Robert C Orchard MD...Specific alpha-1 blockers like prazosin, terazosin and doxazosine are used !...
Transcript of Robert C Orchard MD...Specific alpha-1 blockers like prazosin, terazosin and doxazosine are used !...
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Robert C Orchard MD
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Types of Hypertension
Essential Secondary
A disorder of unknown origin affecting the Blood Pressure regulating mechanisms Secondary to other disease processes
Environmental Factors
Stress Na+ Intake Obesity Smoking
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Normal Blood Pressure Regulation ! Hydraulic equation: Blood Pressure = Cardiac output (CO) X
Resistance to passage of blood through precapillary arterioles (PVR)
! Physiologically CO and PVR is maintained minute to minute by – arterioles (1) postcapillary venules (2) and Heart (3)
! Kidney is the fourth site – volume of intravascular fluid
! Baroreflex, humoral mechanism and renin-angiotensin- aldosterone system regulate the above 4 sites
! Local agents like Nitric oxide ! In hypertensives – Baroreflex and
renal blood-volume control system – set at higher level
! All anti-hypertensives act via interfering with normal mechanisms
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Antihypertensive Drugs
! Diuretics: ! Thiazides: Hydrochlorothiazide, chlorthalidone ! High ceiling: Furosemide ! K+ sparing: Spironolactone,eplerenone, triamterene and
amiloride MOA: Acts on Kidneys to increase excretion of Na and H2O –
decrease in blood volume – decreased BP ! Angiotensin-converting Enzyme (ACE) inhibitors:
! Captopril, lisinopril., enalapril, ramipril, fosinopril etc MOA: Inhibit synthesis of Angiotensin II – decrease in peripheral
resistance and blood volume ! Angiotensin (AT1) blockers:
! Losartan, candesartan, valsartan, telmisartan etc MOA: Blocks binding of Angiotensin II to its receptors
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Antihypertensive Drugs ! Centrally acting:
! Clonidine, methyldopa
MOA: Act on central α2A receptors to decrease sympathetic outflow – fall in BP
! ß-adrenergic blockers: ! Non selective: Propranolol (others: nadolol, timolol, pindolol,
labetolol) ! Cardioselective: Metoprolol (others: atenolol, esmolol, betaxolol)
MOA: Bind to beta adrenergic receptors and blocks the activity ! ß and α – adrenergic blockers:
! Labetolol, Bisoprolol and carvedilol ! α – adrenergic blockers:
! Prazosin, terazosin, doxazosin, phenoxybenzamine and phentolamine
MOA: Blocking of alpha adrenergic receptors in smooth muscles - vasodilatation
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Antihypertensive Drugs – ! Calcium Channel Blockers (CCB):
! Verapamil, diltiazem, nifedipine, felodipine, amlodipine, nicardipine etc.
MOA: Blocks influx of Ca++ in smooth muscle cells – relaxation of SMCs – decrease BP
! K+ Channel activators: ! Diazoxide, minoxidil
MOA: Leaking of K+ due to opening – hyper polarization of SMCs – relaxation of SMCs . Causes increased Beta adrenergic mediated renin production and fluid retention therefore usually given with BB and diuretic.
! Vasodilators: ! Arteriolar – Hydralazine (also CCBs and K+ channel
activators) ! Arterio-venular: Sodium Nitroprusside
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Diuretics
! Drugs causing net loss of Na+ and water in urine ! Mechanism of antihypertensive action:
! Initially: diuresis – depletion of Na+ and body fluid volume – decrease in cardiac output
! Subsequently after 4 - 6 weeks, Na+ balance and CO is regained by 95%, but BP remains low!
