Antihypertensive drug

Antihypertensive therapy seeks to prevent the complications of high blood

pressure, such as stroke and myocardial infarction.
The antihypertensives are a class of drugs that are used to treat
hypertension (high blood pressure).[1] Evidence suggests that reduction of
the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of
ischaemic heart disease by 21%, and reduce the likelihood of dementia,
heart failure, and mortality from cardiovascular disease.[2] There are many
classes of antihypertensives, which lower blood pressure by different means;
among the most important and most widely used are the thiazide diuretics,
the ACE inhibitors, the calcium channel blockers, the beta blockers, and the
angiotensin II receptor antagonists or ARBs.
Which type of medication to use initially for hypertension has been the
subject of several large studies and resulting national guidelines. The
fundamental goal of treatment should be the prevention of the important
endpoints of hypertension, such as heart attack, stroke and heart failure. The
several classes of antihypertensives differ in side effect profiles, ability to
prevent endpoints, and cost. The choice of more expensive agents, where
cheaper ones would be equally effective, may have negative impacts on
national healthcare budgets.[3] As of 2009, the best available evidence favors
the thiazide diuretics as the first-line treatment of choice for high blood
pressure when drugs are necessary.[4]

Contents
1 Available agents
o

1.1 Diuretics

1.2 Adrenergic receptor antagonists

1.3 Adrenergic receptor agonists

1.4 Calcium channel blockers

1.5 ACE inhibitors

1.6 Angiotensin II receptor antagonists

1.7 Aldosterone antagonists

1.8 Vasodilators

1.9 Centrally acting adrenergic drugs

2 Future treatment options

o

2.1 Blood pressure vaccine

3 Choice

Available agents
Diuretics

Hydrochlorothiazide, a popular thiazide diuretic

Diuretics help the kidneys eliminate excess salt and water from the body's
tissues and blood.

Loop diuretics:
o bumetanide
o

ethacrynic acid

furosemide

torsemidet

Thiazide diuretics:

epitizide

hydrochlorothiazide and chlorothiazide

bendroflumethiazide

Thiazide-like diuretics:
o

indapamide

chlorthalidone

metolazone

Potassium-sparing diuretics:
o

amiloride

triamterene

spironolactone

Only the thiazide and thiazide-like diuretics have good evidence of beneficial
effects on important endpoints of hypertension, and hence, should usually be
the first choice when selecting a diuretic to treat hypertension. The reason
why thiazides-type diuretics are better than the others is (at least in part)
thought to be because of their vasodilating properties.[citation needed] Although
the diuretic effect of thiazides may be apparent shortly after administration,
it takes longer (weeks of treatment) for the full anti-hypertensive effect to
develop. In the United States, the JNC7 (The Seventh Report of the Joint
National Committee on Prevention of Detection, Evaluation and Treatment of
High Blood Pressure) recommends starting with a thiazide diuretic if single
therapy is being initiated and another medication is not indicated.[5] This is
based on a slightly better outcome for chlortalidone in the ALLHAT study
versus other anti-hypertensives and because thiazide diuretics are relatively
cheap.[6] A subsequent smaller study (ANBP2) published after the JNC7 did
not show this small difference in outcome and actually showed a slightly
better outcome for ACE-inhibitors in older male patients.[7]
Despite thiazides being cheap, effective, and recommended as the best firstline drug for hypertension by many experts, they are not prescribed as often
as some newer drugs. Arguably, this is because they are off-patent and thus
rarely promoted by the drug industry.[8]

Adrenergic receptor antagonists

Propranolol, the first beta-blocker to be successfully developed

Beta blockers
o atenolol

metoprolol

nadolol

oxprenolol

pindolol

propranolol

timolol

Alpha blockers:
o

doxazosin

phentolamine

indoramin

phenoxybenzamine

prazosin

terazosin

tolazoline

Mixed Alpha + Beta blockers:

bucindolol

carvedilol

labetalol

Although beta blockers lower blood pressure, they do not have as positive a
benefit on endpoints as some other antihypertensives.[9] In particular,
atenolol seems to be less useful in hypertension than several other agents.[10]
They do, however, have an important role in the prevention of heart attacks
in people who have already had a heart attack.[11] In the United Kingdom, the
June 2006 "Hypertension: Management of Hypertension in Adults in Primary
Care"[12] guideline of the National Institute for Health and Clinical Excellence,
downgraded the role of beta-blockers due to their risk of provoking type 2
diabetes.[13]
Despite lowering blood pressure, alpha blockers have significantly poorer
endpoint outcomes than other antihypertensives, and are no longer
recommended as a first-line choice in the treatment of hypertension. [14]
However, they may be useful for some men with symptoms of prostate
disease.

