DRUGS ACTING ON THE RESPIRATORY ORGANS FUNCTION.

-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

budesonide, in children with less severe disease is not clear.

The role of corticosteroids in pulmonary sarcoidosis is also not clear, since the natural
course of the disease is characterized by frequent remissions. Corticosteroids are
generally used for progressive pulmonary impairment or respiratory symptoms. These
agents appear to suppress granuloma formation and may result in symptomatic and
roentgenogram improvement. There is no evidence that therapy will reduce residual
pulmonary dysfunction.
Administration of inhaled corticosteroids can be aided by the use of chambers or
spacers. These devices help decrease systemic absorption and subsequent adverse
reactions of the corticosteroid. Most inhaled therapy is delivered via metered dose
inhalers, although manufacturers have developed other methods such as the breathactuated dry powder inhaler devices. Examples of these devices include the
Rotahaler(r), Diskhaler(r), and the Turbuhaler(r). These devices require less
coordination, but deep, forceful inspiration at high flow rates (>= 60 L/min) are needed
for optimal drug delivery. Delivery methods of respiratory antiinflammatory agents will
continue to progress and change. Chlorofluorocarbons are used as propellants in many
metered-dose inhalers; unfortunately chlorofluorocarbons have been implicated in
destroying the earth's atmospheric ozone layer and their use must be discontinued. By
January 1996, the phase-out of all chlorofluorocarbons in metered-dose inhalers should
be completed.
Mechanism of Action: Mucosal inflammation is characterized by early- and latephases. The early-phase results from IgE-mediated mast cell degranulation. It appears
that both cromolyn and nedocromil are similar in their ability to antagonize antigeninduced mast cell degranulation. This, in turn, prevents the release of histamine and
slow-reacting substance of anaphylaxis (SRS-A), mediators of type I allergic reactions.
Cyclosporine also inhibits the degranulation of mast cells. Neither cromolyn nor
nedocromil interfere with the binding of IgE to the mast cell or with the binding of
antigen to IgE. Orally inhaled corticosteroid hormones may decrease IgE synthesis.

The late-phase bronchospastic response of asthma is characterized by interstitial

edema, mucous glycoprotein release, and eosinophil infiltration of the airways.
Leukotrienes attract cellular infiltrates producing epithelial injury, abnormalities in neural
mechanisms, increases in airway smooth muscle responsiveness, and airway
obstruction. Corticosteroids (oral, parenteral, or inhaled) decrease arachidonic acid
metabolism and decrease the amount of prostaglandins and leukotrienes synthesized.
Corticosteroids increase the number of beta-adrenergic receptors on leukocytes and
increase the responsiveness of beta-receptors of airway smooth muscle. Cromolyn also
may reduce the release of inflammatory leukotrienes. It has been postulated that
cromolyn produces these effects by inhibiting calcium influx, but its exact mechanism of
action is unclear. The mechanism of nedocromil's antiinflammatory effects is also
unknown. Nedocromil prevents bronchoconstriction secondary to non-antigenic stimuli.
Because cromolyn and nedocromil are not bronchodilators, antihistamines, or
vasoconstrictors, their beneficial effects in the treatment of asthma are largely
prophylactic.

An exaggerated bronchoconstrictor response, airway hyperresponsiveness, can be

induced by a variety of causes including cold air, allergens, environmental pollutants, or
exercise. Cromolyn can reduce hyperreactivity of the bronchi, inhibiting asthmatic
responses to antigenic challenge. Nedocromil appears to be equivalent to cromolyn in
preventing exercise-induced asthma. Orally inhaled corticosteroids also reduce airway
hyperresponsiveness.
Other agents affect leukotrienes and T-cell activity. Leukotriene biosynthesis inhibitors,
such as zileuton (Leutrol(r)), directly inhibit 5-lipoxygenase, preventing the formation of
cysteinyl leukotrienes and LTB4. Zafirlukast (Accolate(r)) is an orally active leukotrienereceptor antagonist currently undergoing phase III investigation. It is a selective
antagonist
of
cysteinyl-leukotriene
receptors,
inhibiting
allergen-induced
bronchoconstriction. Cyclosporine, anti-adhesion molecules, anti-cytokines, and antieffector cells all affect T-cells at various stages of activity (synthesis, action,
recruitment, survival, or removal).
During treatment of pneumocystis pneumonia (PCP), destroyed organisms release
antigens which elicit an inflammatory response in the lungs, impairing pulmonary
function. Oral or intravenous corticosteroids are beneficial as adjunct treatment of
severe PCP. Corticosteroids can also prevent the early deterioration in patients with mild
to moderate disease. Corticosteroids improve outcomes in patients with PCP when
used for primary, secondary, or taper rescue therapy.
Corticosteroids are effective in those children with moderate to severe croup, avoiding
intubation or allowing early extubation. The exact mechanism for these results is
unknown, but corticosteroids may decrease subglottic edema by decreasing capillary

permeability and dilatation. Intranasally administered corticosteroids have local

