Pharmacology of Respiratory System

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					  Chapter-2 (Respiratory System)                                                     Lecture Notes (PHRM -501), CVAS, Jhang

                           Pharmacology of Respiratory System

         Functional anatomy and physiology: The respiratory system [divided into upper
         respiratory tract (including pharynx, trachea, and bronchi) and lower respiratory tract
         (including bronchioles, lungs and alveoli)], is responsible for a vital physiological
         process known as breathing (comprising of inspiration and expiration) that occurs for
         the sake of tissue oxygenation. The diaphragm also possesses a pivotal role as far
         as the process of inspiration (or inhalation) and expiration (exhalation) is concerned.
         Respiratory defense mechanism: Although the presence of an effective blood-
         alveolar barrier restricts the entry of blood-born pathogens into respiratory tract, the
         direct interaction of upper respiratory tract with environmental air favors the
         inhalatory route to be employed for the introduction of harmful agents (like
         pollutants, allergens, infectious agents etc. that are expressed as noxious stimuli,
         invade the respiratory tract and subsequently bring about anatomical and/or
         physiological alterations). To overcome this problem nature has provided the
         respiratory system with an efficient defense mechanism in terms of muco-ciliary
         apparatus and mononuclear phagocytic system (MPS). The mucus secretion
         (released by goblet cells, located in external nostrils) forms a protective layer over
         the mucous lining of the nostrils and is capable to entrap foreign particles. The
         upper respiratory tract is lined by pseudostratified columnar streociliated epithelium
         (smoking leads to progressive loss of these streocilia and hence disturbs this
         protective barrier). These cilia oppose the access of any foreign invader by virtue of
         their synchronous movement. Mononuclear phagocytic system (MPS) comprises of
         alveolar macrophages and intravascular macrophages that are meant for the
         phagocytosis (enzymatic break down) of xenobiotics.
                                               Nervous innervation of respiratory smooth muscles

   Type of efferent                Receptor      Neurotransmitter Signaling mechanism                   Response
   pathway
   Parasympathetic
                                                                          Phospholipase C -
                                                 Acetylcholine            mediated conversion of
   (Dominant pathway
                                                                          PIP2into IP3 and DAG.
   which provides                                                                                 Broncho-
                                      M3                                  These second messengers
   baseline tone of mild                                                                          constriction
                                                                          increase intracellular
   bronchoconstriction)
                                                   (ACh)                  calcium level to elicit
                                                                          cellular response.
                                                                                                        Broncho-
   Histaminergic                      H1         Histamine                Same as M3
                                                                                                        constriction
                                                                                                        Broncho-
                                      α1         Norepinephrine           Same as M3
                                                                                                        constriction
                                                                                                        Reduction of
                                                                          Inhibition of adenyl          parasympathetic
   Sympathetic
                                      α2         Norepinephrine           cyclase-mediated cAMP
                                                                          synthesis                     Broncho-
                                                                                                        constriction
                                                                          Activation of adenyl
                                      β2         Norepinephrine           cyclase-mediated cAMP         Broncho-dilation
                                                                          synthesis
   Non-adrenergic                                Vaso-active
                                    Irritant                                                            Reflex
                                                 intestinal peptide Stimulation of vagus
                                   receptors
   non-cholinergic                                                  nerve
                                    (Nose)                                                              Broncho-dilation
   (NANC)                                        (VIP)

