-1
RESPIRATORY STIMULATORS. COUGH REMEDIES. EXPECTORANTS
(Aethymisolum, Sulfocamphocainum, Bemegridum, rbogenum, Codeini phospas,
Glaucinum, Oxeladinum, Libexinum, herba Thermopsidis, Radix Althaeae, Mucaltinum,
Trypsinum crystallisatum, Bromhexinum, Ambroxolum, Acetylcysteinum, Ambroxolum
DRUGS ACTING ON THE RESPIRATORY ORGANS FUNCTION - 2.
BRONCHOLYTICAL PREPARATIONS. DRUGS USED FOR LUNG EDEMA
MANAGEMENT (Orciprenalini sulfas, Salbutamolum, Fenoterolum, Ambroxolum,
Ipratropii bromidum (Atrovent), Cromolinum-sodium, Ketotifenum, Beclometasoni
dypropionas, Triamcinolonum, Strophantinum, Corgliconum, Hygronium, Pentaminum,
Droperidolum, Furosemidum, Mannitum, Morphini hydrochloridum, Phenthanilum,
Spiritus aethylicus)
CARDIOTONIC DRUGS. CARDIAC GLYCOSIDES AND OTHER
INOTROPIC DRUGS. AQENTS USED FOR TREATM OF CONGESTIVE
HEART FAILURE (Strophantinum, Corgliconum, Digoxinum, Digitoxinum, infusum
herbae Adonodis vernalis, Dophaminum, Dobutaminum)
Drugs acting on the respiratory organs function
Respiratory antiinflammatory agents
Background: Respiratory antiinflammatory agents interrupt the pathogenesis of
bronchial inflammation. These drugs can either prevent or modulate an ongoing
inflammatory reaction in the airways. Respiratory antiinflammatory agents are used in a
variety of clinical conditions where respiratory inflammation is a component of the
disease process, most commonly, in asthma and allergic rhinitis, but also as adjunct
treatment of Pneumocysitis carinii pneumonia (PCP), pulmonary eosinophilic
syndromes, croup, and sarcoidosis. Recently, ibuprofen has been shown beneficial in
slowing the rate of decline in lung function in patients with cystic fibrosis.
History: In the recent past, sympathomimetic agents and/or methylxanthine derivatives
were considered primary therapy for the treatment of asthma, while corticosteroids were
often used as alternative therapy. In 1991, guidelines for the diagnosis and management
of asthma were published by the National Asthma Education Program. This report
described the pathophysiology of asthma including airway obstruction, airway
inflammation, and airway hyperresponsiveness. Since then, corticosteroids have moved
to the forefront in the treatment of asthma despite their generalized availability since the
1950s.
In the mid-1970s, the first inhaled corticosteroid (beclomethasone) was made
available. Administering corticosteroids by inhalation limited the systemic adverse
reactions associated with oral or parenteral therapy. Other inhaled corticosteroids have
since been approved (e.g., budesonide, dexamethasone, flunisolide, fluticasone,
triamcinolone).
Cromolyn sodium, approved in 1973, represented a drug with a new mechanism of
action in the prevention of acute asthma. Nedocromil, an agent similar to cromolyn, was
marketed in late 1992. Other antiinflammatory agents are being investigated in asthmatic
patients who do not respond adequately to high systemic doses of corticosteroids.
Cyclosporine has been found efficacious in the treatment of patients with severe
glucocorticoid-dependent asthma. Adverse reactions may limit the role of oral
cyclosporine but the development of an aerosol delivery method might be an effective
alternative. Other investigational antiinflammatory agents with a potential role in the
treatment of asthma include zileuton (Leutrol(r)) a 5-lipoxygenase inhibitor and
zafirlukast (Accolate(r)) a leukotriene-receptor antagonist. Zafirlukast may also have a
role in the treatment of allergic rhinitis and in the prevention of exercise-induced
bronchoconstriction. Methotrexate, gold preparations, and hydroxychloroquine,
although useful in other chronic inflammatory diseases, have not proven their efficacy in
the chronic treatment of asthma. The use of these agents is also limited by their potential
for serious adverse effects. As the understanding of the pathophysiology of asthma
grows, the use of respiratory antiinflammatory agents will expand.
Systemic corticosteroids are the treatment of choice for a number of the pulmonary
eosinophilic syndromes. Chronic eosinophilic pneumonia, acute bronchopulmonary
aspergillosis, and allergic angiitis and granulomatosis can be effectively treated with
systemic corticosteroids. Corticosteroids have been used and beneficial effects have
been reported in the treatment of bronchocentric granulomatosis, although the role in
therapy has not been clarified. Although parasitic eosinophilic pneumonia and mucoid
impaction of bronchi should be treated with specific therapy aimed at the underlying
cause, treatment could include the use of corticosteroids.
Corticosteroids have been studied for the treatment of croup, a common upper airway
disease of children. Corticosteroids are effective in hospitalized children with moderate
to severe disease, preventing the need for intubation or allowing early extubation. Since
the natural course of croup varies greatly (i.e., children often show improvement within
24 hours without therapy), the role of corticosteroids, specifically nebulized
Cromolyn is first line therapy for prophylaxis because it is well tolerated, displaying only
minor adverse reactions.
For the chronic treatment of moderate asthma, cromolyn continues to be the
respiratory antiinflammatory agent of choice, with inhaled corticosteroids an acceptable
option in adults only. If symptoms persist or progress in adults a short course of oral
corticosteroids can be used. The next step in children is inhaled corticosteroids with or
without cromolyn.
As the severity of the disease progresses, therapy becomes more intense. Inhaled
corticosteroids are first line agents for both adults and children, with or without
cromolyn or other agents. If not effectively controlling symptoms, short burst of oral
corticosteroids or chronic alternate day therapy should be considered. If symptoms are
severe enough in children, systemic corticosteroid therapy may be considered; riskbenefit should be weighed in this therapeutic decision. The use of intravenous
corticosteroids is limited to the treatment of acute exacerbations of asthma in patients in
the emergency room or in hospitalized patients.
