resistant hypertension

Resistant Hypertension : 

Resistant Hypertension Problem case

Particulars : 

Particulars 10/10/2009 2 35/M Serving soldier MT Driver Educated till Xth class Native of Faridabad, Haryana

Presentation : 

Presentation 10/10/2009 3 Chest pain Headache Apr 2001 Palpitations

History of presenting complaints : 

History of presenting complaints 10/10/2009 4 Admitted in MH Ambala Sudden onset chest pain with headache( throbbing type) Occuring at rest Increasing on exertion Associated with breathlessness and palpitations Initially continous, pricking and lancinating for 2 days Relieved gradually over a period over 5-6 days Onevaluation found to be normotensive

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10/10/2009 5 Managed as a case of pneumonitis (L) Detected to have digital tremors Transferred to CH(WC) Evaluated and diagnosed as a case of anxiety neurosis and treated in LMC

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10/10/2009 6 Jan 2002 Had recurrence of symptoms Headache/chest pain/palpitations/sweating Admitted in MH Ambala → Transferred to CH(WC)

CH ( WC) Jan 2002 – May 2002 : 

CH ( WC) Jan 2002 – May 2002 10/10/2009 7 Detected to have Hypertension (BP 180/90 mmHg) Systemic Exam: WNL Eval: ↑ urinary catchecholamines(17/05/02) Epi – 19.29 ( 1.7 – 22.4) µg/24 hrs NE - 46.18 ( 12.10 – 85.50 ) µg/24 hrs Epi - 20.00 ( 1.30 – 10.70 ) µg/g creat NE – 40.00 ( 8.90 – 61.60 ) µg/g creat Transferred to AH (RR) for further evaluation

AH(RR) May 2002 – Jan 2003 : 

AH(RR) May 2002 – Jan 2003 10/10/2009 8 BP 180-220/130-140 mm Hg S/E : WNL TOD – Fundus ECG WNL CXR 2 D Echo : Normal LVEF

AH(RR)… : 

AH(RR)… 10/10/2009 9 T Amlodipine 10 mg BD T Atenolol 100 mg BD → T Metoprolol 50 mg BD T Prazocin 5 mg BD → T Ramipril 10 mg BD T Envas 10 mg BD T Nifedipine 20 mg 4 hrly T Losartan 50 mg BD T Clonidine 0.1 mg TDS T Minipress XL 2.5 mg BD T Natrilix SR 1.5 mg OD

AH(RR)… : 

AH(RR)… 10/10/2009 10 U/C Electrolytes 24 hrs urine proteins USG Kidneys Renal doppler WNL CT scan Abdomen MIBG Scan Adrenals CT Brain MRI Brain

AH(RR)… : 

AH(RR)… 10/10/2009 11 Vasculitis w/u : negative Urine for 24 hrs urine Catchecholamines Epi: 31.37 µg/24 hrs ( 1.7 – 22.4) 24.84 µg/g creat ( 1.30 – 10.70 ) NE: 52.15 µg/24 hrs ( 12.10 – 85.50 ) 41.29 µg/g creat ( 8.90 – 61.60 ) Urine osmolality – 439 mOsm/Kg

AH(RR)… : 

AH(RR)… 10/10/2009 12 PRA – 7.03 ng/ml/hr Aldosterone – 1.30 ng/dL Renal Angio – normal T3, T4, TSH – normal USG Thyroid : normal PTH : Normal CT Chest for paraganglionoma : NAD

AH(RR)… : 

AH(RR)… 10/10/2009 13 Was treated with multiple antihypertensives with no response Sent on S/L Re-evaluation Asymptomatic pt BP : 170-230/ 90-160 mm Hg

AH(RR)… : 

AH(RR)… 10/10/2009 14 CXR: fibrotic lesion RUZ ESR 18 mm fall Mx – 14 mm Apicogram : s/o Pulm TB (R) apex Sputum AFB : negative FOB/BAL : Negative CT Chest : Fibrocystic lesion Transferred to MH(CTC) for further evaluation for TB

MH (CTC) Jan 2003 – Mar 2003 : 

MH (CTC) Jan 2003 – Mar 2003 10/10/2009 15 Planned for TBLB for confirmatory diagnosis of TB in view of asymptomatic patient However, in view of uncontrolled HTN pt trf to cardiology for BP control before procedure Pt trf to CH(SC) from MH (CTC) for mutidisciplinary mgmt by endocrinologist, nephrologist and cardiologist.

