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Αντιυπερτασικά 2ης γραμμής β-αποκλειστές, ανταγωνιστές αλδοστερόνης, κεντρικώς δρώντα, κλπ
Πότε και σε ποιους;
Μιχάλης Δούμας Παθολόγος
Β’ΠΠ Κλινική ΑΠΘ
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Erdine. European Society of Hypertension Scientific Newsletter 2000
Hypertension poorly controlled worldwide Percentage of patients with controlled BP (<140/90 mm Hg)
Belgium 25% Canada 16% China 3% England 6% France 33%
Italy 9% Poland 4% Russia 6% Spain 16% USA 24%
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81%
1 additional CV
risk factor
19%
No additional CV risk
factors
Kannel WB. Am J Hypertens. 2000;13:3S-10S.
Framingham Offspring Study: Men aged 18–74
Less than 20% of HTN occurs in the absence of other
risk factors
Συν-νοσηρότητες
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β-αποκλειστές
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NICE – UK guidelines 2012
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Right driving
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God save the queen
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ASH/ISH
J Hypertens 2014
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JNC 8
JAMA 2014
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2013 ESH/ESC guidelines
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Διαβήτης - UKPDS
UKPDS, BMJ 1998
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β-αποκλειστές
στην υπέρταση
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Kaplan Meier curves for primary composite endpoint
Dahlof-LIFE, Lancet, 2002
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ASCOT-BPLA n=19257, ys 5.5
secondary endpoints
Stroke
23%
CV mortality
24%
Total mortality
24%
Total CV events
16%
Lancet, 2005
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INVEST
ατενολόλη έναντι βεραπαμίλης
Pepine, JAMA 2003
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Μετα-ανάλυση β-αποκλειστές
ΑΕΕ
Lindholm, Lancet 2005
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2013 ESH/ESC guidelines
Ενδείξεις αντιυπερτασικών φαρμάκων
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Είναι όλοι οι
β-αποκλειστές ίδιοι ;;;
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Μετα-ανάλυση
Ατενολόλη
Lindholm, Lancet 2005
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Μετα-ανάλυση
β-αποκλειστές εκτός ατενολόλης
Lindholm, Lancet 2005
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Ανταγωνιστές
αλδοστερόνης
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Primary aldosteronism
Douma, Lancet 2008
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Resistant hypertension
Small clinical studies
Nishizaka, Am J Hypertens 2003
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Spironolactone
ASPIRANT study
Vaclavik, Hypertension 2011
Office bp reduction: 6.5 / 2.5 mmHg
ABPM daytime reduction: 5.4 / 1.0 mmHg
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Congestive heart failure - Spironolactone
Pitt, NEJM 1999
30%
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Congestive heart failure – Eplerenone - EMPHASIS
Total mortality
Zannad, NEJM 2011
24%
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Post MI – EPHESUS
Total mortality
Pitt, NEJM 2003
15%
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Σε ποιους ασθενείς;;;
Doumas, 2014
• Primary aldosteronism
• Resistant hypertension
• Congestive heart failure
• Post MI
• Secondary aldosteronism
• Hypokalemia
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Adverse effects - Hyperkalemia
Juurlink, NEJM 2004
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Adverse effects - Gynecomastia
Doumas, 2014
• ASCOT 6%
• EPHESUS 1%
• Lower blockade of androgen and progesteron
receptors
• Cost ???
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Adherence to therapy
Strauch, J Hypertens 2013
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a-blockers
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Third line drug – ASCOT – Metabolic profile
Chapman, Circulation 2008
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0.00
0.02
0.04
0.06
0.08
0.10
0 1 2 3 4
Cu
mu
lati
ve
Eve
nt
Ra
te
Years of Follow-up
doxazosin chlorthalidone
Heart Failure
C: 15,268 D: 9,067
13,644 7,845
5,531 3,089
2,427 1,351
9,541 5,457
Rel Risk 2.04
z = 10.95, p < 0.0001
95% CI 1.79-2.32
ALLHAT
JAMA. 2000;283:1967-1975
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Σε ποιους ασθενείς;;;
Doumas, 2014
• Phaeochromocytoma
• BPH
• Resistant hypertension
• Hypertensive emergencies
• Reynaud's syndrome
• Sexual dysfunction?
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Tips to remember
Doumas, 2014
• Co-administration with PDE-5 inh?