Adrenergic receptor agonists

Alpha-2 agonists:
o clonidine
o

methyldopa

Guanfacine

Calcium channel blockers

Calcium channel blockers block the entry of calcium into muscle cells in
artery walls.

dihydropyridines:
o amlodipine
o

felodipine

isradipine

lercanidipine

nicardipine

nifedipine

nimodipine

nitrendipine

non-dihydropyridines:
o

diltiazem

verapamil

ACE inhibitors

Captopril, the prototypical ACE inhibitor

ACE inhibitors inhibit the activity of Angiotensin-converting enzyme (ACE), an
enzyme responsible for the conversion of angiotensin I into angiotensin II, a
potent vasoconstrictor.

captopril
enalapril

fosinopril

lisinopril

perindopril

quinapril

ramipril

trandolapril

benazepril

Angiotensin II receptor antagonists

Valsartan, an angiotensin II receptor antagonist

Angiotensin II receptor antagonists work by antagonizing the activation of
angiotensin receptors.

candesartan
eprosartan

irbesartan

losartan

olmesartan

telmisartan

valsartan

Aldosterone antagonists
Aldosterone receptor antagonists:

eplerenone
spironolactone

Aldosterone antagonists are not recommended as first-line agents for blood

pressure,[5] but spironolactone and eplerenone are both used in the
treatment of heart failure.

Vasodilators
Vasodilators act directly on the smooth muscle of arteries to relax their walls
so blood can move more easily through them; they are only used in
hypertensive emergencies or when other drugs have failed, and even so are
rarely given alone.
Sodium nitroprusside, a very potent, short-acting vasodilator, is most
commonly used for the quick, temporary reduction of blood pressure in
emergencies (such as malignant hypertension or aortic dissection).[15][16]

Hydralazine and its derivatives are also used in the treatment of severe
hypertension, although they should be avoided in emergencies. [16] They are
no longer indicated as first-line therapy for high blood pressure due to side
effects and safety concerns, but hydralazine remains a drug of choice in
gestational hypertension.[15]

Centrally acting adrenergic drugs

Central alpha agonists lower blood pressure by stimulating alpha-receptors in
the brain which open peripheral arteries easing blood flow. Central alpha
agonists, such as clonidine, are usually prescribed when all other antihypertensive medications have failed. For treating hypertension, these drugs
are usually administered in combination with a diuretic.

Clonidine
Guanabenz

Methyldopa

Moxonidine

Adverse effects of this class of drugs include sedation, drying of the nasal
mucosa and rebound hypertension.
Some adrenergic neuron blockers are used for the most resistant forms of
hypertension:

Guanethidine
Reserpine

Future treatment options

Blood pressure vaccine
Blood pressure vaccinations are being trialed and may become a treatment
option for high blood pressure in the future. Research on the vaccine CYT006AngQb published in The Lancet on the 8 March 2008 titled, Vaccination
against high blood pressure: a new strategy showed patients experienced a
drop in systolic and diastolic blood pressure after taking the vaccine.
Effective blood pressure vaccines would assist those people who forget to
take their medication. It would also help those who stop taking their
medication due to side effects or falsely believing they don't need them
anymore once their blood pressure is lowered. [17]

Choice

The choice between the drugs is to a large degree determined by the

characteristics of the patient being prescribed for, the drugs' side-effects,
and cost. For example, asthmatics have been reported to have worsening
symptoms when using beta blockers. Most drugs have other uses;
sometimes the presence of other symptoms can warrant the use of one
particular antihypertensive (such as beta blockers in case of tremor and
nervousness, and alpha blockers in case of benign prostatic hyperplasia).
The JNC 7 report outlines compelling reasons to choose one drug over the
others for certain individual patients.[5]

See also

Prehypertension
Pulse pressure

Diuretic

This illustration shows where some types of diuretics act, and what they do.
A diuretic is any drug that elevates the rate of urination and thus provides a
means of forced diuresis. There are several categories of diuretics. All
diuretics increase the excretion of water from bodies, although each class
does so in a distinct way.

Contents

1 Types
o 1.1 High ceiling loop diuretics
o

1.2 Thiazides

1.3 Potassium-sparing diuretics

1.4 Calcium-sparing diuretics

1.5 Osmotic diuretics

1.6 Low ceiling diuretics

2 Uses

3 Mechanism of action

4 Adverse effects

Types
High ceiling loop diuretics
High ceiling diuretics are diuretics that may cause a substantial diuresis up
to 20%[1] of the filtered load of NaCl and water. This is huge when compared
to normal renal sodium reabsorption which leaves only ~0.4% of filtered
sodium in the urine.
Loop diuretics have this ability, and are therefore often synonymous with
high ceiling diuretics. Loop diuretics, such as furosemide, inhibit the body's
ability to reabsorb sodium at the ascending loop in the kidney which leads to
a retention of water in the urine as water normally follows sodium back into
the extracellular fluid (ECF). Other examples of high ceiling loop diuretics
include ethacrynic acid, torsemide and bumetanide.

