ANTIANGINAL AGENTS
(Nitroglicerinum,
Sustac, Isosorbidi dinitras, Isosorbidi mononitras, Verapamilum, Amlodipinum, Anaprilinum, Atenololum, Metoprololum, Dipiridamolum, Drotaverinum (No-spanum), Validolum, Trimetasidinum, ADP-long)
ANTIARRHYTHMIC AGENTS
(Chinidini
sulfas, Novocainamidum, Ethmosinum, Ajmalinum, Lidocainum, Trimecainum, Dypheninum, Aethacizinum, Propaphenolum (Rythmilen), Anaprilinum (Propranololum), Atenololum, Talinololum, Metoprololum, Amiodaronum, Verapamilum)
ANTIHYPERTENSIVE AGENTS
(Anaprilinum
(Propranololum), Atenololum,
Talinololum, Metoprololum, Carvediolum, Prasosinum, Doxasosinum, Labetololum, Captoprilum (Capotenum), Enalaprilum, Lisinoprilum, Losartanum, Clopamidum,Fenigidinum,
Amlodipinum, Furosemidum, Dichlothiazidum, Spironolactonum,
Clophelinum, Reserpinum, Octadinum, Methyldopha, Pentoxiphyllinum Agapurinum), Diazoxidum, Natrii nitroprussidum, Drotaverinum,
(No-spa), Magnesii sulfas, Dibasolum, Papaverini hydrohloridum)
Antianginal agents
Angina pectoris is chest pain due to ischemia
(a lack of blood and hence oxygen supply) of the heart muscle,
generally due to obstruction or spasm of the coronary arteries (the heart's blood
vessels). Coronary artery disease, the main cause of
angina, is due to atherosclerosis of the cardiac arteries. The
term derives from the Greek ankhon
("strangling") and the Latin pectus
("chest"), and can therefore be translated as "a strangling
feeling in the chest".
http://www.musc.edu/bmt737/spring2001/Kate/angina2.html
Angina results from a reduction in the
oxygen supply/demand ratio.
Therefore, in order to alleviate
the pain, it is necessary
to improve this ratio. This
can be done
either by increasing blood flow (which increases
oxygen delivery or supply), or
by decreasing oxygen demand (i.e., by decreasing myocardial
oxygen consumption).
Pharmacologic interventions that block coronary vasospasm (coronary vasodilators) or inhibit clot formation
are used to treat variant and unstable
angina, respectively.
These drugs act by increasing
coronary blood flow and oxygen
supply, or by preventing vasospasm
and clot formation, and associated decreases in blood flow.
Drugs that reduce myocardial oxygen demand are
also given to patients with
these two forms of angina
to reduce oxygen demand and
thereby help to alleviate the
pain.
Drugs that reduce myocardial
oxygen demand are commonly used
to prevent and treat episodes
of ischemic pain associated with fixed stenotic
lesions (i.e., chronic stable angina).
Some of these
drugs reduce oxygen demand by
decreasing heart rate (decreased chronotropy) and contractility (decreased inotropy), while
other drugs reduce afterload and
or preload on
the heart. Afterload and preload
reducing drugs act by dilating
peripheral arteries and veins. Direct
vasodilation of the coronary arteries
is ineffective as a therapeutic approach and may
actually worsen the ischemia by
producing coronary vascular steal.
An anginal pain attack
signals a transient hypoxia of the myocardium. As a rule, the oxygen deficit
results from inadequate myocardial blood flow due to narrowing of larger
coronary arteries. The underlying causes are: most commonly, an atherosclerotic change of the vascular
wall (coronary sclerosis with exertional
angina); very infrequently, a spasmodic constriction of a morphologically
healthy coronary artery (coronary spasm with angina at rest; variant
angina); or more often, a coronary spasm occurring in an atherosclerotic
vascular segment. The goal of treatment is to prevent myocardial hypoxia either
by raising blood flow (oxygen supply) or by lowering myocardial blood
demand (oxygen demand) (A).
Factors determining oxygen supply. The force driving myocardial blood flow is the pressure
difference between the coronary ostia (aortic
pressure) and the opening of the coronary sinus (right atrial pressure).
Blood flow is opposed by coronary flow resistance, which includes
three components. (1) Due to their large caliber, the proximal coronary
segments do not normally contribute significantly to flow resistance.
However, in coronary sclerosis or spasm, pathological obstruction of flow
occurs here. Whereas the more common coronary sclerosis cannot be overcome
pharmacologically, the less common coronary spasm can be relieved by
appropriate vasodilators (nitrates, nifedipine).
(2)
The caliber of arteriolar resistancevessels
controls blood flow through the coronary bed. Arteriolar caliber is
determined by myocardial O2 tension and local concentrations of metabolic
products, and is “automatically” adjusted to the required blood flow (B, healthy
subject). This metabolic autoregulation explains
why anginal attacks in coronary sclerosis occur only
during exercise (B, patient). At rest, the pathologically elevated flow
resistance is compensated by a corresponding decrease in arteriolar resistance,
ensuring adequate myocardial perfusion. During exercise, further dilation of
arterioles is impossible. As a result, there is ischemia associated with pain.
Pharmacological agents that act to dilate arterioles would thus be
inappropriate because at rest they may divert blood from underperfused
into healthy vascular regions on account of redundant arteriolar dilation. The
resulting “steal effect” could provoke an anginal
attack. (3) The intramyocardial pressure, i.e.,
systolic squeeze, compresses the capillary bed. Myocardial blood flow is halted
during systole and occurs almost entirely during diastole. Diastolic wall
tension (“preload”) depends on ventricular volume and filling pressure. The
organic nitrates reduce preload by decreasing venous return to the heart.
Factors determining oxygen demand. The heart muscle cell consumes the most energy to
generate contractile force. O2 demand rises with an increase in (1) heart
rate, (2) contraction velocity, (3) systolic wall tension (“afterload”).
The latter depends on ventricular volume and the systolic pressure needed to
empty the ventricle. As peripheral resistance increases, aortic pressure rises, hence the resistance against which ventricular blood
is ejected. O2 demand is lowered by â-blockers and Ca-antagonists,
as well as by nitrates
It is common to equate severity of angina with risk of fatal
cardiac events. There is a weak relationship between severity of pain and
degree of oxygen deprivation in the heart muscle (i.e. there can be severe pain
with little or no risk of a heart attack, and a heart attack can occur without pain). Worsening ("crescendo") angina
attacks, sudden-onset angina at rest, and angina lasting more than 15 minutes
are symptoms of unstable angina (usually grouped with similar conditions
as the acute coronary syndrome). As these may
herald myocardial infarction (a heart attack),
they require urgent medical attention and are generally treated as a presumed
heart attack.
