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Drugs in HypertensionDrugs in HypertensionDrugs in HypertensionDrugs in Hypertensiong ypg ypg ypg yp

Dr. Yuri Clement Dr. Yuri Clement Pharmacology Unit, FMSPharmacology Unit, FMS

Objectives Objectives Objectives Objectives Revision of physiological control of BP.Revision of physiological control of BP.

What is hypertension? Associated risks of uncontrolled hypertensionWhat is hypertension? Associated risks of uncontrolled hypertension

ANTIHYPERTENSIVE DRUGS: ANTIHYPERTENSIVE DRUGS:

1.1. Sympathetic Nervous System inhibitionSympathetic Nervous System inhibitionββ--blockers, blockers, αα11 blockers, mixed blockers, mixed αα, , ββ blockers, central blockers, central αα agonists, agonists, peripheral adrenergic blockers.peripheral adrenergic blockers.

2.2. Sodium/Renin Angiotensin Aldosterone System balanceSodium/Renin Angiotensin Aldosterone System balance2.2. Sodium/Renin Angiotensin Aldosterone System balanceSodium/Renin Angiotensin Aldosterone System balanceDiuretics, ACE inhibitors, AT11 receptors blockersDiuretics, ACE inhibitors, AT11 receptors blockers

3.3. Vasodilators Vasodilators CaCa2+2+--channel blockers, oral and parenteral vasodilators channel blockers, oral and parenteral vasodilators

Mechanisms of action, other indications, contraindications and adverse effectsMechanisms of action, other indications, contraindications and adverse effects

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Hemodynamic factors affecting BPHemodynamic factors affecting BPHemodynamic factors affecting BPHemodynamic factors affecting BP

Arterial Blood Arterial Blood Pressure Pressure

Cardiac OutputCardiac Output(CO)(CO)

Total Peripheral Total Peripheral Resistance (TPR)Resistance (TPR)≈ x

Arteriolar volume

Contractility Heart rate

Filling pressureBlood volume

Venous tone

Arteriolar volume

BP Regulation:BP Regulation:SNS and RAAS SNS and RAAS

↑ th ti↑β1 receptor

cardiac activation↑ CO

Baroreceptor reflex system mediatedBaroreceptor reflex system mediated

↑sympathetic activity

cardiac activation

↑α1 receptor smooth muscle activation ↑ TPR

↑ BP

↓ BP

↑

Renal blood volumeRenal blood volume--pressure systempressure system

↓ Renal flow ↑ renin ↑ Angiotensin II

↓GFR ↑Na+, H2O retention ↑ Blood volume

↑Aldosterone

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What is hypertension? What is hypertension? What is hypertension? What is hypertension? JNC 6 CategoryJNC 6 Category JNC 7 Category JNC 7 Category (2004)(2004)

SBP/DBP (mmHg)SBP/DBP (mmHg)SBP/DBP (mmHg)SBP/DBP (mmHg)

Optimal Optimal <120/80<120/80 NORMAL NORMAL

NormalNormal 120120--129/80129/80--8484PREHYPERTENSIONPREHYPERTENSION

BorderlineBorderline 130130--139/85139/85--8989

HypertensionHypertension >140/90>140/90 HYPERTENSIONHYPERTENSION

A chronic disease of persistent elevated arterial blood pressure.A chronic disease of persistent elevated arterial blood pressure.

Stage 1Stage 1 140140--159/90159/90--9999 STAGE 1STAGE 1

Stage 2 Stage 2 (moderate)(moderate) 160160--179/100179/100--109109STAGE 2STAGE 2

Stage 3 Stage 3 (severe)(severe) ≥180/110≥180/110

ClassificationClassificationClassificationClassification

11oo or essential hypertension (> 95%)or essential hypertension (> 95%)Genetic Genetic Ethnic Ethnic Lifestyle Lifestyle Gender and ageGender and age

22o o hypertension (~5%)hypertension (~5%)Chronic renal disease Chronic renal disease PheochromocytomaPheochromocytomaPheochromocytomaPheochromocytomaCushing’s syndrome and glucocorticoid excess states Cushing’s syndrome and glucocorticoid excess states 11o o aldosteronism and other mineralocorticoid excess statesaldosteronism and other mineralocorticoid excess statesCoarctation of the aorta Coarctation of the aorta DrugDrug--inducedinduced

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Associated risks Associated risks Associated risks Associated risks Chronic Chronic ↑↑arterial BP arterial BP ↑↑ likelihood of morbidity likelihood of morbidity and mortality.and mortality.

1.1. CADCAD2.2. LVH LVH 3.3. CHF CHF 4.4. MIMI55 ArrhythmiasArrhythmias5.5. ArrhythmiasArrhythmias6.6. AnginaAngina7.7. StrokeStroke8.8. DementiaDementia9.9. Renal disease Renal disease

CVD risk doubles for each increment of 20/10 mmHgCVD risk doubles for each increment of 20/10 mmHg

Why treat? Why treat?

Treating hypertension:Treating hypertension:LVH

–– ↓↓stroke by 40% stroke by 40% -- 45%45%–– ↓↓CHF by 40% CHF by 40% -- 50%50%–– ↓↓CAD by 16% CAD by 16% -- 25%25%

>30% unaware>30% unaware>30% unaware>30% unawareEducational intervention Educational intervention ↓↓ BP. BP. In UK, only ~6% adequately treated.In UK, only ~6% adequately treated.