         Bronchodilators: These drugs restore normal bronchial caliber to improve alveolar
         ventilation. They are also used to reverse broncho-constriction (caused by
         allergic/inflammatory reaction, COPD, bronchospasm or bronchial stenosis).These
         agents are preferably administered through inhalatory route (in the form of nasal
         sprays and inhalers) and are categorized into following types.
         1. Sympathomimetics (β agonists): Selective β2 agonists [Salbutamol (Ventolin),
         Terbutaline and Clenbuterol] as well as non-selective β agonists (Ephedrine,
         Pseudoephedrine and Isoproterenol) can be used to cause bronchodilation. But
Dr. Muhammad Adil                                                Page 1                                            8/31/2011
  Chapter-2 (Respiratory System)                                Lecture Notes (PHRM -501), CVAS, Jhang
         non-selective β agonists are linked with undesirable cardiac stimulation that can be
         life-threatening in animals with pre-existing tachycardia (like supraventricular
         tachycardia). The detailed pharmacology and toxicology of sympathomimetics has
         been described in chapter-1 (ANS).
         2. Muscarinic antagonists (Anticholinergics): Ipratropium, Glycopyrrolate and
         Atropine are capable to block M3-mediated broncho-constriction but they should be
         used cautiously to prevent unwanted adverse effects.
         3. Methylxanthines: This group includes both natural substances like Caffeine
         (found in tea, coffee), Theobromine (derived from Cocoa plant, present in chocolate
         and candies) and Theophylline as well as synthetic agents like Aminophylline. They
         act as competitive inhibitors of phosphodiesterase (PDE) enzyme which causes the
         intracellular degradation of cAMP (this indirect increase in the level of
         2nd messenger leads to bronchodilation). Methylxanthines also stimulate CNS,
         cardiac contractility, diuresis, gastric acid secretion (therefore these are
         contraindicated in all conditions of hyperacidity) and skeletal muscle contraction.
         Methylxanthines also block adenosine receptors to display a bronchodilatory effect.
         Primarily, Caffeine and Theobromine are used to cause CNS (cerebral cortical)
         stimulation while Theophylline and Aminophylline are prescribed as expectorants.
         Dogs are unable to properly metabolize Theobromine and commonly suffer from
         chocolate poisoning (there is no specific antidote to treat this intoxication).
         Hyperacidity, tachycardia and seizures [uncontrolled electrical activity in the brain
         (resulting from CNS stimulation), which may produce a physical convulsion, minor
         physical signs, thought disturbances, or a combination of symptoms] are possible
         adverse effects of Methylxanthines.
         4. Leukotriene receptor antagonists: Acolade is a high affinity competitive
         antagonist of Leukotriene (Leukotrienes are inflammatory mediators, released in
         response to the entry of allergens in respiratory tract, undergo receptor occupancy
         and trigger leukocytic infiltration via chemotaxis) that prevents antigen-induced
         bronchospasm.
         Pathophysiology of asthma: Asthma is a common chronic inflammatory disease of
         airways characterized by variable and chronic symptoms [including wheezing
         (continuous,      coarse,    whistling      sound),     coughing,      chest       tightness
         (bronchoconstriction), and dyspnea (shortness of breath)], reversible airflow
         obstruction, and bronchospasm. The pathogenesis of asthma can be summarized in
         the following manner.
         The entry of allergens (like pollens, dust particles and animal dander) into upper
         respiratory tract marks the initiation of this ailment by activating the first-line defense
         mechanism (muco-cilliary apparatus).
         Soon after the degranulation of mast cells results in the release of histamine that
         binds with H1 receptors.
         Membrane damage also occurs during which membrane phospholipids are
         subjected to enzymatic degradation by phopholipase A2 yielding arachidonic acid
         that is converted to prostaglandins and leukotreins.
         Infiltration of mononuclear phagocytic cells mediates chemotaxis to provoke cells
         that are involved in defense mechanism (e.g. leukocytes).
         Histamine, prostaglandins and leukotriens are all inflammatory mediators which
         cause vasodilation, bronchoconstriction and alteration of membrane permeability.
         During later phase the infiltration of cytokine-releasing T-cells and eosinophils
         further aggravate the condition by causing edema, bronchospasm and epithelial
         damage that ultimately lead to obstruction and collapse of airways.
         Anti-asthmatic drugs: These drugs are classified into following categories.
         1. H1 receptor antagonists (Antihistaminic drugs): Chlorpheniramine (Avil),
         Mepheneramine (Meprasone), Cetrizine (Zyrtec), Diphenylhydramine (Benadryl) and
         Dimenhydrinate (Gravinate) are common members of this category. They are also
         termed as anti-allergic agents as they are to relieve almost all sorts of allergic
         reactions. Diphenylhydramine and Dimenhydrinate are also applied as anti-emetics.
         Sedation is the most common side effect of antihistaminic drugs.
         2. Mast cell stabilizers: Cromoglycate (also known as Cromolyn) stabilizes the