Most patients with angina complain of
chest discomfort rather than actual pain: the discomfort is usually described
as a pressure, heaviness, tightness, squeezing, burning,
or choking sensation. Apart from chest discomfort, anginal
pains may also be experienced in the epigastrium (upper central abdomen), back,
neck, jaw, or shoulders. Typical locations for radiation of pain are arms
(often inner left arm), shoulders, and neck into the jaw. Angina is typically
precipitated by exertion or emotional stress. It is exacerbated by having a
full stomach and by cold temperatures. Pain may be accompanied by
breathlessness, sweating and nausea in some cases. It usually lasts for about 1
to 5 minutes, and is relieved by rest or specific anti-angina medication. Chest
pain lasting only a few seconds is normally not angina. Myocardial ischemia
comes about when the myocardia (the heart muscles) fail to take in sufficient
blood and oxygen to function correctly. This inadequate perfusion
of blood and the resulting reduced delivery of oxygen and nutrients, is
directly correlated to blocked or narrowed blood vessels.
Some experience "autonomic symptoms" (related to increased activity of the autonomic nervous system) such as nausea, vomiting and pallor. Major risk factors for angina include cigarette smoking, diabetes, high cholesterol, high blood pressure and family history of premature heart disease. A variant form of angina (Prinzmetal's
Myocardial
ischemia can result from:
1. a
reduction of blood flow to the heart caused by the stenosis or spasm of the
heart's arteries
2. resistance
of the blood vessels
3. reduced
oxygen-carrying capacity of the blood.
Nitroglycerin (NG), also known as nitroglycerine,
trinitroglycerin, and glyceryl trinitrate, is a chemical
compound. It is a heavy, colorless, oily, explosive liquid obtained by nitrating
glycerol.
It is used in the manufacture of explosives,
specifically dynamite,
and as such is employed in the construction
and demolition
industries, and as a plasticizer
in some solid propellants.
It is also used medically
as a vasodilator
to treat heart
conditions.Nitroglycerin was discovered by chemist Ascanio
Sobrero in 1847,
working under TJ
Pelouze at the University
of Torino. The best manufacturing process was developed by Alfred
Nobel in the 1860s. His company exported a liquid combination of
nitroglycerin and gunpowder
as 'Swedish Blasting Oil', but it was extremely dangerous as a result of its
extreme instability, as shown in a number of "appalling
catastrophes," such as the explosion that destroyed a Wells
Fargo office in San
Francisco in 1866. The liquid was widely banned, and this led to the
development of dynamite
(and similar mixtures such as dualine and lithofracteur), by
mixing the nitroglycerine with inert (Nobel used kieselguhr)
absorption (chemistry)|absorbents]] (e.g., nitrocellulose
gel,
blasting
gelatine).
toleance
may develop in less than 48 hours after the initiation of treatment with
nitrates.
Beta-blockers may be classified based
on their ancillary pharmacological properties. Cardioselective agents
have high affinity for cardiac β 1
and less affinity for bronchial and vascular β2 receptors
compared with non-selective agents and this reduces (but does not abolish)
β 2 receptor-mediated side effects. However, with increasing
doses cardiac selectivity disappears. Lipid-soluble agents cross the
blood-brain barrier more readily and are associated with a higher incidence of
central side effects. Some beta-blockers have intrinsic sympathomimetic
activity – ISA (i.e., they stimulate
β receptors when background sympathetic nervous activity is low and block
them when background sympathetic nervous activity is high). Adverse
effects: BBs slow the rate of
conduction at the atrio-ventricular node and are contraindicated in patients
with second- and third-degree heart block. Sinus bradycardia is common and
treatment should be stopped if patient is symptomatic or heart rate falls below
40 b/min. Because of blockade of pulmonary ß2 receptors, even
small doses of BBs can cause bronchospasm (less common with cardioselective
agents), and all beta-blockers are contraindicated in asthma. Blockade of
ß receptors in the peripheral circulation causes vasoconstriction and may
induce particularly in patients with peripheral circulatory insufficiency
adverse affects such as cold extremities, Raynaud’s phenomenon, and
intermittent claudication. Nevertheless, they are reasonably tolerated in
patient with mild peripheral vascular disease. Lipid-soluble agents can cause
central nervous system side effects of insomnia, nightmares and fatigue. Exercise
capacity may be reduced by BBs and patients may experience tiredness and
fatigue. BBs can worsen glucose intolerance
and hyperlipidemia and in diabetic patients mask signs of hypoglycemia.
However, diabetic hypertensive patients with previous MI should not be denied
BB because of concerns about metabolic side effects.
sclerosis,
but not in variant angina.
Myocardial
infarction is caused by acute thrombotic occlusion of a coronary artery
(A).
infarction.
Pain due to ischemia is treated predominantly with antianginal drugs (e.g.,
nitrates).
The
mechanism of drug action is central to the process of choosing a drug to treat
any particular arrhythmia. Thus it is useful to consider first
impulse generation at the cellular level. This in turn demands
consideration of the ion channels underpinning impulse generation in
different cardiac muscle cell types. It is the opening and closing
of a range of different ion channels that leads to the distinct
profiles of membrane potential which comprise cardiac action
potentials. Therefore, we shall initially consider the
electrophysiological characteristics of cardiac action potentials,
aspects of ion channel function, and ion channels as sites of
antiarrhythmic drug action.
Ventricular cells in particular also possess a distinct plateau phase, and the relatively long duration of the ventricular action potential helps make the ventricular tissue refractory to overexcitation which might otherwise tetanise the ventricular myocardium. The distinct action potential phases discussed above are sometimes referred to as phases 0 to 4: phase 0 is the action potential upstroke, phase 1 is the early repolarisation "notch" (evident immediately after the ventricular action potential peak , phases 2 and 3 describe plateau and late repolarisation (pacemaker cell action potentials without a distinct notch or plateau may lack distinct phases 1 and 2), while phase 4 is the period after repolarisation is complete (the resting level in non-pacemaker cells, and the pacemaker depolarisation in pacemaker cells).
repolarising or outward current .
If the inside of the cell is made more negative than EK
the direction of ion flow will be reversed With a knowledge of the normal
intracellular and extracellular ion concentrations, it is possible
to predict the contributions of sodium, calcium, and potassium
channels in generating membrane potential depolarisation or
repolarisation.
