomucoid intimal hyperplasia-> lumen narrowing-> ischemia

(59)

HTN Emergencies

*ICH *SAH *Ischemic stroke *Hypertensive encephalopathy *Retinal hemorrhages/ exudate/papilledema

*Flash pulmonary edema

*MI/angina/LV failure

*Aortic dissection

*Acute GN/renal crisis

*Pheochromocytoma crisis

*Microangiopathic hemolytic anemia (i.e. HUS/TTP)

*Cocaine/sympathomimetics

*MAO inhibitor interaction

*Autonomic hyperreactivity (GBS, acute intermittent

porphyria)

(60)

General principles

• Usually goal is to lower MAP by 25% in first hour, then to

160/100-110 over next 2-6 hrs, then to 130/80 (but generally not less) by 24-48 hrs (J Am Coll Cardiol 2018; UpToDate)

• EXCEPTIONS:

(1) Acute ischemic stroke: no treatment unless >185/110 in

candidates for reperfusion tx or >220/120 in noncandidates; if indicated, cautious lowering by approx 15% during first 24 hrs is suggested

(2) Intracerebral hemorrhage

(61)

Acute Intracerebral

Hemorrhage

• In adults with ICH who present with SBP >220, it is reasonable to use continuous IV drug infusion and close BP monitoring to lower SBP, probably to goal SBP 140-160

• Immediate lowering of SBP to <140 within the first few hours not associated with benefit and may lead to increased renal adverse events

Stroke. 2015 Jul;46(7):2032-60. Circulation. 2018;138(17):e484.

(62)

Am J Health-Sys Pharm. 2009;66:1448-57.

(63)

Acute ischemic stroke

• Perfusion pressure distal to obstructed vessel is low and distal vessels are dilated. Because of impaired cerebral autoregulation, blood flow in these dilated vessels is

thought to be dependent upon systemic BP

• BP can rise spontaneously following cerebral ischemia (acute sympathetic response, other) but transient—

usually falls by as much as 20/10 mm Hg within 10 days • Acute phase (first 24 hrs)—ischemic penumbra may be

at risk of irreversible damage if cerebral perfusion pressure is decreased

(64)

Am J Health-Sys Pharm. 2009;66:1448-57.

(65)

Am J Health-Sys Pharm. 2009;66:1343-52

(66)

DRUG DOSE ONSET DURA-_TION SE ETC

Nitroprus-side

0.25-10 ug/

kg/min Immediate 1-2 min

N/V, twitching, sweating, thiocyanate and cyanide intoxication Caution with cerebral emergency; renal/liver failure;

MI; can have tachyphylaxis Nicardipine 5-15 mg/hr 5-10 min 15-30 min + Tachycardia, HA, flushing, local phlebitis CI in advanced aortic stenosis Clevidipine 1-2 mg/hr rapid titr to 16

1-2 min 5-15 min A fib, N

CI in egg/soy allergy or defective lipid

metabolism

Fenoldopam 0.1-0.3 ug/

kg/min <5 min 30 min

Tachycardia, HA, N, flushing Avoid with glaucoma or incr ICP Nitroglycerin 5-100 ug/

min 2-5 min 5-10 min

HA, V, methemo-globinemia, tolerance For coronary ischemia/CHF ONLY (IMO)

(67)

DRUG DOSE ONSET DURA-TION SE USE/ AVOID Enalaprilat 1.25-5 mg IV q6 15-30 min 6-12 hr Precipitous fall in high renin states Acute LV failure; avoid in AMI Hydralazine 10-20 mg IV 10-20 min 1-4 hr Tachycardia, flushing, HA, V, angina Eclampsia Labetalol 20-80 mg IV bolus q 10 min or 0.5-2 mg/ min 5-10 min 3-6 hr N/V, heart block, bronchocon-striction Avoid in acute heart failure, reactive airway dz Esmolol 250-500 ug/

kg/min 1-2 min 10-30 min

N, heart block, heart failure, asthma Aortic dissection, perioperative

(68)