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Antihypertensive Drugs Clinical Pharmacology of Oral Antihypertensive Drugs

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Pharmacology & Toxicology Wright State University Boonshoft School of Medicine Antihypertensive Drugs Mariana Morris, Ph.D. mariana.morris_at_wright.edu – PowerPoint PPT presentation

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Title: Antihypertensive Drugs Clinical Pharmacology of Oral Antihypertensive Drugs


1
Pharmacology Toxicology Wright State
University Boonshoft School of Medicine
Antihypertensive Drugs
Mariana Morris, Ph.D. mariana.morris_at_wright.edu 93
7 775 2463
2
HYPERTENSION - THE SILENT KILLER
  • Few Symptoms
  • Effects gt 24 Population
  • Increases with Age
  • Major Public Health Problem

3
CONSEQUENCES OFUNCONTROLLED HYPERTENSION
  • Stroke
  • Kidney Disease
  • Heart Attack
  • Vascular Problems

4
P
r
e
v
a
l
e
n
c
e

o
f

H
y
p
e
r
t
e
n
s
i
o
n
20
H
y
p
e
r
t
e
n
s
i
v
e
D
A
P
gt
9
0

m
m
H
g
10
of Patient Population
0
50
60
70
80
90
100
110
Diastolic Blood Pressure (mmHg)
5
Prevalence of Hypertension in the USA
Race/Ethnic Group
40
30
gt 24
Prevalence ()
20
10
0
Hispanic
Blacks
Whites
Overall
6
JNC 7 Seventh Report of the Joint National
Commission
PREVENTION DETECTION TREATMENT OF HIGH BLOOD
PRESSURE
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
National Heart, Lung, and Blood Institute
7
  • Why Do We Need Guidelines for Hypertension?
  • More than 50 million people with hypertension
  • 14 overall, more than half of people gt age 60
  • Only 1 in 2 on drug treatment
  • to lower BP
  • Only 1 in 4 age 18-74 controlled to
  • lt140/lt90 in USA

8
(No Transcript)
9
Antihypertensive Agents
  • Therapeutic goals in hypertension
  • To lower the high blood pressure and reduced
    cardiovascular morbidity and mortality by least
    intrusive means.
  • For most of the HTN patients life-long treatment
    of an asymptomatic disease

10
Antihypertensive DrugsNew End-Points
  • Effects on hard end-points
  • Mortality
  • Stroke
  • Heart attacks
  • Effects on end-organ damage
  • Left ventricular and vascular hypertophy
  • Effects on renal function
  • Effects on metabolic status
  • Blood lipids and glucose

11
  • New BP Goals
  • lt140/lt90 and lower if tolerated
  • lt130/lt80 in diabetics
  • lt130/lt85 in cardiac failure
  • lt130/lt85 in renal failure
  • lt125/lt75 in renal failure with
  • proteinuriagt1.0 g/24 hours

12
Blood Pressure Cardiac Output X
Peripheral Resistance
Preload Contractility Heart Rate

Vasoconstriction
Arteriolar
Venous
Venous
Circulating Fluid Volume
Vascular Smooth Muscle
Renal Sodium Handling
Sympathetic Nervous System
Renin Ang Aldo System
Vascular remodeling
13
Major Antihypertensive Drug Groups
  • Diuretics
  • Sympatholytics
  • Renin Angiotensin System (RAS) Antagonists
  • Vasodilators

14
Use of Antihypertensive Drugs in United States
Diuretics

Ca Antagonist
ACEIs
b - Blockers
Other
Antihypertensive
year
15
Diuretics
  • Thiazides and thiazides-like diuretics
  • Aldosterone antagonists
  • Potassium sparing diuretics
  • Loop diuretics




16
Diuretics
Inhibition of Sodium Reabsorption
Reduced Circulating Volume Reduced
Preload Reduced Cardiac Output
17
(No Transcript)
18
Diuretics Thiazides
  • Initial effects natriuresis, diuresis, reduced
    extracellular and circulating volume)
  • Chronic effect reduction in peripheral vascular
    resistance (direct vasodilating effect)
  • African Americans, elderly, obese
  • Combined with ACEIs and beta blockers

19
Diuretics Thiazides
  • Distal Convoluted Tubule
  • Na/Cl Symport Inhibitors
  • Bendroflumethiazide NATURETIN
  • Benzthiazide EXNA
  • Chlorothiazide DIURIL
  • Hydrochlorothiazide HYDRODIURIL
  • Hydroflumethiazide SALURON
  • Methyclothiazide ENDURON
  • Polythiazide RENESE

20
Diuretics Thiazides-like
  • Distal Convoluted Tubule
  • - Na / Cl Symport Inhibitors
  • Sulfonamide related compounds
  • Chlorthalidone HYGROTON
  • Indapamide LOXOL
  • Metolazone MYKROX, ZAROXOLYN
  • Longer acting and more powerful.

