SYSTEMIC PHARMACOLOGY (RESPIRATORY)

General Introduction

Respiratory system is subjected to a lot of injurers and harms because it is nearly the only system which is in continuous contact with the external environment during the whole life of human being. As a result respiratory system is subjected to pollution smoke, chemicals dust, & microorganism which means it is subjected to everything in the environment.

In particular, I will focus on:

1) Agents used in the treatment of cough (antitussives and expectorants)

2) Agents used as decongestants

3)Agents used in the treatment of asthma and
4)Agents used in the treatment of chronic obstructive pulmonary disease (COPD).

RELIEF OF COUGH

Two types of cough:

- Productive: leads to removal of sputum from the lungs

- Dry cough: no removal of sputum

Treatment of cough mainly consists of treating the underlying cause. A productive cough should not be suppressed except in special circumstances (eg, when it exhausts the patient or prevents rest and sleep) and generally not until the cause has been identified.

Suppressing a productive cough is less advisable because sputum needs to be cleared.

Cough remedies are categorized as antitussives and expectorants.

• Antitussives: Codene, Dextromethorphan

 Either centrally or peripherally acting. Centrally acting antitussives inhibit

or suppress the cough reflex by depressing the medullary cough center or associated

higher centers through sensory inputs from afferent nerves that are stimulated by airway irritation and inflammation. The most commonly used drugs in this group are dextromethorphan and codeine. Other centrally acting antitussives include chlophedianol, levopropoxyphene, and noscapine in the non-narcotic group and hydrocodone, hydromorphone, methadone, and morphine in the narcotic group.

Dextromethorphan is technically not considered an opiate because it does not bind to traditional opiate receptors and is not addictive or analgesic. It is the d-isomer of levorphanol. The l-isomer of levorphanol has addictive and analgesic properties. It does not depress respiration in usual doses, extremely high doses may depress respiration. No evidence of tolerance has been found during long-term use.

Codeine, is methylmorphine; methylation of morphine significantly improves the oral bioavailability by reducing the first-pass effect.It has antitussive, analgesic, and slight sedative effects, is especially useful in relieving painful cough. It also exerts a drying action on the respiratory mucosa that may be useful (e.g., in bronchorrhea) or deleterious (e.g., when bronchial secretions are already viscous). At doses used for cough suppression, codeine has minimal respiratory depressant effects. Nausea, vomiting, constipation, tolerance as well as analgesic effects and physical dependence can occur, but potential for abuse is low.

Morphine is an effective antitussive at doses lower than the doses that produce analgesia and sedation. It is not commonly used for antitussive activity due to adverse effects and the potential for abuse and addiction. Morphine has poor oral bioavailability due to a significant first-pass effect by the liver.

Hydrocodone is chemically and pharmacologically similar to codeine but more potent. It is combined with an anticholinergic drug (homatropine) to discourage abuse by people.

Peripherally acting antitussives may act by reducing the input of stimuli by acting as a mild analgesic or anesthetic on the respiratory mucosa, by modifying the output and viscosity of the respiratory tract fluid, or by relaxing the smooth muscle of the bronchi in the presence of bronchospasm. Peripherally acting agents are grouped as demulcents, local anesthetics, and humidifying aerosols and steam inhalations.

Demulcents are useful for coughs originating above the larynx. They form a protective coating over the irritated pharyngeal mucosa. They are usually given as syrups or lozenges and include acacia, licorice, glycerin, honey, and wild cherry syrups.

Local anesthetics (e.g., lidocaine, benzocaine, hexylcaine hydrochloride, and tetracaine) are used to inhibit the cough reflex under special circumstances (e.g., before

bronchoscopy or bronchography). Benzonatate, a congener of tetracaine, is a local

anesthetic; its antitussive effect may be due to a combination of local anesthesia, depression of pulmonary stretch receptors, and nonspecific central depression.

Humidifying aerosols and steam inhalations exert an antitussive effect by acting as a demulcent and by decreasing the viscosity of bronchial secretions. Inhaling water as an aerosol or as steam, with or without medicaments (sodium chloride, compound benzoin tincture, eucalyptol), is the most common method of humidification. The efficacy of added medicaments has not been clearly proved.

• Mucolytics and Expectorants: Iodides, Guaifenesin

Mucolytic and Expectorant drugs are used to increase the output of bronchial secretions, enhance the clearance of bronchial exudate, and promote a productive cough.