One
further aspect of ion channel function should be covered before considering the
roles played by individual ion channel typeschannel
gating. Voltage operated channels are usually referred to as
voltage gated, as biophysical measurements indicate that specific
membrane potential regulated processes determine the magnitude and
time course of ionic current flow across the range of ion channel
types. This can be explained by considering an ion channel that does
not pass current until a depolarising stimulus is applied. At rest,
the channel is therefore considered to be closed . When a
depolarising stimulus is applied, the membrane potential change is
detected by the voltage sensorthe
channel undergoes a conformational change and opens in order to allow
ionic current to flow. The process describing the transition from
the closed to open state is termed activation. The
probability of channels moving to the open state usually depends on
the magnitude of the voltage change (activation is therefore "voltage
dependent"), and the speed with which channels move from the
closed to the open state will determine the rate of activation. Some voltage dependent channels show only a
voltage dependent activation process, but for many a second process also
influences ionic current flow. If the depolarising stimulus is
maintained, a second conformational change occurs in the ion
channel. Part of the ion channel protein moves to occlude the
channel pore such that, while the channel may be fully activated, it
becomes poorly conducting
RHYTHMIC DRUGS (Continued)
ANTIARRHYTHMIC DRUGSCHANNELS
INVOLVED IN PACEMAKING
In the sinus node,
the T type calcium current (
CHANNELS INVOLVED
IN ACTION POTENTIAL DEPOLARISATION
L type calcium and
sodium channels are of greater importance as antiarrhythmic targets.
POTASSIUM
CHANNELS Some sodium
channel blocking agents, for example disopyramide and
in particular quinidine, are also associated with delayed repolarisation and QT prolongation on the ECG. For both
disopyramide and quinidine, his
effect results from potassium channel blocking actions of the drug.
Excessive action potential and QT prolongation (when the corrected
QT interval (QTc) exceeds ~4402
to 460 ms), carries a risk of proarrhythmia.
However, potassium channel blockade can also be antiarrhythmic, because
moderately delayed action potential repolarisation
can enhance the inactivation of depolarising
currents (INa and ICa),
thereby prolonging the period between successive action potentials. This
can be effective in disrupting arrhythmias caused by reentrant mechanisms.
Different potassium channel types, therefore, offer potential
antiarrhythmic drug targets. Major potassium ion channel types
involved in action potential repolarisation include
the transient outward current, ITO, responsible for the
action potential notch in ventricular cells and prominent during
atrial repolarisation. The rapid and slow
components of delayed rectifier current (IKr
and IKs, respectively) are important in plateau repolarisation. The inward rectifier potassium
current is important for the final stage of repolarisation
and for maintaining the cell resting potential. Owing to their roles
in plateau repolarisation, IKr
and IKs are of particular interest as antiarrhythmic targets.
As
in the case of sodium channel blocking agents, the desirable potassium channel
blocker is one that shows positive use dependence (that is, the drug
effects are greatest at faster action potential rates).
Unfortunately, many potassium channel blocking
drugs appear to be associated with a reverse use dependent
effect: action potential prolongation is greater at slower rather
than at faster rates. The problem with this is that action potential
prolongation at slow rates can be proarrhythmic
through the cellular mechanism of early afterdepolarisations.
By a mechanism originally investigated by January and Riddle and
recently reviewed by Makielski and January,
sufficiently slowed membrane repolarisation during
the action potential facilitates calcium entry through L type calcium
channels, which can result in early afterdepolarisations.
These in turn could give rise to triggered activity and lead to torsade
de pointes. Selective block of IKr (for
example, by the drug E-4031) can be sufficient to induce early afterdepolarisations. Early afterdepolarisations
are relieved at faster rates; therefore IKr
block is most likely to be proarrhythmic at slow
rates. The clinical implications of reverse use dependence and
specific IKr block are
exemplified by sotalol which, as the racemic D-L mix,
possesses blocking and IK blocking actions and
is indicated for the treatment of life threatening ventricular
tachycardia. Racemic sotalol produces some
QT prolongation and is bradycardic. D-sotalol lacks the blocking activity of the racemic mix, but is
an IKr blockerand
shows reverse use dependent effects on the action potential.
Significantly, D-sotalol is associated with
an increased risk of death from presumed arrhythmias.
A simple explanation for reverse use
dependent drug effects on action potential prolongation involves drug binding
to the resting channel (in the interval between action potentials)
and dissociating during membrane depolarisation.
This would produce a greater relief of block at faster rates (at
which there would be shorter intervals between action potentials for
drug binding to occur). However, subsequent experiments on cloned channels
are not consistent with this explanation (for example, Synders and colleagues). Moreover, agents such
as almokalant block IKr
in a use dependent fashion, while producing reverse use dependent
action potential prolongation.In addition, dofetilide has been reported to produce rate
independent effects on IKr, but
reverse rate dependent effects on the action potential. In the same
study, repetitive stimulation was observed to increase the magnitude
of IKs but not of IKr. It has
been proposed, therefore, that reverse use dependence may result
from the interaction between IKr
and IKs during repolarisation at different
heart rates. At slower rates IKr
may be dominant; at faster heart rates the role of IKs
increases owing to incomplete deactivation (the transition of
channels from OC, fig 3A) of the current between action
potentials. Thus specific IKr
inhibition would have a greater effect on repolarisation
at slower than at faster rates.
If this mechanism holds, then an
agent which blocks IKs specifically might be better for treating tachycardias than an IKr
blocker; moreover, an agent that blocks both components of IK
might have an improved safety profile over a specific IKr
blocker. There are few experimental data yet available to support
the first of these possibilities (selective IKs blockers
are only beginning to appear); the second, however, does seem to
hold true. Quinidine and sotalol do not
appear to block IKs. By contrast amiodarone,
which has a much better cardiac safety profile, blocks both IKr and IKs, while also
showing a more consistent effect on action potentials at different
rates.
A further potassium channel should be mentioned, as it
is likely to mediate the antiarrhythmic actions of adenosine. The extremely
short half life of adenosine makes intravenous
administration valuable in terminating tachycardias
involving the AV node (either AV nodal re-entry or AV re-entry). In
bolus form, adenosine has been shown to be highly effective against
paroxysmal supraventricular tachycardias
that require AV nodal conduction for their maintenance.The
cellular basis for the effect of adenosine appears to resemble that
for acetylcholine. Acetylcholine activates a potassium current (IKACh), which is important in mediating
parasympathetic effects on the sinoatrial
and AV nodes. When activated, IKACh produces
membrane potential hyperpolarisation; it thereby
decreases automaticity and excitability. At the cellular
level, adenosine activates a current (IKAdo)
with properties identical to those of IKACh
(for example, Belardinelli and colleagues). Cellular
studies on rabbit AV node suggest that activation of IKAdo
is likely to be predominantly responsible for the action of
adenosine, with possible supplementary effects on L type calcium
channels.