• Orthostatic hypotension
• Urinary incontinence, especially in females, due
to bladder outlet relaxation
• Ophthalmic adverse events
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Sympatholytics
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Centrally acting drugs
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α-μεθυλντοπα
Σε ποιους ασθενείς;;;
Doumas, 2014
• 2nd most prescribed drug in the ’60s and ’70s after
diuretics
• Pregnancy
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Tips to remember
Doumas, 2014
• LVH
• Liver toxicity
• Haemolytic anaemia
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Κλονιδίνη
Σε ποιους ασθενείς;;;
Doumas, 2014
• Phaeochromocytoma diagnosis
• Resistant hypertension
• Hypertensive urgencies
• Stroke
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Κλονιδίνη
Adverse effects
Doumas, 2014
• Sedation
• Dry mouth
• Sodium and water retention
• Rebound hypertension
• Severe hypotension
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Κλονιδίνη
Άλλες καταστάσεις
Doumas, 2014
• Opiate – alcohol withdrawal
• Alcoholic cirrhosis
• Menopausal hot flashes
• Diarrhea in diabetic neuropathy
• Restless legs
• Perioperative use???
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Effects of moxonidine (0.4mg/day for 8 weeks) in hypertensive patients with reduced insulin sensitivity in a double-blind, placebo-controlled, randomised, parallel group study
31. Haenni A, Lithell H. J Hypertens 1999;17(Suppl 3):S29-S35
% change
from baseline
GLUCOSE INFUSION RATE
INSULIN SENSITIVITY INDEX
25 -
20 -
15 -
10 -
5 -
0 -
- 5 -
-10 -
- 6.0%
p=0.004
N.S.
p=0.026
21%
- 6.0%
p=0.027
21%
p=0.056
N.S.
placebo (n=13)
moxonidine (n=25)
Μοξονιδίνη – Γλυκαιμικό προφίλ
Insulin sensitivity evaluated by hyperinsulinaemic euglycaemic clamp test. Insulin sensitivity index = glucose infusion rate/mean insulin concentration at steady-state
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Moxonidine – Heart Failure
MOXCON study
Cohn J, Eur J Heart Fail 2003
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Peripheral acting drugs
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Ρεζερπίνη
Doumas, 2014
• Indian snake Rauwolfia serpentina
• Very effective
• Severe sodium retention – Always with diuretic
• Hygroton-reserpine (0,25-50mg)
• Sedation, depression
• Diarrhea, cramps
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Direct vasodilators
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Υδραλαζίνη
Doumas, 2014
• Restricted use nowadays
• Pregnancy?
• Blacks – Heart failure
• Resistant hypertension
• Oral form not available in Greece (IFET)
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Υδραλαζίνη
Doumas, 2014
• Headache, flush, tachycardia
• Nausea, vomiting, diarrhoea
• Paresthesia, tremor, muscle cramps
• Lupus like syndrome, Fever, Arthritis
• Not in CAD, dissecting aortic aneurysm, recent ICH
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Μινοξιδίλη
Doumas, 2014
• Very potent
• Very useful in CKD
• Always use with b-blockers - 90% ST-T
change within 2 weeks, later resolve
• Fluid retention - Diuretics in high doses
• 2.5-20mg once daily
• Hirsutism
• Pericarditis
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Chateau Lafite
World’s most expensive wine
Doumas, 2014
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Take home message
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Nitrates for ISH
Stokes, Hypertension 2005
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Questions?
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a-methyldopa – LVH
Prevention
Sen, Circ Res 1974
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Peripheral
sympatholytics
Ganglion
blockers
Veratrum
alkaloids
1940’s 1950 1957 1960’s 1970’s 1980’s 1990’s 2001
Effectiveness
Tolerability
Evolution of antihypertensive therapy
Doumas, Loutraki 2011
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But …
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Evolution of
Antihypertensive Therapies
Direct
vasodilators
a-blockers
VPIs
Others
Peripheral
sympatholytics
Ganglion
blockers
Veratrum
alkaloids
Central α2
agonists
Calcium
antagonists-
non DHPs
β-blockers
Spironolactone
Thiazides
diuretics
Calcium
antagonists-
DHPs
ARBs
1940’s 1950 1957 1960’s 1970’s 1980’s 1990’s 2001
ACE
inhibitors
Effectiveness
Tolerability
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Sharon Stone
Doumas, Loutraki 2011
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The devil is in the details
Doumas, Delfoi 2014
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Losartan Atenolol
Drug doses
50 mg only 434 (9%) 436 (10%)
50 mg plus additional drugs* 844 (18%) 930 (20%)
100 mg with or without 2284 (50%) 1979 (43%)
additional drugs*
Alone 95 (2%) 78 (2%)
With HCTZ only 829 (18%) 713 (16%)
With other drugs only 162 (4%) 172 (4%)
With HCTZ and other drugs 1198 (26%) 1016 (22%)
Off study drugs 1043 (23%) 1243 (27%)
*Including hydrochlorothiazide (HCTZ).