Mucolytic drugs are designed to help loosen/break up the disulphide bonds on mucoprotein through the free sulfhydryl group they posses, thus making mucus less viscous/sticky by altering the mucin-containing components. Expectorants help expel bronchial secretions from the respiratory tract by increasing the amount of respiratory tract fluid, thus decreasing their viscosity and facilitating the removal.

The most common type of mucolytic is N-acetylcysteine. Another type is dornase alfa (the new highly purified recombinant human deoxyribonuclease I (rhDNase), seems likely to become important in the treatment of cystic fibrosis, although its place has not been defined).

Examples of Expectorants includes Iodides (Potassium iodide been the most common) and Guaifenesin.

Iodides are used to liquefy tenacious bronchial secretions (e.g., in late stages of bronchitis, bronchiectasis, and asthma). A saturated solution of potassium iodide is the least expensive, most commonly used preparation. Their usefulness is limited by low patient acceptance because they have an unpleasant taste and because side effects (e.g., acneiform skin eruptions, coryza, erythema of face and chest, painful swelling of the salivary glands) are common. The side effects are reversible and subside when the drug is stopped. Iodinated glycerol is better tolerated than potassium iodide solution but is probably less effective. Prolonged use of iodides or iodinated glycerol can lead to hypothyroidism.

Guaifenesin (glyceryl guaiacolate) is a centrally acting muscle relaxant that may also have an expectorant effect. It may stimulate bronchial secretions via vagal pathways. The volume and viscosity of bronchial secretions does not change, but particle clearance from the airways may accelerate. It is a common component of human cold remedies in combination with dextromethorphan. It has no serious adverse effects, but there is no clear evidence of its efficacy.

Many other traditional expectorants include the volatile oils, such as eucalyptus oil and oil of lemon. They are believed to directly increase respiratory tract secretions. Their efficacy is doubtful and not well proven.

 

DECONGESTANTS

These agents are all B₂-adrenergic agonists and are commonly used in people for allergic rhinitis. The α-adrenergic agonist drugs cause local vasoconstriction in mucous membranes, which reduces swelling and edema. They are used topically as nasal decongestants in allergic and viral rhinitis, or systemically in combination with antihistamines as respiratory tract decongestants.

• Short-acting (topical) decongestants: Delivered as nasal sprays, these agents have the benefit of avoiding deleterious side-effects of systemic introduction of B₂-agonists. The most commonly used short-acting agonist decongestant is phenylephrine. Repeated topical use of these compounds can lead to down-regulation of the receptors, and subsequent rebound hyperemia in the nasal blood vessels.

• Long-acting (systemic) decongestants: Used for prolonged duration of action, with an increased potential for systemic side-effects (hypertension, cardiac stimulation, urinary retention, CNS stimulation, and mydriasis). Systemic administration of antihistamines often causes sedation. Psuedoephedrine is the most commonly used long-acting B₂-agonist decongestant. Other agents such as ephedrine and phenylpropanolamine were formerly used, but they have been withdrawn from the OTC market.

  

TREATMENT OF ASTHMA

Asthma is a common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Common symptoms include wheezing, coughing, chest tightness, and shortness of breath.

Pathophysiology of Asthma

-Clinically characterized by recurrent, episodic bouts of coughing, wheezing, and shortness of breath/dyspnea (quantitated by a reduction in FEV1)

-Physiologically characterized by increased responsiveness of trachea and bronchi to various stimuli and by widespread narrowing that changes either spontaneously or in response to therapy.

-Pathologically characterized by contraction of airway smooth muscle, mucosal thickening from edema and cellular infiltration.

 

Figure 5: Before and After Asthma Episode

Pathogenesis of Asthma

-Mediated by IgE antibodies bound to mast cells in airway mucosa

-Following an initial exposure to allergen; which can be by inhalation (of pollen, mold, dust mites etc), ingestion (swallowing a type of food mostly sea foods, or medication), touch (with poison ivy, latex or certain metals such as nickel) or by injection (receiving a medication or being stung by an insect); the body produces IgE designed specifically for that particular allergen, but wont experience reaction yet. The IgE binds to special receptors on mast cells, hence the system is said to be sensitized.

-Re-exposure to allergen/antigen (pollen, fur, etc.), antigen-antibody reaction triggers the release of mediators stored in mast cell granules and synthesis and release of other mediators.