Molecular insights into arrhythmogenesis Some of the most exciting cardiological developments of the last decade relate to advances
in understanding the molecular biology underlying ion channel
function, and the finding that defects in individual ion channels
can underlie particular arrhythmias. This is no better exemplified
than in congenital long QT syndrome. This syndrome illustrates how
various different channelopathies can
manifest themselves clinically as virtually identical electrocardiographic
endpoints. Congenital long QT syndrome is characterised
by abnormally prolonged ventricular repolarisation
leading to QTC prolongation (as discussed earlier), with
an associated risk of malignant ventricular tachyarrhythmias
(torsade de pointes).
Congenital long QT syndrome has been
found to arise from a range of different genetic abnormalities . The two
main forms are the autosomal dominant Romano-Ward syndrome (pure
cardiac phenotype) and the autosomal recessive Jervell-Lange-Nielsen
syndrome (in which cardiac abnormalities coexist with congenital deafness).
Of the genetic abnormalities identified in the Romano-Ward syndrome,
four are associated with identified ion channels. Most of the
mutations causing congenital long QT (LQT) syndrome are missense
mutations. However, substantial phenotypic heterogeneity remains,
even with identical gene abnormalities. LQT1, 2, and 3 all
result in prolongation of the action potential. The extent of
prolongation depends not only upon the gene mutated, but also upon
the exact location of the mutation. As discussed earlier, it is the
risk of afterdepolarisations associated with QT
interval prolongationrather than slowing of action potential repolarisation on its ownthat is arrhythmogenic. The
involvement of L type
As shown in alterations in the genes
underlying IKr and IKs are
associated with LQT-2 and LQT-1. The channels for both IKr and IKs are multimeric,and
alleles from both parents contribute to the channel complexes.
Mutant channels expressed in oocytes or cell lines show loss of
function. Channel kinetics, as well as reduced overall current,
contribute to the loss of function (that is, a reduction in repolarising outward current). In contrast,
mutations of sodium (SCN5A) channels cause a gain of function, in
which a late persistent (depolarising) sodium
current is produced because of defective inactivation of INa. Owing to the heterogeneous basis for congenital
long QT syndrome, identification of the underlying cause is pivotal
in deciding upon appropriate treatment. Provocation may distinguish
between the different congenital LQT syndromes. While the QT
interval shortens only minimally with exercise in LQT1 and LQT2, in
patients with LQT3 it shortens significantly. Furthermore, torsade
de pointes is precipitated by adrenergic stimulation (for example, during
exercise) in LQT1, possibly because IKs normally
predominates at high rates, and therefore reduced IKs
would lead to inadequate shortening of the action potential. In
contrast, most patients with LQT 3 experience more events at
rest than on exertion.
Another interesting group of patients providing a
clear link between cellular abnormalities and clinical treatment are those
with the Brugada syndrome. These patients have
structurally normal hearts and right precordial ST segment elevation
or right bundle branch block. The ECG abnormalities probably reflect
exaggerated transmural differences in action
potential configuration, especially within the right ventricular
outflow tract. The end result is an increased risk of ventricular
fibrillation within these families. One variant of the Brugada syndrome arises from a mutation of the
SCN5A gene (the same gene that is implicated in LQT3), leading to a
gain of function; hence drugs targeting the sodium channel may be
clinically effective.
IMPLICATIONS
OF GENETIC INSIGHTS In addition to the syndromes described
above, our understanding of the role of genes in other conditions has also
increased. The reader is referred to a recent and comprehensive
review by Priori and colleagues.. A clear result of the arrival of
molecular biology in the clinical arena is that genetic testing may
be available not only for diagnostic purposes in patients presenting
with arrhythmias but also possibly for individuals who could benefit
from prophylactic treatment to avoid sudden death. Increased genetic knowledge may also
influence treatment strategy. For example, sodium channel blockers
such as lignocaine and mexiletine may be effective in
LQT-3, while LQT-2 would be expected to be respond to a
different approach. Cloned channels encoded by HERG (the gene underlying
channels for IKr) show currents that
increase in size as external potassium concentration ([K]e)
is raised and decrease as [K]e is lowered.Consistent
with this experimental observation, Compton and colleagues have
shown that abnormal repolarisation in
patients with LQT-2 can be corrected by raising serum potassium.
However, while long QT syndrome and
the Brugada syndrome may provide a clear route from
cell to clinic, some common arrhythmias are not yet so
accommodating. Refractory arrhythmias, for example, may be refractory
because of the complex processes involved in their pathogenesis.
These may include both electrical and structural remodelling.
Electrical remodelling may be physiological and
unrelated to cardiac disease (for example, atrial fibrillation may
become self sustaining), or pathological
in origin (alteration in the distribution of gap junctions between
cells in diseased tissue). Structural remodelling
may also be either physiological (for example, initial ventricular
hypertrophy in response to hypertension) or pathological (cell
hypertrophy in peri-infarct zones and cell loss
with replacement fibrosis within infarcted regions). Therefore
complex arrhythmias with a multifactorial aetiology
may benefit from primary prevention targeted towards alleviation of
diseases such as coronary occlusion or ventricular hypertrophy. A
second line of attack may then be directed towards the electrophysiological
sequelae of upstream events. Treatment must be
tailored towards the aetiology of the arrhythmia,
as drug treatment for ventricular tachycardia
in one patient may be detrimental in another. Indeed, in the
structurally abnormal heartfor
example, after myocardial infarction or during congestive cardiac
failuredrug
efficacy has been limited and in these conditions antiarrhythmic
drugs can have a significant proarrhythmic
potential.
Re-evaluation of antiarrhythmic drug classification Another area that has experienced change owing to the
increased information available from cellular cardiology is that of drug
classification. Early approaches to antiarrhythmic drug development involved
the identification of natural compounds with antiarrhythmic activity
such as cinchona, or identification of antiarrhythmic effects of
drugs licensed for other uses, primarily local anaesthetics,
including lignocaine and its derivatives. Clinical studies verified the
acceptability as antiarrhythmic agents of synthetic molecules such
as procainamide. Further attempts were than made to
produce related compounds with increased potency and reduced
toxicity (for example, flecainide, lorcainide, and encainide). While
this approach has provided many useful drugs for therapeutic use,
the derived compounds have to varying degrees retained the adverse
effect profiles of parent drugs. Progress in the development of
newer antiarrhythmic drugs has not been as great as once anticipated, and
the chance discovery of antiarrhythmic properties of drugs developed
for other conditionsfor example, amiodarone
(initially developed as an antianginal
drug)has contributed significantly to the armoury available to the clinician.