antiinflammatory effects with minimal systemic effects. These agents will affect allergic
and nonallergic/irritant-mediated inflammation. The exact mechanism of this
antiinflammatory action of corticosteroids on nasal mucosa is not known.
Corticosteroids are also effective in the treatment of airway inflammation associated with
cystic fibrosis, however, long-term administration to children is associated with growth
retardation, glucose intolerance, and impairment of host defenses. Nonsteroidal
antiinflammatory agents can inhibit the migration and aggregation of neutrophils and
prevent the release of lysosomal enzymes and have been shown to be beneficial in cystic
fibrosis.
Distinguishing Features: Corticosteroids were originally available as oral and
parenteral agents. Because of a high incidence of adverse reactions, inhaled
corticosteroids were developed. Several corticosteroids are now available for
administration by inhalation and they may be compared in several different ways.
Budesonide, although not available in the U.S., appears to have less systemic
absorption, and possibly less systemic effects than the other orally inhaled
corticosteroids. Budesonide and fluticasone appear to be substantially more potent than
beclomethasone, flunisolide, or triamcinolone. In a head-to-head comparison, inhaled
triamcinolone was found to cause significantly less coughing and less decrease in FEV1
than inhaled beclomethasone. Orally inhaled beclomethasone, dexamethasone, and
triamcinolone are administered 3-4 times daily, compared to flunisolide which has a
prolonged dosage interval at 2 times daily. Although the manufacturer's recommended
dosing frequency may differ between agents, once or twice daily dosing for all may be
acceptable in patients with mild asthma. Despite some of these clinical issues, patients
may ultimately prefer one agent over another based on cost or even degree of aftertaste.
Airway inflammation is an important factor during an asthmatic episode. The
guidelines for the diagnosis and management of asthma recommend the role of the
various respiratory antiinflammatory agents. The severity of disease and patient age are
factors which determine which therapy to initiate. Both adults and children with chronic
mild asthma can effectively prevent asthma attacks with cromolyn. If the patient
becomes symptomatic, the next step is the addition of a beta-agonist. Inhaled
corticosteroids, although considered safer than systemic therapy, still have the risk of
adverse effects. Long term therapy of inhaled corticosteroids in children is restricted
because of the risk growth suppression, adrenal suppression, or osteoporosis.

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

symptomatic relief. Rhinitis. Nasal discharge could be prevented by

parasympatholytics; however, other atropinelike effects would have to be accepted.
Therefore, parasympatholytics are hardly ever used, although a corresponding action is
probably exploited in the case of H1 antihistamines, an ingredient of many cold
remedies. Locally applied
(nasal drops) vasoconstricting -sympathomimetics
decongest the nasal mucosa and dry up secretions, clearing the nasal passage. Longterm use may cause damage to nasal mucous membranes. Sore throat, swallowing
problems.

Demulcent lozenges containing surface anesthetics such as

ethylaminobenzoate (benzocaine) or tetracaine may provide relief; however, the risk of
allergic reactions should be borne in mind. Cough. Since coughing serves to expel
excess tracheobronchial secretions, suppression of this physiological reflex is justified
only when coughing is dangerous (after surgery) or unproductive because of absent
secretions. Codeine and noscapine suppress cough by a central action. Mucous
airway obstruction. Mucolytics, such as acetylcysteine, split disulfide bonds in mucus,
hence reduce its viscosity and promote clearing of bronchial mucus. Other expectorants
(e.g., hot beverages, potassium iodide, and ipecac) stimulate production of watery
mucus. Acetylcysteine is indicated in cystic fibrosis patients and inhaled as an aerosol.
Whether mucolytics are indicated in the common cold and whether expectorants like
bromohexine or ambroxole effectively lower viscosity of
bronchial secretions may be questioned. Fever. Antipyretic analgesics acetylsalicylic
acid, acetaminophen, are indicated only when there is high fever. Fever is a natural
response and useful in monitoring the clinical course of an infection. Muscle aches and
pains, headache. Antipyretic analgesics are effective in relieving these symptoms.
Asthma and COPD are common disorders (affecting 10 and 30 million individuals,
respectively) and show several similarities in their clinical features. The goal of this
lecture and the lecture on anti-inflammatory agents will be to highlight the fundamental
pharmacological basis to manage the pathological changes associated with these
diseases and to restore normal functionality.
Plant origin expectorants

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

inflammation, persistent airway hyperreactivity (AHR), and airway remodeling. The

fundamental pathogenesis of asthma involves several processes. Chronic inflammation
of the bronchial mucosa is prominent, with infiltration of activated T-lymphocytes and
eosinophils. This results in subepithelial fibrosis and the release of chemical mediators
that can damage the epithelial lining of the airways. Many of these mediators are
released following activation and degranulation of mast cells in the bronchial tree. Some
of these mediators act as chemotactic agents for other inflammatory cells. They also
produce mucosal edema, which narrows the airway and stimulates smooth muscle
contraction, leading to bronchoconstriction. Excessive production of mucus can cause
further airway obstruction by plugging the bronchiolar lumen.. Approximately 5% of
asthmatic patients remain poorly controlled. Despite considerable effort by the
pharmaceutical industry, it has proven very difficult to develop new classes of
therapeutic agents for asthma.
COPD (HRONIC OBSTRUCTIVE PULMONARY DISORDERS
COPD is characterized by airflow limitation caused by chronic bronchitis or
emphysema that is usually caused by tobacco smoking. This is usually a slowly
progressive and largely irreversible process, which consists of increased resistance to
airflow, loss of elastic recoil, decreased expiratory flow rate, and overinflation of the
lung. COPD is clinically defined by a low FEV1 value (see lecture on Pulmonary
Function Testing) that fails to respond acutely to bronchodilators, a characteristic that
differentiates it from asthma. The degree of broncodilatory response at the time of
testing, however, does not predict the degree of clinical benefit to the patient and thus
bronchodilators are given irrespective of the acute response obtained in the pulmonary
function laboratory.
PATHOGENESIS OF ASTHMA AND COPD