! Q: Why? Answer: reduction in total peripheral resistance (TPR) due to deficit of amount of Na+ and water (Na+ causes vascular stiffness)
! Similar effect is seen with sodium restriction (low sodium diet)
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Thiazide diuretics – adverse effects ! Adverse Effects:
! Hypokalaemia – muscle pain and fatigue ! Hyperglycemia: Inhibition of insulin release due to K+
depletion (proinsulin to insulin) – precipitation of diabetes
! Hyperlipidemia: rise in total LDL level – risk of stroke ! Hyperurecaemia: inhibition of urate excretion ! Sudden cardiac death – tosades de pointes
(hypokalaemia) ! All the above metabolic side effects – higher doses (50
– 100 mg per day) ! But, its observed that these adverse effects are
minimal with low doses (12.5 to 25 mg) - Average fall in BP is 10 mm of Hg
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Thiazide diuretics – current status ! Effects of low dose:
! No significant hypokalaemia ! Low incidence of arrhythmia ! Lower incidence of hyperglycaemia, hyperlipidemia and
hyperuricaemia ! Reduction in MI incidence ! Reduction in mortality and morbidity
! JNC recommendation: ! JNC recommends low dose of thiazide therapy (12.5 – 25
mg per day) in essential hypertension ! Preferably should be used with a potassium sparing diuretic
in elderly ! If therapy fails – another antihypertensive but do not
increase the thiazide dose ! Loop diuretics are to be given when there is hypertension
with marked fluid retention
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Chlorthalidone vs HCTZ
! Chlorthalidone recommended ! More potent thiazide and longer duration of
action. ! Head to head trials better BP lowering by 4-5
mmHg. ! Watch for hypokalemia.
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Diuretics ! K+ sparing diuretics: ! Spironolactone, Eplerenone, Triamterene
! Thiazide and K sparing diuretics are combined therapeutically – (triamterene + HCTZ) is popular one
! Modified thiazide: indapamide ! Indole derivative and long duration of action (18 Hrs) –
orally 2.5 mg dose ! It is a lipid neutral i.e. does not alter blood lipid
concentration, but other adverse effects may remain ! Loop diuretics:
! Na+ deficient state is temporary, not maintained round –the-clock and t.p.r not reduced
! Used only in complicated cases – CRF, HTN marked fluid retention cases
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Angiotensin Converting Enzyme (ACE) Inhibitors
What is Renin - Angiotensin? (Physiological Background)
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RAS - Introduction ! Renin is a proteolytic enzyme and also called
angiotensinogenase ! It is produced by juxtaglomerular cells of kidney ! It is secreted in response to:
! Decrease in arterial blood pressure ! Decrease Na+ in macula densa ! Increased sympathetic nervous activity
! Renin acts on a plasma protein – Angiotensinogen (a glycoprotein synthesized and secreted into the bloodstream by the liver) and cleaves to produce a decapeptide Angiotensin-I
! Angiotensin-I is rapidly converted to Angiotensin-II (octapeptide) by ACE (present in luminal surface of vascular endothelium)
! Furthermore degradation of Angiotensin-II by peptidases produce Angiotensin-III
! Both Angiotensin-II and Angiotensin-III stimulates Aldosterone secretion from Adrenal Cortex (equipotent)
! AT-II has very short half life – 1 min
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RAS - Physiology
Vasoconstriction Na+ & water retention
(Adrenal cortex)
Kidney
Increased Blood Vol.
Rise in BP
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RAS – actions of Angiotensin-II. 1. Powerful vasoconstrictor particularly arteriolar – direct action and
release of Adr/NA 2. Aldosterone secretion stimulation – retention of Na++ in body 3. Vasoconstriction of renal arterioles – rise in IGP – glomerular damage 4. Decreases NO release 5. Decreases Fibrinolysis in blood 6. Induces drinking behavior and ADH release by acting in CNS –
increase thirst 7. Mitogenic effect – cell proliferation
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Angiotensin-II ! What are the ill effects of chronic excess?