Thiazides
Thiazide-type diuretics such as hydrochlorothiazide act on the distal
convoluted tubule and inhibit the Sodium-chloride symporter leading to a
retention of water in the urine as water normally follows penetrating solutes.
Frequent urination is due to the increase loss of water that has not being
retained from the body as a result of concomitant relationship with sodium
loss from the convoluted tubule.

Potassium-sparing diuretics
These are diuretics which do not promote the secretion of potassium into the
urine; thus, potassium is spared and not lost as much as in other diuretics.
The term "potassium-sparing" refers to an effect rather than a mechanism or
location; nonetheless, the term almost always refers to two specific classes
that have their effect at similar locations:

Aldosterone antagonists: Spironolactone, which is a competitive

antagonist of aldosterone. Aldosterone normally adds sodium channels
in the principal cells of the collecting duct and late distal tubule of the
nephron. Spironolactone prevents aldosterone from entering the
principal cells, preventing sodium reabsorption. A similar agent is
potassium canreonate.

Epithelial sodium channel blockers: amiloride and triamterene.

Calcium-sparing diuretics
The term "calcium-sparing diuretic" is sometimes used to identify agents that
result in a relatively low rate of excretion of calcium.[2]
The reduced concentration of calcium in the urine can lead to an increased
rate of calcium in serum. The sparing effect on calcium can be beneficial in
hypocalcemia, or unwanted in hypercalcemia.
The thiazides and potassium-sparing diuretics are considered to be calciumsparing diuretics.[3]

The thiazides cause a net decrease in calcium lost in urine.[4]

The potassium-sparing diuretics cause a net increase in calcium lost in
urine, but the increase is much smaller than the increase associated
with other diuretic classes.[4]

By contrast, loop diuretics promote a significant increase calcium excretion. [5]

This can increase risk of reduced bone density. [6]

Osmotic diuretics
Compounds such as mannitol are filtered in the glomerulus, but cannot be
reabsorbed. Their presence leads to an increase in the osmolarity of the
filtrate. To maintain osmotic balance, water is retained in the urine.
Glucose, like mannitol, is a sugar that can behave as an osmotic diuretic.
Unlike mannitol, glucose is commonly found in the blood. However, in certain
conditions such as diabetes mellitus, the concentration of glucose in the
blood exceeds the maximum reabsorption capacity of the kidney. When this
happens, glucose remains in the filtrate, leading to the osmotic retention of
water in the urine. Use of some drugs, especially stimulants may also
increase blood glucose and thus increase urination.

Low ceiling diuretics

The term "low ceiling diuretic" is used to indicate that a diuretic has a rapidly
flattening dose effect curve (in contrast to "high ceiling", where the
relationship is close to linear). It refers to a pharmacological profile, not a
chemical structure. However, there are certain classes of diuretic which
usually fall into this category, such as the thiazides.[7]

Uses
In medicine, diuretics are used to treat heart failure, liver cirrhosis,
hypertension and certain kidney diseases. Some diuretics, such as
acetazolamide, help to make the urine more alkaline and are helpful in
increasing excretion of substances such as aspirin in cases of overdose or
poisoning. Diuretics are often abused by sufferers of eating disorders,
especially bulimics, in attempts at weight loss.
The antihypertensive actions of some diuretics (thiazides and loop diuretics
in particular) are independent of their diuretic effect. That is, the reduction in
blood pressure is not due to decreased blood volume resulting from
increased urine production, but occurs through other mechanisms and at
lower doses than that required to produce diuresis. Indapamide was
specifically designed with this in mind, and has a larger therapeutic window
for hypertension (without pronounced diuresis) than most other diuretics.

Mechanism of action
Classification of common diuretics and their mechanisms of action:

Examples

Ethanol, Water

Acidifying salts

CaCl2, NH4Cl

Arginine vasopressin
amphotericin B,
receptor 2 antagonist
lithium citrate
s

Mechanism

inhibits
vasopressin
secretion

Location
(numbered
in distance
along
nephron)

1.
1.

inhibit
vasopressin's
action

5. collecting
duct

Increases blood
flow in kidneys

1.

Na-H
exchanger antagonist dopamine[8]
s

promote Na+
excretion

2. proximal
tubule[8]

Carbonic anhydrase i acetazolamide[8],

nhibitors
dorzolamide

inhibit H+
secretion,
2: proximal
resultant
tubule
promotion of Na+
and K+ excretion

Aquaretics

Goldenrod, Juniper

Loop diuretics

bumetanide[8],
ethacrynic acid[8],
furosemide[8],
torsemide

Osmotic diuretics

glucose (especially
promote osmotic
in uncontrolled
diuresis
diabetes), mannitol

inhibit the Na-K2Cl symporter

3. medullary
thick
ascending
limb
2. proximal
tubule,
descending
limb

inhibition of
Na+/K+
exchanger:
Spironolactone
5. cortical
inhibits
collecting
aldosterone
ducts
action, Amiloride
inhibits epithelial
sodium channels[8]

Potassium-sparing
diuretics

amiloride,
spironolactone,
triamterene,
potassium
canrenoate.