A rational approach to the pharmacotherapy of asthma and COPD depends on a

fundamental understanding of the diseases pathogenesis. The conventional
immunological model suggests asthma is a disease mediated by IgE antibodies bound to
mast cells in the airway mucosa. After re-exposure to the antigen, antigen-antibody
interaction on the surface of the mast cells triggers both the release of mediators stored
in the cells granules and the synthesis and release of other mediators. The agents
responsible for the early reactions, such as immediate brochoconstriction, are a
physiologists and pharmacologists dream: they include histamine, tryptase, other
neutral preoteases, leukotrienes C4 and D4, and prostaglandins. These agents cause
muscle contraction and vascular leakage. Putative mediators for the more sustained
bronchocontriction, cellular infiltration of the airway mucosa, and mucus hypersecretion
of the late asthmatic reaction, which occurs 2-8 hours later, are cytokines produced by
Th2 lymphocytes, especially GM-CSF and IL-4, 5, 9, and 13, which attract and activate
eosinophils and stimulate IgE production by B lymphocytes.
Some of the features of asthma cannot be readily accounted for by the antigen challenge

model. In many patients, bronchospasm can be provoked by non-antigenic stimuli such

as distilled water, exercise, cold air, sulfur dioxide, and rapid respiration.
Bronchoconstruction itself seems to result not simply from the direct effect of the
released mediators but also from the activation of neural or humoral pathways.
PHARMACOTHERAPY OF ATHMA AND COPD
Current therapeutically available agents for the treatment of asthma and COPD can be
divided into two general categories: drugs that inhibit smooth muscle contraction, i.e.
bronchodilators (adrenergic agonists, methylxanthines, and anticholinergics) and agents
that prevent and/or reverse inflammation, i.e., the long-term control medications
(glucocorticoids, leukotriene inhibitors and receptor antagonists, and mast cellstabilizing agents or cromones). The latter will be discussed in the future lecture by
Professor DeFranco on anti-inflammatory agents.
Aerosol Delivery of Drugs
Topical application of drugs to the lungs can be accomplished by use of aerosols. This
approach should in theory produce high local concentrations in the lungs with a low
systemic delivery, thus reducing systemic side effects. The critical delivery determinant
of any particulate matter to the lungs is the size of the particle. Particles >10 m are
deposited primarily in the mouth and oropharynx; particles <0.5 m are inhaled to the
alveoli and exhaled without being deposited in the lungs. The most effective particles
have a diameter of 1-5 m. Other important factors for deposition are rate of breathing
and breath-holding after inhalation. Even under ideal circumstances, only a small fraction
of the aerosolized drug (~2-10%) is deposited in the lungs. A large volume spacer
attached to metered-dose inhalers can markedly improve the ratio of inhaled to
swallowed drug.
The hypothesis suggested by these studiesthat asthmatic bronchospasm results from
a combination of release of mediators and an exaggeration of responsiveness to their
effects predicts that asthma may be effectively treated by drugs with different modes
of action.
Asthmatic bronchospasm might be reversed or prevented, for example, by drugs that
reduce the amount of IgE bound to mast cells (anti-IgE antibody), prevent mast cell
degranulation (cromolyn or nedocromil, sympathomimetic agents, calcium channel
blockers), block the action of the products released (antihistamines and leukotriene

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.

For many years, atropine was known to possess bronchodilatory properties,

however, it was thought that antimuscarinic drugs were to be avoided in the treatment of
asthma. In addition, atropine possessed significant unwanted adverse reactions. It has
since been shown that antimuscarinic anticholinergics are indeed effective
bronchodilators. Ipratropium bromide, released in 1986 and administered by inhalation,
is the primary anticholinergic agent used for bronchodilation. Due to its quaternary
ammonium structure, its systemic bioavailability is low. As a result, systemic side
effects occur much less frequently with ipratropium than with atropine. In 1994, a new
combination product containing ipratropium bromide and the beta2-agonist albuterol
was made available.
Since its release in 1940, theophylline has been the bronchodilator of choice for a
number of bronchoconstrictive pulmonary diseases. Due to its toxicity profile and a
better understanding of the disease processes involved, theophylline therapy has
declined in the treatment of asthma. Glucocorticoids are now regarded as primary
therapy in the treatment of asthma (see "Respiratory Antiinflammatory Agents"
Overview).
The bronchial tree is one of the organs that receive dual sympathetic and
parasympathetic innnervation. The predominant adrenoceptors in the bronchial tree are
2, which cause relaxation. As mentioned below, a subtype of muscarinic cholinergic
receptor, M3, mediates smooth muscle contraction in the lungs. Bronchodilators are a
group of agents that cause rapid relaxation of bronchial smooth muscle. Three classes
of bronchodilators are in current use:
anticholinergic drugs.