-Early mediators include: histamine, tryptase and other neutral proteases, leukotrienes (LTC4, LTD4) and prostaglandins; these mediators cause airway smooth muscle contraction and vascular leakage. Late mediators include: GM-CSF, interleukins (IL4, IL5); these late mediators attract and activate eosinophiles and stimulate IgE production. Released mediators also activate neural pathways that can result in the release of compounds such as ACh at smooth muscle by vagal efferents resulting in contraction.

Therapeutic Approach to Asthma

From the various steps involved in the process, there are several points of attack:

-preventing mast cell degranulation

-reducing bronchial responsiveness

-relax airway smooth muscle

All three approaches are in current use.

• Mast cell stabilizers: Cromolyn & Nedocromil

-Since chloride channels are involved in the process of mast cell activation. Cromolyn sodium and nedocromil sodium are chloride-channel blockers that modulate mast cell mediator release and eosinophil recruitment.

-Effective only when used prophylactically

-Cannot reverse bronchospasm or alter bronchial tone

-Poorly absorbed from the gut, so delivered topically by inhalation of a microfine powder or aerosolized solution.

-Can also be used as a nasal spray to reduce symptoms of allergic rhinitis

-Very few side effects, presumably due in part to the localized application of the drugs

• Methylxanthines: Theophylline, Aminophylline

-They act by reducing the breakdown of cAMP through the inhibition of phosphodiesterases

-cAMP has bronchodilator activity through increasing the rate in inactivation of MLCK, an important component in smooth muscle contraction.

 -Methylxanthines are taken orally, and this can lead to a number of side-effects due to increases in [cAMP] in a number of other systems: CNS (nervousness and tremor), Cardiovascular (tachycardia and palpitation), GIT (nausea, vomiting, and diarrhoea), and Renal (diuretic activity)

- Theophylline is well absorbed from the gut and it is extensively metabolized in the liver; differences in the hepatic metabolism are the principle reason for the wide variation in kinetics both between individuals and within the same individual during the course of illness.

-Average t1/2 in adult is about 8-12hr so it is given 2-3 times daily

-No longer used as a first-line therapy

• Sympathomimetic Agents: B₂ Adrenoceptors agonists or stimulants

Salbutamol:

- Agents as salbutamol, terbutaline and fenoterol are selective stimulants of B₂ receptors; they act on these receptors in bronchi and small airways and on mast cells resulting in relaxation of bronchial smooth muscles and stabilization of mast cells. They cause fewer side effects on heart than adrenadine or isoprenaline which are non-selective (obsolete).

- Salbutamol is best given by inhalation because: It permits direct delivery of the drug to the site of action, it reduces the possibility of general systemic side effect, and it provides large surface area for absorption and rapid onset of action.

- Salbutamol has a relativity long duration of action of about 4 hours or even longer

- Tremor may occur due to Stimulation of B₂ receptors.

Terbutaline & Fenoterol:

-They are selective B₂ - receptor stimulants (Agonist) with actions similar to salbutamol they are available as oral, parenteral & inhalation preparations and their adverse effects and indications are similar to those of salbutamol.

Other selective B₂ stimulants:

Albuterol (Ventolin), metoproterenol (Alupent), isoetharine, rimiterol, and reproterol

• Corticosteroids: Beclomethasone, Hydrocortisone, Prednisolone

- The mechanism of actions on the bronchi are not fully understood but are thought to work mainly via inhibition of the production of cytokines

-They have anti-inflammatory action (through inhibition of the release of inflammatory mediators from macrophages and eosinophils), so reduce the responsiveness of airways.

-They do not reverse bronchospasm

- Reduction of mucosal oedema resulting in increase airflow.

-Increase B₂ - receptor responsiveness to agonist

-Modification of immune response & stabilization of mast cells.

- In the management of airway obstruction they are given by inhalation orally and

IV according to the condition:

Inhalation:

-Steroid inhalation represent a significant advance in the management of bronchospasm because of the adverse effect associated with systemic steroid are minimized (steroids are highly toxic drugs).

-Beclomethasone & betamethasone & administered by aerosol inhalant

-Adverse effects are usually very much less than those of systemic agents but infection of pharynx & larynx with candidiasis may occur.

I.V corticosteroids:

-When there is sever unresponsive asthma, especially when there is respiratory failure. Hydrocortisone (cortisol) is given I.V.

- There is a delay in the onset of any steroid-induced bronchodilation & this occurs because the receptors of steroid are found inside cytoplasm and thus they need more time to exert their effect for this reason Hydrocortisone is not used in case of emergency in addition to that other measures should be pursued at the same time.