In 1970, Vaughan Williams proposed a
classification based on possible ways in which abnormal cardiac rhythms could
be corrected or prevented. In this early classification,
class I drugs act by reducing inward sodium current at
concentrations not affecting the resting membrane potential. Class
II drugs act by blocking sympathetic activity of the heart. Although
not thought to affect the action potential of most myocardial cells,
these drugs reduce the spontaneous rate of depolarisation
of pacemaker cells under adrenergic stimulation and are therefore
negatively chronotropic. They are also
negatively dromotropic, as the AV node tends to be
under greater sympathetic drive than the sinoatrial
node for which vagal tone normally predominates. Class III drugs
prolong action potential duration. They do not specifically affect
any single factor involved in repolarisation
(although in reality most class III drugs exert potassium channel
blocking actions). They are able to alter the activity of several
different ion channel conductances at a
cellular level, making their impact upon the action potential quite
complex. In general, they prolong action potential duration and hence prolong the length of the refractory period.
In a separate class was placed diphenylhydantoin, a
centrally acting drug.
In 1974, Singh and Hauswirth modified the classification, with two major
changes. First, lignocaine and diphenylhydantoin
were placed in a separate class, because at low concentrations and
at low external potassium concentrations, they had little effect
upon the action potential or cardiac conduction. Secondly, a
separate class (now denoted class IV) was introduced to accommodate calcium
channel blockers, which (as described earlier) predominantly affect
regions in which action potential depolarisation
depends on
The "Singh-Hauswirth-Harrison-Vaughan
Williams" (S-H-H-VW) classification is summarised.
Many antiarrhythmic drugs have more than one class of action (for
example, racemic sotalol has class II and
class III activity and amiodarone has class I-IV
actions). Moreover, some drugs within a particular class may differ in
their clinical effects owing to subtle (but significant) differences in
their mechanism of action at the ion channel level. In addition, there
are some antiarrhythmic drugs (for example, digoxin and adenosine)
which cannot be fitted into the S-H-H-VW I-IV classification. While the
S-H-H-VW classification has been valuable, the limitations of inadequate
correlations between drug mechanism, arrhythmia mechanism, and
therapeutic efficacy gave rise to the "Sicilian Gambit"
approach to antiarrhythmic treatment. This approach to arrhythmia
management, formulated by the European Society of Cardiology working
group seeks the critical mechanisms responsible for arrhythmogenesis) to identify a "vulnerable
parameter" or "Achilles heel" of the arrhythmia
concerned. This would enable the clinician to select a drug on the
basis of its mechanism of action and not empirically. This approach
complements well those recent advances in our understanding of
molecular biology (for example, cloning and sequencing of ion
channels and receptors) that have raised hopes for a "target
oriented" approach to antiarrhythmic treatment. There are,
however, two fundamental issues that might hinder this approach to
drug selection. First, an Achilles heel is not always (yet)
identifiable for many arrhythmias, and in some cases there may be
more than one Achilles heel, some of which are not involved in arrhythmogenesis. In addition, there are drugs classified
within the S-H-H-VW classification that have multiple electrophysiological
targets; this may preclude them from being selective for any one
particular Achilles heel. Second, consideration of drug action based
on multiple targets (ion channels, receptors, and second messenger
systems) and the "spread sheet" approach advanced in the
Sicilian Gambit94 generates a degree of complexity
absent from the S-H-H-VW classification, and which may hinder acceptance
of this approach. Against this, however, a major advantage of the
Sicilian Gambit approach is that it provides a framework within
which the ever increasing information on arrhythmogensis
and drug action can be readily accommodated and considered.(for example,
Members of the Sicilian Gambit
Our increasing knowledge of the basic
electrophysiological and genetic characteristics of ion channels, the cellular
actions of antiarrhythmic agents, their effects on animal models,
and the results of clinical trials should help guide future rational
drug development and classification. In a recent article, Camm and
One
of the central issues will be whether approaches which focus on a single ion
channel target offer more promise than approaches based on compounds with "polypharmacological"
(multiple ion channel) effects. Recently discovered ion channelssuch as the ultrarapid delayed
rectifier (IK,
Unfortunately, the emerging picture is not as clear as
this. While the results of the SWORD (survival with oral d-sotalol)
trial indicate that d-sotalol increases
mortality and is therefore unsuitable for use, the same does not
appear to be true for dofetilide. Dofetilide is a potent and selective blocker of IKr, which, although associated with
reverse use dependent effects on the action potential at the
cellular level, has a profile that is not clearly reverse
use dependent in humans (for example, Bashir and colleagues). The
drug appears to be reasonably well tolerated and at some
concentrations is effective at suppressing ventricular tachycardia.
Moreover, its use does not seem to be associated with significantly
increased mortality, and with only a low incidence of torsade de
pointes. Quite why dofetilide appears to
be safer than d-sotalol is not entirely clear, though
there is some experimental evidence that the class III effects of
d-sotalol are much more sensitive to extracellular
potassium levels than those of dofetilide.
At this stage, it would appear premature to rule out selective IKr blockade as a viable antiarrhythmic strategy.
IKs blockade may, in principle, offer an
attractive alternative or supplementary approach to IKr
inhibition. Azimilide is a relatively new
agent effective at inhibiting both IKr and
IKs. Data from experiments in which IKs
blocking effects of the drug on the action potential have been
estimated suggested that the IKs block alone was
associated with rate independent action potential prolongation. The
overall drug effect on the action potential (involving combined IKr and IKs actions) shows some
variations between experimental studies, with reports of either some
reverse use dependence or a rate independent action on effective
refractory period. Azimilide may be effective
against both atrial and ventricular arrhythmiasand,
while it is too early to comment with certainty on its efficacy and
safety in humans, initial signs appear promising. Several clinical
trials including the ALIVE (azimilide
post-infarct survival evaluation) study were ongoing at the time of
writing.
Other investigative agents with polypharmacological
effects include ibutilide and tedisamil.
Ibutilide has an interesting pharmacological
profile in that in addition to affecting IKr
it also appears to induce a sustained sodium current, an effect that
would be synergistic in prolonging the action potential. Tedisamil blocks IKr
and the transient outward potassium current (ITO) It has
been shown to be effective against ventricular fibrillation in a
rabbit model and it prolongs the monophasic action potential in
humans. Dronedarone, an investigational drug related
to amiodarone, may be an agent of
particular interest. Like its parent compound, dronedarone
may be expected to exert multiple S-H-H-VW effects and thereby have
wide ranging efficacy. The results of trials of this and other
agents with polypharmacological effects will
be important in the debate about whether the future development of
antiarrhythmic agents lies in single or multiple ion channel targets.