Cromolyn is recommended for the prevention of exercise-induced asthma, it is not
used for treatment of symptoms following exercise. The nasal solution is indicated for
the treatment and prevention of allergic rhinitis. Nedocromil is only indicated for the
maintenance of bronchial asthma. Nedocromil appears to be equivalent to cromolyn in
preventing exercise-induced asthma, although cromolyn may be longer acting.
Nedocromil was not available when the "guidelines" were written, but could be
substituted when cromolyn is recommended. Nedocromil has similar safety and efficacy
profiles when compared to cromolyn.
Topically administered, intranasal corticosteroids provide a direct local
antiinflammatory effect with minimal systemic adverse reactions. The intranasally
administered products are primarily used for the prevention and treatment of symptoms
associated with seasonal or perennial rhinitis. Intranasal corticosteroids should be
considered before administering systemic corticosteroids because of the risks
associated with systemic therapy. The same corticosteroids administered by oral
inhalation are also available for intranasal administration, as well as fluticasone.
Budesonide is a corticosteroid that is available in Europe as an oral inhaler, but was
approved in the U.S. in 1994 for nasal administration only.
There are few distinctions between the available nasal corticosteroid preparations. All
of these products are indicated for use in allergic rhinitis. Dexamethasone is also
beneficial for the treatment of polyps and beclomethasone helps prevent recurrence of
nasal polyps following surgical removal. Triamcinolone and fluticasone are not
recommended for use in children less than 12 years old, whereas the other nasal
corticosteroid products should not be used in children younger than 6 years of age.
Fluticasone, budesonide, and triamcinolone can all be administered once daily, but may
be given in divided doses. Beclomethasone, dexamethasone, and flunisolide are
administered at least twice daily up to 3-4 times a day.
Adverse Effects: Oral and parenteral corticosteroids are associated with major
systemic adverse reactions; the type and severity of the adverse reactions are dependent
on the duration and dose of therapy. Adverse reactions include metabolic changes, fluid
retention, hypertension, osteoporosis, and adrenal suppression. Inhaled corticosteroids
are associated with local effects including dysphonia, coughing, and oropharyngeal
candidiasis. These adverse effects can be minimized by administration via chamber or
spacer and by rinsing the mouth after each use. Systemic effects are still a concern with
inhalation therapy; specific concerns include growth suppression in children,
osteoporosis, and adrenal suppression. The topical-to-systemic potency ratios are
similar among the inhaled corticosteroids (ratios = 0.05-0.1), but are considerably
reduced compared to budesonide (ratio = 1.0). Budesonide may demonstrate an
improved adverse reaction profile due to decreased systemic absorption and
subsequent toxicities.
Cromolyn sodium and nedocromil are well tolerated, with minimal adverse effects
being reported. Nedocromil produced similar GI and CNS effects as cromolyn.
Bronchospasm, irritated or sore throat, dysgeusia, cough, and headache are the most
common adverse effects from these agents. Oral inhalation preparations of cromolyn
can contain lactose. Administration of cromolyn sodium to patients with lactose
intolerance can cause nausea and vomiting, bloating, abdominal cramps, and flatulence.
Nedocromil also causes nausea and vomiting in approximately 4% of patients.
Dysfunction of the respiratory system, which supplies the body with the oxygen
needed for metabolic activities in the cells and removes carbon dioxide, a product of
cellular metabolism. The respiratory system includes the nose, mouth, throat, larynx,
trachea, bronchi, lungs, and the muscles of respiration such as the intercostal muscles
and the diaphragm. See also Respiration.
The lung has a great reserve capacity, and therefore a significant amount of disease
usually must be present to produce clinical signs and symptoms. Shortness of breath
(dyspnea) on exertion is the most common symptom of a respiratory disorder.
Shortness of breath while at rest is indicative of severe respiratory disease and usually
implies a severe abnormality of the lung tissue. If the respiratory system is so diseased
that normal oxygenation of the blood cannot occur, blood remains dark, and a bluish
color can be seen in the lips or under the fingernails; this condition is referred to as
cyanosis. Other signs and symptoms of respiratory disorder can include fever, chest
pain, coughing, excess sputum production, and hemoptysis (coughing up blood). Most
of these signs and symptoms are nonspecific. See also Hypoxia.
Most diseases of the airways increase the resistance against which air is sucked in and
pushed out of the lungs. Diseases of the nose usually have little influence since collateral
respiration through the mouth compensates easily. Diseases of the throat, larynx, and
trachea can significantly inhibit the flow of air into the lungs. Infections in the back of
the throat, such as in diphtheria, can cause marked swelling of mucous membranes,
resulting in air obstruction. Edema (swelling) of the mucosal lining of the larynx can also
cause a reduction in air flow. Likewise, air flow can be inhibited in asthma, in which the
smooth muscle in the trachea and bronchi episodically constricts. Chronic bronchitis
results in inflammation of and excess mucus production by the bronchi and this also can
lead to a reduction in air flow. Bronchiolitis, a condition that usually occurs in children
and is often caused by a respiratory virus, results in narrowing and inflammation of
small airways and a decrease in air flow.
Pneumonia, cancer, and emphysema are the most common lung diseases and are a
major cause of morbidity and mortality in the United States. Of the four major types of
lung cancer, approximately 90% can be attributed to the carcinogens present in cigarette
smoke.