-adrenergic agonists, theophylline, and

Despite the new focus on inhaled glucocorticoids, traditional bronchodilators may

still be necessary in many patients. Controversy exists regarding the role of theophylline
in the therapy of asthma. Theophylline is generally recommended in patients with
chronic bronchoconstrictive diseases requiring prolonged bronchodilation, in patients
with noctural symptoms, or in patients requiring hospitalization for treatment of asthma.
Efficacy for beta2-agonists in asthma has been demonstrated, however, there is some
evidence that prolonged use of beta 2-agonists may be associated with diminished
control of asthma.
Beta-adrenergic Agonists
-agonists produce bronchodilation by directly stimulating 2-receptors in airway
smooth muscle. Activation of 2 receptors results in activation of adenyl cyclase via a
stimulatory guanine-nucleotide binding protein [G protein (Gs)] and increases
intracellular cyclic 35-adenosine monophosphate (cAMP). This activates protein kinase
A, which then phosphorylates several target proteins within the cell leading to relaxation
of bronchial smooth muscle.
2 agonists have other beneficial effects including inhibition of mast cell mediator
release, prevention of microvascular leakage and airway edema, and enhanced
mucociliary clearance. The inhibitory effects on mast cell mediator release and
microvascular leakage suggests that B2 agonists may modify acute inflammation. 2
agonists, however, have no effect on chronic inflammation.
2 agonists were developed through substitutions in the catecholamine structure of
norepinephrine (NE). NE differs from epinephrine in the terminal amine group, and
modification at this site confers beta receptor selectivity; further substitutions have
resulted in 2 selectivity. The selectivity of 2 agonists is obviously dose dependent.
Inhalation of the drug aids selectivity since it delivers small doses to the airways and
minimizes systemic exposure. As shown in Table , agonists are generally divided into
short (4-6 h) and long (>12 h) acting agents.
Table Beta Agonists
Generic name

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

Short-acting 2 adrenergic receptor agonists, such as albuterol are the preferred

treatment for rapid symptomatic relief of dyspnea associated with asthmatic
bronchoconstriction. With topical delivery, there are relatively few side effects with
these agents at therapeutic doses.
At higher doses, these agents may lead to increased heart rate, cardiac arrhythmias, and
CNS effects associated with adrenergic receptor activation. Side effects such as these
as well as muscle cramps and metabolic disturbances limit oral administration.
Mechanism of Action: There are three types of bronchodilators, each with its own
unique mechanism of action. The beta 2-agonists and methylxanthine derivatives are
considered functional or physiologic antagonists, that is, they cause airway relaxation
regardless of the mechanism of constriction. Conversely, the anticholinergic agents only
cause bronchodilation in cholinergic mediated bronchoconstriction.
Beta2-agonists bind to beta2 receptors on smooth muscle cells located throughout
the airways. Stimulation of beta2-receptor increases intracellular cyclic AMP (cAMP)
which, in turn, mediates bronchodilation. Given at equipotent doses, the beta 2-agonists
will produce the same intensity of response.
It was thought for years that the methylxanthine derivatives caused bronchodilation
by inhibition of phosphodiesterase, preventing enzymatic breakdown of 3',5'-cAMP; it
was subsequently found that these actions only occur at very high doses. A number of
new mechanisms have been proposed; 1) prostaglandin antagonism, 2) inhibition of
calcium ion influx into smooth muscle, 3) stimulation of endogenous catecholamines, 4)
inhibition of release of mediators from mast cells and leukocytes, and 5) adenosine
receptor antagonism.

The currently available anticholinergic bronchodilators are non-selective muscarinic

blockers. Antagonism of cholinergic receptors causes a reduction in cGMP. cGMP
normally causes constriction of bronchial smooth muscle. Because these agents cause a
non-selective muscarinic blockade there can be an increased release of acetylcholine,
thus overcoming the blockade on the smooth muscle receptors. Bronchoselectively is
increased when these agents are administered by inhalation therapy.
All the bronchodilators have an effect on the function of ciliated bronchial epithelium.
The exception is ipratropium bromide which has no effect on ciliary action. Beta 2
agonists cause an increase in ciliary beating. Methylxanthine derivatives cause
stimulation of mucociliary clearance. Conversely, atropine causes marked inhibition on
ciliary beating and mucociliary clearance.

The bronchodilators can also produce nonbronchodilatory effects. Beta 2-agonists

can cause cardiostimulatory effects from their actions on the beta2-receptors
(chronotropic) and beta1 receptors (chronotropic and inotropic). Excessive stimulation
can lead to arrhythmias, hypertension, palpitations, and tachycardia. Methylxanthine
derivatives also cause inotropic and chronotropic effects. Atropine can cause cardiac
stimulation, producing tachycardia.
Stimulation of beta2-receptors in skeletal muscle results in tremors and increased in
strength of contraction while stimulation of beta2-receptors in uterine smooth muscle
causes tocolysis. Beta2 stimulation activates Na+/K+/ATPase causing gluconeogenesis
and increases insulin secretion. These three effects can contribute to hypokalemia by
causing an intracellular shift of potassium. Beta 2 stimulation can produce a metabolic
lactic acidemia.
Methylxanthine derivatives possess nonbronchodilatory effects which can produce
positive effects on the respiratory tract. They have been shown to produce improved
diaphragmatic strength, cause a reduction in fatigue, and improve central respiratory

response to hypoxemia. Other, non-respiratory effects, include 1) stimulation of the