As the underlying basis for the generation and maintenance of
particular arrhythmias becomes increasingly understood, so will our
understanding of the nature of any associated Achilles heel or
vulnerable parameter. This knowledge, together with ongoing revision
of drug classification according to target/action, is likely
to refine pharmacotherapeutic approaches to clinical
arrhythmia management.
This work
was supported by grants from the British Heart Foundation, the United Bristol
Healthcare Trust, and the Wellcome Trust.
KCRP was supported by a British Heart Foundation clinical training
fellowship, and JCH was supported by a Wellcome Trust
research fellowship. We thank Kathryn Yuill for
providing the ionic current record for figure B, and Helen Wallis for
comments on the manuscript.
Antihypertensive Drugs
Goal
The goal
of this session is to make students familiar with the pharmacology of
antihypertensive drugs and with basic principles of rational pharmacotherapy of
essential hypertension, hypertensive urgency and hypertensive emergency.
Learning Objectives
After attending this session and
reading provided information, student should be able to able to:
1.Discuss the pharmacological properties of various oral
antihypertensive drugs
2. List the properties
of an “ideal” antihypertensive drug
3. List the first-line
drugs for treatment of essential hypertension
4. Discuss the main
adverse effects of first-line antihypertensive drugs
5. List target blood
pressure and at least two drugs of choice for hypertensive patients with
co-existing diseases
6. Discuss the rationale
for combining antihypertensive drugs
7. List the drugs for
treatment of hypertensive crisis (emergency and urgency)
8. Discuss the treatment
algorithm for the hypertensive
Diuretics
A. Thiazides:
Bendroflumethiazide [NATURETIN]; Benzthiazide
[EXNA]; Chlorothiazide [DIURIL]; Hydrochlorothiazide [HYDRODIURIL]; Hydroflumethiazide [SALURON]; Methyclothiazide [ENDURON]; Polythiazide
[RENESE]
B. Thiazide-like:
Chlorthalidone [HYGROTON]; Indapamide
[LOXOL]; Metolazone [MYKROX,
ZAROXOLYN]
Mechanism of action:
Inhibition of the sodium/chloride symport in distal
convoluted tubule and subsequent reduction in sodium and chloride
re-absorption. The initial drop in BP is due to increased sodium excretion and
water loss and reduced extracellular fluid and plasma volume, whereas the
chronic action of TZD diuretics is due to reduction of peripheral vascular
resistance. There is evidence that TZDs have some direct vasodilating
properties and decreases vasocontrictor response of
vascular smooth muscle cells to other vasoconstricting
agents.
At low
doses TZDs (12.5-25 mg of hydrochlorothiazide [HCTZ] or its equivalent) are
relatively well tolerated. Very rarely they cause severe rash, thrombocytopenia
and leucopenia. The most common side effect is hypokalemia. Reduction in serum
potassium varies with the dose and is between 0.3-1 mmol.
Thiazides may increase plasma lipid elevation, and induce glucose intolerance
and hyperuricemia. These adverse effects are less
frequent with low doses. Importantly, the metabolic side effects of diuretics
do not compromise their expected beneficial effects on cardiovascular morbidity
and mortality.
As
antihypertensive agents TZDs may be particularly useful in elderly patients,
African Americans, patients with mild or incipient heart failure, when cost is
crucial, and in patients with poor control of salt intake. Low dose TZDs are
combined with other first line antihypertensive drugs. The use of TZDs should be avoided in patients
with NIDDM, hyperlipidemia or gout.
C. Na Channel Inhibitors (K-Sparing): Amiloride [MIDAMOR];
Triamterene [DYRENIUM, MAXZIDE]
Potassium-sparing
diuretics produce little reduction in blood pressure themselves. They may be
useful in combination with other diuretics to prevent hypokalemia.
D. Aldosterone Antagonists (K-Sparing): Sironolactone [ALDACTONE]; Eplerenone [ INSPRA™]
Spironolactone is a specific aldosterone
antagonist, with mild antihypertensive effect. The hypotensive mechanism of
spironolactone is unknown. It is possibly due to the ability of the drug to
inhibit aldosterone's effect on arteriole smooth muscle. Spironolactone also
can alter the extracellular-intracellular sodium gradient across the
membrane. Spironolactone inhibits the
effects of aldosterone on the distal renal tubules. Unlike amiloride
and triamterene, spironolactone exhibits its diuretic effect only in the
presence of aldosterone, and these effects are enhanced in patients with hyperaldosteronism. Aldosterone antagonism enhances sodium,
chloride, and water excretion, and reduces the excretion of potassium,
ammonium, and phosphate. Spironolactone improves survival and reduces
hospitalizations in patients with severe heart failure (NYHA Class IV) when
added to conventional therapy (ACE inhibitor and a loop diuretic, with or
without digoxin).
Eplerenone is
approved for treatment of hypertension and for the treatment of post-myocardial
infarction patients with heart failure. It is a more selective aldosterone
receptor antagonist, similar in action to spironolactone, with lower incidence
of side effects (gynecomastia) due to its reduced
affinity for glucocorticoid, androgen, and progesterone receptors. It is more
expensive than spironolactone.
1.2. Beta Blockers
There are 15
Beta blockers (BB) on the market in the
Beta-blockers
act by blocking the action of catecholamines at
adrenergic receptors throughout the circulatory system and other organs. BBs
major effect is to slow the heart rate and reduce force of contraction. BBs via inhibition of receptors at justaglomerular
cells inhibit renin release.
Beta-blockers may be classified based on
their ancillary pharmacological properties. Cardioselective
agents have high affinity for cardiac β 1 and less affinity
for bronchial and vascular β2 receptors compared with
non-selective agents and this reduces (but does not abolish) β 2 receptor-mediated
side effects. However, with increasing doses cardiac selectivity disappears.
Lipid-soluble agents cross the blood-brain barrier more readily and are
associated with a higher incidence of central side effects. Some beta-blockers have intrinsic
sympathomimetic activity – ISA
(i.e., they stimulate β receptors when background sympathetic
nervous activity is low and block them when background sympathetic nervous
activity is high). Therefore, theoretically BBs with ISA are less likely to
cause bradycardia, bronchospasm, peripheral vasoconstriction,
to reduce cardiac output, and to increase lipids. BBs with ISA are less
frequently used in the treatment of hypertension.
