Hypertension – Drug therapy :Hypertension – Drug therapy Dr. Girish Vaswani
D.N.B. ( Med )
Consulting Physician
Bhatia hospital
Dalvi hospital
What to look for before therapy? :What to look for before therapy? The level of the pressure
Any identifiabale cause
Evidence of target organs damages
Other risk factors
Classifying Blood Pressure by Readings :Classifying Blood Pressure by Readings High Blood Pressure = Elevated systolic pressure and/or elevated diastolic pressure
The highest reading dictates classification
Elevated readings must occur on multiple occasions to be diagnosed
White coat hypertension :White coat hypertension Normal out-of-office BP readings
Present in 20 %
Poses cardiovascular hazard
Masked hypertension :Masked hypertension Normal in-office BP readings
Out-of-office readings high
Present in 20 %
Hazards similar to sustained HT
Morning BP surge :Morning BP surge Occurs within 2 hrs of awakening
Poses increased cardiovascular and stroke risk as well SCD
Nocturnal Dip :Nocturnal Dip May be attenuated
Increased risk of cardiovascular events and sudden cardiac deaths
Primary Hypertension :Primary Hypertension In 90 – 95 % cases no cause is detected. This is essential HT
With or without wide pulse pressure
Includes TOP, AIP
Treatment is necessary
Identifiable causes of hypertension :Identifiable causes of hypertension Renal - macro / microvascular, parenchymal, APCKD, renin producing tumors, obstr uropathy
Endocrinal - Cushing’s, Conn’s, Phaeo, enzyme defects, acromegaly, hypothyroidism, hypercalcemia
Drugs – estrogens, adrenal steroids, decongestants, apetite suppr, TCA, NSAID, MAO inhibitors, cyclosporine
Wide pulse pressure – AR, AVF, PDA, Thyrotox
Identifiable causes of hypertension :Identifiable causes of hypertension Co-arctation aorta
Obstructive sleep apnea
Pregnancy
Neurogenic- psychogenic, raised ICT, acute spinal injury, dysautonomias, polyneritis
Other CVD risk factors :Other CVD risk factors Cigarette smoking
Obesity* (BMI >30 kg/m2)
Physical inactivity
Dyslipidemia*
Diabetes mellitus*
Microalbuminuria or estimated GFR <60 ml/min
Age (older than 55 for men, 65 for women)
Family history of premature CVD
(men under age 55 or women under age 65) *Components of the metabolic syndrome.
Laboratory Tests :Laboratory Tests Routine Tests
Electrocardiogram
Urinalysis
Blood glucose, and hematocrit
Serum potassium, creatinine, or the corresponding estimated GFR, and calcium
Lipid profile, after 9- to 12-hour fast, that includes high-density and low-density lipoprotein cholesterol, and triglycerides
Optional tests
Measurement of urinary albumin excretion or albumin/creatinine ratio
More extensive testing for identifiable causes is not generally indicated unless BP control is not achieved
Slide 14:Renal
function Blood
volume Venous
tone Venous
return Heart
rate Nervous
control Muscular
responsiveness Myocardial
contractility Stroke
volume Cardiac
output CNS
factors Renin
release Angiontensin II
formation Intrinsic vascular
responsiveness Peripheral
resistance Nervous
control Renal
function Mean arterial
pressure Factors that Govern
the Mean Arterial Pressure
Slide 15:Mean Arterial Pressure MAP = CO
CO = HR X SV
SNS Blood volume
Heart contactility Venous tone X PVR
myogenic tone
vascular responsivenes
nervous control
vasoactive metabolites
endothelial factors
circulating hormones
Which drug ? :Which drug ? A – Ace inhibitors, ARB, aldosterone
antagonists, alpha blockers
B – Beta blockers
C – Ca entry blockers, Central agents
D – Diuretics
E – Extras : periph dilators, reserpine
Slide 17:Choice of Treatment
Treatment Goals for BP levels :Treatment Goals for BP levels Less than 130/85 in all patients
With nephropathy less than 120/80
With cardiac disease not to lower greater than 110/70
J – curve