         mast cell membrane and thus inhibits their degranulation.
         3. 5-HT2 receptor antagonists: Cyproheptadiene (basically used as appetite
         stimulant to treat anorexia) has been reported to be effective in feline asthma.
Dr. Muhammad Adil                                 Page 2                                      8/31/2011
  Chapter-2 (Respiratory System)                              Lecture Notes (PHRM -501), CVAS, Jhang
         4. Nonsteroidal anti-inflammatory drugs: Anti-prostaglandinic effect of
         NSAIDS can become advantageous to suppress inflammatory symptoms associated
         with asthma.
         5. Corticosteroids: They inhibit the synthesis of leukotriens which carry out
         leukocytic infiltration and chemotaxis. The pharmacology and adverse effects of
         NSAIDS and Corticosteroids have been discussed in detail in chapter-2.
         6. Adrenergic agonists: Selective β2 agonists [Salbutamol (Ventolin), Terbutaline
         and Clenbuterol] as well as non-selective β agonists (Ephedrine, Pseudoephedrine
         and Isoproterenol) can be used to mitigate (reduce) bronchospasm.
         7. Anticholinergic drugs: Ipratropium, Glycopyrrolate and Atropine can be used to
         induce bronchodilation and improve alveolar ventilation.
         8. Methylxanthines: Theophylline and Aminophylline are used as bronchodilators
         and expectorants.
         Allergic rhinitis (Hay fever or pollenosis): It is an allergic inflammation of the
         nasal mucosa and associated airways. It occurs when allergens such as pollens or
         dust particles are inhaled by an individual with a sensitized immune system, and
         trigger antibody production. The specific antibody is immunoglobulin E (IgE) which
         binds to mast cells and basophils containing histamine. IgE bound to mast cells are
         stimulated by pollen and dust, causing the release of inflammatory mediators such
         as histamine (and other chemicals). This causes itching, swelling and mucus
         production. Inflammatory mediators favor vasodilation that causes nasal congestion
         (passive hyperemia) and ultimately leads to rhinorhea (running nose). Fibrosis of
         nasal septum may also occur in chronic cases. The two categories of allergic rhinitis
         include: Seasonal (occurs particularly during pollen seasons) and Perennial (occurs
         throughout the year) rhinitis.
         Treatment of allergic rhinitis: Any of the following drugs can be used for this
         purpose.
         1. Nasal decongestants: Phenyleprine (selective α1 agonist) can be administered
         to cause peripheral vasoconstriction that will lead to redistribution of accumulated
         blood (and will relieve rhinorrhea). However its use should be avoided in patients
         with pre-existing mydriasis and glaucoma.
         2. Corticosteroids: They prevent the synthesis of leukotriens which perform
         leukocytic infiltration and chemotaxis. In this way the help to avoid further
         inflammatory response.
         3. H1 receptor antagonists (Antihistaminic drugs): Similar to other allergic
         conditions, allergic rhinitis is also responsive to the administration of antihistaminic
         drugs. But they should be used cautiously as their prolonged inhalatory application
         (via aerosol) can lead to rhinitis medicamentosa which is characterized by stiffness
         of the nose.
        Pathophysiology of coughing reflex: Cough is a protective mechanism for the
        removal of foreign particles/allergens or excessive secretion from respiratory tract. It
        is divided into dry cough (mediated by irritation of upper respiratory tract resulting
        from the entry of allergens) and productive cough (that arises for the expulsion of
        sputum). Therefore productive cough is considered a beneficial mechanism, is not
        commonly treated and is nevertheless induced through the use of expectorants.
        Whereas dry cough is suppressed (through the use of anti-tussive drugs) as it can
        damage lungs. The upper respiratory tract (pharynx, larynx and tracheo-bronchial
        tree) consists of chemorecptors and mechanorecptors while lower respiratory tract
        (lungs) contains stretch receptors that are sensitive to noxious stimuli (like allergens
        and excessive secretion) and transmit impulses to cough centre (located in medulla)
        by means of afferent/sensory nerves (like vagus nerve and glossopharyngeal
        nerve). The cough centre (co-ordinated with respiratory centre and vomiting centre,
        which are also present in medulla) analyzes the impulses and then transmits signals
        (via efferent/motor nerves) to thoracic, abdominal and diaphragmatic muscles for
        causing forceful expulsion of air from the lungs that leads to coughing.
        Anti-tussives: These are drugs which are used to suppress coughing (dry cough,
        commonly caused by severe bronchoconstriction) that can inflict damage to the
        lungs.
     1. Centrally acting anti-tussive drugs: These drugs act by depressing cough centre
        and are subdivided into following groups;
Dr. Muhammad Adil                               Page 3                                      8/31/2011
  Chapter-2 (Respiratory System)                               Lecture Notes (PHRM -501), CVAS, Jhang
     (a) Opiod/Narcotic anti-tussives: Morphine, Codeine (Methyl Morphine), Hydrocodone
         and Hydromorphone are included in this class. They bind to opiod receptors (in