Common Cold
The common coldcolloquially the flu, catarrh, or grippe (strictly speaking, the rarer
infection with influenza viruses) is an acute infectious inflammation of the upper
respiratory tract. Its symptoms, sneezing, running nose (due to rhinitis), hoarseness
(laryngitis), difficulty in swallowing and sore throat (pharyngitis and tonsillitis), cough
associated with first serous then mucous sputum (tracheitis, bronchitis), sore muscles,
and general malaise can bepresent individually or concurrently in varying combination or
sequence. The term stems from an old popular belief that these complaints are caused
by exposure to chilling or dampness. The causative pathogens are different viruses
(rhino-, adeno-, parainfluenza v.) that
may be transmitted by aerosol droplets
produced by coughing and
sneezing.Therapeutic measures. First attempts of a causal treatment consist of
zanamavir, an inhibitor of viral neuraminidase, an enzyme necessary for virus adsorption
and infection of cells. However, since symptoms of common cold abate spontaneously,
there is no compelling eed to use drugs. Conventional remedies are intended for
Althea officinalis
Thermopsis
ASTHMA
The clinical hallmarks of asthma are recurrent, episodic bouts of coughing, shortness of
breath, chest tightness, and wheezing. In mild asthma, symptoms occur only
occasionally but in more severe forms of asthma frequent attacks of wheezing and
dyspnea occur, especially at night, and chronic activity limitation is common.
Asthma is characterized physiologically by increased responsiveness of the trachea and
bronchi to various stimuli and by widespread narrowing of the airways. Its chronic
pathological features are contraction of airway smooth muscle leading to reversible
airflow obstruction, mucosal thickening from edema and cellular infiltration with airway
receptor antagonists), inhibit the effect of acetylcholine released from vagal motor
nerves (muscarinic antagonists), or directly relax airway smooth muscle
(sympathomimetic agents, theophylline).
The second approach to the treatment of asthma is aimed not just at preventing or
reversing acute bronchospasm but at reducing the level of bronchial responsiveness.
Because increased responsiveness appears to be linked to airway inflammation and
because airway inflammation is a feature of late asthmatic responses, this strategy is
implemented both by reducing exposure to the allergens that provoke inflammation and
by prolonged therapy with anti-inflammatory agents, especially inhaled corticosteroids.
Bronchodilators
History: Bronchodilators consist of theophylline, beta2-adrenergic agonists, and
inhaled anticholinergics. Although theophylline was not approved for general use until
1940, caffeine, another xanthine with bronchodilatory actions, has been consumed for
centuries. Theophylline, however, is a more potent bronchodilator than caffeine. In
1947, isoproterenol, a potent beta-agonist, was approved and for the next 25 years,
these two drugs were the major bronchodilators used in clinical practice.
Subsequent to isoproterenol, metaproterenol was released in 1973, followed, over
the next decade, by additional beta-agonists, each with increasing specificity for beta 2receptors. The dominant beta-agonist bronchodilator in use today, albuterol, was
approved in 1981. Albuterol is very specific for beta2-receptors and has a longer
duration of action than metaproterenol or isoproterenol. Salmeterol, released in 1994 has
yet a longer duration of action than albuterol and may now become the preferred beta2agonist.
Duration of action
2-selectivity
4-6 h
+++
Short acting
Albuterol
Levalbuterol
8h
+++
Terbutaline
4-8 h
+++
Metaproterenol
4-6 h
++
Isoproterenol
3-4 h
++
Epinephrine
2-3 h
Salmeterol
12+ h
+++
Formoterol
12+ h
+++
Long acting
Injury and repair cycle of the airway epithelium in asthma. Complete repair requires glycosylation as a means
of regulation of essential elements. Aberrant glycosylation would result in a defect in the mechanisms of repair,
the accumulation of epithelial damage and persistent airway inflammation. Modified from Davies D
[. E
Davies, The bronchial epithelium: translating gene and environment interactions in asthma.Curr Opin Allergy
Clin Immunol, 20016771].
The airways in asthma undergo significant structural remodeling. Medium-sized airways from a normal
and severe asthmatic patient were sectioned and stained using Movats pentachrome stain. The epithelium
(Ep) in asthma shows mucous hyperplasia and hyper secretion (blue), and significant basement membrane
(Bm) thickening. Smooth muscle (Sm) volume is also increased in asthma. Bv = blood vessel. Scale bar =
100m.
coexistent cardiopulmonary disease, and the relatively small patient population all
represent challenges for the development of pharmacologic therapy for PAH.
Nonetheless, during the past decade substantial improvements have occurred in our
understanding of the pathogenesis of PAH with new treatments being tested and
approved.
BRIEF REVIEW OF PULMONARY VASCULAR STRUCTURE, ENDOTHELIAL
FUNCTION AND PHARMACOLOGICAL TARGETS for PAH
The pulmonary vascular bed is a high-flow, low-resistance circuit that can accommodate
the entire cardiac output at a pressure that is normally less than 20% of the pressure in
the systemic circulation. The pulmonary circulation has a remarkable capacity to
regulate its vascular tone to adapt to physiologic changes. Vasoactive regulation plays
an important role in the local regulation of blood flow in relation to ventilation (V/Q
matching). Hypoxic pulmonary vasoconstriction results from inhibition of pulmonary
vascular smooth muscle K+ channel conductance, leading to cellular depolarization and
an influx of Ca2+ ions through voltage-gated calcium channels. Although contraction of
vascular smooth muscle narrows pulmonary vessels, the signal for this contraction
originates in the pulmonary endothelium.
In PAH, there is media thickening and hypertrophy, resulting in development of a
muscle layer in an arteriole. The resulting chronic vasoconstriction and fibroblast
proliferation leads to the initiation of remodeling in the intimal and medial layers of the
arteriole.