CNS by adenosine antagonism and cerebral vasoconstriction, 2) lowering of esophageal
sphincter pressure, 3) increased gastric acid secretion, and 4) a diuretic response, which
quickly develops tolerance. Methylxanthine derivatives also cause an increace in mucus
production, and an inhibition of histamine release from mast cells.
Systemic effects of atropine include dryness of secretions, blurred vision, and CNS
stimulation. Ipratropium bromide does not possess any significant systemic effects.
Distinguishing Features: The beta2-agonists produce the most effective
bronchodilation compared to the methylxanthine derivatives and anticholinergic agents.
The beta2-agonists can further be differentiated by their beta-selectivity, oral activity,
beta2 potency, and duration of action.
Non-selective agents (e.g., isoproterenol, metaproterenol, and isoetharine) have both
beta1 and beta2 activity. The beta1 activity can produce cardiac stimulation resulting in
arrhythmias and a positive inotropic effect. The beta2-selective agents (albuterol,
bitolterol, pirbuterol, terbutaline, and salmeterol) have limited beta1 activity, therefore
avoiding the cardiac stimulatory effects. Ethylnorepinephrine, ephedrine and epinephrine
are bronchodilators but are seldom used for this purpose because of their alphareceptor effects. Beta1 activity and systemic beta2 effects (e.g. tremors, hypokalemia)
occurs after systemic absorption of the agent from the lungs. Both beta 1 and beta2
effects become even more apparent and potentially serious when the agent is
administered orally or parenterally. Metoproterenol, albuterol, pirbuterol, and terbutaline
are available as oral preparations. Procaterol, an investigational beta2-selective-agonist,
is being studied in an oral formulation. Terbutaline, ethylnorepinephrine, ephedrine and
epinephrine are available as parenteral products.
Salmeterol is the most potent beta2 agonist on a molar basis while metaproterenol is
the least potent beta2 agonist. In general, when given in equipotent doses, these agents
produce the same intensity of response.
Beta2-agonists can be further differentiated according to their duration of action.
Isoproterenol and isoetharine, the shortest acting, have a duration of bronchodilation of
0.5-2 hours, with protection against bronchoconstriction for only 0.5-1 hour.
Metaproterenol has a duration of bronchodilation of 3-4 hours, with protection against
bronchoconstriction for 1-2 hours. Albuterol, bitolterol, pirbuterol, and terbutaline have
an intermediate duration of bronchodilation of 4-8 hours, with protection against

bronchoconstriction for 2-4 hours. Bitolterol is given as a prodrug and is metabolized

by esterases to its active drug, colterol. Salmeterol has the longest duration of activity of
12 hours, with protection against bronchoconstriction for 12 hours. Procaterol, an
investigational beta2-agonist, has a duration of action of 8-12 hours, similar to
salmeterol.
There are a number of methylxanthine derivatives which produce bronchodilation.
These include theophylline, caffeine, and dyphylline. Oxtriphylline is a choline salt of
theophylline. Theophylline is the most widely used oral methylxanthine derivative.
Aminophylline (ie., a theophylline-ethylenediamine complex) is the preferred parenteral
preparation.
Theophylline is available in a variety of different preparations. Liquid products and
immediate release products generally need to be dosed every 4-6 hours. Theophylline is
released over a 24 hour period from sustained-release products such as Theodur(r) and
Slo-bid(r); these products can be dosed at intervals of 8-12 hours. The less frequent
dosing interval may help improve compliance.
Aminophylline, used primarily for parenteral use, contain approximately 85%
anhydrous theophylline. Oxtriphylline contains approximately 64% anhydrous
theophylline. Theophylline is also available in a rectal preparation. Although rectal
administration is generally not recommended due to erratic bioavailability, it has been
used to treat Cheyne-Stokes respirations.
There are two anticholinergic agents commonly used for bronchodilation, atropine
and ipratropium bromide. When administered intravenously, they produce similar
physiologic effects, including tachycardia, inhibition of salivation, and bronchodilation.
When administered via inhalation therapy, there are some distinct differences.
Ipratropium bromide has low systemic bioavailability due to its quaternary ammonium
structure, producing low or no systemic side effects. Atropine has high systemic
absorption, producing undesirable systemic side effects. Ipratropium bromide lacks
appreciable effects on the CNS and causes a greater inhibitory effect on ganglionic
transmission.
Adverse Reactions: Adverse reactions of the beta2 agonists are usually minor. As
the absorption of the agent from the lung into the blood stream increases, systemic
effects become more prominent. This is also true of oral and parenteral administration
of the beta2 agonists. Cardiovascular side effects can be serious and include
palpitations, tachycardia, hypertension, and arrhythmias, and are associated with beta1

stimulation. Local respiratory effects include cough, wheezing, dyspnea, bronchospasm,