CH (SC) Mar 2003 – Sep 2003 : 

CH (SC) Mar 2003 – Sep 2003 10/10/2009 16 Clinically Ht 172 cm Wt 62 kg P: 80/min , regular, all peripheral pulses felt BP: RUL- 146/94, LUL- 144/96 RLL- 150/90, LLL- 148/88 No other positive findings on general/ systemic examination

CH (SC)… : 

CH (SC)… 10/10/2009 17 Rx T Nifedipine SR 60mg/0/80mg T Clonidine (200µg) 1 TDS T Prazocin XL (15mg) 1TDS T Enalapril (20 mg) BD T Atenolol (50mg) OD T Ditide 1OD T Flunarazine (5mg) 1OD Placed in LMC for possible evolving causes of reno-vascular/adrenal hypertension

Course of events… : 

Course of events… 10/10/2009 18

AH(RR) 2003 - 2007 : 

AH(RR) 2003 - 2007 10/10/2009 19 From CH(SC) transferred back to AH(RR) where pt stayed for 2 mths and was discharged on regular follow up with daily BP monitoring at MIR and weekly check up at MOPD

CH(SC) Jan2008 – Feb 2009 : 

CH(SC) Jan2008 – Feb 2009 10/10/2009 20 Posted to SC Admitted in Jan for evaluation Complaints : Headache, sweating, palpitations, tremulousness of hands Eval: BP : 210/130 mmHg Fine digital tremors present S/E: WNL

CH (SC)… : 

CH (SC)… 10/10/2009 21 Inv: Hemogram Boichemistry Lipid profile ECG WNL 24hrs urine proteins USG KUB 2DEcho

CH (SC)… : 

CH (SC)… 10/10/2009 22 Urine 24hrs Metanephrines : normal PRA : normal Thyroid profile: normal

CH (SC)… : 

CH (SC)… 10/10/2009 23 Coronary angio Renal angio CT Abdomen MRI Abdomen WNL MIBG Scan MRI Brain

CH (SC)… : 

CH (SC)… 10/10/2009 24 Rx T Enalapril 20 mg BD T Telmisartan 40 mg BD T Nifedipine 30 mg QID T Clonodine 200µg TDS T Minoxidil 5 mg BD T Metoprolol 150 mg BD T HCTZ 25 mg BD T Prazocin 10 mg BD Discharged in LMC

CH(SC) May2009 – till date : 

CH(SC) May2009 – till date 10/10/2009 25 Admitted with complaints of Swelling around eyes Exam BP 184 - 240/130 - 140 mm Hg Periorbital edema present S/E : NAD Possibilities Angioedema Cellulitis Drug rash

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10/10/2009 26 Rx T Enalapril 20 mg BD T Telmisartan 80 mg BD T Aliskarin 300 mg BD T Clonodine 200µg TDS T Minoxidil 10 mg BD T Metoprolol 150 mg BD T Aldomet 1 gm QID

discussion : 

discussion 10/10/2009 27

What is the “difficult patient”? : 

What is the “difficult patient”? 10/10/2009 28

The “Difficult Patient” : 

The “Difficult Patient” 10/10/2009 29 Resistant Hypertension Intolerant of Multiple Medicines

Definition of Hypertension : 

Definition of Hypertension 10/10/2009 JNC VII 30 Normal<= 120/80 Prehypertensive 120-139/80-89 Stage 1 Htn 140-159/90-99 Stage 2 Htn >= 160/100

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Blood pressure remaining above goal in spite of concurrent use of 3 antihypertensive agents of different classes. Ideally, 1 of the 3 agents should be a diuretic & all agents should be prescribed at optimal dose amounts. Resistant Hypertension 10/10/2009 31

What are the goals of therapy? : 