! Volume overload and increased t.p.r ! Cardiac hypertrophy and remodeling ! Coronary vascular damage and remodeling
! Hypertension – long standing will cause ventricular hypertrophy
! Myocardial infarction – hypertrophy of non-infarcted area of ventricles
! Renal damage ! Risk of increased CVS related morbidity and mortality
! ACE inhibitors reverse cardiac and vascular hypertrophy and remodeling
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ACE inhibitors
! Captopril, lisinopril., enalapril, ramipril and fosinopril etc.
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ACE inhibitors in Hypertension Captopril ! Sulfhydryl containing dipeptide and abolishes
pressor action of Angiotensin-I and not Angiotensin-II and does not block AT receptors
! Pharmacokinetics: ! Available only orally, 70% - 75% is absorbed ! Partly absorbed and partly excreted
unchanged in urine ! Food interferes with its absorption ! Half life: 2 Hrs, but action stays for 6-12 Hrs
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Captopril – Pharmacological actions
1. In Normal: ! Depends on Na+ status – lowers BP marginally on single dose ! When Na+ depletion – marked lowering of BP
2. In hypertensive: ! Lowers PVR and thereby mean, systolic and diastolic BP ! RAS is overactive in 80% of hypertensive cases and contributes
to the maintenance of vascular tone – inhibition causes lowering of BP
! Initially correlates with renin-angiotensin status but chronic administration is independent of renin activity
! Captopril decreases t.p.r on long term – arterioles dilate – fall in systolic and diastolic BP
! No effect on Cardiac output ! Postural hypotension is not a problem - reflex sympathetic
stimulation does not occur ! Renal blood flow is maintained – greater dilatation of vessels
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Captopril – Adverse effects ! Cough – persistent brassy cough in 20% cases – inhibition of
bradykinin and substanceP breakdown in lungs ! Hyperkalemia in renal failure patients with K+ sparing diuretics,
NSAID and beta blockers (routine check of K+ level) ! Hypotension – sharp fall may occur – 1st dose ! Acute renal failure: CHF and bilateral renal artery stenosis ! Angioedema: swelling of lips, mouth, nose etc. ! Rashes, urticaria etc ! Dysgeusia: loss or alteration of taste ! Foetopathic: hypoplasia of organs, growth retardation etc ! Neutripenia ! Contraindications: Pregnancy, bilateral renal artery stenosis,
hypersensitivity and hyperkalaemia
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ACE inhibitors - Enalapril ! It’s a prodrug – converted to enalaprilate ! Advantages over captopril:
! Longer half life – OD (5-20 mg OD) ! Absorption not affected by food ! Rash and loss of taste are less frequent ! Longer onset of action but still BID ! Less side effects
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ACE inhibitors – Ramipril
! It’s a popular ACEI now ! It is also a prodrug with long half life ! Tissue specific – Protective of heart and
kidney ! Uses: Diabetes with hypertension, CHF, AMI
and cardio protective in angina pectoris ! Blacks in USA are resistant to Ramipril –
addition of diuretics help ! Dose: Start with low dose; 2.5 to 10 mg daily
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ACE inhibitors – Lisinopril
! It’s a lysine derivative ! Not a prodrug ! Slow oral absorption – less chance of 1st dose
phenomenon ! Absorption not affected by food and not
metabolized – excrete unchanged in urine ! Long duration of action – single daily dose ! Doses: available as 1.25, 2.5, 5, 10 1nd 20
mg tab – start with low dose
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ACE inhibitors and hypertension ! 1st line Drug:
! No postural hypotension or electrolyte imbalance (no fatigue or weakness)
! Safe in asthmatics and diabetics ! Prevention of secondary hyperaldosteronism and K+
loss. May moderate K loss with diurertics ! Renal perfusion well maintained ! Reverse the ventricular hypertrophy and increase in
lumen size of vessel ! No hyperuraecemia or deleterious effect on plasma
lipid profile ! No rebound hypertension ! Minimal worsening of quality of life – general wellbeing,
sleep and work performance etc.