The central role of the endothelium in regulating vascular smooth muscle action was first
convincingly revealed with the discovery of endothelium-derived relaxing factor (EDRF)
in the 1980s by Furchgott and others using isolated vascular smooth muscle
preparations. In these experiments, they found vasodilation following acetylcholine or
carbachol treatment but paradoxical vasoconstriction when the vascular endothelium
was stripped or removed from the preparation. This short-lived vasodilator substance
was called endothelium-derived relaxing factor (EDRF) because it promoted relaxation
of pre-contracted smooth muscle preparations. EDRF was subsequently discovered to
be nitric oxide (NO). Products of inflammation and platelet aggregation (e.g., serotonin,
histamine, bradykinin, purines, and thrombin) exert all or part of their actions by
stimulating the production of NO. NO diffuses to smooth muscle cells, where it
activates soluble guanylyl cyclase to generate cGMP that leads to smooth muscle
relaxation. In addition to NO, the endothelial cell produces other vasodilators, including
prostacycline (PGl2). The endothelial cell also produces vasoconstrictors, such as
endothelin 1 (ET-1) and thromboxane A2 (TXA2), and catalyzes the conversion of
angiotensin I to angiotensin II. ET-1 is the most potent known vasoconstrictor; it
causes prolonged vasoconstriction and increases vascular tone and pulmonary vascular
resistance (PVR), and this is mediated by ET receptors. These vasoactive molecules act
on local vascular smooth muscle, mostly in a paracrine fashion, although TXA2 also
stimulates platelet aggregation, which can result in in situ thrombosis and increased
PVR. While many other endothelium-derived vasoactive molecules and growth factors
have been implicated as potentially important in pulmonary vasoconstriction and
remodeling leading to pulmonary hypertension, only those molecules that are currently
therapeutic targets in pulmonary hypertension will be emphasized here.
PHARMACOLOGY OF PULMONARY HYPERTENSION
No other area of pharmacology provides you with a wider array of delivery modalities.
There are underlying physiological issues that limit the pharmacological options in PAH.
First, pulmonary hypertension results from loss of normal cross-sectional area of the
pulmonary vasculature, and this loss of capacitance may limit right ventricular cardiac
output. Although the mechanism is different, the physiologic effect is similar to that of
aortic stenosis. Designing feasible approaches to increase the cross-sectional area of
the pulmonary vasculature is difficult. Second, limiting right ventricular cardiac output,
limits left ventricular cardiac output, because the left ventricle cannot pump more blood
than it receives. The reduction in biventricular cardiac output underlies the unique
difficulties in the treatment of pulmonary hypertension. Patients with pulmonary
hypertension frequently have low systemic blood pressure and cannot tolerate agents
that lead to systemic vasodilation. Endothelial cells in both the pulmonary and systemic
circulations share many of the same receptors and produce the same vasoactive
molecules, so agents that might dilate the pulmonary vasculature, often act more
prominently on the systemic vasculature. There are, however, differences in receptor
type and density and in the quantitative production of vasoactive molecules in different
vascular beds. Exploiting these differences therapeutically has been the goal of modern
therapy.
Preparations Available
Sympathomimetics Used in Asthma
Albuterol (generic, Proventil, Ventolin, others)
Inhalant: 90 g/puff aerosol; 0.083, 0.5% solution for nebulization
Oral: 2, 4 mg tablets; 2 mg/5 mL syrup
Oral sustained-release: 4, 8 mg tablets
Albuterol/Ipratropium (Combivent, DuoNeb)
Inhalant: 103 g albuterol + 18 g ipratropium/ puff; 3 mg albuterol + 0.5 mg ipratropium/3
mL
solution for nebulization
Bitolterol (Tornalate)
Inhalant: 0.2% solution for nebulization
Ephedrine (generic)
Oral: 25 mg capsules
Parenteral: 50 mg/mL for injection
Epinephrine (generic, Adrenalin, others)
Inhalant: 1, 10 mg/mL for nebulization; 0.22 mg epinephrine base aerosol
Parenteral: 1:10,000 (0.1 mg/mL), 1:1000 (1 mg/mL)
Formoterol (Foradil)
Inhalant: 12 g/puff aerosol; 12 g/unit inhalant powder
Isoetharine (generic)
Inhalant: 1% solution for nebulization
Isoproterenol (generic, Isuprel, others)
Inhalant: 0.5, 1% for nebulization; 80, 131 g/puff aerosols
Parenteral: 0.02, 0.2 mg/mL for injection
Levalbuterol (Xenopex)
Inhalant: 0.31, 0.63, 1.25 mg/3 mL solution
Metaproterenol (Alupent, generic)
Inhalant: 0.65 mg/puff aerosol in 7, 14 g containers; 0.4, 0.6, 5% for nebulization
Pirbuterol (Maxair)
Inhalant: 0.2 mg/puff aerosol in 80 and 300 dose containers
Salmeterol (Serevent)
Inhalant aerosol: 25 g salmeterol base/puff in 60 and 120 dose containers
Chapter
39:
Adrenocorticosteroids
&
(for asthma)
Nasal aerosol (Nasalcrom):* 5.2 mg/puff (for hay fever)
Oral (Gastrocrom): 100 mg/5 mL concentrate (for gastrointestinal allergy)
Nedocromil sodium (Tilade)
Pulmonary aerosol: 1.75 mg/puff in 112 metered-dose container
*OTC preparation.