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SNS inhibitionMi dMi d ββ t i tt i t CentralCentral αα agonistsagonists

Drug classification Drug classification Drug classification Drug classification

ββ antagonistsantagonists

αα11 antagonistsantagonists

Mixed Mixed αα,,ββ antagonistsantagonists

Peripheral adrenergic Peripheral adrenergic antagonistsantagonists

Central Central αα2 2 agonists agonists

Sodium/RAAS balance

ACE InhibitorsACE InhibitorsDiureticsDiuretics ATII antagonistsATII antagonistsACE InhibitorsACE Inhibitors ATII antagonistsATII antagonists

Vasodilators

CaCa2+2+ channel blockerschannel blockers OthersOthers

ββ antagonistsantagonistsββ antagonistsantagonistsGeneric nameGeneric name Trade name(s)Trade name(s) Doses available Doses available

PropranololPropranolol Inderal®Inderal® Oral: 10, 20, 40, 60, 80, 90mg; 4, 8mg/mL oral Oral: 10, 20, 40, 60, 80, 90mg; 4, 8mg/mL oral soln; Inderal LA: 60, 80, 120, 160mgsoln; Inderal LA: 60, 80, 120, 160mgParenteral: 1mg/mL solnParenteral: 1mg/mL soln

Nadolol Nadolol Corgard®Corgard® Oral: 20, 40, 80, 120, 160mgOral: 20, 40, 80, 120, 160mg

Pindolol Pindolol Visken®Visken® Oral: 5, 10mgOral: 5, 10mg

Acebutolol (*)Acebutolol (*) Sectral®Sectral® Oral: 200, 400mgOral: 200, 400mg

Metoprolol (*)Metoprolol (*) Toprol®, Toprol®, Lopressor®Lopressor®

Oral: 50, 100mg; XL: 25, 50, 100, 200mgOral: 50, 100mg; XL: 25, 50, 100, 200mgParenteral: 1mg/mL solnParenteral: 1mg/mL solnLopressor®Lopressor® gg

Atenolol (*)Atenolol (*) Tenormin® Tenormin® Oral: 25, 50, 100mg; Oral: 25, 50, 100mg; Parenteral: 0.5mg/mL solnParenteral: 0.5mg/mL soln

Betaxolol (*)Betaxolol (*) Kerlone®Kerlone® Oral: 10, 20mgOral: 10, 20mg

Bisoprolol (*)Bisoprolol (*) Zebeta®Zebeta® Oral:5, 10mgOral:5, 10mg

(*) cardioselective(*) cardioselective

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Mechanism of ActionMechanism of ActionMechanism of ActionMechanism of ActionAcute effect Long term effect

β1 blockade in myocardial cells β1 blockade in juxtaglomerular cells-ve inotropic-ve chronotropic

↓↓ COCO

Shift in whole bodyautoregulation

↓ Renin release

↓ [Angiotensin II]plasma

Change in arterial ↓ arterial

↓ aldosterone

↓ Na+ retention

↓ Blood volumeg

remodellingvasoconstriction

↓↓ TPRTPR

↓↓ BPBP

OtherOther IndicationsIndicationsOtherOther IndicationsIndications

Angina pectorisAngina pectoris

Arrhythmias

Glaucoma (applied topically)

Migraineg

IHD and prevention of 2nd MI.

Useful as monotherapy in Stage 1 HTN Useful as monotherapy in Stage 1 HTN or with vasodilators (and diuretics) in stage 2.or with vasodilators (and diuretics) in stage 2.

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ContraindicationsContraindicationsContraindicationsContraindications

CHF and nodal conduction diseases. CHF and nodal conduction diseases. But carvedilol (Coreg®) misoprolol and metoprololBut carvedilol (Coreg®) misoprolol and metoprolol–– But, carvedilol (Coreg®), misoprolol and metoprolol But, carvedilol (Coreg®), misoprolol and metoprolol ↓↓ mortality in CHFmortality in CHF

NonNon--selective selective ββ blockersblockers in asthma. Cardioin asthma. Cardio--selective selective drugs lose selectivity at higher doses.drugs lose selectivity at higher doses.

Use with caution in insulinUse with caution in insulin--dependent diabetic patients. dependent diabetic patients. –– Glycogenolysis is adrenergically mediated. Glycogenolysis is adrenergically mediated. ββ

blockersblockers antagonize sympathetic response to antagonize sympathetic response to hypoglycemia and blunt recovery. hypoglycemia and blunt recovery.

Adverse Effects Adverse Effects Adverse Effects Adverse Effects

CNS: Sedation, depression, lethargy, sleep disturbancesCNS: Sedation, depression, lethargy, sleep disturbances

CV: CHF in LV dysfunction, heart block, bradyarrhythmiasCV: CHF in LV dysfunction, heart block, bradyarrhythmias

Bronchospasms (nonBronchospasms (non--selective blockers) in asthma and selective blockers) in asthma and COPD. COPD.

↓↓HDL dHDL d ↑↑ l t i l l ll t i l l l↓↓HDL and HDL and ↑↑plasma triacylglycerolplasma triacylglycerol

Abrupt cessation may induce unstable angina, MI or death in Abrupt cessation may induce unstable angina, MI or death in patients predisposed to ischemic myocardial events. Taper patients predisposed to ischemic myocardial events. Taper over 14 days.over 14 days.

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α1 antagonistsα1 antagonists

Generic nameGeneric name Trade name(s)Trade name(s) Doses available Doses available

PrazosinPrazosin Minipress®Minipress® Oral: 1, 2, 5mgOral: 1, 2, 5mgTerazosinTerazosin Hytrin®Hytrin® Oral: 1, 2, 5, 10mgOral: 1, 2, 5, 10mg

DoxazosinDoxazosin Cardura®Cardura® Oral: 1, 2, 4, 8mgOral: 1, 2, 4, 8mgCardura®Cardura® Oral: 1, 2, 4, 8mgOral: 1, 2, 4, 8mgTamsulosin Tamsulosin Flomax®Flomax® Oral: 0.4mgOral: 0.4mg

α1 antagonistsα1 antagonistsMechanism of Action:Mechanism of Action:

Arterial and venous relaxation Arterial and venous relaxation -- ↓↓ TPR ; TPR ; ↓↓ BP.BP.Minimal Minimal ↑↑ CO, renal blood flow or GFR. No longCO, renal blood flow or GFR. No long--term tachycardia term tachycardia and and ↑↑ reninrenin release.release.