Thiazides

bendroflumethiazid inhibit
4. distal
e,
reabsorption by
convoluted
hydrochlorothiazide Na+/Cl- symporter tubules

Xanthines

caffeine,
theophylline

inhibit
reabsorption of
Na+, increase
glomerular
filtration rate

1. tubules

Chemically, diuretics are a diverse group of compounds that either stimulate

or inhibit various hormones that naturally occur in the body to regulate urine
production by the kidneys. Herbal medications are not inherently diuretics.
They are more correctly called aquaretics.

Adverse effects

The main adverse effects of diuretics are hypovolemia, hypokalemia,

hyperkalemia, hyponatremia, metabolic alkalosis, metabolic acidosis and
hyperuricemia [8]. Each are at risk of certain types of diuretics and present
with different symptoms.
Adverse
effect

Diuretics

Hyperkalemia

thirst[8]

thiazides[8]

muscle cramps[8]

acetazolamides[8]

hypotension[8]
muscle weakness[8]

loop diuretics[8]

paralysis[8]

thiazides[8]
amilorides[8]

arrhythmia[8]
arrhythmia[8]

triamterenes[8]

muscle cramps[8]

spironolactone[8]
thiazides[8]

paralysis[8]
CNS symptoms[8]

furosemides[8]
loop diuretics[8]

coma[8]
arrhythmia[8]

thiazides[8]

hyponatremia

metabolic
acidosis

hypercalcemia

lassitude[8]

loop diuretics[8]

metabolic
alkalosis

Hypovolemia

hypokalemia

Symptoms

acetazolamides[8]

amilorides[8]

triamterene[8]

thiazides

[8]

CNS symptoms[8]
Kussmaul respirations[8]

muscle weakness

neurological
symptoms[8]
o

lethargy

coma

seizures

stupor

gout

tissue calcification[8]

thiazides

fatigue

depression

confusion

anorexia

nausea

vomiting

constipation

pancreatitis

increased urination

gout[8]

[8]

hyperuricemia

loop diuretics

[8]

See also

antidiuretic

Beta blocker

Skeletal formula of propranolol, the first clinically successful beta blocker

Beta blockers (sometimes written as -blocker) is a class of drugs used for
various indications, but particularly for the management of cardiac
arrhythmias, cardioprotection after myocardial infarction (heart attack), and
hypertension. Propranolol was the first clinically useful beta adrenergic
receptor antagonist. Invented by Sir James W. Black, it revolutionized the
medical management of angina pectoris and is considered to be one of the
most important contributions to clinical medicine and pharmacology of the
20th century.[1] Beta blockers may also be referred to as beta-adrenergic
blocking agents, beta-adrenergic antagonists, or beta antagonists.

Contents

1 Pharmacology
o 1.1 -Receptor antagonism
o

1.2 Intrinsic sympathomimetic activity

1.3 1-Receptor antagonism

1.4 Other effects

2 Clinical use
o

2.1 Congestive heart failure

2.2 Anxiety and performance enhancement

3 Adverse effects

4 Toxicity

5 Examples of beta blockers

o

5.1 Non-selective agents

5.2 1-Selective agents

5.3 2-Selective agents

6 Adverse effects

7 Comparative information
o

7.1 Pharmacological differences

7.2 Indication differences

Pharmacology
There are three known types of beta receptor, designated 1, 2 and 3. 1Adrenergic receptors are located mainly in the heart and in the kidneys. 2Adrenergic receptors are located mainly in the lungs, gastrointestinal tract,
liver, uterus, vascular smooth muscle, and skeletal muscle. 3-receptors are
located in fat cells.
Examples of beta-blockers include: acebutolol, bisoprolol, esmolol,
propranolol, atenolol, labetalol, carvedilol, metoprolol, and nebivolol.

-Receptor antagonism
Stimulation of 1 receptors by epinephrine induces a positive chronotropic
and inotropic effect on the heart and increases cardiac conduction velocity
and automaticity. Stimulation of 1 receptors on the kidney causes renin
release. Stimulation of 2 receptors induces smooth muscle relaxation,
induces tremor in skeletal muscle, and increases glycogenolysis in the liver
and skeletal muscle. Stimulation of 3 receptors induces lipolysis.
Beta blockers inhibit these normal epinephrine-mediated sympathetic
actions, but have minimal effect on resting subjects. That is, they reduce the
effect of excitement/physical exertion on heart rate and force of contraction,
dilation of blood vessels and opening of bronchi, and also reduce tremor and
breakdown of glycogen.
It is therefore expected that non-selective beta blockers have an
antihypertensive effect. The antihypertensive mechanism appears to involve
reduction in cardiac output (due to negative chronotropic and inotropic
effects), reduction in renin release from the kidneys, and a central nervous
system effect to reduce sympathetic activity (for those -blockers that do
cross the blood-brain barrier, e.g. Propranolol).
Antianginal effects result from negative chronotropic and inotropic effects,
which decrease cardiac workload and oxygen demand. Negative chronotropic
properties of beta blockers allow the lifesaving property of heart rate control.
Beta blockers are readily titrated to optimal rate control in many pathologic
states.
The antiarrhythmic effects of beta blockers arise from sympathetic nervous
system blockade resulting in depression of sinus node function and
atrioventricular node conduction, and prolonged atrial refractory periods.
Sotalol, in particular, has additional antiarrhythmic properties and prolongs
action potential duration through potassium channel blockade.
Blockade of the sympathetic nervous system on renin release leads to
reduced aldosterone via the renin angiotensin aldosterone system with a
resultant decrease in blood pressure due to decreased sodium and water
retention.