Most never reach TARGET
Diuretics-Disadvantages :Diuretics-Disadvantages Hypovolemia
Electrolyte imbalances
Acid – base imbalances
Hyperlipidemia
Hyperglycemia
Hyperuricemia
Others – skin rashes, bone marrow, GI symps, sulfa allergies
No effect LVH
Diuretics – Best used :Diuretics – Best used Elderly, black
Mild to moderate HT
Those with renal and cardiac failure & fluid overloaded states
Good potentiators of other anti-hypertensives
Diuretics - mechanism :Diuretics - mechanism BP = CO x PVR
So dehydrate
Duration short
Escape
Ceiling effect
Diuretics - Types :Diuretics - Types Thiazides
Loop
Aldosterone antagonists
Osmotic
Carbonic anhydrase inhibitors
Beta blockers-disadvantages :Beta blockers-disadvantages Cardiac – SA node, AV node, ventricle
Vascular – PVD, gangrene, vasculitides, Raynaud’s, TAO
Pulmonary
Renal
Liver
CNS
Metabolic – sugar, lipids, K
Beta blockers – best used :Beta blockers – best used All stages of ischemic heart disease
Tachycardias – supraventricular, ventricular
MVP, HOCMP, LVH
Thyrotoxicosis
Pheochromocytoma already on alpha block
Heart failure
Two groups :Two groups Non DHP - primary action on heart
Dihydropyridines - primary action on arterioles
nifedipine
nimodipine
amlodipine
felodipine
isradipine
Ca channel blockers :Ca channel blockers
Ca channel blockers :Ca channel blockers
Ca channel blockers :Ca channel blockers
CCBs-Common SE :CCBs-Common SE Headache
Edema (nifedipine)
Constipation (verapamil)
Gingival hyperplasia
AV block & heart failure (verapamil and diltiazem)
Drug interactions: beta blockers (verapamil and diltiazem), cimetidine
Calcium Channel Blockers :Calcium Channel Blockers Divided into 2 groups chemically and pharmacologically
Common property: they all antagonize Ca++ movement across cell membranes by blocking L type channels
decrease frequency of opening in response to depolarization
Also called:
Slow Ca++ channel blockers
Ca++ channel antagonists
Ca++ entry blockers
Cardiac effects :Cardiac effects Verapamil and diltiazem type reduce Ca++ entry in the heart
Slow pacemaker activity - HR decreases
Slows conduction between atria and ventricles
Lessens strength of contraction - decreased stroke volume
Dihydropyridines have minimal effects on Ca++ entry in heart muscle
Vascular effects :Vascular effects dihydropyridines
Arteries and arterioles dilate more than veins
Fall in BP due to reduced TPVR
Reflex tachycardia
verapamil and diltiazem - lesser effect on arterioles and more depression of heart (no tachycardia)
CCB Safety :CCB Safety DO NOT USE SHORT ACTING DHP’S!!!!!!
DHP except plendil and norvasc may be detrimental in CHF
Discontinue slowly tapering dose if used for angina
Diltiaziem/verapamil contraindicated in sick sinus syndrome, 2nd or 3rd degree heart block, severe CHF, cardiogenic shock, interact with statins…dramatically increasing levels (except pravachol and lescol)
Ace inhibitors/ArBs :Ace inhibitors/ArBs Serum Na < 125
Creatinine normal
No dehydration or other acute unstable renal or cardiac condition
Stenotic valvular heart disease, HOCMP
Renal artery stenosis
Sensitivity to drug
Ace inhibitors / Arbs - Beware :Ace inhibitors / Arbs - Beware Angioedema
Cough
Hyperkalemia
Metabolic acidosis
Skin rashes
Neutropenia
Ace inhibitors / ArBs – best used :Ace inhibitors / ArBs – best used Diabetes
Heart disease
Peripheral vasc disease
Renal disease
Respiratory
Metabolic – sugar, lipids, uric acid
Proteinuria
Ace v/s AT2RA :Ace v/s AT2RA More cough
For microalb
Better cardiac failure
CNS AT2RA better Less cough
For macroalb
No added adv
Better CNS
Slide 38:Angiotensinogen Angiotensin I Angiotensin II Angiotensin III Renin ACE Aminopeptidase Non-ACE
(eg. Chymase
in heart) Endopeptidase Angiotensin 1-7
Releases ADH; ↑ PG;
Natriuretic; ↓ RVR;
↓ BP (brain stem inj.)
