Transcript Document

Antihypertensive Drugs
Fall ‘09
DIURETICS
(only those used for antihypertensive therapy)
SYMPATHOLYTICS
Peripheral adrenergic receptor blockers
Centrally acting
RENIN-ANGIOTENSIN SYSTEM INHIBITORS
Angiotensin Converting Enzyme (ACE) Inhibitors
Angiotensin II receptor blockers
VASODILATORS
Ca2+ -channel blockers
Others
Treatment Guidelines from The Medical Letter
Drugs for Hypertension January 2009
Hypertension
The most common cardiovascular disease
• Affecting ~50 million people in the US
• Defined as sustained systolic BP 140 mmHg
and/or
• Sustained diastolic BP 90 mmHG
Causes:
~90-95% unknown origin (essential or primary
hypertension)
~5-10% due to renal, endocrine or neurogenic
disease
Risks associated with chronic elevated BP
Stroke
Heart Disease
Heart Failure
Arrhythmias
Myocardial Infarcts
Renal Failure
Strategies for treating hypertension
Stepped care approach:
•Life style changes (e.g., lower dietary Na+, weight loss)
•Single-drug therapy
•Multiple-drug therapy
Careful consideration should be taken when
patients present with co-morbidities:
diabetes, lipid disorders, ischemic heart
disease and failure, migraines, asthma, etc...
Specific patients may respond better to certain therapies
(factors include; ethnicity, age, etc…)
JDM is an 81 year old caucasian male who has been active until the last 6 months. He lives in New England for 4
months of the year, and in the Bahamas for the remainder of the year. He exercises every day (typically a long
walk), fishes and gardens. His longstanding PCP retired last year, and complains to his new PCP that he has
bouts of light headedness and elevated heart rates. His wife is a retired nurse so she makes him take his blood
pressure and heart rate often. Systolic pressure is usually normal, but diastolic pressure is low.
AM Meds:
Digitek (digoxin) 250 mcg
Verapamil SR Tab, 180 mg
Hydralazine 25mg
Fish Oil 1000 units
Enalapril Mal Tabs (5 mg in AM, 5mg in PM)
ASA 350mg
Chlorathalidone 25mg
Multivitamin
Ester C 1000 units/ MSM 1000 units
Glucosamine/chondroitin/MSM 1000 units
Acetaminophen 1000 mg (for arthritis discomfort)
PM Meds:
Terazosin (5 mg at noon, 5mg in PM)
Hydralazine 25mg
Lipitor 10mg
Fish Oil 1000 units
Flomax .4mg
Singulair 10mg
Acetaminophen 1000 mg (for arthritis discomfort)
Glucosamine/chondroitin 1000 units/ MSM 1000 units
For allergies/ asthma:
Advair Discus 100/50, 1 one puff in AM, PM
Fluticasone, 2 puffs each nostril once a day
Maxair Autohailer, q4-6hr (rescue only)
Claritin (generic) 10mg
Can you identify potential interactions among the drugs based on sympotoms?