21
Diuretics Thiazides
  • Side Effects
  • At low doses thiazides are well tolerated
  • Hypokalemia
  • Lipid elevation
  • Glucose intolerance
  • Hyperuricemia
  • Hypercalcemia

22
Diuretics Thiazides
  • Side Effects
  • The metabolic side-effects of diuretics
  • do not compromise their expected
  • beneficial (blood pressure lowering )
  • effects on cardiovascular mortality.

23
Diuretics Thiazides
  • YES (useful in)
  • Elderly patients
  • African Americans
  • When cost is crucial
  • When salt intake is high
  • Combined with other first line antihypertensive
    drugs
  • No (avoid in)
  • Patients with NIDDM
  • Patients with
  • hyperlipidemia, gout or
  • arrhythmias
  • Glomerular Filtration Rate
  • lt 30ml/min

24
Loop Diuretics
  • Act in Loop of Henle
    (blocks Na/K/2Cl- symporter)
  • Furosemide LASIX
  • Bumetanide BUMEX
  • Ethacrynic Acid EDECRIN
  • Second line anti-hypertensive drug
  • Used in hypertensive patient with chronic
  • renal disease for volume/salt control
  • Toxicity K depletion, hypokalemia

25
Diuretics - Potassium Sparing
  • Potassium-Sparing Diuretics
  • Amiloride MIDAMOR
    Triamterene DYRENIUM, MAXZIDE
  • Acts in distal convoluted tubule and collecting
    duct to inhibit ENac channel
  • Promotes Na excretion without K
  • Second line antihypertensive drug
  • Used in combination drugs
  • sed in combination or for correction of
    hypokalemia

26
Aldosterone Antagonists
27
Afterload
a2
Vasomotor center
Volume Kidneys
Cardiac Output Heart
b1
Renin
b1
V
V
Ang I
Preload
Ang II
b2
a1
BP CO x TPVR
Aldosterone
VSMCs
Capacitance venules
Resistance arterioles
Aldosterone Antagonists
TPVR
28
Aldosterone Antagonists
Vascular inflammation and injury
Prothrombotic effects
Potassium and magnesium loss
Myocardial Fibrosis
Central hypertensive effects
Deleterious Effects of Aldosterone
Catecholamine potentiation
Endothelial dysfunciton
Ventricular arrhythtmias
Sodium Retention
Cardiovascular Disease
McMahon EG Current Opinion Pharmacol, 1190-196,
2001
29
Aldosterone Antagonists
  • Aldosterone Functions
  • Classical Renal-Ion Transport
  • Site of Action Collecting duct
  • Increases Na reabsorption (Active)
  • Increases K excretion (Passive?)
  • Increases H excretion (Active passive)

30
Spironolactone ALDACTON - Hyperaldosteronism
- In severe heart failure (NYHA Class IV),
improves survival and reduces
hospitalization (RALES Study) -
Hyperkalemia, Gynecomastia
Eplerenone INSPRA - Hypertension and
post-MI heart failure (EPHESUS study) -
Anti-oxidant effects (?) - Less adverse
effect - Expensive
Aldosterone Antagonists
31
Beta Blockers ( lol)
32
Afterload
?
a2
Vasomotor center
Volume Kidneys
Cardiac Output Heart
b1
Renin
b1
V
V
Ang I
Preload
Ang II
b2
a1
?
BP CO x TPVR
Aldosterone
VSMCs
Capacitance venules
Resistance arterioles
b - Blockers
TPVR
33
_________________________ - Reduction in cardiac
output - Inhibition of renin release - Central
neural effects - Reduction in venous return
and plasma volume - Reduction in peripheral
resistance - Improvement in vascular compliance -
Resetting of baroreceptor function - Attenuation
of pressor response to catecholamines (stress,
exercise) _________________________
ß Blockers
Negative Chronotropic Inotropic Effects
Inhibition of Renin Release
34
  • ß Blockers
  • Cardioselectivity (ß -1 vs ß -2 )
  • Intrinsic Sympathomimetic Activity (ISA partial
    agonistic activity)
  • Affinity for a -1 adrenergic receptors
    (Labetalol, Carvedilol)

35
  • ß Blockers
  • Pharmacokinetics
  • Lipophilic vs. Hydrophilic
  • Renal vs. hepatic elimination
  • Distribution (CNS)
  • Membrane-Stabilizing Activity (MSA)
  • Quinidine-like or local anesthetics effects on
    cardiac action potential
  • Clinically not relevant