? Role in effects of ACEI 1 2 3 7 8 9 10 NH2-Asp-Arg-Val…Pro-Phe-COOH 1 2 3 7 8 9 10 NH2-Asp-Arg-Val…Pro-Phe-COOH 1 2 3 7 8 NH2-Arg-Val…Pro-Phe-COOH 2 3 7 8 NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu…COOH + 1. ↓ Renal Perfusion
Pressure
2. ↓ Na at Macula
Densa cells
3. ↑ Sympathetic
nerve activity (ß-1) ±PG The Renin-Angiotensin System
LV remodelling :LV remodelling Myocyte hpertrophy
Altered contractile properties
Myocyte necrosis, apoptosis and autophagia
Beta adrenergic desensitisation
Abnormal myocardial metabolism
Collagen and extracellular matrix disorganisation and dissolution
AT2 - Actions :AT2 - Actions Cardiac-hypertrophy, fibrosis
Vasc-endoth dysfunc
Renal-Incr IGP, protein leak, growth & fibr
Adrenals-aldosterone excess
Coagulation system-incr fibrinogen & PAI
Regulatory Functions of the EndotheliumNormal Dysfunction :Regulatory Functions of the EndotheliumNormal Dysfunction Vasodilation Vasoconstriction NO, PGI2, EDHF, BK, C-NP ROS, ET-1, TxA2, A-II, PGH2 Thrombolysis Thrombosis Platelet Disaggregation
NO, PGI2 Adhesion Molecules
CAMs, P,E Selectins Antiproliferation
NO, PGI2, TGF-, Hep Growth Factors
ET-1, A-II, PDGF, ILGF, ILs Lipolysis Inflammation
ROS, NF-B PAI-1, TF-α, Tx-A2 tPA, Protein C, TF-I, vWF LPL Vogel R
Endothelial functions :Endothelial functions Vasodilatation
Antiplatelet
Antithrombotic
Profibrinolytic
Antioxidant
Anti inflammatory
antiproliferative Vasoconstriction
Pro-aggregatory
Prothrombotic
Antifirinolytic
Pro-oxidant
Pro-inflammatory
Pro-proliferative
Slide 44:Angiotensin II Vasoconstriction Aldosterone
Secretion Direct Renal
Sodium Retention ↑ Thirst ADH Release ↑ Cardiac
Contractility Sympathetic
Facilitation:
Central
Nerve terminal
(ganglionic ?) Cardiac & Vascular
Hypertrophy All known physiologic effects are mediated
by the angiotensin II type 1 receptor ANGIOTENSIN II - SUPPORT OF THE BLOOD PRESSURE
Circulating and local (tissue) RAS influence on the cardiovascular system :Circulating and local (tissue) RAS influence on the cardiovascular system Circulating RAS
Short-term effects Sodium/water reabsorption via aldosterone secretion Local RAS
Long-term effects Intraglomerular hypertension Vascular hypertrophy Heart Heart Vasoconstriction Positive chronotropic effects/ arrhythmogenic effects Myocardial hypertrophy ANGIOTENSIN II
ACEI :ACEI Bradykinin Angiotensin I Angiotensin II ACE inhibitor Inactive metabolites AT1-blocker Vasodilation
Natriuresis
Extracellular matrix degradation
Cough
Angioedema Hypertension
Aldosterone
Transforming growth factor
Plasminogen activator Vasodilatation
Natriuresis
Antiproliferative effects AT1Receptor AT2Receptor
Angiotensin II Interaction With Secondary Mediators :Angiotensin II Interaction With Secondary Mediators Yusuf. Am J Cardiol. 2002;89(suppl):18A-26A. LDL BP Diabetes Smoking Oxidative stress Endothelial dysfunction and smooth muscle activation NO Local mediators Tissue ACE AII Endothelin catecholamines PAI-1, platelet aggregation, tissue factor VCAM/ICAMcytokines Proteolysis inflammation Growth factors cytokines matrix Vasoconstriction Thrombosis Inflammation Plaque rupture Vascular lesion and remodeling