Intrinsic sympathomimetic activity

Also referred to as intrinsic sympathomimetic effect, this term is used
particularly with beta blockers that can show both agonism and antagonism
at a given beta receptor, depending on the concentration of the agent (beta
blocker) and the concentration of the antagonized agent (usually an

endogenous compound such as norepinephrine). See partial agonist for a

more general description.
Some beta blockers (e.g. oxprenolol, pindolol, penbutolol and acebutolol)
exhibit intrinsic sympathomimetic activity (ISA). These agents are capable of
exerting low level agonist activity at the -adrenergic receptor while
simultaneously acting as a receptor site antagonist. These agents, therefore,
may be useful in individuals exhibiting excessive bradycardia with sustained
beta blocker therapy.
Agents with ISA are not used in post-myocardial infarction as they have not
been demonstrated to be beneficial. They may also be less effective than
other beta blockers in the management of angina and tachyarrhythmia.[2]

1-Receptor antagonism
Some beta blockers (e.g. labetalol and carvedilol) exhibit mixed antagonism
of both - and 1-adrenergic receptors, which provides additional arteriolar
vasodilating action.

Other effects
Beta blockers decrease nocturnal melatonin release, perhaps partly
accounting for sleep disturbance caused by some agents.[3]
Beta blockers protect against social anxiety: "Improvement of physical
symptoms has been demonstrated with beta-blockers such as propranolol;
however, these effects are limited to the social anxiety experienced in
performance situations." (example: an inexperienced symphony soloist) [4]
Beta blockers can impair the relaxation of bronchial muscle (mediated by
beta-2) and so should be avoided by asthmatics.It causes constipation.
They can also be used to treat glaucoma because they decrease intraocular
pressure by lowering aqueous humor secretion.[5]

Clinical use
Large differences exist in the pharmacology of agents within the class, thus
not all beta blockers are used for all indications listed below.

Indications for beta blockers include:

Hypertension
Angina

Mitral valve prolapse

Cardiac arrhythmia

Atrial fibrillation

Congestive heart failure

Myocardial infarction

Glaucoma

Migraine prophylaxis

Symptomatic control (tachycardia, tremor) in anxiety and

hyperthyroidism

Essential tremor

Phaeochromocytoma, in conjunction with -blocker

Beta blockers have also been used in the following conditions:

Hypertrophic obstructive cardiomyopathy

Acute dissecting aortic aneurysm

Marfan syndrome (treatment with propranolol slows progression of

aortic dilation and its complications)

Prevention of variceal bleeding in portal hypertension

Possible mitigation of hyperhidrosis

Social anxiety disorder and other anxiety disorders

Congestive heart failure

Although beta blockers were once contraindicated in congestive heart failure,
as they have the potential to worsen the condition, studies in the late 1990s
showed their positive effects on morbidity and mortality in congestive heart
failure.[6] [7] [8] Bisoprolol, carvedilol and sustained-release metoprolol are
specifically indicated as adjuncts to standard ACE inhibitor and diuretic
therapy in congestive heart failure.

Beta blockers are primarily known for their reductive effect on heart rate,
although this is not the only mechanism of action of importance in
congestive heart failure. Beta blockers, in addition to their sympatholytic B1
activity in the heart, influence the renin/angiotensin system at the kidneys.
Beta blockers cause a decrease in renin secretion, which in turn reduce the
heart oxygen demand by lowering extracellular volume and increasing the
oxygen carrying capacity of blood. Beta blockers sympatholytic activity
reduce heart rate, thereby increasing the ejection fraction of the heart
despite an initial reduction in ejection fraction.
Trials have shown that beta blockers reduce the absolute risk of death by
4.5% over a 13 month period. As well as reducing the risk of mortality, the
number of hospital visits and hospitalizations were also reduced in the trials.
[9]

Anxiety and performance enhancement

Some people, particularly musicians, use beta blockers to avoid stage fright
and tremor during public performance and auditions. The physiological
symptoms of the fight/flight response associated with performance anxiety
and panic (pounding heart, cold/clammy hands, increased respiration,
sweating, etc.) are significantly reduced, thus enabling anxious individuals to
concentrate on the task at hand. Officially, beta blockers are not approved
for anxiolytic use by the U.S. Food and Drug Administration. [10]
Since they lower heart rate and reduce tremor, beta blockers have been
used by some Olympic marksmen to enhance performance, though beta
blockers are banned by the International Olympic Committee (IOC).[11]
Although they have no recognisable benefit to most sports, it is
acknowledged that they are beneficial to sports such as archery and
shooting. A recent, high-profile transgression took place in the 2008 Summer
Olympics, where 50 metre pistol silver medallist and 10 metre air pistol
bronze medallist Kim Jong-su tested positive for propranolol and was stripped
of his medals.