=
4
SYMPATHOLYTICS
VASODILATORS
ANGIOTENSIN INHIBITORS
Angiotensin Converting Enzyme (ACE) Inhibitors
Angiotensin II receptor blockers
Renin inhibitor
DIURETICS
8
Brenner Fig 10-1
SYMPATHOLYTICS (see Table 9-1, Brenner)
Peripheral adrenergic receptor blockers
-blockers:
propranolol, pindolol, metoprolol, atenolol
-blockers:
prazosin (1-blocker), phenoxybenzamine (1- and 2-blocker)
1-, 2- and 1- blockers:
carvedilol, labetalol
Centrally acting drugs
clonidine (2-agonist)
methyldopa (false transmitter)
Ganglionic blockers: trimethaphan
(rarely used in the US, if at all, only for hypertensive emergencies only)
Relative Receptor Affinities
Alpha agonists
Phenylephrine
Clonidine
1>2>>>> 
2 >1>>>> 
Mixed alpha and beta agonists
Norepinephrine (NE) 1=2; 1>> 2
Epinephrine (Epi)
1=2; 1= 2
Beta agonist
Dobutamine
1> 2 >>>>
Dopamine agonist
Dopamine
D1=D2>> >>
modified from Katzung Table 9-2
1
ADH
Lippincott Fig 19-7
Not on same tissue
vasoconstriction
(NE)
vasodilation
Presynaptic inhibition
(Epi)
of NE release
NE
blood glucose
(from muscle and liver)
Brenner Fig 8-1 bronchodilation
+ inotropic
+ chronotropic
See Drugs for angina and heart failure for details
-Adrenergic Receptor Blockers
Non-selective: 1-, 2-blocker
propranolol
Selective:
1-blocker
metoprolol, atenolol
1-, 2- and 1- blocker:
carvedilol, labetalol
both indicated for hypertension
carvedilol also approved for heart failure
patients
Note: Nebivolol (approved 1/08) 1-blocker with antioxidant
and increases endothelial nitric oxide release (vasodilator)
-blockers: Prazosin
Selective 1-blockers
•   TPR because of vasodilation
(not typically first line drugs)
•No adverse metabolic or lipid effects
**therefore, advantage over –blockers with
co-morbidities
•Side effects: (Why might these be expected?)
Postural hypotension (especially after first dose)
Occasional reflex tachycardia – tries to
compensate
Fluid retention
Doxazosin significant increase in CHF compared to diuretics
alone (ALLHAT) perhaps because of fluid retention
Intact feedback inhibition of NE
release by 2 receptors
vascular
1 receptors
Prazosin
1
Brenner Fig 9-4
unless dose is too high
= ? blockers
TPR
Before
After
Before
After
Before
After
CO
MAP
Brenner Fig 9-3
= ? blockers
Centrally acting sympatholytics:    TPR
Clonidine (2-agonist)
For severe, refractory hypertension
Side effects include:
sedation, dry mouth, and
rebound hypertension upon withdrawal after chronic use
-Methyldopa (false neurotransmitter)
Chronic therapy
Replaces NE:
Less effective for stimulating 1-receptors
More effective for stimulating 2-receptors
*Clonidine
*
X
2
X
-Methyldopa
Brenner Fig 8-1
RENIN-ANGIOTENSIN SYSTEM INHIBITORS
Angiotensin Converting Enzyme (ACE) Inhibitors:
Captopril, Lisinopril
(many on the market: enalapril, ramipril...)
Angiotensin II receptor blockers (ARBs):
Losartan
(many on the market: candesartan, irbesartan, valsartan...)
Direct renin inhibitor (DRI):
Aliskiren
Examples of indications and clinical uses:
Mild/moderate essential hypertension
Heart Failure (especially early stages)
Diabetic nephropathy!!!!
PGs = prostaglandins
PGs
+ NO
Brain
Antidiuretic
Hormone
(ADH = vasopressin)
H2O retention &
vasoconstriction
(AT1)
Na+ retention
modified Brenner Fig 10-3
ACE-Inhibitors
• Differ in their pharmacokinetics
Half-life (T1/2), metabolism
•No adverse effects on lipid profiles or glycemic control
•All have cardioprotection independent of BP
especially in CAD patients (HOPE Trials, NEJM 2000)
• Also effective in reducing vascular complications
associated with diabetes (type 1 definitely, maybe type 2)
especially effective with nephropathies
(via anti-inflammatory mechanisms?)
Captopril (prototype)
•Highest oral bioavailability
•Shortest t1/2
How would this affect dosing?
Less effective in blacks unless combined with thiazide diuretics
(Medline 2003; Circulation 2005; 112:3654-3666)
ACE-Inhibitors (con’t)
Side effects related to:
Suppression of angiotensin II (AngII)
(hypotension and renal insufficiency)
Increased in bradykinin
(cough and edema)
Why?