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ACE inhibitors – other uses
! Hypertension ! Congestive Heart Failure ! Myocardial Infarction ! Prophylaxis of high CVS risk subjects ! Diabetic Nephropathy ! Schleroderma crisis
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Angiotensin Receptor Blockers (ARBs) - Angiotensin Receptors: ! Specific angiotensin receptors have been discovered, grouped
and abbreviated as – AT1 and AT2 ! They are present on the surface of the target cells ! Most of the physiological actions of angiotensin are mediated
via AT1 receptor ! Transducer mechanisms of AT1 receptors: In different tissues
show different mechanisms. For example - ! PhospholipaseC-IP3/DAG-intracellular Ca++ release
mechanism – vascular and visceral smooth muscle contraction
! In myocardium and vascular smooth muscles AT1 receptor mediates long term effects by MAP kinase and others
! Losartan is the specific AT1 blocker
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Angiotensin Receptor Blockers (ARBs) - Losartan ! Competitive antagonist of AT1 receptor ! Does not block AT2 receptor. ! Blocks all the actions of A-I - vasoconstriction,
sympathetic stimulation, aldosterone release and renal actions of salt and water reabsorption
! No inhibition of ACE
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Losartan ! Pharmacokinetic:
! Absorption not affected by food but unlike ACEIs its bioavailability is low
! High first pass metabolism ! Carboxylated to active metabolite E3174 ! Highly bound to plasma protein ! Do not enter brain ! Slightly less BP drop vs other ARB’s
! Adverse effects: ! Foetopathic like ACEIs – not to be administered in
pregnancy ! Rare 1st dose effect hypotension ! Low dysgeusia and dry cough ! Lower incidence of angioedema
! Available as 25, 50 and 100 mg tablets
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Beta-adrenergic blockers ! Non selective: Propranolol (others: nadolol, timolol, pindolol,
labetolol) ! Cardioselective: Metoprolol (others: atenolol, esmolol,
betaxolol) ! All beta-blockers similar antihypertensive effects – irrespective of
additional properties
! Reduction in CO but no change in BP initially but slowly ! Adaptation by resistance vessels to chronically reduced CO –
antihypertensive action ! Other mechanisms – decreased renin release from kidney (beta-1
mediated) ! Reduced NA release and central sympathetic outflow reduction ! Non-selective ones – reduction in g.f.r but not with selective ones ! Drugs with intrinsic sympathomimetic activity may cause less
reduction in HR and CO
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Beta-adrenergic blockers ! Advantages:
! No postural hypotension ! No salt and water retention ! Low incidence of side effects ! Low cost ! Once a day regime ! Preferred in young non-obese patients, prevention of sudden
cardiac death in post infarction patients and progression of CHF
! Drawbacks (side effects): ! Fatigue, lethargy (low CO?) – decreased work capacity ! Loss of libido – impotence ! Cognitive defects – forgetfulness ! Difficult to stop suddenly ! Therefore cardio-selective drugs are preferred now
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Beta-adrenergic blockers ! Advantages of cardio-selective over non-selective:
! In asthma ! In diabetes mellitus ! In peripheral vascular disease
! Current status: ! Preferred in young non-obese hypertensive ! Angina pectoris and post angina patients ! Post MI patients – useful in preventing mortality ! In old persons, carvedilol – vasodilatory action
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Αlpha-adrenergic blockers ! Non selective alpha blockers are not used in chronic
essential hypertension (phenoxybenzamine, phentolamine), only used sometimes as in phaechromocytoma
! Specific alpha-1 blockers like prazosin, terazosin and doxazosine are used
! PRAZOSIN is the prototype of the alpha-blockers ! Reduction in t.p.r and mean BP – also reduction in
venomotor tone and pooling of blood – reduction in CO