Methylxanthines: Theophylline & Derivatives
Aminophylline (theophylline ethylenediamine, 79% theophylline) (generic, others)
Oral: 105 mg/5 mL liquid; 100, 200 mg tablets
Oral sustained-release: 225 mg tablets
Rectal: 250, 500 mg suppositories
Parenteral: 250 mg/10 mL for injection
Theophylline (generic, Elixophyllin, Slo-Phyllin, Uniphyl, Theo-Dur, Theo-24, others)
Oral: 100, 125, 200, 250, 300 mg tablets; 100, 200 mg capsules; 26.7, 50 mg/5 mL
elixirs, syrups,
and solutions
Oral sustained-release, 812 hours: 50, 60, 75, 100, 125, 130, 200, 250, 260, 300 mg
capsules
Oral sustained-release, 824 hours: 100, 200, 300, 450 mg tablets
Oral sustained-release, 12 hours: 100, 125, 130, 200, 250, 260, 300 mg capsules
Oral sustained-release, 1224 hours: 100, 200, 300 tablets
Oral sustained-release, 24 hours: 100, 200, 300 mg tablets and capsules; 400, 600 mg
tablets
Parenteral: 200, 400, 800 mg/container, theophylline and 5% dextrose for injection
Other Methylxanthines
Dyphylline (generic, other)
Oral: 200, 400 mg tablets; 33.3, 53.3 mg/5 mL elixir
Parenteral: 250 mg/mL for injection
Oxtriphylline (generic, Choledyl)
Oral: equivalent to 64, 127, 254, 382 mg theophylline tablets; 32, 64 mg/5 mL syrup
Pentoxifylline (generic, Trental)
Oral: 400 mg tablets and controlled-release tablets
Note: Pentoxifylline is labeled for use in intermittent claudication only.
Antimuscarinic Drugs Used in Asthma
Heart Failure occurs when decreases in contractility prevent the heart from contracting
forcefully enough to deliver blood to meet the demands of the body. Decreases in
C.O. activate reflex responses in the SNS which attempt to compensate for the reduced
C.O.: These reflex responses include 1. increases in heart rate (tachycardia), 2.
increased preload (salt and water retention increase blood volume through activation of
the renin-angiotensin-aldosterone pathway -this leads to peripheral and pulmonary
edema. Since the volume returned is greater than the ability of the heart to pump, blood
remains in the heart with each stroke leading to enlargement of the heart), and 3.
increased afterload (through vasoconstriction via a receptors as well as through the
production of angiotensin II) resulting in compensated heart failure. Ultimately, SNS
activation can no longer compensate, and the heart fails. Drug treatment is directed
towards 1) enhancing cardiac output with + inotropic drugs (cardiac glycosides) , 2)
decreasing preload with diuretics and Angiotensin Converting Enzyme (ACE)
inhibitors , and/or 3) decreasing afterload with vasodilators like organic nitrates and
ACE inhibitors.
SYMPTOM/DEFECT DRUG/PHARMACODYNAMICS
THERAPEUTIC VALUE
decreased
contractility (decrease
in ability of muscle to
contract) results in SNS
activation to
compensate for
decreased cardiac
output
Increase contractility
increases cardiac emptying,
decreases preload, heart size
and oxygen demand. Increase
C.O. decreases SNS tone,
heart rate and venous tone
short-term support of a
failing heart
increased vascular
ACE inhibitors - decrease
production of AngII which is a potent
tone (increase blood
pressure) due to SNS vasoconstrictor
activation in an attempt Nitrovasodilators - dilate both veins
to compensate for
and arteries
decreased contractility
Cardiac Glycosides
Increasing the force of contraction of the heart (positive inotropic activity) is very
important for most heart failure patients. There are several mechanisms by which this
could be achieved. Cardiac steroids are perhaps the most useful and are being
discussed here. Phosphodiesterase inhibitors, such as amrinone and milrinone, have also
been explored and so are direct adenylate cyclase stimulants, such as forskolin. These
drugs all act by affecting the availability of intracellular Ca+2 for myocardial contraction
or increasing the sensitivity of myocardial contractile proteins.
The cardiac glycosides are an important class of naturally occurring drugs whose
actions include both beneficial and toxic effects on the heart. Plants containing cardiac
steroids have been used as poisons and heart drugs at least since 1500 B.C. Throughout
history these plants or their extracts have been variously used as arrow poisons,
emetics, diuretics, and heart tonics. The therapeutic properties of cardiac glycosides
(eg, digoxin, a product of the foxglove plant) have been known since the days of the
Roman Empire. The ancient Romans used red squill, a cardiac glycoside derived from
the sea onion, as a diuretic and heart medicine. Cardiac glycosides are found in certain
flowering plants such as oleander and lily-of-the-valley. Certain herbal dietary
supplements also contain cardiac glycosides. Cardiac steroids are widely used in the
modern treatment of congestive heart failure and for treatment of atrial fibrillation and
flutter. Yet their toxicity remains a serious problem
Purple Foxglove
Stophantus
Structure
Cardiac glycosides are composed of two structural features : the sugar (glycoside) and
the non-sugar (aglycone - steroid) moieties. (figure below)
The R group at the 17-position defines the class of cardiac glycoside. Two classes
have been observed in Nature - the cardenolides and the bufadienolides. The
cardenolides have an unsaturated butyrolactone ring while the bufadienolides have an apyrone ring.
Nomenclature : The cardiac glycosides occur mainly in plants from which the names
have been derived. Digitalis purpurea, Digitalis lanata, Strophanthus grtus, and
Strophanthus kombe are the major sources of the cardiac glycosides. The term 'genin' at
the end refers to only the aglycone portion (without the sugar). Thus the word digitoxin
refers to a agent consisting of digitoxigenin (aglycone) and sugar moieties (three). The
aglycone portion of cardiac glycosides is more important than the glycone portion.
The steroid nucleus has a unique set of fused ring system that makes the aglycone
moiety structurally distinct from the other more common steroid ring systems. Rings
A/B and C/D are cis fused while rings B/C are trans fused. Such ring fusion give the
aglycone nucleus of cardiac glycosides the characteristic ' U' shape as shown below.
The steroid nucleus has hydroxyls at 3- and 14- positions of which the sugar attachment
uses the 3-OH group. 14-OH is normally unsubstituted. Many genins have OH groups at
12- and 16- positions. These additional hydroxyl groups influence the partitioning of the
cardiac glycosides into the aqueous media and greatly affect the duration of action.