Number of participants on study drug at endpoint or end of follow-up
Dahlof-LIFE, Lancet, 2002
LIFE STUDY
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ASCOT-BPLA n=19257, ys 5.5
Primary endpoints (Non-fatal MI and fatal CHD)
Lancet, 2005
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ASCOT: BP over time by treatment group 78% combination treatment
136.1/77.4 137.7/79.2 Final
Mean ΔBP
3 month
163.4/94.8 163.6/95.1 Baseline
Amlodipine/Perind Atenolol/Diur Time point
2.7/1.9
1.6/1.8
Δ (mmHg)
5.9/2.4
Dahloff, Lancet, 2005
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Doumas, Delfoi 2014
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Συνεπώς…
Doumas, Delfoi 2014
Οι β-αποκλειστές
έχουν ένδειξη
τουλάχιστον για κάποιες
ομάδες ασθενών
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Συμπεράσματα
Καθημερινή κλινική πράξη
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2013 ESH/ESC guidelines
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Resistant hypertension
Low PRA
Doumas, Loutraki 2011
100 ―
80 ―
60 ―
40 ―
20 ―
0 ― Birmingham Oslo
67%
75%
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Aldosterone antagonists
Reduce the number of sacks on the wagon
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Aldosterone effects on the kidney and heart
Dluhy, NEJM 2004
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Post MI –EPHESUS
Sudden Cardiac Death
Pitt, NEJM 2003
21%
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Post MI – EPHESUS
Total mortality – HTN history
Pitt, Hypertension 2008
29%
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Tips to remember
Doumas, Loutraki 2011
• How to use – When to stop
• Proteinouria
• Left ventricular hypertrophy
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Hyperkalemia -EPHESUS
Pitt, Circulation 2008
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Hyperkalemia -EPHESUS
Pitt, Circulation 2008
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Case report
Doumas, Loutraki 2011
• Vasilis H.
• 42 years old, Reporter
• Albuminuria: 3.8 gr/day, SCr: 1.6 mg/dl
• Unsuccessful renal biopsy – Denied retry
• Candesartan 32mg
• Albuminuria: 2.9 gr/day
• Spironolactone: 50mg
• Urinary albumin: 250 mg/day
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Spironolactone -Albuminuria
Mehdi, JASN 2009
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Eplerenone -Albuminuria
Epstein, Clin J Am Soc Nephrol 2006
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Case report
Doumas, Loutraki 2011
• Hristos K.
• 58 years old, Doctor
• On triple therapy for 3y
• Severe LVH: 192 gr
• BP: 156/96 mmHg
• Spironolactone: 50 25mg for 1y
• LVMI: 154 gr
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Left ventricular hypertrophy
Pitt, Circulation 2003
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Alpha blockers
Doumas, Loutraki 2011
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Some a-receptor blocking agents
Tolazoline
Prazosine
NNH
CH2
NNH
CH2
N
CH3
OH
Phentolamine
O
N
N
N
N
CH3OCH
3O
NH2
O
block both a1 and a2 blocks a1 selectively
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ESH guidelines
Thiazide diuretics
ACE inhibitors
β-blockers Angiotensin receptor antagonists
Calcium antagonists α- blockers
The preferred combinations in the general hypertensive population are represented as thick lines. The frames indicate classes of agents proven to be beneficial in controlled intervention trials
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Decision to Drop
an ALLHAT Arm
January 24, 2000 – NHLBI Director accepts the
recommendation of an independent review group to
terminate doxazosin arm
Futility of finding a significant difference for primary outcome
Statistically significant 25 percent higher rate of major secondary endpoint, combined CVD outcomes
ALLHAT
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Comparison of Doxazosin with Chlorthalidone - Conclusions
Doxazosin is not recommended as first-line therapy in hypertension.