What are the goals of therapy? <140/90 for patients without diabetes or renal disease( Cr 1.5gm), proteinurea > 300 mg/24hr Most patients who achieve their systolic goal will also achieve their diastolic goal <130/80 for patients with diabetes or renal disease

What is the Benefit? : 

What is the Benefit? 10/10/2009 33 Number Needed to Treat to Prevent 1 Death Over 10 Years by Lowering Systolic Pressure by 12 mmHg in Stage 1 Hypertension: 11 In the Presence of CV Disease or Target Organ Damage the NNT falls to 9

What is the Benefit? : 

What is the Benefit? 10/10/2009 34 Stroke Incidence Reduction 35-40% Heart Failure Reduction > 50% Myocardial Infarction Reduction 20-25%

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Definition Highlights Use of diuretic recommended but not required before diagnosing resistant hypertension. Doses should be optimal but not necessarily maximal before diagnosing resistant hypertension. Controlled resistant hypertension: high blood pressure controlled but with use of 4 of more agents should be considered resistant. 10/10/2009 35

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Prevalence Prevalence is unknown, but observational and clinical trials suggest it is a common clinical problem. In a recent analysis of National Health and Nutrition Examination Survey (NHANES) participants being treated for hypertension, only 53% were controlled to <140/90 mm Hg. 1 Of NHANES participants with CKD, only 37% were controlled to <130/80 mm Hg2 and only 25% of diabetic participants were controlled to <130/85 mm Hg.1 1Hajjar I, Kotchen TA. JAMA 2003; 2Peralta CA et al. Hypertension 2005 10/10/2009 36

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10/10/2009 2Peralta CA et al. Hypertension 2005; 3Cushman WC et al. Clin Hypertens. 37 In the Antihypertensive and Lipid Lowering Treatment To Prevent Heart Attack Trial (ALLHAT) after nearly 5 years of treatment, 27% of 33,000 subjects had resistant hypertension² Based on the five-year observations in ALLHAT, the authors estimate that the incidence of refractory hypertension was approximately 15% In the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial in individuals older than 55 years, 18% had resistant hypertension³ In the Valsartan Anti hypertension long-term use evaluation (VALUE) trial, at least 15% of subjects had resistant hypertension after 30 months of therapy with three or more drugs

Patient Characteristics Associated with Resistant Hypertension : 

Patient Characteristics Associated with Resistant Hypertension High baseline blood pressure Older age Obesity Excessive dietary salt ingestion Chronic kidney disease Diabetes Left ventricular hypertrophy African American race Female gender 10/10/2009 38

Causes of Resistance to Hypertension Treatment : 

Causes of Resistance to Hypertension Treatment 10/10/2009 39 Poor adherence with prescribed medications Inaccurate blood pressure measurement White coat hypertension

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Approach to Resistant Hypertension : 

Approach to Resistant Hypertension Establish “true resistance” Measure BP accurately Consider “White Coat Hypertension” Consider “pseudoresistance” Consider secondary causes

Approach to Management of the Patient with Difficult-to-Control Hypertension : 

Approach to Management of the Patient with Difficult-to-Control Hypertension 10/10/2009 Circulation. 2008;117(25):e516. 42 Reiterate the importance of lifestyle modifications Make adherence to medication regimen as easy as possible Consider secondary causes Intensify pharmacologic therapy (should already be on three agents at moderate doses, usually a diuretic, an angiotensin converting enzyme inhibitor or angiotensin receptor blocker and a CCB or beta blocker)

Lifestyle Modifications to Manage Hypertension : 

Lifestyle Modifications to Manage Hypertension 10/10/2009 43

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Lifestyle Modifications Reduce weight to normal BMI (<25kg/m2): 5-20 mmHg/10kg loss DASH eating plan: 8-14 mmHg Dietary sodium reduction: 2-8 mmHg Increase physical activity: 4-9 mmHg Reduce alcohol consumption: 2- 4 mmHg

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DASH Diet Dietary Approaches to Stop Hypertension Emphasizes: Fruits, vegetables, low fat dairy foods, and reduced sodium intake Includes whole grains, poultry, fish, nuts Reduced amounts of red meat, sugar, total and saturated fat, and cholesterol Sacks FM et al: NEJM 344;3-10, 2001