36
  • ß Blockers
  • There are numerous ß blockers on the market
  • Approved for hypertension and for one or more of
    following indications
  • Angina pectoris
  • Myocardial Infarction
  • Ventricular arrhythmia
  • Migraine prophylaxis
  • Heart Failure
  • Perioperative Hypertension

37
ß Blockers ( lol)
  • ß -1-Selective
  • Acebutolol SECTRAL
  • Atenolol TENORMIN
  • Betaxolol KERIONE
  • Bisoprolol ZEBETA
  • Esmolol BREVIBLOC
  • Metoprolol LOPRESSOR
  • ß-1,2-Non-Selective
  • Propranolol INDERAL
  • Nadolol CORGARD
  • Carteolol CARTROL
  • Timolol BLOCADREN
  • Pindolol VISKEN
  • Sotalol BETAPACE
  • Penbutol LEVATOL

- ISA
  • ß -1,2/Alpha 1Selective
  • Labetalol TRANDATE, NORMODYNE
  • Carvedilol COREG

38
  • ß Blockers
  • Side Effects
  • Bronchospasm
  • Bradicardia/heart block
  • Mask and prolong the symptoms of hypoglycemia
  • Abrupt withdrawal can precipitate MI
  • Cold extremities, Raynauds phenomenon
  • Decreased exercise tolerance fatigue,
    depression and impotence
  • CNS sleep disturbance, vivid dreams, nightmares
  • Effects of plasma lipids

39
  • ß Blockers
  • YES (useful in)
  • Younger patients
  • Anxious patients
  • Angina pectoris
  • Post-MI patient
  • No (avoid in)
  • Patients with COPD
  • Patients with peripheral
  • vascular disease
  • 2nd and 3rd degree block

40
Angiotensin Converting Enzyme Inhibitors (ACEIs)
41
Afterload
a2
Vasomotor center
Volume Kidneys
Cardiac Output Heart
b1
Renin
b1
V
V
Ang I
Preload
Ang II
b2
a1
BP CO x TPVR
Aldosterone
VSMCs
Capacitance venules
Resistance arterioles
ACE Inhibitors
TPVR
42
Angiotensin Converting Enzyme
Angiotensinogen
Kininogens
Kallikrein Renin
Angiotensin I
Bradykinin
ACEIs
A C E
ACEIs
Angiotensin II
Inactive Peptides
BK receptors
AT-1 receptors
43
ACE Inhibitors Antihypertensive Mechanisms
  • Inhibition of circulating RAS
  • Inhibition of tissue and vascular RAS
  • Modulation of sympathetic activity
  • Decreased formation of endothelin from
    endothelium
  • Increased formation of bradykinin and
    vasodilatory prostaglandins
  • Decreased sodium retention (decreased aldosterone
    secretion, and/or increased renal blood flow)

44
ACEIs Prevention of vascular disease
VSMC growth VSMC migration Matrix
synthesis Platelet aggregation t-PA t-PA inhibitor
Ang II BK
ACEIs
- HOPE Study
45
mRNA
mRNA
mRNA
Angiotensinogen
A C E
Renin
Local (tissue) RAS Intrinsic Extrinsic
Ang I
Ang II
Angiotensinogen
Angiotensinogen
(myocyte )
Renin
(VSM cells)
tissue
A T1
A T1
endothelial cell
ACE
(autocrine)
blood vessel
Ang I
Renin (renal)
Ang II
(paracrine)
ACE
Ang I
Angiotensinogen
Ang II
(endocrine)
(liver)
A C E
mRNA
mRNA
mRNA
Angiotensinogen
Renin
A C E
46
ACEIs Prevention of renal disease
INTRAGLOMERULAR PRESSURE
Angiotensin II
Arterial pressure
Angiotensin II



Afferent arteriole
Efferent arteriole
20 mmHg
excess glomerular pressure hyperfiltration
microalbuminuria
Bowmans capsule
47
ACE Inhibitors ( pril)
  • Captopril CAPOTEN
  • Enalapril VASOTEC
  • Lisinopril PRINIVIL, ZESTRIL
  • Benazepril LOTENSIN
  • Fosinopril MONOPRIL
  • Quinapril ACCUPRIL
  • Ramipril ALTACE
  • Spirapril RENOMAX