Indication:Indication:Benign prostatic hypertrophy and hypertension (prostate capsule Benign prostatic hypertrophy and hypertension (prostate capsule relaxation decreases resistance to urinary flow) relaxation decreases resistance to urinary flow)

Adverse Effects:Adverse Effects:1.1. 11stst dose dizziness or syncope dose dizziness or syncope ––give at bedtime (caution in elderly). give at bedtime (caution in elderly). 2.2. Initial reflex tachycardia (Initial reflex tachycardia (propranololpropranolol to counteract) to counteract) 3.3. Postural hypotensionPostural hypotension4.4. Infrequent and mild CNS: vivid dreams, lassitude and depression.Infrequent and mild CNS: vivid dreams, lassitude and depression.

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Mixed Mixed αα, , ββ antagonistsantagonistsMixed Mixed αα, , ββ antagonistsantagonists

Generic nameGeneric name Trade name(s)Trade name(s) Doses available Doses available LabetalolLabetalol Normodyne® Normodyne® Oral:100, 200, 300mgOral:100, 200, 300mg

Parenteral: 5mg/mL soln Parenteral: 5mg/mL soln CarvedilolCarvedilol Coreg® Coreg® Oral: 3.125, 6.25, 12.5, 25mgOral: 3.125, 6.25, 12.5, 25mg

LabetalolLabetalolLabetalolLabetalol

Equimolar mixture of 4 stereoisomers:Equimolar mixture of 4 stereoisomers:2 i ti 12 i ti 1 bl k thbl k th l til ti ββ bl k dbl k d2 inactive, 1 2 inactive, 1 αα11--blocker, other nonblocker, other non--selective selective ββ--blocker and blocker and ββ22-- partial agonist.partial agonist.Useful in hypertensive emergencies (as Useful in hypertensive emergencies (as iv)iv)Similar efficacy and sideSimilar efficacy and side--effects as effects as ββ-- and and αα11--antagonists antagonists when given orally. when given orally.

Mechanism of action:Mechanism of action:1.1. αα1 1 blockade and blockade and ββ22 stimulation stimulation cause rapid vasodilatation, cause rapid vasodilatation, ↓↓

TPR leading to TPR leading to ↓↓BPBP

Contraindications same as nonContraindications same as non--selective selective ββ blockers blockers

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Peripheral adrenergic antagonists Peripheral adrenergic antagonists Peripheral adrenergic antagonists Peripheral adrenergic antagonists

Generic nameGeneric name Trade name(s)Trade name(s) Doses available Doses available

ReserpineReserpine -- Oral: 0.1, 0.25mgOral: 0.1, 0.25mg

GuanethidineGuanethidine Ismelin®Ismelin® Oral: 10, 25mgOral: 10, 25mgGuanadrelGuanadrel Hylorel®Hylorel® Oral: 10, 25mgOral: 10, 25mg

Reserpine: Reserpine: Mechanism of actionMechanism of actionReserpine: Reserpine: Mechanism of actionMechanism of action

1.1. Binds avidly to NE and 5Binds avidly to NE and 5--HT storage vesicles in HT storage vesicles in t l d i h lt l d i h l d id icentral and peripheralcentral and peripheral adrenergic neurons adrenergic neurons

inducing catecholamine leakage. inducing catecholamine leakage.

2.2. Overall Effect: Minimal active transmitter Overall Effect: Minimal active transmitter discharged from depolarized nerve endings. discharged from depolarized nerve endings.

3.3. Neurotransmitter depletion in brain and Neurotransmitter depletion in brain and myocardium leads to sedation, depression and myocardium leads to sedation, depression and ↓↓CO.CO.

Rauwolfia serpentinaRauwolfia serpentina root used in Ayuvedic medicine, root used in Ayuvedic medicine, isolated in 1950’s and used in Western medicineisolated in 1950’s and used in Western medicine

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ReserpineReserpineReserpineReserpine

↓↓CO, CO, ↓↓TPR TPR ↓↓HR (NHR (N ++ d Hd H O t ti )O t ti )↓↓HR, (NaHR, (Na++ and Hand H22O retention)O retention)Low doses + diuretic Low doses + diuretic ≅≅ diuretic + propranolol or methyldopa diuretic + propranolol or methyldopa

Adverse Effects Adverse Effects 1.1. CNS: Sedation, inability to concentrate, nightmares, doseCNS: Sedation, inability to concentrate, nightmares, dose--

related psychotic depression related psychotic depression –– contraindicated in precontraindicated in pre--existing depression. existing depression. e st g dep ess o .e st g dep ess o .

2.2. Unabated parasympathetic activity Unabated parasympathetic activity -- nasal stuffiness, nasal stuffiness, ↑↑gastric acid secretion (contraindicated in peptic ulcer), gastric acid secretion (contraindicated in peptic ulcer), diarrhea and bradycardiadiarrhea and bradycardia

Central α2 agonistsCentral α2 agonists

Generic nameGeneric name Trade Trade name(s)name(s)

Doses available Doses available

ClonidineClonidine Catapress®Catapress® Oral: 0.1, 0.2, 0.3mgOral: 0.1, 0.2, 0.3mgTransdermal patch: 0.1, 0.2, 0.3mg/24hrs Transdermal patch: 0.1, 0.2, 0.3mg/24hrs

MethyldopaMethyldopa -- Oral:250, 500mgOral:250, 500mgGuanabenzGuanabenz Wytensin®Wytensin® Oral: 4, 8mgOral: 4, 8mgGuanfacineGuanfacine Tenex®Tenex® Oral:1, 2mgOral:1, 2mg

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Mechanism of actionMechanism of actionMechanism of actionMechanism of action

Selective Selective αα22 agonists in the CNS:agonists in the CNS:Selective Selective αα22 agonists in the CNS:agonists in the CNS:↓↓ CNSCNS sympathetic outflow sympathetic outflow –– enhanced enhanced parasympathetic activity parasympathetic activity -- ↑↑vagal tone vagal tone -- ↓↓BPBP

↓↓HR, HR, ↓↓CO, CO, ↓↓ TPR, TPR, ↓↓plasma renin, blunted plasma renin, blunted baroreceptor reflexes.baroreceptor reflexes.