The lactone moiety at C-17 position is an important structural feature. The size and
degree of unsaturation varies with the source of the glycoside. Normally plant sources
provide a 5-membered unsaturated lactone while animal sources give a 6-membered
unsaturated lactone.
Sugar moiety : One to 4 sugars are found to be present in most cardiac glycosides
attached to the 3b-OH group. The sugars most commonly used include L-rhamnose, Dglucose, D-digitoxose, D-digitalose, D-digginose, D-sarmentose, L-vallarose, and D-
fructose. These sugars predominantly exist in the cardiac glycosides in the bconformation. The presence of acetyl group on the sugar affects the lipophilic character
and the kinetics of the entire glycoside. Because the order of sugars appears to have
little to do with biological activity Nature has synthesized a repertoire of numerous
cardiac glycosides with differing sugar skeleton but relatively few aglycone structures.
Structure - Activity Relationships
The sugar moiety appears to be important only for the partitioning and kinetics of
action. It possesses no biological activity. For example, elimination of the aglycone
moiety eliminates the activity of alleviating symptoms associated with cardiac
failure.
The "backbone" U shape of the steroid nucleus appears to be very important.
Structures with C/D trans fusion are inactive.
Conversion to A/B trans system leads to a marked drop in activity. Thus although
not mandatory A/B cis fusion is important.
The 14b-OH groups is now believed to be dispensible. A skeleton without 14bOH group but retaining the C/D cis ring fusion was found to retain activity.
Lactones alone, when not attached to the steroid skeleton, are not active. Thus the
activity rests in the steroid skeleton.
The unsaturated 17-lactone plays an important role in receptor binding. Saturation
of the lactone ring dramatically reduced the biological activity.
The lactone ring is not absolutely required. For example, using a,b-unsaturated
nitrile (C=C-CN group) the lactone could be replaced with little or no loss in
biological activity.
Pharmacokinetics of Cardiac Glycosides
The commercially available cardiac steroids differ markedly in their degree of
absorption, half-life, and the time to maximal effect (see table below).
Agent
GI absorption
Onset (m)
Peak (h)
Half-life
Ouabain
Unreliable
5-10
0.5-2
21 h
Deslanoside
Unreliable
10-30
1-2
33 h
Digoxin
55-75%
15-30
1.5-5
36 h
Digitoxin
90-100%
25-120
4-12
4-6 days
Usually this is due to the polarity differences caused by the number of sugars at C-3 and
the presence of additional hydroxyls on the cardenolide. Although two cardiac
glycosides may differ by only one sugar residue their partition co-efficients may be
significantly different resulting in different pharmacokinetics. For example, lanatoside C
and digoxin differ only by a glucose residue and yet the partition co-efficient measured
in CHCl3/16% aqueous MeOH are 16.2 and 81.5, respectively.
Glycoside
Partition
Coefficient
Lanatoside C (glucose-3-acetyldigitoxose-digitoxose2-digoxigenin)
16.2
Digoxin (digitoxose3-digoxigenin)
81.5
Digitoxin (digitoxose3-digitoxigenin)
96.5
Acetyldigoxin (3-acetyldigitoxose-digitoxose2-digoxigenin)
98.0
G-Strophanthin (rhamnose-ouabagein)
very low
In general, cardiac glycosides with more lipophilic character are absorbed faster and
exhibit longer duration of action as a result of slower urinary exretion rate.
Lipophilicity is markely influenced by the number of sugar residues and the number of
hydroxyl groups on the aglycone part of the glycoside. Comparison of digitoxin and
digoxin structures reveals that they differ only by an extra OH group in digoxin at C-12,
yet their partition coefficients differ by as much as 15 % points.
Biochemical Mechanism of Action
The mechanism whereby cardiac glycosides cause a positive inotropic effect and
electrophysiologic changes is still not completely clear. Several mechanisms have been
proposed, but the most widely accepted involves the ability of cardiac glycosides to
inhibit the membrane bound Na+-K+-ATPase pump responsible for Na+-K+ exchange.
The process of muscle contraction can be pictured as shown below.
The process of membrane depolarization / repolarization is controlled by the movement
of three cations, Na+, Ca+2, and K+, in and out of the cell. At the resting stage, the
concentration of Na+ is high on the outside. On membrane depolarization sodium
fluxes-in leading to an immediate elevation of the action potential. Elevated intracellular
Na+ triggers the influx of free of Ca++ that occurs more slowly. The higher intracellular
[Ca++] results in the efflux of K+. The reestablishment of the action potential occurs
later by the reverse of the Na+-K+ exchange. The Na+ / K+ exchange requires energy
which is provided by an enzyme Na+-K+-ATPase. Cardiac glycosides are proposed to
inhibit this enzyme with a net result of reduced sodium exchange with potassium that
leaves increased intracellular Na +. This results in increased intracellular [Ca++]. Elevated
intracellular calcium concentration triggers a series of intracellular biochemical events
that ultimately result in an increase in the force of the myocardial contraction or a
positive inotropic effect.
Digoxin
In 1785, Withering published an account of digitalis (dried leaves of the purple
foxglove) and some of its medical uses.12 Although digoxin continues to be viewed as
beneficial in patients with heart failure and atrial fibrillation, its role in patients with heart
failure and sinus rhythm has been increasingly challenged. Mackenzie and Christian, two
eminent clinicians and coeditors of Oxford Medicine, debated this issue in 1922.
Mackenzie advocated the use of digitalis only in heart failure with associated atrial
arrhythmias, whereas Christian argued that digitalis was effective irrespective of an
irregular pulse. In 1938, Cattell and Gold first showed a direct inotropic effect of
digitalis on cardiac muscle. For many more years, digitalis continued to be an important
part of heart failure management. The detrimental aspects of digoxin therapy were not
considered important until excess mortality was reported in survivors of myocardial
infarction who received digitalis. Uncontrolled observations that the withdrawal of
digoxin produced no ill effects also raised concerns about the efficacy of the drug.