Adverse effects
Adverse drug reactions (ADRs) associated with the use of beta blockers
include: nausea, diarrhea, bronchospasm, dyspnea, cold extremities,
exacerbation of Raynaud's syndrome, bradycardia, hypotension, heart
failure, heart block, fatigue, dizziness, abnormal vision, decreased
concentration, hallucinations, insomnia, nightmares, clinical depression,
sexual dysfunction, erectile dysfunction and/or alteration of glucose and lipid

metabolism. Mixed 1/-antagonist therapy is also commonly associated with

orthostatic hypotension. Carvedilol therapy is commonly associated with
edema.[2]
Central nervous system (CNS) adverse effects (hallucinations, insomnia,
nightmares, depression) are more common in agents with greater lipid
solubility, which are able to cross the blood-brain barrier into the CNS.
Similarly, CNS adverse effects are less common in agents with greater
aqueous solubility (listed below).
Adverse effects associated with 2-adrenergic receptor antagonist activity
(bronchospasm, peripheral vasoconstriction, alteration of glucose and lipid
metabolism) are less common with 1-selective (often termed
"cardioselective") agents, however receptor selectivity diminishes at higher
doses. Beta blockade, especially of the beta-1 receptor at the macula densa
inhibits renin release, thus decreasing the release of aldosterone. This causes
hyponatremia and hyperkalemia.
A 2007 study revealed that diuretics and beta-blockers used for hypertension
increase a patient's risk of developing diabetes while ACE inhibitors and
Angiotensin II receptor antagonists (Angiotensin Receptor Blockers) actually
decrease the risk of diabetes.[12] Clinical guidelines in Great Britain, but not in
the United States, call for avoiding diuretics and beta-blockers as first-line
treatment of hypertension due to the risk of diabetes.[13]
Beta blockers must not be used in the treatment of cocaine, amphetamine,
or other alpha adrenergic stimulant overdose. The blockade of only beta
receptors increases hypertension, reduces coronary blood flow, left
ventricular function, and cardiac output and tissue perfusion by means of
leaving the alpha adrenergic system stimulation unopposed. [14] The
appropriate antihypertensive drugs to administer during hypertensive crisis
resulting from stimulant abuse are vasodilators like nitroglycerin, diuretics
like furosemide and alpha blockers like phentolamine. [15]

Toxicity
Glucagon has been used in the treatment of overdose.[16][17] Glucagon has a
positive inotropic action on the heart and decreases renal vascular
resistance. It is therefore useful in patients with beta-blocker cardiotoxicity
Cardiac pacing should be reserved for patients unresponsive to
pharmacological therapy

Examples of beta blockers

Dichloroisoprenaline, the first beta blocker.

Non-selective agents

Alprenolol
Bucindolol

Carteolol

Carvedilol (has additional -blocking activity)

Labetalol (has additional -blocking activity)

Nadolol

Penbutolol (has intrinsic sympathomimetic activity)

Pindolol (has intrinsic sympathomimetic activity)

Propranolol

Timolol

1-Selective agents

Acebutolol (has intrinsic sympathomimetic activity)

Atenolol

Betaxolol

Bisoprolol

Celiprolol

Esmolol

Metoprolol

Nebivolol

2-Selective agents

Butaxamine (weak -adrenergic agonist activity) - No common clinical

utility, used in experimental situations.

Adverse effects

Low Blood Pressure

Slow Heart Rate

Impaired Circulation

Loss of Sleep

Heart Failure

Asthma

Nausea

Headaches

Dizziness

Muscle Cramps

Peyronie's disease

Insomnia (potentially because the drug blocks melatonin - melatonin

supplements can treat this side effect) [1]

Comparative information
Pharmacological differences

Agents with intrinsic sympathomimetic action (ISA)

o Acebutolol, carteolol, celiprolol, mepindolol, oxprenolol, pindolol

Agents with greater aqueous solubility

o

Agents with membrane stabilising activity

o

, celiprolol, nadolol, sotalol

Acebutolol, betaxolol, pindolol, propranolol

Agents with antioxidant effect

o

Carvedilol

Nebivolol

Indication differences

Agents specifically indicated for cardiac arrhythmia

o Esmolol, sotalol, landiolol

Agents specifically indicated for congestive heart failure

o

Agents specifically indicated for glaucoma

o

Betaxolol, carteolol, levobunolol, metipranolol, timolol

Agents specifically indicated for myocardial infarction

o

Bisoprolol, carvedilol, sustained-release metoprolol, nebivolol

Atenolol, metoprolol, propranolol

Agents specifically indicated for migraine prophylaxis

o

Timolol, propranolol

Propranolol is the only agent indicated for control of tremor, portal

hypertension and esophageal variceal bleeding, and used in conjunction with
-blocker therapy in phaeochromocytoma.[2]