         CNS) and depress CNS (including cough centre located in medulla). These agents
         are also used to induce sedation and analgesia. They are linked with certain side
         effects like dependence/addiction and sedation.
     (b) Non-narcotic anti-tussives: Dextromethorphan (free from addictive potential)
         increases the cough threshold set by cough centre and thus it depresses coughing.
     2. Locally acting anti-tussives: These are further divided into following categories;
     (a) Demulcents: They cause soothing effect on respiratory mucosa, reduce irritation
         and suppress coughing. Glycerine [C3H5(OH)3], Honey and Liquorice (Mulaithi) are
         examples of such agents.
     (b) Mucosal anesthetics: Benzotate desensitizes the pulmonary stretch receptors and
         blocks the sensory impulses of coughing.
     (c) Bronchodilators: Ephedrine and Theophylline can also be used to suppress
         coughing by relieving bronchospasm.
         Expectorants (Mucokinetics; muco = mucus, kinesis = movement): These drugs
         enhance the flow/fluidity of airway mucus (also known as sputum) either by
         increasing its volume or by decreasing its viscosity and thus facilitate its removal
         through coughing and ciliary action. Expectorants are used to induce productive
         cough in case of tracheobronchitis, bronchopneumonia and COPD. Expectorants
         are divided into following categories.
         1. Stimulant/Secretory expectorants: These are further subdivided into following
         types.
         (a) Direct acting stimulant expectorants: These directly stimulate the submucosal
         tracheobronchial glands to increase their secretion. Guaicol and Guaiphenesin (also
         used as skeletal muscle relaxant) are examples of such drugs.
         (b) Indirect acting (reflex acting) stimulant expectorants: They indirectly stimulate
         tracheobronchial glands via vagal reflex. Ipecacuanha (obtained from Cephalis
         ipecacuanha) is included in this class. It is basically used as emetic/nauseant but it
         can cause expectpration when used in sub-therapeutic doses. Most common side
         effects are profused salivation and lacrymation.
         (c) Mixed acting (or saline) stimulant expectorants: They utilize both mechanisms
         (direct and indirect) to induce mucokinesis. KI is orally given to treat chronic
         bronchitis but its overdosage can cause iodinism-induced goiter [excessive iodine
         inhibits its own active transport to thyroid follicle by saturating the transporter/carrier
         system. Therefore no iodination of thyroglobulin occurs inside the thyroid follicle
         (due to lack of iodine in the follicle) and deficient level of thyroid hormones in the
         blood triggers the release of thyroid stimulating hormone (TSH) from anterior
         pituitary gland (to stimulate thyroid glands) which facilitates the accumulation of
         more and more thyroglobulin in thyroid glands that leads to enlargement of thyroid
         glands (goiter)]. The use of KI is also contraindicated in lactating animals (as iodine
         will be released in milk) and pregnant animals (to avoid congenital goiter). NH 4Cl
         (ammonium chloride or Noshadar) and (NH4)2Co3 (ammonium carbonate) are also
         expectorants with similar mode of action but their overdosage leads to
         hyperammonemia followed by dypnea and pulmonary edema.
         2. Mucolytic expectorants: They cause depolymerization or hydrolysis of
         glycoprotein strands in mucus (called mucolysis) which leads to decline in mucus
         viscosity. Bromohexine and Acetylcysteine are such expectorants. Sulfhydral group
         of Acetylcysteine disintegrates disulfide bonds of mucus glycoproteins thus causing
         mucolysis. Acetylcysteine (also used as antidote of Paracetamol/Acetaminophen
         intoxication) is a precursor of Glutathione (anti-oxidant that arrests and inactivates
         reactive oxygen species (ROS) and prevents them from causing cellular damage).
         3. Diluent expectorants: These agents dilute/hydrate the airway mucus and thus
         increase its fluidity. Steam can be used to liquefy viscous sputum but it is effective
         only in case of large airways (as the size of water molecules is about 10 μm which
         cannot penetrate inside smaller airways). Application of steam is not an easy
         procedure as far as animals are concerned.
         4. Miscellaneous agents: 5% CO2 is capable to cause bronchial hyperemia that is
         followed by expectoration. Antimony Potassium Tartrate is a nauseant expectorant
         that can also be used to induce productive cough. Additionally it has been found that
         dietary usage of chili (Capsicum annum) can cause expectoration (probably by
Dr. Muhammad Adil                                 Page 4                                     8/31/2011
  Chapter-2 (Respiratory System)                             Lecture Notes (PHRM -501), CVAS, Jhang
         acting as stimulant expectorant) and application of water over the head region (and
         even bathing) can liquefy/dilute the mucus to facilitate its removal. However the use
         of chili should be avoided in persons with pre-existing gastric ulcer, hyperacidity and
         digestive disturbances (as it can aggravate the conditions).




Dr. Muhammad Adil                               Page 5                                     8/31/2011

				
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