! Does not produce tachycardia as presynaptic auto (alpha-2) receptors are not inhibited – autoregulation of NA release remains intact
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Αlpha-adrenergic blockers. ! Adverse effects:
! Prazosin causes postural hypotension – start 0.5 mg at bed time with increasing dose and upto 10 mg daily
! Fluid retention in monotherapy ! Headache, dry mouth, weakness, dry mouth, blurred vision,
rash, drowsiness and failure of ejaculation in males ! Current status:
! Several advantages – improvement of carbohydrate metabolism – diabetics, lowers LDL and increases HDL, symptomatic improvement in BHP
! But not used as first line agent, used in addition with other conventional drugs which are failing – diuretic or beta blocker
! Doses: Available as 0.5 mg, 1 mg, 2.5 mg, 5 mg etc. dose:1-4 mg thrice daily (Minipress/Prazopress)
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Calcium Channel Blockers - Classification
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Calcium Channel Blockers – Mechanism of action ! Three types Ca+ channels in smooth muscles – Voltage
sensitive, receptor operated and leak channel ! Voltage sensitive are again 3 types – L-Type, T-Type and N-
Type ! Normally, L-Type of channels admit Ca+ and causes
depolarization – excitation-contraction coupling through phosphorylation of myosin light chain – contraction of vascular smooth muscle – elevation of BP
! CCBs block L-Type channel: ! Smooth Muscle relaxation ! Negative chronotropic, ionotropic and chronotropic effects in heart
! DHPs have highest smooth muscle relaxation and vasodilator action followed by verapamil and diltiazem
! Other actions: DHPs have diuretic action
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Calcium Channel Blockers
! Advantages: ! Unlike diuretics no adverse metabolic effects but
mild adverse effects like – dizziness, fatigue etc. ! Do not compromise haemodynamics – no
impairment of work capacity ! No sedation or CNS effect ! Can be given to asthma, angina and PVD patients ! No renal and male sexual function impairment ! No adverse fetal effects and can be given in
pregnancy ! Minimal effect on quality of life
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Calcium Channel Blockers – current status ! JNC 8 now recommends as 1st line therapy. ! However its also used as 1st line by many because of
excellent tolerability and high efficacy ! Preferred in elderly and prevents stroke ! CCBs are effective in low Renin hypertension ! They are next to ACE inhibitors in inhibition of
albuminuria and prevention of diabetic nephropathy ! Immediate acting Nifedipine is not encouraged
anymore
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Calcium Channel Blockers
! Contraindications: ! Unstable angina ! Heart failure ! Hypotension ! Post infarct cases ! Severe aortic stenosis
! Preparation and dosage: ! Amlodipine – 2.5, 5 and 10 mg tablets (5-10 mg
OD)
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Vasodilators - Hydralazine ! Directly acting vasodilator ! MOA: hydralazine molecules combine with receptors in the
endothelium of arterioles – NO release – relaxation of vascular smooth muscle – fall in BP
! Subsequenly fall in BP – stimulation of adrenergic system leading to ! Cardiac stimulation producing palpitation and rise in CO even in
IHD and patients – anginal attack ! Tachycardia ! Increased Renin secretion – Na+ retention ! These effects are countered by administration of beta blockers and
diuretics ! Uses: 1) Moderate hypertension when 1st line fails – with beta-blockers
and diuretics 2) Hypertension in Pregnancy, Dose 25-50 mg OD
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Vasodilators - Minoxidil ! Powerful vasodilator, mainly 2 major uses – antihypertensive
and alopecia ! Prodrug and converted to an active metabolite which acts by
hyperpolarization of smooth muscles and thereby relaxation of SM – leading to hydralazine like effects
! Rarely used in hypertension due to side effects except in renal patients.
! More often in alopecia to promote hair growth ! Topically as 2-5% lotion/gel and takes months to get effects !