Pharmacology of digoxin
Action
Increases vagal tone (central effect), leading to slowed ventricular response in atrial
fibrillation.
Reduces sympathetic tone, especially when this is abnormally high, as in heart
failure. This is probably mediated partly via vagotonic actions and partly
via direct effects.
Positive inotropic action mediated via direct blockade of Na+K+-ATPase on cell
membranes. This leads to increased intracellular Na+ concentration, which in turn
increases intracellular Ca++ concentration via the Na+Ca++ exchanger.
patients have coronary artery disease without extensive scar tissue. Such patients also
commonly have diabetes mellitus.
Approach to Patients with Diastolic Dysfunction In patients with diastolic
dysfunction, appropriate measures include the diagnosis and treatment of myocardial
ischemia (if present) and the aggressive treatment of hypertension (if needed). Digitalis
therapy has been considered inappropriate in these patients. In some patients, treatment
with diuretics and nitrates could reduce pulmonary congestion. In the DIG trial, a
subgroup of nearly 1,000 patients with a left ventricular ejection fraction of 45 percent or
greater experienced a reduction in congestive heart failure end points similar to patients
with a left ventricular ejection fraction of 25 to 45 percent. One group of investigators
suggested that this effect may be the result of digoxin's ability to reduce neurohormonal
activities. However, they concluded that information about the effect of digoxin in
patients with congestive heart failure and preserved left ventricular systolic function is
limited and does not warrant routine use of the drug in this setting until the results of
more studies are available. At present, the consensus is that digoxin therapy is probably
inappropriate in patients with preserved left ventricular systolic function. In addition,
digoxin therapy may not be useful in patients with congestive heart failure and a high
cardiac output syndrome such as anemia or thyrotoxicosis.
Adverse Effects of Digoxin
Adverse reactions to digoxin are usually dose dependent and occur at dosages higher
than those needed to achieve a therapeutic effect. The actual incidence of digoxin
toxicity may be lower than is historically reported. Adverse reactions are less common
when digoxin is used in the recommended dosage range and careful attention is given to
concurrent medications and medical conditions. The principal manifestations of digoxin
toxicity include cardiac arrhythmias (ectopic and reentrant cardiac rhythms and heart
block), gastrointestinal tract symptoms (anorexia, nausea, vomiting and diarrhea) and
neurologic symptoms (visual disturbances, headache, weakness, dizziness and
confusion). Most adult patients with clinical toxicity have serum digoxin levels greater
than 2 ng per mL (2.6 nmol per L). Conditions such as hypokalemia, hypomagnesemia
or hypothyroidism may predispose patients to have adverse reactions even at lower
serum digoxin concentrations.
Dosages of Digoxin
Although some investigators advocate the use of serum levels to guide digoxin dosing,
little evidence supports this approach.30 The serum level of digoxin may be used to
assist in evaluating a patient for toxicity, but not to determine the efficacy of the drug.
When digoxin was considered to be mainly an inotrope, higher dosages (greater than
0.25 mg per day) were generally used, and the incidence of toxicity was much higher. In
the PROVED and RADIANCE trials, the mean digoxin dosage was 0.375 mg per day.
However, a study of a subset of patients in the RADIANCE trial showed that increasing
the digoxin dosage from a mean of 0.2 mg per day to 0.39 mg per day did not
significantly improve heart failure symptoms, exercise time or serum norepinephrine
levels. When lower dosages are used, the side effects of digoxin, especially ventricular
arrhythmias, decrease. Use of lower dosages is particularly important in the elderly,
because digitalis toxicity may be difficult to recognize in this patient population. It is
generally agreed that digoxin should be given in a dosage of 0.125 to 0.25 mg per day.
Dosages higher than 0.25 mg per day are probably unwarranted. Renal function plays a
major role in the pharmacokinetics of digoxin and is an important factor in determining
the dosage. Medications such as quinidine, amiodarone (Cordarone) and verapamil
(Calan) can increase the serum digoxin concentration. Thus, safe and effective dosing
requires recognition of concomitant disease states and medications that could change
digoxin pharmacokinetics, along with a recognition of digoxin toxicity.
Digoxin and Other Medications for Congestive Heart Failure
ACE inhibitors, beta blockers and spironolactone have been shown to improve survival
in patients with heart failure. Consequently, the role of digoxin in the treatment of heart
failure remains secondary, despite renewed interest in its use. Digoxin has been shown
to reduce the morbidity associated with congestive heart failure but to have no
demonstrable effect on survival.
In the absence of a survival benefit, the goal of digoxin therapy is to improve quality of
life by reducing symptoms and preventing hospitalizations. Digoxin should be used
routinely, in conjunction with diuretics, ACE inhibitors, beta blockers and
spironolactone, in all patients with severe congestive heart failure and reduced systolic
function. It also should be added to the therapy of patients with mild to moderate
congestive heart failure if they have not responded adequately to an ACE inhibitor or a
beta blocker. If digoxin acts primarily by reducing neurohormonal activation, its value is
in question in patients with heart failure who are already being treated with beta blockers.
While there is little doubt that appropriate doses of digoxin will slow the resting
ventricular rate in most patients with chronic atrial fibrillation (E1), it has been known for
many years that digoxin is far less successful in controlling exercise-induced or stressinduced tachycardia in atrial fibrillation in many patients, even when plasma drug
concentrations are near the upper end of the accepted therapeutic range.1 A study of 12
patients with chronic atrial fibrillation confirmed that medium-dose diltiazem was
comparable, in terms of rate control at rest, to a therapeutic dose of digoxin and
superior to digoxin during exercise. High-dose diltiazem (360 mg/day) was superior to
digoxin, both at rest and during exercise
Digoxin Toxicity
Toxicity
Common (seen in 10%20% of patients on long-term digoxin therapy).