↓↓ NE plasma levels directly NE plasma levels directly ↓↓ TPR with TPR with ↓↓BP.BP.

Clonidine useful in pheochromocytoma diagnosisClonidine useful in pheochromocytoma diagnosis

∝∝--MethyldopaMethyldopa∝∝--MethyldopaMethyldopa

D f h i i thi l f l li it d bD f h i i thi l f l li it d bDrug of choice in this class; usefulness limited by Drug of choice in this class; usefulness limited by adverse effects. adverse effects.

Chronic use results in Chronic use results in NaNa++ and fluid retention (and fluid retention (diureticdiuretic).).

Metabolized to its active form (Metabolized to its active form (αα--methylnorepinephrine) methylnorepinephrine) in the brainin the brain

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∝∝-- MethyldopaMethyldopa∝∝-- MethyldopaMethyldopa

tt1/21/2: 2hrs; peak effect: ~6: 2hrs; peak effect: ~6--8hrs; Duration of action: 8hrs; Duration of action: 24h24h~24hr~24hr

In elderly: In elderly: ↓↓HR and HR and ↓↓ stroke volume resulting in stroke volume resulting in ↓↓CO, in young uncomplicated patient no such effect.CO, in young uncomplicated patient no such effect.

Adverse effects:Adverse effects:S d ti l it d i ht d iS d ti l it d i ht d iSedation, lassitude, nightmares, depression, Sedation, lassitude, nightmares, depression, vertigo, vertigo, galactorrheagalactorrhea (men & women). (men & women).

ClonidineClonidineClonidineClonidine↓↓ CO and CO and ↓↓ TPRTPR

↓↓ cardiac sympathetic tone leads to cardiac sympathetic tone leads to ↓↓ iontropyiontropy, , ↓↓ chronotropychronotropy

Adverse Effects:Adverse Effects:1.1. CNS CNS –– Sedation; avoid in depressionSedation; avoid in depression2.2. Dry mouthDry mouth2.2. Dry mouthDry mouth

Not 1Not 1stst line therapyline therapy

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ClonidineClonidine

Caution:Caution:

DoseDose--related withdrawal syndrome within 18related withdrawal syndrome within 18--36 hrs; 36 hrs; ↑↑sympathetic discharge leading to rebound hypertension sympathetic discharge leading to rebound hypertension or overshoot hypertension. or overshoot hypertension.

Symptoms: headache, apprehension, tremors, abdominal Symptoms: headache, apprehension, tremors, abdominal pain, sweating, and tachycardia.pain, sweating, and tachycardia.

ACE InhibitorsACE InhibitorsACE InhibitorsACE Inhibitors

Generic nameGeneric name Trade name(s)Trade name(s) Doses available Doses available

EnalaprilEnalapril Vasotec®Vasotec® Oral: 2.5, 5, 10, 20mgOral: 2.5, 5, 10, 20mg

CaptopilCaptopil Capoten®Capoten® Oral: 12.5, 25, 50, 100mgOral: 12.5, 25, 50, 100mg

LisinoprilLisinopril Zestril®, Prinivil®Zestril®, Prinivil® Oral: 2.5, 5, 10, 20, 40mgOral: 2.5, 5, 10, 20, 40mg

FosinoprilFosinopril Monopril®Monopril® Oral:10, 20, 40mgOral:10, 20, 40mgBenazeprilBenazepril Lotensin®Lotensin® Oral: 5, 10, 20, 40mgOral: 5, 10, 20, 40mgQuinaprilQuinapril Accupril®Accupril® Oral: 5, 10, 20, 40mgOral: 5, 10, 20, 40mg

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Renin-Angiotensin-Aldosterone SystemRenin-Angiotensin-Aldosterone SystemAngiotensinogen

Angiotensin I

Renin

g

Angiotensin IIAngiotensin Converting Enzyme

Aldosterone↑ Na+, H2O retention

↑ Blood volume Facilitates NE transmission

Vasoconstriction

↑COCO ↑TPRTPR

↑BPBP

X

ACE inhibitors block bradykinin degradation, stimulate PEACE inhibitors block bradykinin degradation, stimulate PE2 2 & prostacyclin& prostacyclin

ACE InhibitorsACE InhibitorsACE InhibitorsACE Inhibitors

As effective as diuretics and β-blockersAs effective as diuretics and β-blockers

Supervise 1st dose

↓TPR without reflex ↑CO, HR or inotrophy

Fetotoxic (absolutely contraindicated in pregnacy)

Initiate with very low dose with slow titration.Initiate with very low dose with slow titration.

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Other IndicatorsOther Indicators

CHF (↓nonfatal and fatal events).

LVH (may prevent or partial regression).