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Sodium Nitroprusside ! Rapidly and consistently acting vasodilator ! Relaxes both resistance and capacitance vessels and reduces
t.p.r and CO (decrease in venous return) ! Unlike hydralazine it produces decrease in cardiac work and no
reflex tachycardia. ! Improves ventricular function in heart failure by reducing preload ! MOA: RBCs convert nitroprusside to NO – relaxation also by
non-enzymatically to NO by glutathione ! Uses: Hypertensive Emergencies, 50 mg is added to 500 ml of
saline/glucose and infused slowly with 0.02 mg/min initially and later on titrated with response (wrap with black paper)
! Adverse effects: All are due release of cyanides (thiocyanate) – palpitation, pain abdomen, disorientation, psychosis, weakness and lactic acidosis.
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Centrally acting Drugs ! Alpha-Methyldopa: a prodrug
! Precursor of Dopamine and NA ! MOA: Converted to alpha methyl noradrenaline which acts
on alpha-2 receptors in brain and causes inhibition of adrenergic discharge in medulla – fall in PVR and fall in BP
! Various adverse effects – cognitive impairement, postural hypotension, positive coomb`s test etc. – Not used therapeutically now .
! Clonidine: Imidazoline derivative, partial agonist of central alpha-2 receptor ! Not frequently used now because of tolerance and
withdrawal hypertension
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Direct Renin Inhibitors
! Aliskerin- 150 mg-300mg once daily ! No dosage adjustment in ESRD ! Avoid in combination with ARB/ACE-I as
causes hyperkalemia. ! No clinical benefit for proteinuria in diabetics ! Use as 3rd line agent in patients intolerant to
ACE-I or ARB.
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NEW MEDS -ENTRESTO
! Entresto (sacubitril/valsartan) ! ARB and Neprilysin inhibitor ! Both inhibits vasoconstriction and stimulates
vasodilatation. ! Potent vasodilator ! Now in clinical trials
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Treatment of Hypertension: classification Categories
BP Systolic Diastolic Normal <120 <80
Elevated >130 >80 Stage1 130-139 80-89 Stage2 >140 >90
Risk factors 1. Age above 55 and 65 in
Men and Woman respectively
2. Family History 3. Smoking 4. DM and Dyslipidemia 5. Hypertension 6. Obesity 7. Microalbuminuria
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What’s New in Meds
! When to start- ACC/AHA 2017 Guidelines-HTN defined as >130/80.
! Use of ASCVD-Risk-Estimator in Stage 1 hypertension. >10% 10 year risk start with meds and lifestyle changes.
! Initial agents from 4 Classes-ACE-I, ARB, Ca Blockers and Thiazide type diuretics. BB no longer recommended as first line.
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SPRINT TRIAL
! 9361 patients with systolic BP 130-180 and high CVS risk assigned to BP target of 120 mmHg vs 140 mmHg.
! Trial stopped early 3.3 years for demonstrated benefit of composite outcome and mortality (hazard ratio 0.75 and 0.73 respectively).
! 2.8 drugs vs 1.8 drugs ! Increased risk of hypotension, syncope,
electrolyte abnormalities and ARI.
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HS dosing
! Increasing use of HS dosing. ! Better 24 hour coverage ! Coverage of early morning stress period-
circadian rhythm. ! Fewer side effects that giving all meds in AM.
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Increased Recognition of Spironolactone Benefit ! Resistant hypertension ! Hypertension/Sleep apnea/Obesity triad. ! Hypertension in LV dysfunction. ! Antiarrhythmic effect- atrial fibrillation and
ventricular fibrillation.
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Low dose spironolactone in resistant hypertension
! 76 patients 34 of whom had primary aldosteronism.12.5 to 25 mg spironolactone.
! Drug regimes include a diuretic and ACE inhibitor or angiotensin receptor blocker.
! Low dose spironolactone associated with additional main decrease in BP of 21/10 mmHg at 6 weeks and 25/12 mm Hg at 6 months.
! Blood pressure reduction similar with and without primary aldosteronism.
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Spironolactone
! Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm-1411 patients-.
! Spironolactone administered as additional antihypertensive therapy to patients with continued hypertension (157/85) despite three drugs.