ALLHAT does not allow an assessment of the effect of doxazosin compared with placebo on the incidence of CVD.
The use of doxazosin as a step-up drug for treating hypertension was not tested in this trial.
These findings are likely to apply to all alpha-blockers.
ALLHAT
JAMA. 2000;283:1967-1975
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Case report
Doumas, Loutraki 2011
• Maria K.
• 68 years old, HTN-DM
• Resistant hypertension
• Hytrin 5mgX2
• First dose: 1mg
• Severe orthostatic hypotension
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Case report
Doumas, Loutraki 2011
• Kostas V.
• 74 years old, HTN-BPH
• Cataract surgery
• Retinal detachment
• Tamsulozin
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Case report
Doumas, Loutraki 2011
• Vasiliki A.
• 64 years old, HTN
• ACE-inh- diuretic fixed combo
• Hytrin 3 months
• Urinary incontinence
• Gynecological – Urological exams: Within normal
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a2-Adrenergic Agonists Reduce Blood Pressure by
Reducing Sympathetic Output from the Brain
Brain
Brain Stem (Cardiovascular Control Center)
Kidney
Heart
Sympathetic ganglion
b1 Receptors
a2 Receptors
b1 Receptors
a1 Receptors
Decreased sympathetic tone
• Decr. HR
• Decr. Contractility
• Decr. Renin release
• Decr. Vasoconstriction
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a-Methyldopamine acts as a ‘false transmitter’
in the central nervous system
G
a2
Release
Reuptake Feedback
inhibition
a2 Postsynaptic
inhibition a1
Postsynaptic
stimulation
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Case report
Doumas, Loutraki 2011
• Hristos K.
• 58 years old, Doctor
• On triple therapy for 3y
• Severe LVH: 192 gr
• BP: 156/96 mmHg
• Spironolactone: 50 25mg for 1y
• LVMI: 154 gr
Aldomet 500mgX2 BP: 134/82 mmHg LVMI: 121 gr
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Case report
Doumas, Loutraki 2011
• Andriani A.
• 72 years old, HTN
• Aldomet 500mg X3
• SGOT:76, SGPT:94, Bil: 3,8, Albumin: 2.8, INR: 1,4
• Alcohol: no – Viral: negative
• Biopsy
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Liver biopsy
Doumas, Loutraki 2011
Steroids
Partial improvement
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Case report
Doumas, Loutraki 2011
• Niki D.
• 76 years old, HTN
• Aldomet 500mg X2
• Anemia, Splenomegaly, Ht: 28, LDH:1200, Ret:6%
• Hemolytic anemia
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(+)
Nor-Ad
a1, b1
a2
(-)
Directly stimulates pre-synaptic brain a-2 receptors
& sympathetic activity
Clonidine
Mode of action
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Clonidine - Perioperative
Wallace, Anesthesiology 2004
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Reserpine inhibits the vesicular accumulation of
catecholamines and of serotonin
n H+ ATP ADP + Pi
n H+
Dopamine+
n H+
H+
Dopamine+
Dopamine
Reserpine
Dopamine
H+
•Blocks reuptake of catecholamines at sympathetic nerve endings
•Depletes store & release of nordrenaline, dopamine & 5-HT in peripheral & central
neurons
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Vasodilators
minoxidil
hydralazine
NO
Ca++
Ca++ Na+ K+
DA
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Combination of isosorbide and
hydralazine in blacks with HF • V-HeFT I suggests
that black patients more likely to benefit
• 1050 blacks randomized to fixed dose iso/hydra or placebo + standard therapy
• NYHA III & IV
• Improved survival and QOL
Taylor. NEJM 2004;351:2049-2057
Over
all
surv
ival
(%
) Days since baseline visit
Iso + Hydra
Placebo
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Minoxidil - pericarditis
Krehlik, BMJ 1985
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Adverse effects
Doumas, Loutraki 2011
• Hyperkalemia
• Renal function deterioration
• Gynecomastia
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0.00
0.05
0.10
0.15
0.20
0.25
0.30
0 1 2 3 4
Cu
mu
lati
ve
Eve
nt
Ra
te
Years of Follow-up
doxazosin
chlorthalidone
Cardiovascular Disease
C: 15,268 D: 9,067
12,990 7,382
9,443 5,285
4,827 2,654
2,010 1,083
Rel Risk 1.25
z = 6.77, p < 0.0001
95% CI 1.17-1.33
ALLHAT
JAMA. 2000;283:1967-1975
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a-blockers prescription patterns
Stafford, JAMA 2004
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Adverse effects
Doumas, Loutraki 2011
• First dose effect
• Orthostatic hypotension
Graham, BMJ 1976
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Female urinary incontinence
Thien, Br Med J 1978 – Rubu J Am Geriatr Soc 2010
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How to?