Slide 48:Angiotensinogen Angiotensin I Angiotensin II Vasoconstriction Increased peripheral vascular resistance Increased blood pressure Aldosterone secretion Increased sodium and water retention Kininogen Bradykinin Inactive Increased prostaglandin synthesis Vasodilation Decreased peripheral vascular resistance Decreased blood pressure Kalikrein Converting Enzyme 2 2 1 1 X
ACE Inhibitors :ACE Inhibitors
Alpha blockers - Fears :Alpha blockers - Fears Postural hypotension
Reflex tachycardia
May aggravate angina
Alpha blockers – best used :Alpha blockers – best used Phaeochromocytoma
Peripheral vascular disease
Pregnancy
Prostatic hypertrophy, renal disease
Early morning BP surge
Metabolically neutral drug
Pregnancy and hypertensives :Pregnancy and hypertensives Safely use CCB, AB, labetolol and methyldopa
Never use diuretics, BB, Ace/Arb and other agents
Causes of Resistant Hypertension :Causes of Resistant Hypertension Improper BP measurement
Excess sodium intake
Inadequate diuretic therapy
Medication
Inadequate doses
Drug actions and interactions (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), illicit drugs, sympathomimetics, oral contraceptives)
Over-the-counter (OTC) drugs and herbal supplements
Excess alcohol intake
Identifiable causes of HTN
Antihypertensive treatment: Preferred drugs as per new European guidelines :Mancia G et al. J Hypertens 2007; 25:1105-1187. Antihypertensive treatment: Preferred drugs as per new European guidelines LVH=left ventricular hypertrophy
ESRD=end-stage renal disease
PAD=peripheral arterial disease
ISH=isolated systolic hypertension
Antihypertensive treatment: Preferred drugs as per new European guidelines :Mancia G et al. J Hypertens 2007; 25:1105-1187. Antihypertensive treatment: Preferred drugs as per new European guidelines LVH=left ventricular hypertrophy
ESRD=end-stage renal disease
PAD=peripheral arterial disease
ISH=isolated systolic hypertension
Antihypertensive treatment: Preferred drugs as per new European guidelines :Mancia G et al. J Hypertens 2007; 25:1105-1187. Antihypertensive treatment: Preferred drugs as per new European guidelines LVH=left ventricular hypertrophy
ESRD=end-stage renal disease
PAD=peripheral arterial disease
ISH=isolated systolic hypertension
Antihypertensive treatment: Preferred drugs as per new European guidelines :Mancia G et al. J Hypertens 2007; 25:1105-1187. Antihypertensive treatment: Preferred drugs as per new European guidelines LVH=left ventricular hypertrophy
ESRD=end-stage renal disease
PAD=peripheral arterial disease
ISH=isolated systolic hypertension
Summary :Summary Left ventricular hypertrophy
LV faliure, cardiac failure
ACS
HOCMP
MVP, regurgitant valve Indapamide, and all except diuretics
AceI, ArB, diuretics, BB, vasodilators
BB, Ace/Arb
BB, nonDHP
Ace/Arb, diuretics, BB
Summary :Summary Stenotic cardiac valves
Aortic dissection
B/L RAS
CNS disease, stroke, hemorrhage
Thyrotoxicosis
Pheochromocytoma Avoid Ace/Arb, D
BB, Ace/ Arb.
Avoid Ace/ARB
Avoid central agent, BB. Arb over Ace.