! Mean blood pressure decrease was 22/10 with spironolactone (mean dose 25 mg).
! Particularily effective in older obese patients.
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Obesity, sleep apnea and hypertension.
! Strong association. ! OSA results in persistently increased sympathetic
activity. ! Studies suggest an important adipose tissue depot
linking obesity with sympathetic neural activation is abdominal visceral fat.
! May have selective renal sympathetic activation mediating sodium retention and hypertension.
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OSA, obesity and hypertension
! Renin angiotensin system activated in obesity. Positive correlation between BMI and plasma aldosterone levels, angiotensinogen levels, plasma renin activity.
! OSA may be associated with significantly higher levels of angiotensin II and aldosterone compared with healthy control subjects.
! Significant correlation between aldosterone levels and daytime blood pressure.
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Combination Meds
! Compliance rates: ! - 79% one daily dose ! - 69% two doses ! - 65% three doses ! - 51% four doses
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Treatment of Hypertension –
! compelling Indications: ! Heart failure ! Coronary artery disease ! H/o MI ! H/o stroke ! Diabetes ! Chronic Renal failure
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Treatment of Hypertension – General principles ! Stage I:
! Initial therapy should include Thiazide diuiretic,CCB and ACE-I or ARB either alone or in combination – CCB in case of elderly and stroke prevention. If required increase the dose moderately
! Partial response or no response – add from another group of drug, but remember it should be a low dose combination
! If not controlled – change to another low dose combination
! In case of side effects lower the dose or substitute with other group
! Stage 2: Start with 2 drug combination –normally one should be diuretic. Also consider ACE-I/Amlodipine combination (Accomplish trial).
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ACE-I/ ARB and Diuretic synergism ! ACE-I and ARB as monotherapy may cause
reflex fluid retention. ! Diuretic as monotherapy may cause
hypovolemia-induced increase in renin and therefore angiotensin II therefore limiting effect.
! While ACE-I are ineffective in black patients the addition of even a small dose of a diuretic to ACE-I leads to BP drop comparable to that seen in white patients.
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Approach to treatment
! If patient is receiving 3 drugs including a diuretic, at full doses:
! Limit sodium consumption ! Use a diuretic specific to the patient’s renal
status ! Serum creatinine< 1.5 consider thiazide
diuretic. Serum creatinine> 1.5 consider loop diuretic
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Approach to treatment contd.
! Consider an aldosterone inhibitor – spironolactone or eplerenone. Follow serum potassium level carefully used with ACE I or ARB.
! Consider changing beta blocker to alpha/beta blocker.
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Treatment contd. ! If still resistant: ! Heart rate lowering agents – beta-blockers or
non-dihydropyridine CCB’s such as diltiazem and verapamil.
! Diuretics – If on HCTZ try Chlorthalidone ! Always try to use different MOA drug:If
receiving ACE I or ARB + diuretic plus beta-blocker, add dihydropyridine CCB or if receiving ACE I or ARB + diuretic + dihydropyridine calcium channel blocker, add beta-blocker.
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Treatment contd.
! If still resistant and heart rate greater than 55 add diltiazem or verapamil.
! If still resistant and heart rate less than 55 add an additional vasodilators such as an alpha blocker.
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If still resistant, further actions:
! Add centrally acting agent – clonidine tablet or weekly patch.
! Begin direct vasodilators – hydralazine with adjunctive beta-blocker and loop diuretic to offset reflex tachycardia and edema, or minoxidil ( also requiring beta blockers and loop diuretics with difficulty use in women because of hirsuit effects).
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Treatment contd.
! If still resistant, consult with a hypertension specialist.
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Treatment of Hypertension – combination therapy
! In clinical practice a large number of patients require combination therapy – the combination should be rational and from different patterns of haemodynamic effects
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Treatment of Hypertension.