Type 1 diabetic nephropathyType 1 diabetic nephropathy

Adverse EffectsAdverse EffectsAdverse EffectsAdverse Effects

Acute hypotension Acute hypotension (at onset, esp in severe Na(at onset, esp in severe Na++& volume depletion)& volume depletion)

Ski h ( ti t i t)Ski h ( ti t i t)Skin rash (sometimes transient)Skin rash (sometimes transient)Cough (10% Cough (10% -- 20%)20%)

To a lesser extent (<1%)To a lesser extent (<1%)::Hematologic toxicity: neutropenia, agranulocytosisHematologic toxicity: neutropenia, agranulocytosisA i dA i d i Af ii Af iAngioedema Angioedema –– more in Africansmore in AfricansAcute renal failure Acute renal failure –– esp. in unilateral/bilateral renal artery stenosisesp. in unilateral/bilateral renal artery stenosisGlomerulonephritisGlomerulonephritisProteinuria (captopril)Proteinuria (captopril)Hyperkalemia Hyperkalemia –– esp. in renal disease, DM, on NSAIDs, Kesp. in renal disease, DM, on NSAIDs, K++ supp. or K+supp. or K+--sparing diureticssparing diureticsFeverFever

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Angiotensin II receptor antagonistsAngiotensin II receptor antagonistsAngiotensin II receptor antagonistsAngiotensin II receptor antagonists

Generic nameGeneric name Trade name(s)Trade name(s) Doses available Doses available

LosartanLosartan Cozaar®Cozaar® Oral: 25, 50, 100mgOral: 25, 50, 100mg

ValsartanValsartan Diovan®Diovan® Oral: 40, 80, 160, 320mgOral: 40, 80, 160, 320mg

CandesartanCandesartan Atacand®Atacand® Oral: 4, 8, 16, 32mgOral: 4, 8, 16, 32mg

OlmesartanOlmesartan Benicar®Benicar® Oral: 5, 10, 20, 40mgOral: 5, 10, 20, 40mgTelmisartanTelmisartan Micardis®Micardis® Oral: 20, 40, 80mgOral: 20, 40, 80mgIrbesartanIrbesartan Avapro®Avapro® Oral: 75, 150, 300mgOral: 75, 150, 300mg

Mechanism of ActionMechanism of ActionBlockade of AgII receptors

↓ vasocontriction ↓Na+ retention

↓↓BPBP

↓ Blood volume

↓↓COCO

↓↓TPRTPRAcute effect

Ag II Stimulation of arterial wall growth

Ag I

growth

↑wall to lumen ratio(remodelling)

↑ vasoconstriction

Long term effect

No effect on bradykinin breakdownNo effect on bradykinin breakdown

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Angiotensin II receptor subtypes Angiotensin II receptor subtypes ATAT1 1 (site of action of ATII antagonists)(site of action of ATII antagonists)–– VasoconstrictionVasoconstriction–– AldosteroneAldosterone releaserelease–– Sympathetic activationSympathetic activation–– ADH releaseADH release–– Constriction of efferent Constriction of efferent glomerularglomerular arteriolesarterioles

ATAT2 2 (beneficial effect not blocked)(beneficial effect not blocked)–– VasodilationVasodilation

AgII also produced by enzymic reactions of chymasesAgII also produced by enzymic reactions of chymases

Other IndicationsOther IndicationsOther IndicationsOther Indications

“ACE inhibitor without the cough”

Heart failure

Intolerance to other hypertensive drugs

All have similar antihypertensive efficacy with flat doseAll have similar antihypertensive efficacy with flat dose--response curveresponse curve

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Adverse Effects Adverse Effects Adverse Effects Adverse Effects

Renal insufficiency (Renal insufficiency (↓↓glomerular perfusion pressure)glomerular perfusion pressure)

HyperkalemiaHyperkalemia

Caution: History of ACE inhibitorCaution: History of ACE inhibitor--induced angioedema induced angioedema

DiureticsDiureticsDiureticsDiureticsGeneric nameGeneric name Trade Trade

name(s)name(s)Available dosesAvailable doses

ChlorothiazideChlorothiazide Diuril®Diuril® Oral: 250, 500; 250mg/mL oral suspensionOral: 250, 500; 250mg/mL oral suspension

HydrochlorothiazideHydrochlorothiazide Hydrodiuril®Hydrodiuril® Oral: 25, 50, 100mg tabs; 12.5mg capsulesOral: 25, 50, 100mg tabs; 12.5mg capsulesParenteral: 10mg/mLsolnParenteral: 10mg/mLsolnParenteral: 10mg/mLsolnParenteral: 10mg/mLsoln

ChlorthalidoneChlorthalidone Thalitone®Thalitone® Oral: 250, 500 mg; 250 mg/5mL oral Oral: 250, 500 mg; 250 mg/5mL oral suspensionsuspension

IndapamideIndapamide Lozol®, othersLozol®, others Oral: 1.25, 2.5mgOral: 1.25, 2.5mg

MetolazoneMetolazone Zaroxolyn®Zaroxolyn® Oral: 0.5mgOral: 0.5mg

FurosemideFurosemide Lasix®Lasix® Oral: 20, 40, 80 mg; Parenteral: 10mg/mLOral: 20, 40, 80 mg; Parenteral: 10mg/mL

BumetamideBumetamide Bumex® Bumex® Oral: 0.5, 1, 2 mg; Parenteral: 0.5mg/2mLOral: 0.5, 1, 2 mg; Parenteral: 0.5mg/2mL

TorsemideTorsemide Demadex®Demadex® Oral: 5, 10, 15, 20mg; Parenteral: 10mg/mLOral: 5, 10, 15, 20mg; Parenteral: 10mg/mL

Ethacrynic AcidEthacrynic Acid Edecrin®Edecrin® Oral: 25, 50mg; Parenteral: 50mg/mLOral: 25, 50mg; Parenteral: 50mg/mL

SpironolactoneSpironolactone Aldactone®Aldactone® Oral: 25, 50, 100mgOral: 25, 50, 100mg

