Drugs ActingDrugs Acting onRespiratory System

Assoc. Prof. Ivan Lambeve-mail: itlambev@mail.bg

(Summary)

I. Drug Therapy of Bronchial AsthmaThe term asthma is derived from the Greek wordmeaning difficulty in breathing. Asthma is achronic inflammatory allergic disease: the patientssuffer with reversible episodes of airways obstructiondue to bronchial hyper-responsiveness. In the early (acute) phase there are smooth musclespasm and excessive bronchial secretion of mucus. In the late (chronic or delayed) phase, inflammationcontinues, accompanied by fibrosis, oedema and necrosis of bronchial epithelial cells.

FACTORS THAT EXACERBATE ASTHMA

The cardinal symptoms of asthma are breathlessnesswheezing, cough and chest tightness with worsening ofthese symptoms at night. In the acute attack there are ra-pid respiratory rate and tachycardia. The majority of patientssuffer with atopic extrinsic asthma, which is associatedwith exposure to specific allergen (pollen or house-dustmite) . In non-atopic extrinsic asthma the attack may bestimulated with some non-specific stimulus, e.g. chemicalirritants. In such cases, IgG and Ig antibodies circulate inthe blood but are not attached to the mast cells orbasophils. Neutrophils destroy these antigen-antibidycomplexes. As a result, the liberated lysosomal enzymes

can digest the remaining mucoproteins. Drugs whichstabilize the lysosomal membrane, e.g. GCS providerelief to these patients. In contrast, the many patientswho acquire asthma after the age of 40 years have noidentifiable external precipitating factor or immunologicalbasis for asthmatic attack. This can be described as intrinsic asthma. Many patients suffer from both extrinsicand intrinsic forms of asthma. In comparison with intrinsicasthma, extrinsic asthma is episodic and less prone todevelop into status asthmaticus. Status asthmaticusis a severe acute asthma, which is a life-threateningcondition involving exhaustion, cyanosis, bradycardia,hypotension, dehydration and metabolic acidosis.

Cardiac asthma is a bronchospasm precipitated by uncompensated congestive heart failure.

Pathophysiology of AsthmaAntigens (pollen and house-dust mites) sensitize patientsby eliciting the production of IgE type of antibodies, whichremain either circulating in the blood or become attached tothe mast cells of nasal or bronchial tissues and basophils. On re-exposure the same antigen, the resulting antigen-antibody reaction in the early phase causes degranulationof the lung mast cells and releasing of the powerfulbronchoconstrictors: histamine, 5-HT, PGD2 andcysteinyl leucotriens (LTB4, LTC4 and LTD4).

Lung mast cells also release ILs (IL-4, IL-5 and IL-13).In the late (delayed) phase of asthma, these mediatorsactivate additional inflammatory cells (eosinophils,basophils, and alveolar macrophages) which also releaseLTs and ILs.Other mediators of inflammation, in delayed phase,are: adenosine (causing bronchconstriction), neuropeptides(SP, causing mucus secretion and increase in vascularpermeability; neurokinin A, causing bronchoconstriction),PAF etc.The normal tone of bronchial smooth muscle is influencedby a balance between parasympathetic, sympathetic andnon-adrenergic–non-cholinergic (NANC) mediators activity.

Activation of M3-receptors by the release ACh results inincrease in cGMP levels and leads to bronchoconstrictionand increase in mucus secretion. β2-receptor stimulationleads to an increase of cAMP levels which results inbronchodilation.

The main NANC inhibitory neurotransmitter is NO.

The main NANC excitory transmitters are neuropeptides(neurokinin A and SP), released from unmyelinatedsensory C-fibres when stimulated by inflammatorymediators and irritant chemicals (SO2, cigarette smoke).