See Also

Alpha blockers

Alpha blocker
blockers or (adrenergic) -antagonists are pharmacological agents
that act as antagonists of adrenergic receptors (-adrenoceptors).[1]

Classification

1 blockers or antagonists act at 1-adrenoceptors

2 blockers or antagonists - act at 2-adrenoceptors

When the term "alpha blocker" is used without further qualification, it

sometimes refers to 1 blockers, and sometimes refers to agents that act at
both types of receptors.[citation needed]
Non-selective -adrenergic blockers include:

Phenoxybenzamine
Phentolamine

The agents carvedilol and labetalol are both - and -blockers.

Uses
blockers are used in the treatment of several conditions, such as
Raynaud's disease, hypertension, and scleroderma.

Adrenergic receptor

Adrenaline

Noradrenaline
The adrenergic receptors (or adrenoceptors) are a class of G proteincoupled receptors that are targets of the catecholamines, especially
noradrenaline (norepinephrine) and adrenaline (epinephrine). Although
dopamine is a catecholamine, its receptors are in a different category.
Many cells possess these receptors, and the binding of an agonist will
generally cause a sympathetic response (i.e. the fight-or-flight response). For
instance, the heart rate will increase and the pupils will dilate, energy will be
mobilized, and blood flow diverted from other non-essential organs to
skeletal muscle.

Contents

1 Subtypes
o 1.1 Roles in circulation
o

1.2 Comparison

1.3 receptors

1.3.1 1 receptor

1.3.2 2 receptor

1.4 receptors

1.4.1 1 receptor

1.4.2 2 receptor

1.4.3 3 receptor

Subtypes
There are two main groups of adrenergic receptors, and , with several
subtypes.

receptors have the subtypes 1 (a Gq coupled receptor) and 2 (a Gi

coupled receptor). Phenylephrine is a selective agonist of the
receptor.
receptors have the subtypes 1, 2 and 3. All three are linked to Gs
proteins (although 2 also couples to Gi)[1], which in turn are linked to
adenylate cyclase. Agonist binding thus causes a rise in the
intracellular concentration of the second messenger cAMP (cyclic
adenosine monophosphate). Downstream effectors of cAMP include
cAMP-dependent protein kinase (PKA), which mediates some of the
intracellular events following hormone binding. Isoprenaline is a
selective agonist.

Epinephrine binds its receptor, that associates with an heterotrimeric G

protein. The G protein associates with adenylate cyclase that converts ATP to
cAMP, spreading the signal (more details...)

The mechanism of adrenergic receptors. Adrenaline or noradrenaline are

receptor ligands to either 1, 2 or -adrenergic receptors. 1 couples to Gq,
which results in increased intracellular Ca2+ which results in smooth muscle
contraction. 2, on the other hand, couples to Gi, which causes a decrease of
cAMP activity, resulting in e.g. smooth muscle relaxation. receptors couple
to Gs, and increases intracellular cAMP activity, resulting in e.g. heart muscle
contraction, smooth muscle relaxation and glycogenolysis.

Roles in circulation
Adrenaline reacts with both - and -adrenoreceptors, causing
vasoconstriction and vasodilation, respectively. Although receptors are less
sensitive to epinephrine, when activated, they override the vasodilation
mediated by -adrenoreceptors. The result is that high levels of circulating
epinephrine cause vasoconstriction. At lower levels of circulating
epinephrine, -adrenoreceptor stimulation dominates, producing an overall
vasodilation.

Comparison

Agonist
Rece
potency
ptor
order

Selected
action
Mechan
of
ism
agonist

Agonists

(Alpha-1
agonists)

1:
A, B,
D

epinephri
ne
norepine
phrine
>>
isoprenal
ine

Gq:
phospho
lipase C
smooth
(PLC)
muscle
activate
contractio
d, IP3
n
and
calcium
up

Noradrenali
ne
Phenylephri
ne

Methoxami
ne

Cirazoline

Xylometazo
line

Antagonists

(Alpha-1 blockers)
Alfuzosin
Doxazosin

Phenoxyben
zamine

Phentolamin
e

Prazosin

Tamsulosin

Terazosin

(Alpha-2
agonists)