EplerenoneEplerenone Inspra®Inspra® Oral: 25, 50mgOral: 25, 50mg

AmilorideAmiloride Midamor ®Midamor ® Oral: 5mgOral: 5mg

TriamtereneTriamterene Dyrenium®Dyrenium® Oral: 50, 100mg Oral: 50, 100mg

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Diuretics Diuretics –– Thiazides Thiazides (1(1stst line)line)Diuretics Diuretics –– Thiazides Thiazides (1(1stst line)line)

Block renal tubule Na+-Cl- reabsorption

ve effect

Acute effect

↑ urinary loss of Na+ and H2O

↓ extracellular volume

↓CO ↓BP

↑ angiotensin II

↑ renin release

-ve effect

Long term effect•CO returns to normal•CO returns to normal•Slight ↓ in body Na+

•Opening of K+ channels(hyperpolarization)

↓[Ca2+] in vascular smooth muscle cells↓affinity of vascular smooth muscle cells

for vasoconstrictor hormones

↓ Contractility of vascularsmooth muscle cells

↓BP ↓TPR

Diuretics Diuretics –– Furosemide Furosemide (not 1(not 1stst line)line)Diuretics Diuretics –– Furosemide Furosemide (not 1(not 1stst line)line)

Binds to Cl- binding site of Na+-K+-2 Cl- cotransporter in thick ascending loop of Henle

Acute effectthick ascending loop of Henle

↑ loss of Na+ and H2O

↓ Extracellular fluid volume

↓↓ COCO ↓↓BPBP

↑ Angiotensin II

↑ Renin release

L t ff tLong term effect•CO returns to normal•Slight ↓ in body Na+

↓ Contractility of VSMC

↓↓TPRTPR? ? ↓↓BP ?BP ?

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Loop Diuretic – FurosemideLoop Diuretic – Furosemide

Indications:Indications:Resistant hypertension (not 1st line)

Edema (renal impairment or volume overload)

HypercalcemiaHypercalcemia

Hyperkalemia

CaCa2+2+ channel blockerschannel blockersCaCa2+2+ channel blockerschannel blockersGeneric nameGeneric name Trade Trade

name(s)name(s)Doses available Doses available

BenzothiazepineBenzothiazepineDiltiazemDiltiazem

Cardizem®Cardizem® Oral: 30, 60, 90, 120mg; sustained release: 60, Oral: 30, 60, 90, 120mg; sustained release: 60, 90, 120, 180, 240, 300, 360, 420mg.90, 120, 180, 240, 300, 360, 420mg.Parenteral: 5mg/mL solnParenteral: 5mg/mL solnParenteral: 5mg/mL solnParenteral: 5mg/mL soln

DiphenylalkylamineDiphenylalkylamineVerapamilVerapamil

Calan®, Calan®, Isoptin®Isoptin®

Oral: 40, 80, 120mg; sustained release: 120, Oral: 40, 80, 120mg; sustained release: 120, 180, 240mg180, 240mgParenteral: 2.5mg/mL solnParenteral: 2.5mg/mL soln

DihydropyridineDihydropyridineNifedipineNifedipine

Adalat® CC, Adalat® CC, Procardia®Procardia®XLXL

Oral: 10, 20mg. Extended release: 30, 60, 90mgOral: 10, 20mg. Extended release: 30, 60, 90mg

AmlodipineAmlodipine Norvasc®Norvasc® Oral: 2 5 5 10mgOral: 2 5 5 10mgAmlodipineAmlodipine Norvasc®Norvasc® Oral: 2.5, 5, 10mgOral: 2.5, 5, 10mg

FelodipineFelodipine Plendil®Plendil® Oral extended release: 2.5, 5, 10mgOral extended release: 2.5, 5, 10mg

IsradipineIsradipine DynaCirc®DynaCirc® Oral:2.5, 5mg; controlled release: 5, 10mgOral:2.5, 5mg; controlled release: 5, 10mg

NicardipineNicardipine Cardene®Cardene® Oral:20, 30mg; sustained release: 30, 45, 60mgOral:20, 30mg; sustained release: 30, 45, 60mgParenteral: 2.5mg/mL solnParenteral: 2.5mg/mL soln

NisoldipineNisoldipine Sular®Sular® Oral extended release: 10, 20, 30, 40mgOral extended release: 10, 20, 30, 40mg

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Mechanism of ActionMechanism of ActionMechanism of ActionMechanism of Action

DihydropyridinesNifedipine Amlodipine

Verapamil, DiltiazemNifedipine, Amlodipine

Block L-type Ca2+ channelsin arterial smooth muscle

Block L-type Ca2+ channelsin SA and AV node

↓↓ TPRTPR ↓ or abolishes reflex tachycardia

↓↓ BPBP

Baroreceptor-mediated reflex tachycardia

Inhibit influx of CaInhibit influx of Ca++++ ions thru’ voltageions thru’ voltage--gated channelsgated channels

Relative efficacyRelative efficacyRelative efficacyRelative efficacy

DrugDrug VasodilationVasodilation --ve inotropyve inotropy AutomaticityAutomaticity AVAVDrugDrug Vasodilation Vasodilation (coronary (coronary

flow)flow)

--ve inotropyve inotropy Automaticity Automaticity (SA node) (SA node)

suppressionsuppression

AV AV conduction conduction suppressionsuppression

DiltiazemDiltiazem 33 22 55 44

NifedipineNifedipine 55 11 11 00

VerapamilVerapamil 44 44 55 55

Relative cardiovascular effect: 0=no effect, 5=maximum effectRelative cardiovascular effect: 0=no effect, 5=maximum effect

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IndicationsIndicationsIndicationsIndications

Mild to moderate HTN associated with exercise-induced, variant and unstable angina.