Classification of Antiasthmatic DrugsClassification of Antiasthmatic Drugs1. Bronchodilators1. Bronchodilators• Selective Selective ββ22-agonists:-agonists: Clenbuterol, Salbutamol, Clenbuterol, Salbutamol, Fenoterol, Indacaterol, Levosalbutamol, Salmeterol, Fenoterol, Indacaterol, Levosalbutamol, Salmeterol, TerbutalineTerbutaline• Nonselective Nonselective ββ-agonists:-agonists: Epinephrine, Isoprenaline, Epinephrine, Isoprenaline, Orciprenaline; EphedrineOrciprenaline; Ephedrine• M-cholinolytics:M-cholinolytics: Ipratropium, Tiotropium, Oxitropium Ipratropium, Tiotropium, Oxitropium• Methyl Xanthines:Methyl Xanthines: Theophylline, Aminophylline, Theophylline, Aminophylline, TheotardTheotard2. Mast Cell Stabilizers:2. Mast Cell Stabilizers: Sodium Cromoglycate, Sodium Cromoglycate, Ketotifen, NedocromilKetotifen, Nedocromil

3. Glucocorticosteroids (GCS)3. Glucocorticosteroids (GCS)• Oral:Oral: Prednisone, Methylprednisolone Prednisone, Methylprednisolone• Parenteral:Parenteral: Methylprednisolone, Betamethasone Methylprednisolone, Betamethasone• Inhalational:Inhalational: Beclomethasone, Budenoside, Beclomethasone, Budenoside, Fluticasone, TriamcinoloneFluticasone, Triamcinolone4. Inhalational 4. Inhalational ββ22-agonists/Glucocorticosteroids-agonists/Glucocorticosteroids

SeretideSeretide®® (fluticasone/salmeterol) (fluticasone/salmeterol) SymbicortSymbicort®® (budenoside/formoterol) (budenoside/formoterol)

5. Leukotriene Modulators5. Leukotriene Modulators• 5-Lipoxygenase Inhibitor: 5-Lipoxygenase Inhibitor: ZileutonZileuton• LTDLTD44-antgonists:-antgonists: Zafirlukast, Montelukast Zafirlukast, Montelukast

6. Monoclonal Anti-IgE Antibody:6. Monoclonal Anti-IgE Antibody: Omalizumab Omalizumab7. Miscellaneous:7. Miscellaneous: NO-donors, Calcium antagonists NO-donors, Calcium antagonists

Bronchodilators – relievers (β-agonists,M-cholinolytics, Methyl Xanthins) provide a rapid sympto-matic relief but they do not control the disease process.

Selective β2-agonists activate β2-receptors present on airway smooth muscle and mast cells too. These agentsrelax airway smooth muscle, inhibit the release ofbronchoconstricting mediators from the adipocytesand increase the mucociliary transport by increasing themucociliary activity.ADRs: tremor, tachycardia, desensitization/down-regulation.of β2-receptors that results in diminished responsiveness.

Adrenaline (1&2)

Gs AC

ATPcAMP

PKA Effects

Ex

In

(+)

Short acting beta-2agonists: the onsetof effect (per inhalation) begins after 3 to 5 minand continues 4–6 h:

•Salbutamol (albuterol)•Fenoterol, Terbutaline

Highly lipid, soluble long-acting agents(t1/2 12 h)

Effect: after 15–20 min, duration 12 h:•Salmeterol, Formoterol

Beta-2-agonists are available as metered-dose aerosol.

Selective β2-adrenomimetics with tocolytic effect

•Fenoterol (Partusisten: tab. 5 mg)•Hexoprenaline•Salbutamol (Salbupart)•Terbutaline

Primarily, the site of bronchodilation action of inhaled β2-adrenergicagonists is mainly the bronchiolar smooth muscle. Atropinic drugscause bronchodilation by blocking cholinergic constrictor tone,act primarily in large airways.

Anticholinergicsin asthma

•Ipratropium

•Tiotropium

Methyl Xanthines(Theophylline, Aminophylline, Theotard):

a) inhibit phosphodiesterase III (present in airwaymuscle) and IV (present in eosinophil and mast cells), the two specific isoenzymes responsible for thedegradation of cAMP; b) block the adenosine-1-receptors on airway muscleand adenosine-3-receptors, present on mast cells.The main use of methyl xanthins is in the managementof asthma and COPD (Chronic Obstructive PulmonaryDisease), usually as combination therapy withbeta-2-agonists.