Oral corticosteroid:

-Patients with severe exacerbation of asthma require high doses of prednisolone by mouth after I.V hydrocortisone.

-Treatment with oral corticosteroids is usually for a fixed period only 7-10 days

• Leukotriene Pathway Inhibitors: Zileuton, Zafirlukasts

-Leukotrienes (in particular LTC4 and LTD4) are involved in the inflammatory response, so blocking their production or action can be a useful form of treatment

-Leukotrienes are synthesized from arachidonic acid via 5-lipoxygenase, and bind to receptors on target tissues to initiate inflammatory responses along with other mediators

-Blocking production with 5-lipoxygenase inhibitors has been shown to be effective in both blocking response to antigen challenge. Currently used orally-active compounds include zileuton; which possesses a short half-life; blocks antigen and exercise induced bronchospasm.

-Blocking actions of LTD4 at its receptor also reduces inflammatory response. Currently used orally active compounds include zafirlukast, montelukast. Zafirlukast prevents aspirin sensitive asthma and antigen induced and exercise induced bronchospasm and better to be used with B₂ receptor agonist (additive effect).

• Anti-cholinergic drugs: Ipratropium

-Cholinergic stimulation causes bronchoconstriction; asthmatic individuals appear to have excessive stimulation of cholinergic receptors. The anticholinergic (parasympatholytic) drugs are effective bronchodilators that act by reducing the sensitivity of irritant receptors and by inhibiting vagally mediated cholinergic smooth muscle tone in the respiratory tract.

- The parasympathetic cholinergic bronchoconstrictor effect can be blocked by the use of atropine like drugs such as Ipatropium bromide; a synthetic derivative of atropine with less anticholinergic adverse effect than atropine itself.

- It is given by pressurized aerosols or from nebulizers.

• Oxygen: High and Low cone

-When oxygen is given to supplement the amount normally present in the inspired air it should be regarded as drug.

-It is given in two forms: High cone and Low cone (Controlled: 24 %-28%)

-High cone is given to all hypoxic patients except those with established potential narcosis. It is usually delivered at the rate of 5 litres/ min or more.

-Low cone is usually reserved for patients with exacerbation of COPD with respiratory failure and may be administered by using the ventori principle to supply a calibrated inspired oxygen conc. of 24-28%.

• Respiratory stimulants: Nikethamide, Ooxapram

-Some patients with respiratory failure require intubations and artificial ventilation.

The place of respiratory stimulants is controversial. They may occasionally lead to improvement in ventilation and obviate the need for assisted respiration.

Nikethamide:

-It is a convulsant or analeptic used in sub-convulsive doses.

-Its central activity is not selective for the respiratory centre

-Its effect is transient lasting about 5 minutes.

-Adverse effects include vomiting, restlessness and convulsion.

-It may be used in respiratory depression following inappropriate oxygen therapy.

Ooxapram:

-It acts like nikethamide but it is given by continuous IV infusion

-It is used to stimulate respiration in patients who fail to ventilate spontaneously after general anaesthesia or in chronic respiratory failure with CO₂ retention.

TREATMENT OF COPD

-COPD is characterized by persistent, partially or non-reversible airflow limitation, dyspnea, cough and expectoration.

-Cigarette smoking is the most important risk factor.

-Manifests as one of three pathological entities:

a.) chronic bronchitis

b.) chronic obstructive bronchitis

c.) emphysema

-No drug treatment can affect the natural history of COPD; treatment is designed toward correction of symptoms, maintenance of lung function, and improvement of quality of life.

-Since obstruction to airflow is the most typical characteristic of COPD, bronchodilators are drugs of first choice.

-In mild forms, a short-acting B₂ agonist such as albuterol followed by the muscarinic antagonist ipratropium are used on as “as needed” basis or before exercise.

-For more severe cases, short-acting B₂ agonists with ipratropium are prescribed on a regular basis (like 3-4 times per day)

-Theophylilline is used when B₂ agonists and ipratropium are ineffective; however, due to systemic effects of theophylline; its use is declining.

-The efficacy of corticosteroids in the treatment of COPD is still under debate, but recent evidence suggests that inhaled corticosteroids, either alone or in combination with

salmeterol, can result in a significant increase in FEV1 in COPD patients. Chronic use of oral or systemic corticosteroids should be avoided.

-Leukotriene synthesis inhibitors or leukotriene receptor antagonists have not been adequately tested in COPD patients, so their use cannot be recommended at present.