Moexipril UNIVASC Perindopril
ACEON Trandolapril MAVIK
48
ACE Inhibitors
Indications 80s - Hypertension 90s -
Heart Failure 95 - Left Ventricular
Dysfunction 95 - Diabetic Nephropathy 96
- Acute Myocardial Infarction
49
ACE Inhibitors Classification
  • Chemical classification
  • Sulfhydryl-group
  • Captopril
  • Carboxyl-group
  • benazepril, enalapril, lisinopril, quinapril,
    ramipril, spirapril
  • Phosphoryl -group
  • fosinopril
  • Pharmacokinetic classification
  • Class I Captopril - like
  • Captopril
  • Class II Pro-Drug
  • benazepril, enalapril, fosinopril, quinapril,
    ramipril, spirapril
  • Class III Not Metabolized
  • lisinopril

50
ACE Inhibitors ( pril)
  • Side effects
  • Cough
  • Hypotension
  • Hyperkalemia
  • Angioedema
  • Renal Insufficiency
  • Fetal injury renal damage
  • High-dose Captopril Adverse effects
  • ( Neutropenia, Impaired taste, Proteinuria )

51
  • ACE Inhibitors ( pril)
  • YES (useful in)
  • Younger patients
  • Post MI LV dysfunction
  • Patient with heart failure
  • Diabetic patients
  • Metabolic disorders
  • (hyperlipidemia, gout)
  • No (avoid in)
  • Renal artery stenosis
  • Fluid-depleted patients
  • Pregnancy

52
Angiotensin Receptor Blockers (ARBs)
53
Afterload
a2
Vasomotor center
Volume Kidneys
Cardiac Output Heart
b1
Renin
b1
V
V
Ang I
Preload
Ang II
Ang II
b2
a1
BP CO x TPVR
Aldosterone
VSMCs
Capacitance venules
Ang II
Resistance arterioles
Ang II Receptor Blockers
TPVR
54
Ang II Receptor Blockers (...sartans)
  • Sartans are selective and competitive antagonists
    of angiotensin II type 1 (AT1) receptors and do
    not inhibit AT2 receptors
  • The physiological function of angiotensin II is
    mediated by AT1 receptors (vasoconstriction,
    catecholamine release, aldosterone synthesis, and
    renal sodium and water retention)
  • Blockade of AT1 receptors increases plasma levels
    of Angiotensin I, Angiotensin II, and PRA

55
Actions of Angiotensin II
Site of Action Cellular Effect
Consequence
Myocyte, IP3 and Ca increase Constriction
Cardiocyte Protein kinase C Expression
of proto- Fibroblast stimulation
oncogenes cell growth Sympathetic Nerve
Endings Enhanced NE release Enhanced
Vasoconstriction Glomeruli Efferent arteriolar
Promotes constriction microalbuminuria Enl
arges glomerular pores Proteinuria
Juxtaglomerular Renin inhibition Relief
of raised Apparatus intraglomerular
pressure Adrenal Cortex Synthesis of
Aldosterone Increased sodium retention and
kaliuresis Fibrinolytic Increase of
plasminogen Impaired fibrinolysis System
activator inhibitor-1
56
A n g i o t e n s i n II
Peripheral resistance
Renal function
Cardiovascular structure

1. Non-hemodynamic effects - Increased
expression of proto-oncogenes -
Increased production of growth factors
- Increased synthesis of extracellular
matrix proteins 2. Hemodynamic effects
- Increased afterload (cardiac)
- Increased wall tension (vascular)
1. Direct vasoconstriction 2. Enhancement of
peripheral noradrenergic
neurotransmission 3. Increased central (CNS)
sympathetic discharge 4. Release of
catecholamines from adrenal medulla
1. Increases Na reabsorption 2. Releases
aldosterone from adrenal cortex 3.
Altered renal hemodynamics - renal
vasoconstriction - increased noradrenergic
neurotransmission in kidney -
Increased renal sympathetic tone (CNS)
Rapid Pressor Response
Slow Pressor Response
Cardiovascular Hypertrophy and Remodeling
57
Ang II Receptor Blockers (...sartans)
  • Losartan COZAAR
  • Valsartan DIOVAN
  • Irbesartan AVAPRO
  • Candesartan ATACAND
  • Eprosartan TEVETEN
  • Tasosartan VERDIA
  • Telmisartan MICARDIS

58
Ang II Receptor Blockers (...sartans)
  • Side effects
  • Dizziness
  • Angioedema has been reported rarely
  • Hyperkalemia, comparable with that seen in
    patients treated with ACEIs
  • Risk of fetal injury and death
  • Risk of symptomatic hypotension in hypovolemic
    patients
  • Except for the absence of cough, Yes (useful
    in)
  • and No (avoid in) same as for ACE
    inhibitors

59
ACE and Non-ACE Pathways of Angiotensin II
Production
  • Non-Renin Pathway
  • Cathepsin G and Tonin
  • Non-Renin Pathway
  • Chymase