Beta Blocker |
Relative Cardiac Selectivity |
Intrinsic Sympathomimetic Activity |
Daily Dosing Frequency |
Lipid Solubility |
b1 + a1 |
Acebutolol SECTRAL |
++ |
+ |
2 |
Moderate |
- |
Atenolol TENORMIN |
++ |
- |
1 |
Low |
- |
Betaxolol KERIONE |
++ |
- |
1 |
Low |
- |
Bisoprolol ZEBETA |
++ |
- |
1 |
Low |
- |
Carteolol CARTROL |
- |
++ |
1 |
Low |
- |
Carvedilol COREG |
- |
- |
2 |
High |
+ |
Esmolol BREVIBLOC |
+ |
- |
i.v. |
Moderate |
- |
Labetalol TRANDATE NORMODYNE |
- |
- |
2 |
Moderate |
+ |
Metoprolol LOPRESSOR |
+ |
- |
1 or 2 |
Mod. / High |
- |
Nadolol CORGARD |
- |
- |
1 |
Low |
- |
Penbutol LEVATOL |
- |
+ |
1 |
High |
- |
Pindolol VISKEN |
|
+++ |
2 |
Moderate |
- |
Propranolol INDERAL |
- |
- |
2 |
High |
- |
Timolol BLOCADREN |
- |
- |
2 |
Low / Mod. |
- |
Lipophilic beta
blockers may enter CNS more extensively and readily which may lead to increased
CNS side effects. Labetalol and carvedilol have both β1- and α1-blocking
properties, and decrease heart rate and peripheral vascular resistance. Both
agents possess the side effects common for both classes of drug. Beta-blockers
tend to be less effective in the elderly and in black hypertensives.
To reduce side effects in hypertensive patients it is recommended to use a
beta-blocker with high cardioselectivity, low lipid
solubility and long half-life that allows once daily dosing.
Adverse
effects: BBs slow the rate of conduction at the atrio-ventricular node and are contraindicated in patients
with second- and third-degree heart block. Sinus bradycardia
is common and treatment should be stopped if patient is symptomatic or heart
rate falls below 40 b/min. Because of blockade of pulmonary ß2
receptors, even small doses of BBs can cause bronchospasm (less common with cardioselective agents), and all beta-blockers are
contraindicated in asthma. Blockade of ß receptors in the peripheral
circulation causes vasoconstriction and may induce particularly in patients
with peripheral circulatory insufficiency adverse affects
such as cold extremities, Raynaud’s phenomenon, and intermittent claudication.
Nevertheless, they are reasonably tolerated in patient with mild peripheral
vascular disease. Lipid-soluble agents can cause central nervous system side
effects of insomnia, nightmares and fatigue. Exercise capacity may be reduced
by BBs and patients may experience tiredness and fatigue. BBs can worsen glucose intolerance and
hyperlipidemia and in diabetic patients mask signs of hypoglycemia. However,
diabetic hypertensive patients with previous MI should not be denied BB because
of concerns about metabolic side effects.
1.3. Alpha-1 adrenergic receptor blockers ( …. OSIN )
Prazosin [MINIPRESS] Terazosin [HYTRIN] Doxazosin
[CARDURA]
Alfuzosin [UROXATRAL] Tamsulosin
[FLOMAX]
The β1-adrenoceptor
blockers produce vasodilatation by blocking the action of norepinephrine at
post-synaptic β1 receptors in arteries and veins. This results
in a fall in peripheral resistance, without a compensatory rise in cardiac
output. Doxazosin, terazosin, and, less commonly, prazosin are used as oral agents in the treatment of
hypertension. They are relatively more selective for a1b - and a1d-receptors
which are involved in vascular smooth muscle contraction. Alfuzosin and tamsulosin are used for symptomatic treatment of begin
prostatic hyperplasia (BPH), since compared to other oral α1-blockers,
they have less antihypertensive effects and are relatively more selective as
antagonists at the α1a subtype, the primary subtype located in
the prostate.
Based on
ALLHAT study data, alpha blockers are not longer
considered first-line drug for treatment of hypertension. They are drugs of
choice for treatment of hypertensive patient with BPH. Adverse effects include
first dose hypotension, dizziness, lethargy, fatigue, palpitation, syncope,
peripheral edema and incontinence.
1.4. Angiotensin Converting Enzyme Inhibitors (ACEIs; ... PRIL)
Benazepril
[LOTENSIN] Captopril [CAPOTEN] Enalapril [VASOTEC]
Fosinopril [MONOPRIL]
Lisinopril [PRINIVIL, ZESTRIL] Moexipril [UNIVASC]
Perindopril [ACEON] Quinapril [ACCUPRIL]
Ramipril [ALTACE] Spirapril
[RENOMAX] Trandolapril
[MAVIK]
ACEIs
block the renin-angiotensin system activity by inhibiting the conversion of the
biologically inactive angiotensin I to angiotensin II, a powerful
vasoconstrictor and stimulator of release of sodium-retaining hormone
aldosterone. These effects result in decreased peripheral vascular resistance
and reduction in aldosterone plasma levels. ACE inhibitors also reduce the
breakdown of the vasodilator bradykinin, which may
enhance their action but is also responsible for their most common side effect,
cough. ACE inhibitors reduce central
adrenergic tone and influence renal hemodynamics (i.e., reduce intraglomerular hypertension) that may have beneficial
effects in proteinuric renal disease.
The ACEIs tend to be less effective
as antihypertensives in patients who tend to have
lower renin levels (African Americans and elderly). This relative ineffectiveness
can be overcome by using high doses of ACEI or by adding a diuretic. Captopril
is short acting, sulfhydryl-group containing agent; Beenazepril,
enalapril, fosinopril, moexipril, quinapril, ramipril, spirapril are pro-drugs that in the body have to be
converted to active metabolites; and lisinopril is
active non metabolized ACEI.
In addition to treatment of
hypertension, various ACEIs are approved for treatment of heart failure, left
ventricular dysfunction, diabetic nephropathy, and acute MI.
Adverse effects include cough (most
frequent 3-10%), hypotension (particularly in volume depleted patients),
hyperkalemia, angioedema, renal Insufficiency, and fetal injury (2nd & 3rd
trimesters).
1.5. Angiotensin II Receptor Antagonists (ARBs; ...SARTAN )
Losartan
[COZAAR] Valsartan [DIOVAN] Irbesartan [AVAPRO]
Candesartan [ATACAND]
Eprosartan [TEVETEN] Tasosartan
[VERDIA] Telmisartan [MICARDIS}
Similar to ACEI, angiotensin II
receptor antagonists inhibit the activity of renin-angiotensin-aldosterone
system. Sartans act by blocking the angiotensin II
type-1 receptors. As they do not inhibit the breakdown of bradykinin,
they do not cause cough. However, they may lack the additional physiological
benefits that rises in bradykinin levels may bring.