Secondary causes of hypertension : 

Secondary causes of hypertension 10/10/2009 46

Rare Mendelian Forms of hypertension : 

Rare Mendelian Forms of hypertension 10/10/2009 47

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Moser M, Setaro J. N Engl J Med 2006;355:385-392

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Dickerson et al. Lancet 353:2008-11;1999

Drugs in our arsenel : 

Drugs in our arsenel 10/10/2009 53

: 

Antihypertensive Drugs Classification Diuretics Sympatholytics Vasodilators Agents affecting Renin Angiotensin System (RAS) Ca channel blockers

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Diuretics Used as initial therapy alone or in combination with drugs from other groups Adverse effects: renin secretion due to volume and Na depletion Thiazides: chlorothiazide, hydrochorothiazide Loop Diuretics: furosemide, bumetanide, ethacrynic acid Potassium sparing diuretics: spironolactone, triamterene, amiloride

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About Diuretics Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): Diuretics have been virtually unsurpassed in preventing the cardiovascular complications of hypertension. Diuretics enhance the antihypertensive efficacy of multidrug regimens, can be useful in achieving BP control, and are more affordable than other anti-hypertensive agents. Despite these findings, diuretics remain under-utilized.

Agents that affect adrenergic function : 

Agents that affect adrenergic function Agents that prevent adrenergic transmission (reserpine, guanethedine, guanadrel) Agents that act on the CNS (methyldopa, clonidine, guanabenz, guanfacine) Selective alpha-1 adrenergic receptor blockers (prazosin, terazosin, doxazosin) Beta-adrenergic blocking agents (propranolol and others) Mixed antagonists ( labetalol, carvedilol)

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a) Agents that prevent adrenergic transmission: Reserpine (Serpasil) Mechanism: depletes neurotransmitters (NE, DA, 5HT) in the storage vesicle of the central and peripheral nerve endings Main effects: depress SNS function centrally and peripherally  decreased HR, contractility and PVR Adverse effects: depression, insomnia, nightmares, ulcers, diarrhea, abdominal cramping, nasal stuffiness, orthostatic hypotension, dry mouth, impotence Pharmacokinetics: onset is slow and full effect is seen in weeks Use: infrequently

a) Agents that prevent adrenergic transmission: Guanethedine (Ismelin) : 

Mechanism: Depletes the nerve ending of NE in the periphery Main effects: decrease in PVR and decrease in HR  decrease in BP Adverse effects: Orthostatic hypotension, Na+ and water retention. Other side-effects similar to reserpine except the CNS effects Pharmacokinetics: Poorly absorbed from the G.I. Onset slow (1-2 weeks). Metabolites excreted in urine Use: Not used anymore because of severe side effects a) Agents that prevent adrenergic transmission: Guanethedine (Ismelin)

a) Agents that prevent adrenergic transmission: Guanadrel (Hylorel) : 

Mechanism and main effects Similar to guanethidine Adverse effects are less than gunethidine: less orthostatic hypotension, less diarrhea, less effect on sexual function. Pharmacokinetics: better absorption, rapid onset, shorter duration of action than guanethidine a) Agents that prevent adrenergic transmission: Guanadrel (Hylorel)

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b) Selective alpha-1 adrenergic receptor blockers (prazosin-Minipres, terazosin-Hytrin, doxazosin-Cardura) They favorably influence plasma lipid profile, and do not interfere with glucose metabolism. Mechanism: block 1 receptors in vasculature Main effects: decreased PVR  decrease BP Adverse effects: 1st dose phenomenon, fluid retention, dizziness, headache Pharmacokinetics: t1/2= 4.5, 12, 20, respectively Use: used in stage 1 and stage 2 HT in combination with a diuretic and a -blocker

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c) Beta-adrenergic blocking agents Classification Nonselective (1st generation) Cardioselective (b-1 selective, 2nd generation) b-blockers with intrinsic sympathomimetic activity (ISA) With additional CV actions (3rd generation) Proposed mechanisms: Block cardiac 1 receptors  lower CO Block renal 1 receptors  lower renin, lower PVR Decrease SNS output