Angiotensinogen Ang I
Ang II Renin
ACE
60
ACE Inhibitors vs AT1 Antagonists
Example Fibrinolytic System
Angiotensinogen
Kininogens
Bradykinin Inactive Peptides
Kallikrein Renin
A C E Is
Angiotensin I
A C E
Angiotensin II
tPA
PAI-1
Plasminogen Activators
PAI-1


Endothelial Cell
61
  • Ang II Receptor Blockers (...sartans)
  • Angiotensin Receptor Blockers vs ACE Inhibitors
  • ACEIs effects of bradykinin
  • Effects of ARBs on non-ACE and non-renin
    pathways of Ang II production
  • Combination of ACEI ARB for treatment of renal
    disease

62
Calcium Channel Blockers (CCBs)
63
Afterload
a2
Vasomotor center
Volume Kidneys
Cardiac Output Heart
b1
Renin
b1
V
V
Ang I
AV
Preload
Ang II
BP CO x TPVR
Aldosterone
Ca
Capacitance venules
L-type Ca channels
Resistance arterioles
Calcium Channel Blockers
TPVR
64
Calcium Channel Blockers Mechanisms and Sites of
Action
Block transmembrane entry of calcium into
arteriolar smooth muscle cells and cardiac
myocytes thus inhibiting excitation-contraction
Negative Inotropic and Chronotropic Effects
Produce Vasorelaxation at Arterioles
L-type Ca channels
Reduced Peripheral Resistance
VerapDiltigtNifed
NifedgtDiltiVerap
65
Calcium Channel Blockers
  • Phenylalkylamine
  • Verapamil CALAN, ISOPTIN,VERELEN
  • Benzothiazepine
  • Diltiazem CARDIZEM, DILACOR
  • Dihydropyridines
  • Amlodipine NORVASC
  • Felodipine PLENDIL
  • Isradipine DYNACIRC
  • Nicardipine CARDENE
  • Nimodipine NIMOTOP
  • Nifedipine PROCARDIA, ADALAT
  • long-acting or slow-release
  • formulations should be used
  • for high blood pressure

66
Calcium Channel Blockers
Pharmacologic Effects of Calcium Channel Blockers Pharmacologic Effects of Calcium Channel Blockers Pharmacologic Effects of Calcium Channel Blockers Pharmacologic Effects of Calcium Channel Blockers
Effect Verapamil Diltiazem Dihydropyridines
Peripheral Vasodilation ? ? ??
Heart Rate ?? ? ?
Cardiac Contractility ?? ? 0 / ?
SA / AV Nodal Conduction ? ? 0
Coronary Blood Flow ? ? ??
67
  • Calcium Channel Blockers
  • Side effects
  • Facial Flushing
  • Headaches
  • Non-pitting ankle edema
  • Constipation
  • Increased CHD mortality controversy
  • 1995 vs. 1997-2000 data (SYST-EUR study)

68
  • YES (useful in)
  • Elderly patients
  • African Americans
  • Patients with peripheral vascular disease
  • Patients with cerebrovascular disease
  • Patients with angina pectoris
  • No (avoid in)
  • Patients with heart failure
  • Patients with heart block
  • Patients receiving b-blockers
  • Short-acting dihydropiridines
  • Unstable angina
  • Recent MI

69
a1 - Adrenergic Receptors Blockers
70
Afterload
a2
Vasomotor center
Volume Kidneys
Cardiac Output Heart
b1
Renin
V
V
b1
Ang I
Preload
Ang II
a1
a1
BP CO x TPVR
Aldosterone
a1
a1
Capacitance venules
Resistance arterioles
a1 Receptors Blockers
TPVR
71
a1- Receptor Blockers
Inhibition of Vasoconstriction Induced by
Endogenous Catecholamines at Arterioles and Veins
Reduced Peripheral Resistance and Reduced Preload
72
a1- Receptor Blockers
  • Prazosin MINIPRESS
  • Terazosin HYTRIN
  • Doxazosin CARDURA
  • Tamsulosin FLOMAX for BPH
  • Old drugs
  • Alpha-1 Alpha 2 Blockers
  • Phenoxybenzamine DIBENZYLIN
  • Phentolamine REGITINE

73
a1- Receptor Blockers
  • Side effects
  • First dose hypotension
  • Dizziness, lethargy, fatigue
  • Palpitation, syncope
  • Peripheral edema
  • Incontinence
  • ALLHAT study results
  • Not to be used as first-line agents