Doumas, Loutraki 2011
• Start: 250mg X2
• Maximum 1500mg X2
• CKD: Half dose
• Maximum efficacy: 4h
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a-methyldopa – LVH
Therapy
Sen, Circ Res 1974
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a-methyldopa
Liver toxicity
Toghill, Br Med J 1974
Methyldopa withdrawal
Full recovery
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a-methyldopa
Hemolytic anemia
McGuinnes – Surveyor 1968
Steroids Methyldopa withdrawal
Full recovery
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How to?
Doumas, Loutraki 2011
• Start: 0.075mg X2 (1/2 X2)
• Maximum: 0.6mg X2 (4 X2)
• Action: 30min
• Maximum efficacy: 2-4h
• Duration: 8-12h
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Centrally acting drugs
Adapted from van Zwieten PA. J Hypertens 1997; 15 (Suppl. 1): S3S8.
a -Methyldopa
a αδρενεργικοί υποδοχείς I1- Ιμιδαζολινικοί υποδοχείς
ΚΛΟΝΙΔΙΝΗ
Μη- εκλεκτικά
Εκλεκτικά Εκλεκτικά
ΜΟΞΟΝΙΔΙΝΗ
Σιελογόνοι
αδένες
ΞΗΡΟΣΤΟΜΙΑ ΚΑΤΑΣΤΟΛΗ
NTS RVLM Υπομέλας
πυρήνας
Αναστολή της συμπαθητικής δραστηριότητας
Αναστολή της απελευθέρωσης νοραδρεναλίνης
Μείωση της αγγειοσυστολής
Αγγειοδιαστολή
ΜΕΙΩΣΗ ΤΗΣ
ΑΡΤΗΡΙΑΚΗΣ ΠΙΕΣΗΣ
NTS = τελικός πυρήνας του πνευμονογαστρικού RVLM = Ρυγχοειδής πυρήνας προσθιοπλάγιας
και του γλωσσοφαρυγγικού νεύρου περιοχής του προμήκη μυελού
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The VA Cooperative Study, 1967
Cohort 143 men
Mean age 51 years
Eligibility Diastolic BP 115-129 mmHg
Design Double blind; placebo control
Therapy HCTZ, reserpine, hydralazine
Duration 1.5 years
BP change -43/30 mmHg
VA Cooperative Study Group. JAMA. 1967;202:1028-1034.
HCTZ=hydrochlorothiazide
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Aldosterone - Discovery
Simpson and Tait 1951
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Aldosterone-Mediated Vascular Injury
Joffe, Heart Fail Rev 2005
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Hyperkalemia – Renal function
Doumas, Loutraki 2011
• Check serum potassium at 3d, 1w, 3w, 3 to 6m
according to potassium levels
• Check serum creatinine at the same timepoints
• Extreme caution when GFR<30 or Creatinine
>2.5mg/dl or potassium >4.8
• Stop if creatinine >4 or potassium >6mg/dl
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ΑΡΤΗΡΙΑΚΕΣ ΠΙΕΣΕΙΣ
50
75
100
125
150
175
200
225
250
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
ΗΜΕΡΑ ΝΟΣΗΛΕΙΑΣ
Phaeochromocytoma – Pre-op use
Doumas, Loutraki 2011
ΧΕΙΡΟΥΡΓΕΙΟ
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Third line drug - ASCOT
Chapman, Circulation 2008
10/6 mmHg
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Cindy Crawford
Doumas, 2014
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Υπάρχει θέση για τα
αντιυπερτασικά 2ης γραμμής???
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Resistant hypertension
ASCOT trial
Chapman, Hypertension 2007