BB
AB + BB
Summary :Summary Renal failure
Hyperkalemia
Periph vasc disease
Hyperlipidemia
Hyperglycemia
Hyperuricemia CCB, D, Ace/Arb
Avoid Ace/Arb, BB
Avoid BB. USE AB
Avoid BB, D
Avoid BB, D
Avoid D
Slide 61:Consider prescription if:
• Sustained diastolic blood pressure of > 90 mm Hg or
• Isolated systolic hypertension of > 160 mm Hg and
• No other risk factors
Prescribe if:
• Target-organ damage or CVD, or
• Concomitant diseases such as diabetes mellitus or
• Other cardiovascular risk factors
Prescribe if:
• Diastolic blood pressure readings average > 100 mm Hg,
regardless of other factors Indications for PharmacotherapyAdults under 60 years (summary)
Slide 63:Standardized Therapy AlgorithmAdults over 60 years
Slide 64:Standardized Therapy Algorithm Adults under 60 years
ARBs Uses :ARBs Uses Usually Secondary to ACEi
Hypertension
CHF
Renal Insufficiency
Diabetes
Migraine prophylaxis
MOA of ACE Inhibitors :MOA of ACE Inhibitors Block formation of angiotensin II
Lowers TPVR
Reduces the release of aldosterone
Increases Na+ excretion
Increases K+ retention
Blocking the Renin-Angiotensin System :Blocking the Renin-Angiotensin System BP decreases MAINLY by lowered TPVR
Cardiac output is usually NOT significantly affected
For some reason, reflex sympathetic stimulation DOES NOT OCCUR
Absence of cardiostimulation makes these drugs safe in patients with ischemia
ACE Inhibitors- Side Effects :ACE Inhibitors- Side Effects Angioedema possible (0.1%)
Hypotension (especially with diuretics)
Acute renal failure in patients with renal artery stenosis (what with NSAIDs)
Hyperkalemia in patients taking potassium supplements or potassium sparing diuretics
ACE Inhibitors- Side Effects :ACE Inhibitors- Side Effects Dry, non-productive cough – 25% incidence
Alteration of taste
Allergic skin rashes, drug fevers
Absolutely contraindicated during 2nd and 3rd trimesters of pregnancy
Fetal hypotension
Fetal renal failure
Fetal malformation or death
Angiotensin Receptor Blockers :Angiotensin Receptor Blockers
Angiotensin Receptor Blockers: Mechanisms :Angiotensin Receptor Blockers: Mechanisms Agents block Angiotensin type 1 receptors (NOT angiotensin I receptors!!!)
Have no effect on bradykinin metabolism
Probably reduced cough and angioedema possibilities
Contraindicated during pregnancy
Losartan (Cozaar) and Valsartan (Diovan)
Slide 72:Angiotensinogen Angiotensin I Angiotensin II Vasoconstriction Increased peripheral vascular resistance Increased blood pressure Aldosterone secretion Increased sodium and water retention Kininogen Bradykinin Inactive Increased prostaglandin synthesis Vasodilation Decreased peripheral vascular resistance Decreased blood pressure Kalikrein Converting Enzyme 2 2 1 1 X X
ARB Side effects :ARB Side effects Hyperkalemia
Precipitate renal failure in bilateral renal artery stenosis
Contraindicated in patients experiencing angioedema from ACEi
Contraindicated during pregnancy
ARB Efficacy :ARB Efficacy ADA recommends ARBs for type 2 diabetics with microalbuminuria
As effective in blood pressure lowering as ACEi
May reduce overall cardiovascular death in diabetics with LVH, and in non-deabetic hypertensives (LIFE)
Decreases progression of microalbuminuria in type 2 diabetics
Decreases mortality in CHF (ELITE)
Slide 75:Indications for PharmacotherapyAdults under 60 years
Slide 76:Indications for PharmacotherapyAdults under 60 years
Slide 77:Indications for PharmacotherapyAdults under 60 years
Indications for Pharmacotherapy Adults over 60 years :Indications for Pharmacotherapy Adults over 60 years
Slide 79:Indications for PharmacotherapyDiabetics
Slide 80:Indications for PharmacotherapyDiabetics
Slide 81:Symp. Activity
(alpha adrenergic activity) Baroreceptor sensitivity RAARAASS activity Plasma cortisol, catecholamine
levels MBPS Thromboembolic tendency
Platelet aggregation
Hematocrit
Fibrinogen, PAI-1
Blood viscosity
Hypercoagulability
Fibrinolytic activity Impaired
endothelial function NO production atherosclerosis Shear stress
on vascular wall Vascular tone Cardiovascular events
MI
Sudden cardiac death
Ventricular fibrillation
Ventricular
tachyarrhythmia
Stroke
Target organ damage Hypertension 2005;45:485-86
AJH 2005; 18: 145-181