ARBs have similar physiological effects to ACE inhibitors, produce similar
falls in blood pressure and have same indications and adverse effects profile
(except for the cough).
1.6. Calcium Channel Blockers (CCBs)
CCBs exert
their clinical effects by blocking the L-class of voltage gated calcium
channels. By blocking transmembrane entry of calcium
into arteriolar smooth muscle cells and cardiac myocytes,
CCBs inhibit the excitation-contraction process. CCBs are a heterogeneous group
of drugs. Dihydropyridines are primarily potent
vasodilators of peripheral and coronary arteries. Non-dihydropiridines
Verapamil and Diltiazem are moderate vasodilators
with significant cardiac effects (Table2).
Pharmacologic Effects of Calcium Channel Blockers |
|||
Effect |
Verapamil CALAN, CALAN SR
COVERA-HS, ISOPTIN, ISOPTIN SR
VERELAN VERELAN PM |
Diltiazem Cardizem, Cardizem CD Cardizem LA, Cardizem Lyo-Ject, Cardizem SR
Cartia XT, Dilacor
XR Diltia XT, Taztia XT Tiamate, Tiazac® |
Dihydropyridines Amlodipine [NORVASC] Felodipine [PLENDIL] Isradipine [DYNACIRC] Nicardipine [CARDENE] Nifedipine PROCARDIA ADALAT]
|
Peripheral Vasodilation |
|
|
|
Heart Rate |
¯¯ |
¯ |
|
Cardiac Contractility |
¯¯ |
¯ |
0 / ¯ |
SA/AV nodal conduction |
¯ |
¯ |
0 |
Coronary Blood Flow |
|
|
|
Adverse
effects: Most common side effect of CCBs is ankle edema.
This is caused by vasodilatation, which also causes headache, flushing and palpitation,
especially with short-acting dihydropyridines. Some
of these side effects can be offset by combining a calcium channel blocker with
a beta blocker. Verapamil and Diltiazem cause
constipation. More seriously, they can cause heart block, especially in those
with underlying conduction problems. Verapamil, diltiazem
and short-acting dihydropyridines should be avoided
in patients with heart failure.
Central Alpha-2 Agonist
Methyl-dopa [ALDOMET],
Clonidine [CATAPRES]
These drugs
stimulate central a2 adrenergic receptors in rostral ventrolateral medulla which control sympathetic outflow.
The resulting decrease in central sympathetic tone leads to a
fall in both cardiac output and peripheral vascular
resistance.
The
drugs cause sedation, dry mouth and fluid retention. Methyl-dopa
requires conversion to alpha-methyl norepinephrine, and clonidine does not.
Methyl-dopa is safe in pregnancy and this is the only indication
for its use as a first line agent in hypertension. Clonidine has rapid onset of action (30-60
min) and is used in hypertensive urgency. However, it is short acting agent,
and transdermal patch system was developed to provide 7-day constant dose of
drug. Abrupt withdrawal of clonidine therapy may result in “rebound
hypertension.”
A new
centrally acting drug, moxonidine, acts on central imidazoline receptors and is hoped to have less side
effects.
Peripheral Vasodilators
Hydralazine [APRESOLINE], Minoxidil [LONITEN]
These
agents act directly to relax vascular smooth muscle, thereby reducing
peripheral vascular resistance. Within this class
of drugs, the oral vasodilators Hydralazine
and Minoxidil
are used for long-term outpatient therapy of hypertension. They are second line
of drugs for treatment of hypertension and must be combined with first line antihypertensives to offset some of their adverse effects. Decreased arterial resistance and blood pressure elicit
compensatory responses, mediated by baroreceptors and the sympathetic nervous
system and renin-angiotensin-aldosterone system (reflex tachycardia, fluid and
sodium retention). High doses of hydralazine may also induce, particularly in
slow acetilators, “lupus-like” syndrome (arthralgia,
myalgia, skin rashes, and fever). The effect of minoxidil appears to
result from the opening of potassium channels in smooth muscle membranes by its
active metabolite minoxidil sulfate. Even more than with hydralazine, the use of minoxidil
is associated with reflex sympathetic stimulation and sodium and fluid
retention. Minoxidil must be used in combination with
a b-blocker and a loop diuretic. Headache,
sweating, and hirsutism, are common adverse effects
of minoxidil. Topical minoxidil
(as Rogaine) is now used as a stimulant to hair growth for correction of
baldness.
The parenteral vasodilators (nitroprusside
1.9. Adrenergic Neural Terminal Inhibitors
Guanethidine
[ISMELIN], Guanadrel [HYCOREL], Reserpine
1.10.
Ganglionic Blockers (Mecamylamine [INVERSINE])
II.
Antihypertensive Drugs for Treatment of Hypertensive Crisis
1. Definition
of Hypertensive Crisis
§ Normal
blood pressure: SBP <120, DBP <80 mmHg
§ Prehypertension:
SBP 120-139; DBP 80-89 mmHg
§ Hypertension Stage 1: SBP140-159; DBP 90-99 mmHg
§ Hypertension
Stage 2: SBP >160; DBP >100
mmHg
§
Hypertensive
crisis (Hypertensive Emergency vs.
Hypertensive Urgency)
Therapeutic
principles in hypertensive crisis
Therapeutic
objectives in hypertensive crisis:
·
For
hypertensive urgency therapeutic goal is to reduce BP during the period of 1-24
hours.
8.
Drugs given by intermittent intravenous infusion:
- Labetalol:
combined a+b adrenergic receptor blocker
- Enalaprilat: ACE inhibitor, active metabolite of pro-drug enalapril.
III.
Selection of Antihypertensive Drug (s)
·
Properties
of the “ideal” antihypertensive drug
·
Presence
of other risk factors for cardiovascular disease & target organ damage
·
JNC
VII Therapeutic Algorithm
1. http://www.youtube.com/watch?v=JwB7VG6WaaY&feature=related
2.
http://www.youtube.com/watch?v=oHTGtYsEJBo&feature=channel
3.
http://www.youtube.com/watch?v=VKxQgjj2yVU&feature=related
4.
http://www.youtube.com/watch?v=oHTGtYsEJBo&feature=channel
5.
http://www.youtube.com/watch?v=wJKkYGe7a3k&feature=related
6.
http://www.youtube.com/watch?v=OT9HhHtQruA&feature=related
7.
http://www.youtube.com/watch?v=xw4nDMgTOrw&feature=related
8.
http://www.youtube.com/watch?v=x67vRkooZDc&feature=related