Also:
Hyperkalemia (caution with K+ sparing diuretics)
Fetotoxic (do not use with pregnancies)
Renal failure (with bilateral renal a. stenosis)
Bonus:
Bradykinin stimulates vasodilation and
Prostraglandin/NO vasodilation
(high doses of NSAIDs may interfere with PGI2-mediated
vasodilation)
Losartan
Blocks AngII from binding to AT1 receptors
Allows AT2 receptors to be stimulated by circulating AngII
(promoting vasodilation????)
Relatively few side effects
less cough than with ACE-I
but fetotoxic like ACE-I
Diabetes: slows progression of nephropathy (RENNAAL)
Cardioprotection (maybe??): reduces cardiac remodeling
Typically reserved for patients who do not tolerate ACE-I
Some evidence ACE2 metabolizes AngII to Ang1-7 (a vasodilator), and there are
non-ACE sources of AngII, therefore ARB’s might be more effective than ACE-I
(stay tuned, more data is needed)
Less effective antihypertensive in blacks (same as with ACE-I)
Aliskiren:
Direct renin inhibitor (DRI)
New class of nonpeptide, oral inhibitor
Binds to a site on renin, preventing formation of angiotensin
(Ang) I
Lowers plasma renin activity, Ang I, Ang II, and aldosterone
Safety and tolerance appear similar to ACE-I and ARBs
Significance of inhibiting renin?
ACE-I and ARBs may increase renin
(because no negative feedback)
Hydrochlorothiazides also increase renin
Pro(renin) receptors were recently identified
• Activate MAP kinases and profibrotic signaling
• May be involved in vascular remodeling (e.g., with diabetes)
VASODILATORS
Ca2+ -channel blockers:
DHPs: amlodipine, nifedipine
Diltiazem
Verapamil
Others: less frequently used for chronic Tx
Hydralazine
Minoxidil
Note: nitrates not used for chronic hypertensionTx
sodium nitroprusside (SNP):
used for hypertensive emergencies and surgery)
(cyanide toxicity due to metabolite – obsolete story)
VASODILATORS (con’t)
• Promote vascular smooth muscle relaxation, TPR
• Most (not all) produce concomitant reflexes if not
dosed properly:
 cardiac contractility and HR
 myocardial O2 consumption
 renin-angiotensin-aldosterone system
• Usually no effects on serum lipids
Why would this be an advantage over other drugs
such as -blockers?
Ca2+ channel blockers (CCBs)
Site of action dependent on tissue selectivity
•Verapamil
most cardiac selective (nodal cells and myocytes)
•Diltiazem
intermediate selectivity
•Dihydropyridines (DHPs)
most vascular selective
All have some coronary vasodilatory effects
Which is most likely used for antihypertensive therapy?
Which is most likely to cause reflex tachycardia?
See also Angina drug & Antiarrhythmic drug lectures
Toxicities associated with DHPs
(selected)
Short acting DHPs
Immediate-release nifedipine, nisoldipine, felodipine
May cause reflex tachycardia
Longer acting DHPs
Sustained-release nifedipine, amlodipine, isradipine
Do not cause significant increases in HR
(neither do verapamil or diltiazem)
Why?