MI (ACE inhibitors>protective than dihydropyridines)

Antiarrhythmic (diltiazem and verapamil for (supraventricular tachycardia atrial fibrillation and(supraventricular tachycardia, atrial fibrillation and atrial flutter).

Not clinically superior to diuretics or Not clinically superior to diuretics or ββ--blockers,blockers,uusually 2sually 2ndnd & 3& 3rdrd line therapy.line therapy.

Vasodilatory-related (more with

Adverse Effects Adverse Effects

Vasodilatory-related (more with dihydropyridines): dizziness, flushing, headache, peripheral edema

Gingival hyperplasia

Mood swings & fatigueMood swings & fatigue

Verapamil causes constipation (7%) and contraindicated in CHF

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Oral and parenteral vasodilatorsOral and parenteral vasodilatorsOral and parenteral vasodilatorsOral and parenteral vasodilators

Generic nameGeneric name Trade name(s)Trade name(s) Doses available Doses available

HydralazineHydralazine Apresoline®Apresoline® Oral: 10, 25, 50, 100mgOral: 10, 25, 50, 100mgParenteral: 20mg/mL solnParenteral: 20mg/mL soln

NitroprussideNitroprusside Nitropress®Nitropress® Parenteral: 50mg/vialParenteral: 50mg/vial

MinoxidilMinoxidil Loniten®Loniten® Oral: 2.5, 10mgOral: 2.5, 10mgTopical (Rogaine®, etc): 2% solnTopical (Rogaine®, etc): 2% soln

DiazoxideDiazoxide Hyperstat® IVHyperstat® IV Oral: 50mg capsuleOral: 50mg capsuleParenteral: 15mg/mLParenteral: 15mg/mL

FenoldopamFenoldopam Corlopam®Corlopam® Parenteral: 10mg/mL soln Parenteral: 10mg/mL soln

HydralazineHydralazineHydralazineHydralazine

Well absorbed orally, short tWell absorbed orally, short t1/21/2 (1 hr), peak effect (1/2 hr to (1 hr), peak effect (1/2 hr to 2 hrs) & duration of action (12hr)2 hrs) & duration of action (12hr)2 hrs) & duration of action (12hr). 2 hrs) & duration of action (12hr).

Bioavailability determined by acetylator status: Bioavailability determined by acetylator status: 16% in ‘fast’ and 35% in ‘slow’ acetylators.16% in ‘fast’ and 35% in ‘slow’ acetylators.

Adverse effects limit use. Reserved for Adverse effects limit use. Reserved for refractory severe refractory severe hypertension used concomitantly with diuretics and hypertension used concomitantly with diuretics and ββ--yp yyp y ββblockers (never as monotherapy).blockers (never as monotherapy).

Used occasionally with isosorbide dinitrate in CHF.Used occasionally with isosorbide dinitrate in CHF.

Contraindicated in CAD and > 40yearsContraindicated in CAD and > 40years

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HydralazineHydralazineHydralazineHydralazine

Direct relaxation of arteries (not veins), cAMP Direct relaxation of arteries (not veins), cAMP ect e a at o o a te es ( ot ve s), cect e a at o o a te es ( ot ve s), cmediated.mediated.

Vasodilatation causes baroreceptorVasodilatation causes baroreceptor--mediated reflex, mediated reflex, sympathetic stimulation sympathetic stimulation →→ tachycardia tachycardia →→ ↑↑ CO; CO; ↑↑renin release renin release →→ ↑↑ NaNa++ and Hand H22O retention. O retention.

↑↑CO and fluid retentionCO and fluid retention cause tachyphylaxis, unless cause tachyphylaxis, unless used in combination with used in combination with ββ--blockers (blockers (↓↓reflex reflex tachycardia) and diuretics (tachycardia) and diuretics (↓↓fluid retention).fluid retention).

Hydralazine: Adverse EffectsHydralazine: Adverse EffectsHydralazine: Adverse EffectsHydralazine: Adverse Effects

Direct extension of pharmacological activity:Direct extension of pharmacological activity:Direct extension of pharmacological activity:Direct extension of pharmacological activity:headache, nausea, flushing, dizziness, hypotension, headache, nausea, flushing, dizziness, hypotension, palpitation, tachycardia, angina pectoris, MIpalpitation, tachycardia, angina pectoris, MI

Immunological reactions (unknown mechanism):Immunological reactions (unknown mechanism):–– Serum sickness, hemolytic anemia, Serum sickness, hemolytic anemia, vasculitisvasculitis, rapidly , rapidly

progressing progressing glomerulonephritisglomerulonephritis–– 1010--20%incidence of reversible dose20%incidence of reversible dose--related lupus related lupus

erythematosuserythematosus--like syndrome like syndrome –– high dose or after high dose or after >6mth chronic use. (Use <200mg daily) >6mth chronic use. (Use <200mg daily) Effect > in females and ‘slow Effect > in females and ‘slow acetylatorsacetylators’.’.

Limited usefulness in hypertensionLimited usefulness in hypertension

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MinoxidilMinoxidilMinoxidilMinoxidil

Direct relaxation of arteries (not veins).Direct relaxation of arteries (not veins).

↑↑blood flow to skin, skeletal muscles, GI blood flow to skin, skeletal muscles, GI tract, heart.tract, heart.

Reflex Reflex ↑↑CO, renal vasodilatation and CO, renal vasodilatation and ↑↑renin secretionrenin secretion.

MinoxidilMinoxidilMinoxidilMinoxidil

> potency than > potency than hydralazinehydralazinep yp y yy

Well absorbed orally, short tWell absorbed orally, short t1/21/2:3:3--4 hrs, duration of action: 4 hrs, duration of action: 12hr. 12hr.