throat dryness or irritation, and pharyngitis. Salmeterol has a high incidence of
respiratory side effects (e.g. upper respiratory tract infections, nasopharyngitis)
compared to the other beta2-agonists. Beta2 activity in the skeletal muscle can produce
tremors. Beta2 agonists also cause vasodilation which can subsequently cause dizziness,
headache, flushing, and sweating. CNS side effects include shakiness, nervousness,
tension, excitement, and insomnia. Other effects include unusual or bad taste, anorexia,
hypokalemia, lactic acidemia, and gluconeogenesis.
Methylxanthine derivatives, specifically theophylline, have a very narrow therapeutic
range. Serious toxicities, such as seizures, permanent neurologic deficits, and death, can
occur before minor side effects are seen; this is the reason for serum concentration
monitoring. Other serious effects include tachycardia, arrhythmias, tachypnea, and
behavioral disturbances in children secondary to CNS stimulation. Minor side effects
include nausea and vomiting, anorexia, diarrhea, restlessness, irritability, insomnia, and
headache. Diuresis is seen early in therapy, but tolerance tends to develop. Relaxation of
the detrusor muscle can cause difficulty in urination in men with enlarged prostates.
Metabolic alterations include hyperglycemia and hypokalemia.
The two most commonly used anticholinergic agents used for bronchodilation are
atropine and ipratropium bromide. Ipratropium bromide has a very favorable side effect
profile. Xerostomia is its most predominant effect and because of low bioavailability it
generally lacks systemic effects. Atropine causes both local and systemic side effects. It
causes dryness of secretions, blurred vision, cardiac stimulation and CNS stimulation.
Theophylline
The methylxantine theophylline shares a similar structure to the dietary xanthine
caffeine. Many salts of theophylline have been marketed, the most common being
aminophylline, which is the ethylenediamine salt. Theophylline has been in clinical use
since the 1930s. It is a weak, non-selective inhibitor of phosphodiesterase (PDE). There
are at least 10 PDE family members, all of which catabolize cyclic nucleotides in the cell.
PDE inhibition results in increased concentrations of cAMP and cGMP. Another
hypothesized mechanism of action is adenosine receptor inhibition, which may prevent
the release of mediators from mast cells.
The dose of theophylline required to yield therapeutic concentrations varies among
subjects, largely because of differences in clearance. Increased clearance is seen in
children and in cigarette and marijuana smokers. Concurrent administration of

phenobarbitol or phenytoin increases activity of cytochrome P-450 (CYP), which

results in increased metabolic breakdown. Reduced clearance is also seen with certain
drugs that interfere with the CYP system, such as cimetidine, erythromycin,
ciprofloxacin, allopurinol, zileuton, and zafirlukast. Viral infections and vaccinations
may also reduce clearance.
Unwanted side effects may be seen at higher plasma concentrations, although they may
occur in some patients even at low concentrations. The most common side effects are
anorexia, nausea and vomiting, headache, abdominal discomfort, and restlessness.
Anticholinergic Drugs
Human airways are innervated by a supply of efferent, cholinergic, parasympathetic
autonomic nerves. Motor nerves derived from the vagus form ganglia within and around
the walls of the airways. This vagally derived innervation extends along the length of the
bronchial tree but predominates in the large and medium-sized airways. Postganglionic
fibers derived from the vagal ganglia supply the smooth muscle and submucosal glands
of the airways as well as the vascular structures. Release of acetylcholine (ACh) at
these sites results in stimulation of muscarinic receptors and subsequent airway smooth
muscle contraction and release of secretions from the submucosal airway glands.
Three pharmacologically distinct subtypes of muscarinic receptors exist within the
airways: M1, M2, and M3 receptors. M1 receptors are present on peribronchial
ganglion cells where the preganglionic nerves transmit to the postganglionic nerves. M2
receptors are present on the postganglionic nerves; they are activated by the release of
acetylcholine and promote its reuptake into the nerve terminal. M3 receptors are present
on smooth muscle. Activation of these M3 receptors leads to a decrease in intracellular
cAMP levels resulting in contraction of airway smooth muscle and bronchoconstriction.
Atropine is the prototype anticholinergic bronchodilator. Ipratropium is a quaternary
amine, which is poorly absorbed across biologic membranes. Atropine and ipratropium
antagonize the actions of Ach at parasympathetic, postganglionic, effector cell junctions
by competing with Ach for M3 receptor sites. This antagonism of Ach results in airway
smooth muscle relaxation and bronchodilation.
Ipratropium is given exclusively by inhalation from a metered-dose inhaler or a
nebulizer. Inhaled ipratropium has a slow onset (about 30 minutes) and a relatively long

duration of action (about 6 hours). Recently, tiotropium (trade name: Spiriva), a

structural analog of ipratropiem, has been approved for treatment of COPD. Like
iprotropiem, tiotropiem has high affinity for all mucscarinic receptor subtypes but it
dissociates from the receptors much more slowly than ipratropium, esp. M3 receptors.
This permits once a day dosing. It is formulated for use with an oral inhalator.
Clinical trials of anticholinergic therapy have generally failed to show significant benefit
in asthma. This relative lack of efficacy in asthma contrasts with COPD, in which
anticholinergic agents are among the most effective therapies.

FUTURE PHARMACOLOGICAL DIRECTIONS FOR ASTHMA AND COPD

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].

Vasoactive intestinal peptide analogs

Vasoactive intestinal peptide (VIP) is a potent relaxant of constricted human airways in
vitro but it is degraded in the airway epithelium and ineffective in asthmatic patients. A
more stable cyclic analogue of VIP (Ro-25-1553) has a more prolonged effect in vitro
ad in vivo and is effective in asthmatic patients by inhalation.
Prostaglandin E2
PGE agonists that are selective for lung receptor subtypes are being considered for

exploration as bronchodilator/anti-inflammatory drugs.