74
Central a2- Agonists
75
X
Afterload
a2
Vasomotor center
Volume Kidneys
Cardiac Output Heart
b1
X
Renin
X
V
V
b1
Ang I
X
Preload
X
Ang II
BP CO x TPVR
Aldosterone
VSMC
Capacitance venules
Resistance arterioles
Central a2 Agonists
TPVR
76
Central a2- Agonists
Activation of Pre-synaptic Alpha-2 Receptors
Reduces NE EPI Release at Synapse
Diminished CNS Sympathetic Outflow
Alpha-2 Agonist
Post-synaptic Effector
Rostral Ventrolateral Medulla
Pre-synaptic Neuron
Alpha-1 Receptor Beta Receptor
Alpha-2 Receptor
NE EPI
77
  • Central a2- Agonists
  • Clonidine CATAPRES
  • Methyldopa ALDOMET
  • Old drugs
  • Guanfacine TENEX
  • Guanabenz WYTENSIN

78
Clonidine Proposed Action via Imidazoline
Receptors
  • Cl
  • Chemical structure ofclonidine imidazoline
  • Sites in brain and peripheraltissues that bind
    imidazolinesbut not catecholamines (i.e., sites
    are not alpha receptors)
  • Hypotensive responses to imidazolines may
    bemediated via imidazoline receptors in VL
    medulla
  • MOXONIDINE (Imidazoline receptor agonist- Europe)
  • NH
  • NH
  • Cl
  • N

79
Peripheral Vasodilators
80
Afterload
a2
Vasomotor center
Volume Kidneys
Cardiac Output Heart
b1
Renin
V
V
b1
Ang I
Preload
b2
a1
Ang II
BP CO x TPVR
Aldosterone
NO ? cGMP ? Ca
Capacitance venules
Resistance arterioles
Peripheral Vasodilators
TPVR
81
Activators of NO/guanylate cyclase
pathway Hydralazine ? Nitroprusside
Nitroglycerin
a1 Adrenoreceptor antagonists
Doxazosin Prazosin
Ca2 - channel blockers
Dihydropiridines
Verapamil Diltiazem

NO
Ca2
VSMCs
Ang II receptor antagonists
Losartan
K
K - channels activators Minoxidile Diazoxide
Peripheral Vasodilators
82
Peripheral Vasodilators
  • Hydralazine APRESOLINE
  • Minoxidil LONITEN
  • Sodium Nitroprusside
  • Diazoxide

83
  • Peripheral Vasodilators
  • Hydralazine
  • Arteriolar vasodilation by mechanism not
    well-defined (NO ?)
  • Minoxidil
  • Arteriolar vasodilation by activation of
    ATP-modulated potassium channels resulting in
    hyperpolarization of arteriolar VSMCs
  • Second-third line of drugs for hypertension
  • Induce reflex tachycardia, fluid and sodium
    retention
  • Have be combined with first-line antihypertensive
    drugs

84
  • Peripheral Vasodilators
  • Hydralazine
  • In slow acetilators, lupus-like syndrome
    (arthralgia, myalgia, skin rashes, and fever).
  • For patients with CHF, pre-eclampsia
  • Minoxidil
  • Last choice for treatment of hypertension
  • Minoxidil Headache, sweating, and hirsutism,
  • Topical minoxidil (Rogaine) used for correction
    of baldness.

85
X
Afterload
a2
Vasomotor center
Volume Kidneys
Cardiac Output Heart
b1
Renin
X
V
V
b1
Ang I
X
Preload
X
Ang II
BP CO x TPVR
Aldosterone
VSMC
Capacitance venules
Resistance arterioles
Autonomic Ganglionic Inhibitors
TPVR
86
Autonomic Ganglionic Inhibitors
  • Mecamylamine INVERSINE

87
Autonomic Ganglionic Inhibitors
Reduced peripheral resistance and venous return
Inhibit neurotransmission in autonomic ganglia
by competing with acetylcholine for ganglionic
cholinergic receptor sites.
Autonomic Ganglionic Inhibitor
Post-ganglionic Neuron
Pre-ganglionic Neuron
Ganglionic ACh Receptor
Acetylcholine
88
Afterload
a2
Vasomotor center
Volume Kidneys
Cardiac Output Heart
b1
Renin
V
V
b1
Ang I
Preload
Ang II
BP CO x TPVR
Aldosterone
Capacitance venules
Resistance arterioles
Adrenergic Neural Terminal Inhibitors
TPVR
89
Adrenergic Neural Terminal Inhibitors
  • Reserpine
  • Guanethidine ISMELIN
  • Guanadrel HYCOREL
  • Metyrosine DEMSER