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Non-Selective Propranolol Timolol (hydrophylic) *Pindolol *Penbutolol *Cartelol *Labetolol ( & ) Carvedilol ( & ) *Carteolol b1-Selective (in low dose) Metoprolol *Acebutolol Atenolol (hydrophylic) Betaxolol Bisoprolol (Diabetes and Asthma) Intrinsic (ISA) Pindolol Acebutolol Penbutolol Cartelol Labetolol ( & ) (Reynaud’s) *has ISA as well 3rd generation

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Propranolol (Inderal) Mechanism: Block cardiac 1 receptors  lower CO Block renal 1 receptors  lower renin, lower PVR Decrease SNS output Main effects: decrease HR and PVR Adverse effects: bradycardia, depression, 2 blockade in airways, glucose and lipid metabolism, vasocnstriction in extremities Pharmacokinetics: GI, 30-50% metabolized in the first-pass in liver. T1/2: 3-5 hours, Slow release propranolol available Use: used in stage 1 and 2 HT alone or in combinations with a diuretic and/or vasodilator Drug Interactions: verapamil, diltiazem, digitalis (caution AV Block)

Labetolol (Trandate) : 

Labetolol (Trandate) A combined alpha-1, beta-1, and beta-2 blocker. Beta blocking action is more prominent. It also has some ISA property. Can be given i.v. for hypertensive emergencies

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d) Agents that act on the CNS(a-methyldopa-Aldomet, clonidine- Catapres, guanabenz-Wytensin, guanfacine-Tenex) Favorable effect: lower PRA Mechanism: a-me-dopa metabolized to -me-norepinephrine, an -2 agonist, that suppresses SNS output from the CNS. Others are -2 agonist themselves. Main effects: decreases PVR and HR Adverse effects: sedation, drowsiness, dry mouth, impotence, bradycardia, withdrawal syndrome (rebound HT), false (+) Coombs’ antiglobulin test Pharmacokinetics: oral or parenteral, transdermal; T1/2 = 2, 10, 6, 14-17 h, respectively Use: stage 1 and 2 HT

Vasodilator DrugsCommon adverse effects: fall in BP  reflex tachycardia, also fall in BP  renin  Na/H2O retention : 

Vasodilator DrugsCommon adverse effects: fall in BP  reflex tachycardia, also fall in BP  renin  Na/H2O retention Calcium entry blockers (nifedipine and others) Potassium channel openers (minoxidil, diazoxide i.v., pinacidil) Direct acting vasodilators (hydralazine, Na-nitroprusside i.v.)

a) Calcium entry blockers(mechanism: inhibit Ca entry through L-type voltage gated channels) : 

a) Calcium entry blockers(mechanism: inhibit Ca entry through L-type voltage gated channels) Phenylalkylamines: verapamil Benzothiazepines: diltiazem Dihydropyridines: nifedipine, nicardapine, isradapine, felodopine, amlodipine

Nifedipine (Procardia) : 

Nifedipine (Procardia) Mech: selective blockade of vascular Ca channels Main effect: vasodilatation  lower PVR  lower BP Adverse effects: headache, flushing, nausea, ankle edema, dizziness, reflex tachycardia with short acting version (now have Procardia SR) (no reflex tachycardia with verapamil and diltiazem) Use: Hypertension (more effective in African-Americans), angina. Not useful as an antiarrhythmic drug

Verapamil and Diltiazem : 

Verapamil and Diltiazem Mechanism: Blockade of Ca channels in the vasculature, heart muscle and the AV node Main effects: same as nifedipine group Adverse effects: Similar to nifedipine except that they do not cause reflex tahycardia Drug interactions: Caution for AV block with beta blockers, and digitalis

b) Potassium channel openers (minoxidil, pinacidil) : 

b) Potassium channel openers (minoxidil, pinacidil) Mechanism: open K-channels of vascular smooth muscle cells  K-efflux  hyperpolarization  vasodilatation Main effect: vasodilation  lower PVR  lower BP Adverse effects: reflex tachycardia, Na and fluid retention, (minoxidil: hirsutism-Rogaine. Diazoxide: hyperuricemia, hyperglycemia –used in hypoglycemia) Use: Diazoxide i.v. in hypertensive emergencies