Atrial natriuretic peptides (ANP)
Intravenous infusion of ANP produces a significant bronchodilator response and
protects against bronchoconstriction induced by inhaled broncoconstrictors such as
methacholine. ANP, however, is a peptide and subject to rapid enzymatic degradation.
A related peptide, urodilatin, is less susceptible to degradation and has a longer duration
of action. It is as potent as salbutamol when given intravenously.
Phosphodiesterase 4 (PDE4) inhibitors
Based on the actions of theophylline, there has been interest in developing PDE4
inhibitors. In animal models of asthma, PDE4 inhibitors reduce eosinophil infiltration
and airway hyperresponsiveness to allergens. The PDE4 inhibitor cilomilast has been
clinically tested in COPD, but the drug causes emesis, which is a common side effect
with this drug class (this could be due to inhibition of PDE4D). There is hope that
selective inhibitors of PDE4B might have more therapeutic potential.
Pharmacogenomics
Current data suggest that the 16 th amino acid position of the 2 adrenergic receptor is
associated with a major, clinically significant pharmacogenomic effect, namely down
regulation of the receptor and responsiveness of patients using -agonists.
Investigations of the effect of this and other polymorphisms on the response to longacting -agonists is currently being conducted.

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.

CHALLENGES FOR THE PHARMACOLOGICAL TREATMENT OF

PULMONARY HYPERTENSION
As you know from a previous lecture, pulmonary arterial hypertension (PAH) is
hemodynamically defined as an elevated mean pulmonary artery pressure (>25 mm Hg)
with a normal pulmonary capillary or left atrial pressure (< 15 mm Hg), which can be
caused by an isolated increase in pulmonary arterial pressure or by increases in both
pulmonary arterial and pulmonary venous pressure. Until recently, management of PAH
was generally ineffective in alleviating symptoms or improving survival. The
asymptomatic aspects of PAH, the complexity of differential diagnosis, involvement of

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

Inhalant powder: 50 g/unit

Salmeterol/Fluticasone (Advair Diskus)
Inhalant: 100, 250, 500 g fluticasone + 50 g salmeterol/unit
Terbutaline (Brethine, Bricanyl)
Inhalant: 0.2 mg/puff aerosol
Oral: 2.5, 5 mg tablets
Parenteral: 1 mg/mL for injection
Aerosol Corticosteroids (See Also
Adrenocortical
Antagonists.)
Beclomethasone (QVAR, Vanceril)

Chapter

39:

Adrenocorticosteroids

&

Aerosol: 40, 80 g/puff in 200 dose containers

Budesonide (Pulmicort)
Aerosol powder: 160 g/activation
Flunisolide (AeroBid)
Aerosol: 250 g/puff in 100 dose container
Fluticasone (Flovent)
Aerosol: 44, 110, and 220 g/puff in 120 dose container; powder, 50, 100, 250
g/activation
Fluticasone/Salmeterol (Advair Diskus)
Inhalant: 100, 250, 500 g fluticasone + 50 g salmeterol/unit
Triamcinolone (Azmacort)
Aerosol: 100 g/puff in 240 dose container
Leukotriene Inhibitors
Montelukast (Singulair)
Oral: 10 mg tablets; 4, 5 mg chewable tablets; 4 mg/packet granules
Zafirlukast (Accolate)
Oral: 10, 20 mg tablets
Zileuton (Zyflo)
Oral: 600 mg tablets
Cromolyn Sodium & Nedocromil Sodium
Cromolyn sodium
Pulmonary aerosol (generic, Intal): 800 g/puff in 200 dose container; 20 mg/2 mL for
nebulization

(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

Ipratropium (generic, Atrovent)

Aerosol: 18 g/puff in 200 metered-dose inhaler; 0.02% (500 g/vial) for nebulization
Nasal spray: 21, 42 g/spray
Antibody
Omalizumab (Xolair)
Powder for SC injection, 202.5 mg
Cardiotonic drugs. Cardiac glycosides and other inotropic drugs
Heart diseases can be primarily grouped into three major disorders: cardiac failure,
ischemia and cardiac arrhythmia. Cardiac failure can be described as the inability of the
heart to pump blood effectively at a rate that meets the needs of the metabolizing
tissues. This occurs when the muscles that perform contraction and force the blood out
of heart are performing weakly. Thus cardiac failures primarily arise from the reduced
contractility of heart muscles, especially the ventricles. Reduced contraction of heart
leads to reduced heart output but new blood keeps coming in resulting in the increase in
heart blood volume. The heart feels congested. Hence the term congestive heart failure.
Congested heart leads to lowered blood pressure and poor renal blood flow. This
results in the development of edema in the lower extremities and the lung (pulmonary
edema) as well as renal failure.

The conducting system of the heart. Impulses

originating in the SA node are transmitted through the atria to the AV
node down the bundle of His and the bundle branches through the
Purkinje fibers to the ventricles.

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.

Management of left ventricular systolic dysfunction.

Drugs to treat Heart Failure

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

cardiac glycosides inhibit the Na

pump allowing Ca to inc. inside cells
and increase the force of contraction
non-selective/b1-selective agonists
increase contractility

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 preload due

to Na/water retention
caused by activation
of the renin - angiotensin
- aldosterone pathway.
Na/water retention lead
to edema

diuretics - increase Na and water

excretion
ACE inhibitors -decrease production of angiotensin II (a potent
vasoconstrictor). Decreased AngII
decreases aldosterone thus decreasing
salt and water retention

decreases preload (dec.

blood volume causes
decreased venous return)
decreased afterload (dec.
AngII causes vasodilation or
decreased PVR) and
decreased preload due to
decreased aldosterone and
increase Na and water
excretion)

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

decrease afterload due to

arterial dilation (dec. PVR)
decrease preload and
afterload due to venous and
arterial dilation, respectively

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

Lily of the valley

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.