! Never combine: ! ACE-I and ARB or ACEI/ARB and Direct Renin
Inhibitor ! Alpha or beta blocker and clonidine - antagonism ! Hydralazine with DHP or prazosin – same type of
action ! ACE-I and BB-similar MOA-reduced renin and AT II ! Diltiazem and verapamil with beta blocker –
bradycardia ! Hypertension and pregnancy:
! No drug is safe in pregnancy ! Avoid diuretics, propranolol, ACE inhibitors, Sodium
nitroprusside etc ! Safer drugs:Dihydropyridine CCB, Hydralazine,,
cardioselective beta blockers and prazosin
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Hypertensive Emergencies ! Cerebrovascular accident or head injury with high BP ! Left ventricular failure with pulmonary edema due to
hypertension ! Hypertensive encephalopathy ! Angina or MI with raised BP ! Acute renal failure with high BP ! Eclampsia ! Pheochromocytoma, cheese reaction and clonidine withdrawal ! Drugs:
! Nicardipine 5-15mg/hour infusion. I avoid nitroprusside. ! GTN (5-20 mcg/min) – cardiac surgery, LVF, MI and angina ! Esmolol (0.5 mg/kg bolus) and 50-200mcg/kg/min - useful in
reducing cardiac work ! Phentolamine – pheochromocytoma, cheese reaction and clonidine
withdrawal (5-10 mg IV)
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Hypertensive Emergencies
! Nitroglycerine 5-100 ug/min ! Nicardipine 5-15 mg/hour ! Esmelol 250-500 ug/kg/min ! Labetolol 20-80 mg bolus ! Enalaprilat 1.25-5mg IV ( Only IV ACE-I) ! Sodium Nitroprusside 0.25-10 ug/kg/min
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Specific Populations
! Black population-including those with diabetes-thiazide diuretic or CCB.
! CKD-Initial or add on should include ACE-I or ARB
! Elderly- CCB, Thiazide diuretic or ARB.
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CASE ! 66 year old “retired” Lehman Brothers stockbroker
visits physician’s office on the 31st of the month, complaining that his home blood pressure one jumps to around 190/100 mmHg just before breakfast and declines only after 11 a.m., typically running around 130-138/84-88 mmHg in the afternoon and evening.
! He has had hypertension for 20 years and dyslipidemia for 10 years, both of which were well controlled before he was restricted to drugs on the four dollar per month formulary.
! His current medications include: Furosemide 20 mg, atenolol 100 mg, enalapril 20 mg and pravastatin 40 mg all with breakfast around 7 a.m.
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Social History
! Since his divorce 8 months ago, he eats oatmeal for breakfast, a salami/cheese sandwich for lunch and a Weight Watchers entrée for dinner after the evening news.
! He abstains from alcohol and has never used tobacco or illicit drugs.
! Labs drawn yesterday at 9 a.m. included: Serum potassium of 3.7 mEq/liter, BUN/creatinine of 22/1.3 mg/dL (GFR equals 59 ML/minute/1.73 m2), and an LDL cholesterol of 138 mg/dL.
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Physical Examination ! 240 pounds on a 6-foot frame. BMI equals 32.6 kg/
m2. ! His blood pressure and pulse rates in the office at
8:30 a.m. were: ! -194/102 mmHg and 92 beats/minute right arm
seated. ! -196/106 mmHg and 92 beats/minute left arm
seated. ! -188/100mmHg right arm seated and 92 beats/
minute. ! The rest of the physical examination is unremarkable.
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Recommendations
! 2000 mg/d Sodium Diet. ! Swap furosemide for chlorthalidone 12.5 mg/
d. ! Swap atenolol 100 mg/d for nadolol 40 mg/d. ! Swap enalapril 20 mg/d for benazapril 40 mg/
d. ! Take pravastatin between dinner and
bedtime. ! Review 4 weeks.
! Four-week follow-up – home BPs all <135/85, office BP 132/82 mmHg.
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