DRUGS ACTING ON THE RESPIRATORY ORGANS FUNCTION.-1

RESPIRATORY STIMULATORS. COUGH REMEDIES. EXPECTORANTS

(Aethymisolum, Sulfocamphocainum, Bemegridum, Саrbogenum, 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 breath-

actuated 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 late-

phases. The early-phase results from IgE-mediated mast cell degranulation. It appears

that both cromolyn and nedocromil are similar in their ability to antagonize antigen-

induced 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 leukotriene-

receptor 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 anti-

effector 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; risk-

benefit 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 cold—colloquially 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 atropine–like 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 б-sympathomimetics

decongest the nasal mucosa and dry up secretions, clearing the nasal passage. Long-

term 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 (СHRONIC 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

physiologist’s and pharmacologist’s 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 cell-

stabilizing 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 studies—that 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 2-

receptors. 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 beta2-

agonist.

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: -adrenergic agonists, theophylline, and

anticholinergic drugs.

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 beta2-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 3′5′-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

Short acting

Albuterol 4-6 h +++

Levalbuterol 8 h +++

Terbutaline 4-8 h +++

Metaproterenol 4-6 h ++

Isoproterenol 3-4 h ++

Epinephrine 2-3 h -

Long acting

Salmeterol 12+ h +++

Formoterol 12+ h +++

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 beta2-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 beta2-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. Beta2-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. Beta2 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 alpha-

receptor 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 16th 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 long-

acting -agonists is currently being conducted.

The airways in asthma undergo significant structural remodeling. Medium-sized airways from a normaland severe asthmatic patient were sectioned and stained using Movat’s 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 =100μm.

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 Chapter 39: Adrenocorticosteroids &

Adrenocortical

Antagonists.)

Beclomethasone (QVAR, Vanceril)

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, 8–12 hours: 50, 60, 75, 100, 125, 130, 200, 250, 260, 300 mg

capsules

Oral sustained-release, 8–24 hours: 100, 200, 300, 450 mg tablets

Oral sustained-release, 12 hours: 100, 125, 130, 200, 250, 260, 300 mg capsules

Oral sustained-release, 12–24 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

decreasedcontractility (decreasein ability of muscle tocontract) results in SNSactivation tocompensate for decreased cardiacoutput

cardiac glycosides inhibit the Napump allowing Ca to inc. inside cellsand increase the force of contractionnon-selective/b1-selective agonistsincrease contractility

Increase contractilityincreases cardiac emptying,decreases preload, heart sizeand oxygen demand. IncreaseC.O. decreases SNS tone,heart rate and venous tone short-term support of afailing heart

increased preload dueto Na/water retentioncaused by activationof the renin - angiotensin- aldosterone pathway. Na/water retention leadto edema

diuretics - increase Na and waterexcretionACE inhibitors -decrease pro-duction of angiotensin II (a potentvasoconstrictor). Decreased AngIIdecreases aldosterone thus decreasingsalt and water retention

decreases preload (dec.blood volume causesdecreased venous return)decreased afterload (dec.AngII causes vasodilation ordecreased PVR) anddecreased preload due to decreased aldosterone andincrease Na and waterexcretion)

increased vasculartone (increase bloodpressure) due to SNSactivation in an attemptto compensate fordecreased contractility

ACE inhibitors - decreaseproduction of AngII which is a potentvasoconstrictor Nitrovasodilators - dilate both veinsand arteries

decrease afterload due toarterial dilation (dec. PVR) decrease preload andafterload due to venous andarterial 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 a-

pyrone 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, D-

glucose, D-digitoxose, D-digitalose, D-digginose, D-sarmentose, L-vallarose, and D-

fructose. These sugars predominantly exist in the cardiac glycosides in the b-

conformation. 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 14b-

OH 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.

GlycosidePartition

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 nodeo Decreases ventricular response to atrial rateo Controls heart rate in atrial fibrillation

Slows depolarization rate of SA nodeo Decreases sinus rateo 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 stress-

induced 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-of-

the-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 β-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. http://www.youtube.com/watch?v=S04dci7NTPk&NR=1

2. http://www.youtube.com/watch?v=vlZ7R07OrR4&feature=related

3. http://www.youtube.com/watch?v=7EDo9pUYvPE&NR=1

4. http://www.youtube.com/watch?v=aktIMBQSXMo&feature=fvw

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9. http://www.youtube.com/watch?v=GERsMFWYZrw&NR=1

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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

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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