Negative Chronotropic Effect of Digoxin

Stimulates vagus centrally
Increases refractoriness of AV node
o
Decreases ventricular response to atrial rate
o
Controls heart rate in atrial fibrillation
Slows depolarization rate of SA node
o
Decreases sinus rate
o
Decreases heart rate in Sinus Tachycardia
Digoxin in Patients with Mild to Moderate Heart Failure
In the DIG trial, digoxin therapy was most beneficial in patients with ejection fractions of
25 percent or lower, patients with enlarged hearts (cardiothoracic ratio of greater than
0.55) and patients in NYHA functional class III or IV. The findings of the DIG trial also
indicated that digoxin was clinically beneficial in subgroups of patients with less severe
forms of heart failure. Using direct clinical measures of heart failure, the PROVED and
the RADIANCE trials showed definite clinical improvement in patients who were treated
with digoxin, even patients with mild heart failure. Based on the study findings, digoxin
therapy may be effective in patients with mild or moderate heart failure, although the
magnitude of the effect may be quite modest.
Digoxin in Patients with Preserved Left Ventricular Systolic Function
Much has been learned about the effective treatment of patients who have congestive
heart failure associated with left ventricular systolic dysfunction. In contrast, little is
known about how best to treat patients with preserved left ventricular systolic function.
As many as 30 percent of patients with congestive heart failure have a normal or nearly
normal left ventricular ejection fraction. In these patients, congestive heart failure is often
described as "left ventricular diastolic dysfunction." Left ventricular diastolic
dysfunction is considered to be a diagnosis of exclusion (or assumption) in patients
with congestive heart failure and preserved left ventricular systolic function. Diagnostic
tools such as radionuclide angiography and Doppler echocardiography have made it
possible to identify patients who have normal or nearly normal left ventricular systolic
function but abnormal left ventricular filling parameters. The majority of patients with
congestive heart failure who have only diastolic dysfunction have no identified
diagnosis. Most of these patients are elderly or have a history of hypertension. Some

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)

Only 10 to 40% of the dose excreted unchanged in urine

4 conjugated metabolites have been detected
considerable potential for species differences
Toxicity aggravates outflow obstruction (contraindicated with aortic or pulmonic
valvular disease, hypotension (1.5%), arrhythmia (3% - consider other risks here),
thrombocytopenia (dose dependent - decreased platelet survival> nausea, vomiting,
abdominal pain, anorexia (1%), hepatic toxicity (9 - 32 mg/kg/day in dogs - enzyme
elevation, hepatic cell necrosis>, hypersensitivity
Clinical Uses
intravenous infusion only
only for emergency situations
clinical experience is slight
Topic Summary (Positive Inotropes)
1. Cardiac glycosides are definitely indicated for control of tachycardia associated
with congestive heart failure. The heart rate effects can be monitored (contractility
effects cannot).
2. Cardiac glycoside therapy is inherently risky and difficult. You will produce some
toxicity in some patients or you are not treating aggressively enough.
3. Digoxin dosage must be individualized for each patient.
4.
Bioavailability of digoxin dose forms varies considerably (relative to the
therapeutic index). Patient monitoring should be increased when a change is
made.
5. Non-glycoside inotropes are available for emergency treatment. Some evidence
exists to suggest that a short course of dobutamine may have lasting (weeks)
effects on patient performance.
1.
2.
3.
4.
5.
6.
7.
8.

http://www.youtube.com/watch?v=S04dci7NTPk&NR=1
http://www.youtube.com/watch?v=vlZ7R07OrR4&feature=related
http://www.youtube.com/watch?v=7EDo9pUYvPE&NR=1
http://www.youtube.com/watch?v=aktIMBQSXMo&feature=fvw
http://www.youtube.com/watch?v=v-qr78Wj4xM&feature=related
http://www.youtube.com/watch?v=7EDo9pUYvPE&feature=related
http://www.youtube.com/watch?v=NYlVVyCKZdI&feature=related
http://www.youtube.com/watch?v=HiT621PrrO0&feature=related

9. http://www.youtube.com/watch?v=GERsMFWYZrw&NR=1
10.
http://www.youtube.com/watch?v=sU_8juD3YzQ&feature=related
11.
http://www.youtube.com/watch?v=Htelg8Xe6Ws&feature=related
12.
http://www.youtube.com/watch?v=eV8_h-bEruI&feature=related
13.
http://www.youtube.com/watch?v=hc1YtXc_84A&feature=related
14.
http://www.youtube.com/watch?v=JVBYg03rfd8&feature=related
15.
http://www.youtube.com/watch?v=UZjuTQiTKUU&feature=related
16.
http://www.youtube.com/watch?v=aktIMBQSXMo&feature=fvw
17.
http://www.youtube.com/watch?v=ttdma8PnFJI&feature=channel
18.
http://www.youtube.com/watch?v=aktIMBQSXMo&feature=channel
19.
http://www.youtube.com/watch?v=82gn_rDRpHk&feature=channel
20.
http://www.youtube.com/watch?v=aGDi5tI5vTk&feature=channel
21.
http://www.youtube.com/watch?v=Xwi04qYU6kc&feature=channel
22.
http://www.youtube.com/watch?v=vlZ7R07OrR4&NR=1
23.
http://www.youtube.com/watch?v=qW2KL6TsFCk&feature=related