Side effects of DHPs include:
•Headaches
•Peripheral edema
Doses to achieve BP goals will likely differ from anti-anginal goals,
therefore side effects may be different
Hydralazine and Minoxidil
• Typically reserved for severe hypertension
• Often co-administered with a diuretic and/or -blocker
• Dilates arterioles, not veins
contraindicated for patients with angina, ischemic
heart disease
Hydralazine
• May act by increasing cGMP (similar to NO)
(in combination with isosorbide dinitrate – see HF lecture)
Minoxidil (oral, not topical)
• Opens KATP channels, thus hyperpolarizes cells
Vascular Smooth Muscle Cell
sites of antihypertensive
CCB
drug action
DHP
hibitor
ARB
Losartan
A1 Blocker
Prazosin
NE
Sildenafil
cGMP PDE5 inhibitor (not used
for systemic hypertension, but
maybe pulmonary arterial
hypertension)
blocker
agonist
Ca2+
Minoxidil
1
AII
K+ATP
AT1
SR
 Ca2+
Ca2+
PDE
GMP cGMP
contraction
MLCK
PDE
cAMP
AMP
2
Hydralazine
Endothelial cell NO
PDE = phosphodiesterase
Epi
Acetylcholine
Bradykinin
DIURETICS:
(those used for antihypertensive therapy)
•Thiazide diuretics:
hydrochlorothiazide
•Loop diuretics:
furosemide
•Potassium-sparing diuretics:
amiloride, spironolactone, eplerenone
Discussed previously
Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT) Arch Int Med
2008, 168(2)
update
Thiazides are DOC in hypertensive patients with
metabolic syndrome
No evidence that ACEI, CCB, alpha blockers offer
any advantage of clinical outcomes over thiazides in
these patients (particularly in blacks with metabolic
syndrome)
chlorthalidone, lisinopril, amlodipine, doxazosin
Doxazosin arm stopped early because of increased CV events,
with 2x more HF compared to thiazide group
JNC VII Compelling Indications for Drug Classes
Compelling Indication
Initial Therapy Options
Clinical-Trial Basis
Heart Failure
Diuretic, BB, ACEI,
ARB, Aldo Ant
MERIT-HF, COPERNICUS, CIBIS,
SOLVD, AIRE, TRACE, Val-HeFT, RALES
Post-MI
BB, ACEI, Aldo Ant
ACC/AHA Post-MI Guideline, BHAT,
SAVE, Capricorn, EPHESUS
High CAD Risk
Diuretic, BB, ACEI, CCB
ALLHAT, HOPE, ANBP2,
LIFE, CONVINCE
Diabetes Mellitus
ACEI, Diuretic, BB,
ARB, CCB
Chronic Kidney Disease
ACEI, ARB
Recurrent Stroke Prevention
Diuretic, ACEI
NKF-ADA Guideline,
UKPDS, ALLHAT
NKF Guideline, Captopril Trial,
RENAAL, IDNT, REIN, AASK
PROGRESS
ACEI=Angiotensin converting enzyme inhibitor, Aldo Ant=Aldosterone antagonist, ARB=Angiotensin receptor blocker,
BB=b-blocker, CAD=Coronary artery disease, CCB=Calcium channel blocker, MI=Myocardial Infarction
Chobanian AV et al. JAMA. 2003;289:2560-2572
Clinical considerations:
Most effective treatment, ethnicity differences*
Least side effects (most patients are asymptomatic)
Frequency of dosing
Cost
Fixed-drug combinations:
-blocker and thiazide diuretic
ACE inhibitor and thiazide diuretic
AII receptor blocker and diuretic
Ca2+ channel blocker and ACE inhibitor
What are advantages and disadvantages of fixed-drug
combinations?
Presence of co-morbidities (considerations)
Thiazide diuretics and -blockers:
• Often used in combination
• However, both may adversely affect lipid profiles and
insulin sensitivity (exaccerbate CAD, atherosclerosis,
type 2 diabetes)
ACE inhibitors:
• May also be beneficial for diabetic nephropathies
ACE inhibitors and diuretics:
• Useful for patients with CHF
-blockers or Ca2+ channel blockers:
• Useful for patients with angina
Diuretics and Ca2+ channel blockers:
• Blacks respond better to each, rather than to
-blockers and ACE inhibitors
Antihypertensive Targets
(-)
ARBs = angiotensin receptor blockers; AT-1 = angiotensin II sub-type 1;
DHPs = dihydropyridines; SVR = systemic vascular resistance. (LH Opie, 2004.)
Guidelines for treatment and prevention of hypertension
are published by the Joint National Committee (JNC) on the
Detection, Prevention and Treatment of Hypertension
http://www.nhlbi.nih.gov/guidelines/hypertension/
http://www.nhlbi.nih.gov/guidelines/hypertension/
Guidelines and updates (including power point presentations,
treatment algorhythms, etc…) can be found (free) through
the NHLBI website
http://www.nhlbi.nih.gov/health/prof/heart/index.htm#hbp
http://www.nhlbi.nih.gov/health/prof/heart/index.htm#hbp