c) Direct acting vasodilators (Na-nitroprusside) : 

c) Direct acting vasodilators (Na-nitroprusside) Mechanism: metabolite is nitric oxide  cGMP. NO is a rapid acting venous and arteriolar vasodilator Main effect: vasodilation  lower PVR  lower BP Adverse Effects: Reflex tachycardia, severe hypotension, possible cyanide poisoning Pharmacokinetics: rapid acting, i.v. drip, short plasma half-life Use: Hypertensive emergencies

c) Direct acting vasodilators (hydralazine) : 

c) Direct acting vasodilators (hydralazine) Mechanism: Direct vasodilator of arterioles Main effect: vasodilation  lower PVR  lower BP Adverse effects: reflex tachycardia, Na retention, hirsutism, lupus–like syndrome Pharmacokinetics: oral, slow onset Use: with a beta blocker and a diuretic

Agents that affect RAS : 

Agents that affect RAS a) ACE inhibitors captopril, enalapril, lisinopril b) Angiotensin II receptor blockers (ARB) losartan, valsartan, irbesartan

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a) ACE inhibitors (captopril-Capoten, enalapril-Vasotec, lisinopril-Privinil, rampiril-Altace)No adverse effects on plasma lipids, glucose, sexual function. Drug of choice in diabetes-related early stage proteinuria. Contraindicated in pregnancy. Not as effective in African-Americans Mechanism: inhibit ACE  low circulating Ang II  decreased PVR Main effects: decreased PVR  decreased BP Adverse effects: skin rash, taste, cough, hyperkalemia Pharmacokinetics: T1/2 = 3, 11, 12, respectively Use: used in stage 1 and 2 HT; also for congestive heart failure

b) Angiotensin II receptor blockers (ARB) (losartan-Coozar, valsartan-Diovan, irbesartan-Avapro) : 

b) Angiotensin II receptor blockers (ARB) (losartan-Coozar, valsartan-Diovan, irbesartan-Avapro) Mechanism: selectively block Ang II AT-1 receptor  decrease PVR  decrease BP Adverse effects: No Cough, very few adverse similar to ACE inhibitors

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BP  BV  Na+ depletion NE release from nerve ending RENIN RELEASE BP  BV  Na+ retention + - Vasoconstriction Aldosterone secretion Angiotensin release + + + + + + +

Pheochromocytoma : 

Pheochromocytoma 10/10/2009 78

Presentation : 

Presentation 10/10/2009 79 Pheochromocytomas and paragangliomas are catecholamine-producing tumors derived from the sympathetic (e.g., adrenal medulla) or parasympathetic (e.g., carotid body, glomus vagale) nervous system. Incidence:2–8 out of 1 million persons per year 0.1% of hypertensive patients harbor a pheochromocytoma The mean age at diagnosis is about 40 years, although the tumors can occur from early childhood until late in life

Clinical features : 

Clinical features 10/10/2009 80

Diagnosis : 

Diagnosis 10/10/2009 81

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Drugs acting on therenin-angiotensin systemBrown MJ. Matching the right drug to the right patient. Heart 2001;86:113-120. : 

Drugs acting on therenin-angiotensin systemBrown MJ. Matching the right drug to the right patient. Heart 2001;86:113-120. Angiotensinogen AI AII Renin arteries kidneys adrenal glands Aldosterone

Drugs acting on therenin-angiotensin systemBrown MJ. Matching the right drug to the right patient. Heart 2001;86:113-120. : 

Drugs acting on therenin-angiotensin systemBrown MJ. Matching the right drug to the right patient. Heart 2001;86:113-120. Angiotensinogen AI AII Renin arteries kidneys adrenal glands Aldosterone

AB/CD Rule for optimisation of antihypertensive treatment : 

AGE Younger (<55) Older (>55) AB/CD Rule for optimisation of antihypertensive treatment Dickerson et al. Lancet 353:2008-11;1999

Problems?? : 

Problems?? Etiology ? Treatment?

thanks : 

thanks 10/10/2009 88