90
Adrenergic Neural Terminal Inhibitors
  • Reserpine binds to catecholamine storage
    vesicles in peripheral and central neurons,
    rendering them unable to store or release NE and
    EPI
  • Guanethidine and Guanadrel stored in peripheral
    neurosecretory granules and released as
    inactive neurotransmitter in place of NE and
    EPI
  • Metyrosine reduces catecholamine biosynthesis in
    peripheral nerves and adrenal by inhibiting
    rate-limiting enzyme, tyrosine hydroxylase

91
Combination Drugs in Hypertension
  • ACE Inhibitor Diuretic
  • Benazepril HCTZ ( Lotensin HCT )
  • Captopril HCTZ ( Capozide)
  • Enalapril HCTZ (Vaseretic )
  • Lisinopril HCTZ ( Prinzide , Zestoretic )
  • Moexipril HCTZ ( Uniretic )
  • Quinapril HCTZ ( Accuretic )
  • Ang II Receptor Antagonist Diuretic
  • Losartan HCTZ( Hyzaar )
  • Irbesartan HCTZ( Avalide )
  • Valsartan HCTZ ( Diovan HCT )

92
Combination Drugs in Hypertension
  • Beta-Blocker Diuretic
  • Atenolol Chlorthalidone ( Tenoretic )
  • Bisoprolol HCTZ ( Ziac )
  • Metoprolol HCTZ ( Lopressor HCT )
  • Propranolol HCTZ ( Inderide , Inderide LA )
  • Timolol HCTZ (Timolide )
  • Betaxolol Chlorthalidone ( Kerledex )
  • Labetalol HCTZ ( Normozide , Trandate HCT )


93
Combination Drugs in Hypertension
  • ACE Inhibitor Calcium Channel Blocker
  • Amlodipine Benazepril (Lotrel )
  • Enalapril Diltiazem ( Teczem )
  • Felodipine Enalapril ( Lexxel )


94
Oral antihypertensive drugs
Usual dose range
Usual Daily
Class
Drug (Trade Name)
in mg/day
Frequency
Thiazide diuretics
Chlorothiazide (Diuril)
125-500
1-2
chlorthalidone (generic)
12.5-25
1
hydrochlorothiazide (HydroDIURIL)
12.5-50
1
polythiazide (Renese)
2-4
1
indapamide (Lozol)
1.25-2.5
1
metolazone (Mykrox)
0.5-1.0
1
metolazone (Zaroxolyn)
2.5-5
1
Loop diuretics
bumetanide (Bumex)
0.5-2
2
furosemide (Lasix)
20-80
2
torsemide (Demadex)
2.5-10
1
Potassium-sparing diuretics
amiloride (Midamor)
5-10
1-2
triamterene (Dyrenium)
50-100
1-2
Aldosterone blockers
eplerenone (Inspra)
50-100
1
spironolactone (Aldactone)
25-50
1
Beta Blockers
atenolol (Tenormin)
25-100
1
betaxolol (Kerlone)
5-20
1
bisoprolol (Zebeta)
2.5-10
1
metoprolol (Lopressor)
50-100
1-2
metoprolol extended release (Toprol XL)
50-100
1
nadolol (Corgard)
40-120
1
propranolol (Inderal)
40-160
2
propranolol long-acting (Inderal LA)
60-180
1
timolol (Blocadren)
20-40
2
BBs with intrinsic
acebutolol (Sectral)
200-800
2
sympathomimetic activity
penbutolol (Levatol)
10-40
1
pindolol (generic)
10-40
2
Combined alpha- and BBs
carvedilol (Coreg)
12.5-50
2
labetalol (Normodyne, Trandate)
200-800
2 9
95
Oral antihypertensive drugs
(continued)
Usual dose range
Usual Daily
Class
Drug (Trade Name)
in mg/day
Frequency
ACEIs
benazepril (Lotensin)
10-40
1
captopril (Capoten)
25-100
2
enalapril (Vasotec)
5-40
1-2
fosinopril (Monopril)
10-40
1
lisinopril (Prinivil, Zestril)
10-40
1
moexipril (Univasc)
7.5-30
1
perindopril (Aceon)
4-8
1
quinapril (Accupril)
10-80
1
ramipril (Altace)
2.5-20
1
trandolapril (Mavik)
1-4
1
Angiotensin II antagonists
candesartan (Atacand)
8-32
1
eprosartan (Teveten)
400-800
1-2
irbesartan (Avapro)
150-300
1
losartan (Cozaar)
25-100
1-2
olmesartan (Benicar)
20-40
1
telmisartan (Micardis)
20-80
1
valsartan (Diovan)
80-320
1-2
CCBsnon-Dihydropyridines
Diltiazem extended release
180-420
1
(Cardizem CD, Dilacor XR, Tiazac
)
diltiazem extended release (Cardizem LA)
120-540
1
verapamil immediate release (Calan, Isoptin
)
80-320
2
verapamil long acting (Calan SR, Isoptin SR)
120-480
1-2
verapamilCoer, Covera HS, Verelan PM)
120-360
1
CCBsDihydropyridines
amlodipine (Norvasc)
2.5-10
1
felodipine (Plendil)
2.5-20
1
isradipine (Dynacirc CR)
2.5-10
2
nicardipine sustained release (Cardene SR)
60-120
2
nifedipine long-acting (Adalat CC, Procardia XL)
30-60
1
nisoldipine (Sular)
10-40
1
96
Oral antihypertensive drugs(continued)
Usual dose range
Usual Daily
Class
Drug (Trade Name)
in mg/day
Frequency
1-16
1
doxazosin (Cardura)
2-20
2-3
Alpha-1 blockers
1-20
1-2
prazosin (Minipress)
terazosin (Hytrin)
0.1-0.8
2
clonidine (Catapres)
Central alpha-2 agonists and
clonidine patch (Catapres-TTS)
0.1-0.3
1 wkly
other centrally acting drugs
methyldopa (Aldomet)
250-1,000
2
reserpine (generic)
0.1-0.25
1
guanfacine (Tenex)
0.5-2
1
Direct vasodilators
hydralazine (Apresoline)
25-100
2
minoxidil (Loniten)
2.5-80