NEVER as as monotherapymonotherapy, use with , use with ββ--blockers and blockers and diuretics (loop diuretic). diuretics (loop diuretic). ( p )( p )

Reserved for refractory severe hypertension.Reserved for refractory severe hypertension.

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Minoxidil Minoxidil –– Adverse EffectsAdverse EffectsMinoxidil Minoxidil –– Adverse EffectsAdverse Effects

↑↑More dramatic More dramatic ↑↑fluid retention than fluid retention than hydralazinehydralazine (n(not ot ↑↑reninrenin and and aldosteronealdosterone secretion related). secretion related). ↓↓ renal renal perfusion pressure and reflex stimulation of renal tubular perfusion pressure and reflex stimulation of renal tubular αα--receptors. receptors.

Headache, sweating Headache, sweating

HypertrichosisHypertrichosis::Used topically to treat of maleUsed topically to treat of male--pattern baldness.pattern baldness.

Sodium nitroprussideSodium nitroprussideSodium nitroprussideSodium nitroprussideGiven by Given by iviv continuous infusion. Onset: 30sec; peak continuous infusion. Onset: 30sec; peak effect: 2 mins.effect: 2 mins.effect: 2 mins. effect: 2 mins.

Metabolized to NO and cyanide. Metabolized to NO and cyanide. 1.1. NO causes vasodilatation.NO causes vasodilatation.2.2. Cyanide is poisonous, and further metabolized to Cyanide is poisonous, and further metabolized to

thiocyanate. thiocyanate.

Very potent vasodilator of both arteries and veins Very potent vasodilator of both arteries and veins

Drug of choice in hypertension emergencies Drug of choice in hypertension emergencies (BP>210/150mmHg).(BP>210/150mmHg).

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Sodium nitroprussideSodium nitroprussideSodium nitroprussideSodium nitroprusside

M dM d ↑↑HRHR dd ↓↓ di ldi l OO d dd dModest Modest ↑↑HR HR and and ↓↓myocardial myocardial OO22 demanddemand

Other indications: Other indications: –– Acute aortic dissection (propranolol given first Acute aortic dissection (propranolol given first

to prevent reflex sympathetic activation).to prevent reflex sympathetic activation).–– In CHF toIn CHF to ↑↑COCOIn CHF to In CHF to ↑↑COCO–– In acute MIIn acute MI to to ↓↓myocardial myocardial OO22 demanddemand

Sodium Nitroprusside: Sodium Nitroprusside: Adverse EffectsAdverse EffectsSodium Nitroprusside: Sodium Nitroprusside: Adverse EffectsAdverse Effects

Cyanide and thiocyanate poisoning: Cyanide and thiocyanate poisoning: –– Anorexia, nausea, fatigue, disorientation, toxic Anorexia, nausea, fatigue, disorientation, toxic

psychosis.psychosis.Closely monitor BP and plasma thiocyanate (<0.1Closely monitor BP and plasma thiocyanate (<0.1μμg/mL). g/mL). Antidote: Infusion of sodium thiosulphate Antidote: Infusion of sodium thiosulphate →→ thiocyanatethiocyanate↑risk of poisoning in impaired renal function

Worsens arterial hypoxemia in COPDWorsens arterial hypoxemia in COPD

Abrupt cessation after shortAbrupt cessation after short--term use causes rebound HTN.term use causes rebound HTN.

29

Prescribed Antihypertensive Drugs in Trinidad (n=442)Prescribed Antihypertensive Drugs in Trinidad (n=442)

Drug Class/Generic Drug name All HTN N (%) HTN alone N (%) HTN with DM N (%)

ACE Inhibitors (ACEI)EnalaprilLisinoprilFosinoprilCaptopril

281 (63.6)2473022

113 (58.9)951512

168 (67.2)1521510

β-blockers (BB)AtenololPropranololBisoprolol

129 (29.2)11793

65 (33.9)6141

64 (25.6)5652

DiureticsThiazide (bendrofluazide)Furosemide

114 (25.8)8925

66 (34.4)5016

48 (19.2)399

Calcium channel blockers (CCB)NifedipineAmlodipineVerapamil

53 (12.0)4553

23 (12.0)2201

30 (12.0)2352

α-blockersTerazosinDoxasosin

3 (0.7)12

1 (0.5)10

2 (0.8)02

Angiotensin receptor blockers (ARB)ValsartanPresartan

10 (2.3)91

5 (2.6)50

5 (2.0)41

Other drugsMethydopaReserpine

27 (6.1)234

18 (9.4)162

9 (3.6)72

Antihypertensive drug therapy in Trinidadian patients with complete accessible drug records (n=442)Antihypertensive drug therapy in Trinidadian patients with complete accessible drug records (n=442)

Antihypertensive drug therapy All HTN patients N (%)

HTN alone N (%)

HTN with DM N (%)

No drug therapy 26 (5.9) 8 (4.2) 18 (7.2)

Monotherapy 242 (54.8) 86 (44.8) 156 (62.4)

Dual drug therapy 121 (27.3) 62 (32.3) 59 (23.6)

Triple drug therapy 45 (10.2) 30 (15.6) 15 (6.0)

Quadruple drug therapy 8 (1.8) 6 (3.1) 2 (0.8)

TOTAL 442 192 250

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↑sympathetic activity

↑β1 receptor cardiac activation

↑ CO

↑ BP

ββ--blockersblockers αα11--blockersblockers

y↑α1 receptor

smooth muscle activation ↑ TPR↑ BP

↓ BP

↓ Renal flow ↑ renin ↑ Angiotensin II

CaCa2+2+--channel channel blockersblockers

ACE inhibitorsACE inhibitorsVasodilators Vasodilators

↓GFR ↑Na+, H2O retention ↑ Blood volume

↑Aldosterone

DiureticsDiuretics

AgII receptor AgII receptor blockersblockers