2:
A, B,
C

norepine
phrine
epinephri
ne >>
isoprenal
ine

smooth
muscle
constrictio
n and
neurotran
smitter
inhibition

Gi :
adenylat
e
cyclase
inactivat
ed,
cAMP
down

Isoprenal heart
Gs :
ine >
muscle
adenylat
epinephri contractio e

Dexmedeto
midine
Medetomidi
ne

Romifidine

Clonidine

Detomidine

Lofexidine

Xylazine

Tizanidine

Guanfacine

Amitraz

Noradrenali (Beta blockers)

Metoprolol
ne

Isoprenalin

(Alpha-2 blockers)
Yohimbine
Idazoxan

Atipamezole

ne >>
norepine
phrine

cyclase
activate
d, cAMP
up

Dobutamin
e

Atenolol

Propranolol

(Short/long)
Salbutamol
(Albuterol
in USA)
Bitolterol
mesylate
Gs :
adenylat
Isoprenal
e
ine >
smooth
cyclase
epinephri
muscle
activate
ne >>
relaxation d, cAMP
norepine
up (also
phrine
Gi, see
2)

Isoprenal
ine =
norepine Enhance
phrine > lipolysis
epinephri
ne

Gs :
adenylat
e
cyclase
activate
d, cAMP
up

Formoterol

Isoprenalin
e

Levalbutero
l

Metaproter
enol

Salmeterol

Terbutaline

Ritodrine

L-796568

Amibegron

Solabegron

(Beta blockers)
Butoxamine

Propranolol

SR 59230A

[2]

There is no 1C receptor. At one time, there was a subtype known as C, but

was found to be identical to one of the previously discovered subtypes. To
avoid confusion, naming was continued with the letter D.

receptors
receptors have several functions in common, but also individual effects.
Common (or still unspecified) effects include:

Vasoconstriction of arteries to heart (coronary artery).[3]

Vasoconstriction of veins[4]

Decrease motility of smooth muscle in gastrointestinal tract[5]

1 receptor
Main article: Alpha-1 adrenergic receptor
Alpha1-adrenergic receptors are members of the G protein-coupled receptor
superfamily. Upon activation, a heterotrimeric G protein, Gq, activates
phospholipase C (PLC). The PLC cleaves phosphatidylinositol 4,5bisphosphate (PIP2) which in turn causes an increase in inositol triphosphate
(IP3) and diacylglycerol (DAG). The former interacts with calcium channels of
endoplasmic and sarcoplasmic retuculum thus changing the calcium content
in a cell. This triggers all other effects.
Specific actions of the 1 receptor mainly involves smooth muscle
contraction. It causes vasoconstriction in many blood vessels including those
of the skin & gastrointestinal system and to kidney (renal artery)[6] and
brain[7]. Other areas of smooth muscle contraction are:

ureter
vas deferens

hair (erector pili muscles)

uterus (when pregnant)

urethral sphincter

bronchioles (although minor to the relaxing effect of 2 receptor on

bronchioles)

blood vessels of ciliary body (stimulation causes mydriasis)

Further effects include glycogenolysis and gluconeogenesis from adipose

tissue[8] and liver, as well as secretion from sweat glands[8] and Na+
reabsorption from kidney.[8]
Antagonists may be used in hypertension.
2 receptor
Main article: Alpha-2 adrenergic receptor
There are 3 highly homologous subtypes of 2 receptors: 2A, 2, and 2C.

Specific actions of the 2 receptor include:

inhibition of insulin release in pancreas.[8]

induction of glucagon release from pancreas.

contraction of sphincters of the gastrointestinal tract

negative feedback in the neuronal synapses

platelet aggregation

receptors
1 receptor
Main article: Beta-1 adrenergic receptor
Specific actions of the 1 receptor include:

Increase cardiac output, by raising heart rate (positive chronotropic

effect) and increasing impulse conduction and increasing contraction
thus increasing the volume expelled with each beat (increased ejection
fraction).
Renin release from juxtaglomerular cells.[8]

Lipolysis in adipose tissue.[8]

2 receptor
Main article: Beta-2 adrenergic receptor
The 3D crystallographic structure of the 2-adrenergic receptor has been
determined (PDB 2R4R, 2R4S, 2RH1).[9][10][11]
Specific actions of the 2 receptor include:

Smooth muscle relaxation, e.g. in bronchi.[8]

Lipolysis in adipose tissue.[12]

Anabolism in skeletal muscle.[13][14]

Relax non-pregnant uterus

Relax detrusor urinae muscle of bladder wall

Dilate arteries to skeletal muscle

Glycogenolysis and gluconeogenesis

Contract sphincters of GI tract

Thickened secretions from salivary glands.[8]

Inhibit histamine-release from mast cells

Increase renin secretion from kidney

3 receptor
Main article: Beta-3 adrenergic receptor
Specific actions of the 3 receptor include:

Enhancement of lipolysis in adipose tissue. However, acitvation of

Beta-3 receptors often causes tremors, which is the paramount reason
that Beta-3 activating pharmacological agents are not utilized as
weight loss agents Clarify