Cardiotoxicity is most serious and may manifest as ventricular or supraventricular
arrhythmias, including sudden increased prevalence of cardiac death (this was almost
exactly balanced in Digitalis Investigation Group trial by reduction in "pump failure"
deaths). Also, vagotonic actions can produce bradyarrhythmias, including prolonged
PR interval and high-grade heart block.
Non-cardiac toxicity includes nausea, vomiting, diarrhoea, visual effects, including
"yellow" vision, and gynaecomastia.
Digitalis toxicity can occur fairly easily and quickly. Digitalis can accumulate in tissues
even when taken as prescribed. Symptoms of digoxin toxicity are:
weakness
nausea, vomiting, or diarrhea
seeing colored lights
loss of appetite or
an uneven, very slow or very fast heartbeat
Several medications can affect the way digitalis works, causing either an increase or
decrease in the drug's actions on the heart. Some of the medicines are:
diuretics or water pills
other cardiac medications
antacids
laxatives and some diarrhea medications
thyroid and asthma medications
decongestants found in cough, cold, and sinus products and
diet pills
Physicians first studied digoxin in the 18th century. The syndrome of digoxin toxicity
originally was described in 1785. Digoxin's inotropic effect results from the inhibition of
the sodium-potassium adenosine triphosphatase (NA+/K+ ATPase) pump. The
subsequent rise in intracellular calcium (Ca++) and sodium (NA+) coupled with the loss
of intracellular potassium (K+) increases the force of myocardial muscle contraction
(contractility), resulting in a net positive inotropic effect. Digoxin also increases the
automaticity of Purkinje fibers but slows conduction through the atrioventricular (AV)
node. Cardiac dysrhythmias associated with an increase in automaticity and a decrease
in conduction may result. The relationship between digoxin toxicity and the serum
digoxin level is complex; clinical toxicity results from the interactions between digitalis,
various electrolyte abnormalities, and their combined effect on the Na+/K+ ATPase
pump. Cardiac glycoside toxicity from plants, such as oleander, foxglove, and lily-ofthe-valley, is uncommon but potentially lethal. Case reports of toxicity from these
sources implicate the preparation of extracts and teas as the usual culprit.
Frequency:
In the US: Approximately 0.4% of all hospital admissions, 1.1% of outpatients on
digoxin, and 10-18% of nursing home patients develop toxicity.
The overall incidence of digoxin toxicity has decreased because of a number of
factors including increased awareness of drug interactions, decreased use of
digoxin to treat heart failure and arrhythmias, and the availability of accurate rapid
radioimmunoassays to monitor drug levels.
Internationally: Approximately 2.1% of inpatients on digoxin and 0.3% of all
admissions develop toxicity.
Mortality/Morbidity:
Morbidity is usually 4.6-10%; however, morbidity is 50% if the digoxin level is
greater than 6 ng/mL.
Mortality varies with the population studied. Adult mortality depends on underlying
comorbidity. In general, older people have a worse outcome than adults who, in
turn, have a worse outcome than children.
Age: Advanced age (>80 y) is an independent risk factor and is associated with
increased morbidity and mortality.
Digitalis toxicity occurs in 5 to 20 percent of patients treated with digitalis
glycosides. Because the therapeutic and toxic ranges are relatively narrow, toxicity may
occur from an accidental overdose, unpredictable changes in renal function or
electrolyte imbalance. Most cases of digoxin toxicity are minor, and treatment consists
of temporary withdrawal or reduction in the dose. However, several thousand patients
each year require more aggressive treatment, often in the coronary care unit. Mortality
rates in patients with digoxin toxicity have ranged from 3 to 25 percent. Digoxin immune
Fab (ovine) fragments (Digibind) have been shown to reverse digitalis toxicity and
substantially reduce the risk of death. Fab fragments are presently indicated for use in
patients with potentially life-threatening arrhythmias or other evidence of severe digitalis
intoxication. Such patients require continuous monitoring until digoxin levels return to
the therapeutic range. Mauskopf and Wenger used data from uncontrolled studies of
patients treated with Fab fragments and data from symptomatically treated patients to
estimate the difference in clinical outcomes and medical care costs when Fab fragments
are used. Treatment with Fab fragments produces a greater reduction in mortality risk in
patients with serious toxicity than in patients with less serious toxicity. Treatment is
associated with increased total medical costs for patients with serious toxicity, because
more of these patients survive and require further hospitalization and care. For these
patients, the estimated cost per year of life saved is between $1,900 and $5,400. When
Fab fragments are used to treat patients with less serious toxicity, total medical costs are
decreased because the number of days in the coronary care unit and the need for
pacemakers and other aggressive treatments are reduced.
Treatment of Toxicity
Stop giving the drug (for a time)
antiarrhythmics (lidocaine, procainamide, propranolol, phenytoin) IF the
arrhythmias appear to be life-threatening in their own right (multi-focal pvcs, high
rate ventricular tachycardia) or if the arrhythmias severely compromise cardiac
output.
Potassium (if hypokalemic)
Cholestyramine, activated charcoal etc. to bind digoxin in GI tract and shorten
half-life
Digoxin Antibodies (therapeutic monitoring becomes irrelevant).
Phosphodiesterase inhibitors
Amrinone
Mechanism(s) of Action
Increased force of contractionPhosphodiesterase inhibition increased cyclic AMP in
myocardial cell (same biochemical effect as -1,-2 stimulation)
Reduced preload and afterload Direct inhibition of smooth muscle arterial and
venous>
Pharmacokinetics (humans)
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