97
Oral antihypertensive drugs combinations
(continued)
Combination Type
Trade Name
Fixed-Dose Combination, mg
ACEIs and CCBs
Amlodipine-benazepril hydrochloride (2.5/10,
5/10, 5/20, 10/20)
Lotrel
Enalapril-felodipine (5/5)
Lexxel
Trandolapril-verapamil (2/180, 1/240, 2/240,
4/240)
Tarka
ACEIs and diuretics
Benazepril-hydrochlorothiazide (5/6.25, 10/12.5,
20/12.5, 20/25)
Lotensin HCT
Captopril-hydrochlorothiazide (25/15, 25/25,
50/15, 50/25)
Capozide
Enalapril-hydrochlorothiazide (5/12.5, 10/25)
Vaseretic
Fosinopril-hydrochlorothiazide (10/12.5, 20/12.5)
Monopril/HCT
Lisinopril-hydrochlorothiazide (10/12.5, 20/12.5,
20/25)
Prinzide, Zestoretic
Moexipril-hydrochlorothiazide (7.5/12.5, 15/25)
Uniretic
Quinapril-hydrochlorothiazide (10/12.5, 20/12.5,
20/25)
Accuretic
ARBs and diuretics
Candesartan-hydrochlorothiazide (16/12.5,
32/12.5)
Atacand HCT
Eprosartan-hydrochlorothiazide (600/12.5, 600/25)
Teveten-HCT
Irbesartan-hydrochlorothiazide (150/12.5,
300/12.5)
Avalide
Losartan-hydrochlorothiazide (50/12.5, 100/25)
Hyzaar
Olmesartan medoxomil-hydrochlorothiazide
(20/12.5,40/12.5,40/25)
Benicar HCT
Telmisartan-hydrochlorothiazide (40/12.5,
80/12.5)
Micardis-HCT
Valsartan-hydrochlorothiazide (80/12.5, 160/12.5,
160/25)
Diovan-HCT
BBs and diuretics
Atenolol-chlorthalidone (50/25, 100/25)
Tenoretic
Bisoprolol-hydrochlorothiazide (2.5/6.25, 5/6.25,
10/6.25)
Ziac
Metoprolol-hydrochlorothiazide (50/25, 100/25)
Lopressor HCT
Nadolol-bendroflumethiazide (40/5, 80/5)
Corzide
Propranolol LA-hydrochlorothiazide (40/25, 80/25)
Inderide LA
Timolol-hydrochlorothiazide (10/25)
Timolide
Centrally acting drug
Methyldopa-hydrochlorothiazide (250/15, 250/25,
500/30, 500/50)
Aldoril
and diuretic
Reserpine-chlothalidone (0.125/25, 0.25/50)
Demi-Regroton,
Regroton
Reserpine-chlorothiazide (0.125/250, 0.25/500)
Diupres
Reserpine-hydrochlorothiazide (0.125/25,
0.125/50)
Hydropres
Diuretic and diuretic
Amiloride-hydrochlorothiazide (5/50)
Moduretic
Spironolactone-hydrochlorothiazide (25/25, 50/50)
Aldactazide
Triamterene-hydrochlorothiazide (37.5/25, 75/50)
Dyazide, Maxzide
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