Glucocorticosteroids provide long-termstabilization of the symptoms due to their anti-inflammatoryeffects. Inhaled GCS, along with beta-2-agonists are thefirst choice drugs for chronic asthma. GCS inhibit the release of PGs and LTs and thus preventsmooth muscle contraction, vascular permeability andairway mucus secretion.GCS produce eosinopenia which prevents cytotoxic effectsof the mediators released from eosinophils.GCS enhance beta-2-adrenergic response by up-regulatingthe beta-2-receptors in lung cells and leuckocytes. Severalhours are required for DNA transcription and RNAtranslation to occur after administering GCS.

The anti-inflammatory actions of GCS are mediated bystimulation of synthesis of lipocortin, which inhibits pathwaysfor production of PGs, LTs and PAF. These mediatorswould normally contribute to increased vascularpermeability and subsequent changes includingoedema, leucocyte migration, fibrin deposition.

HydrocortisoneHydrocortisone

PrednisolonePrednisolone

NonfluorinatedNonfluorinatedprednisolonesprednisolones

Fluorinated prednisolonesFluorinated prednisolones

MethylprednisoloneMethylprednisoloneBetamethasone, DexamethasoneBetamethasone, DexamethasoneFluticasone, Triamcinolone Fluticasone, Triamcinolone

The most used glucocorticoidsThe most used glucocorticoids

• Cushing’s syndrome• Osteoporosis• Tendency to hyperglycaemia• Negative nitrogen balance• Increased appetite• Increased susceptibility to infections• Obesity etc.

Adverse effectsof GCS

Cushing’ssyndrome

Leukotriene Modulators

Metabolism of arachidonic acid via 5-lipoxigenasepathway yields the cysteinyl LTs – C4, D4 and E4,which activate cysteinyl leukotriene receptors tocause bronchoconstriction, stimulate mucussecretion and increase capillary permeability, leadingto pulmonary oedema. Zileuton (p.o.) inhibits the 5-lipoxigenase and blockssynthesis of LTs.Zafirlukast, Montelukast and Pranlukast (new agent)block cysteinyl LT-receptors and used withinhaled GCS in poorly respond asthmatic patients.

Arachidonic acidArachidonic acid

5-Lipoxigenase5-Lipoxigenase

Leukotrienes (LTs)Leukotrienes (LTs)

LTCLTC44--receptorreceptor

LTDLTD44--receptorreceptor

LTELTE44--receptorreceptor

Montelukast, ZafirlukastMontelukast, Zafirlukast

((––))((––))((––))

Cromoglycate – per inh. (Cromolyn – USAN)Ketotifen (p.o.)Nedocromil – per inh.

Mast cell stabilizers prevent transmembrane influxof calcium ions, provoked by antigen-IgE antibodyreaction on the mast cell membrane. They preventdegranulation and release of histamine and other autacoids from mast cells. They also inhibit leukocyteactivation and chemotaxis.

Indications: prophylactic treatment of asthma.

Monoclonal Anti-IgE Antibody

Omalizumab is a recombinant humanized monoclonalantibody. (1) It inhibits the binding of IgE to mast cells andbasophils; (3) it inhibits the activation of IgE already boundto mast cells and prevents their degranulations; (3) itdown-regulates Fc epsilon receptor-1, present on mastcells and basophils.

Omalizumab is indicated for asthmatic patients who arenot adequately controlled by inhaled GCS and whodemonstrate sensitivity to aero-allergens.

Treatment of Status Asthmaticus

It is a potentially life-threatening acute attack of severeasthma needing immediate treatment. Most oftenhospitalization is necessary.

(1) A high concentration (40–60%) of O2 is administered.(2) High doses of inhaled short acting beta-2-agonist.(3) High doses of systemic GCS (p.o./i.v.)(4) Ipratropium through inhalation.

II. Drug Therapy of Cough

The cough is a physiological useful protective reflex thatclears the respiratory pathway of the accumulated mucusand foreign substances. Many times it occurs as asymptom of an underlying disorder and needs treatment.The cough may be non-productive (dry) and productive.The productive cough is characterized by the presence ofexcessive sputum and may be associated with chronicbronchitis and bronchiectasis.

1. Antitussive Agents1. Antitussive Agents are used for the treatment are used for the treatment of non-productive cough which increases discomfort toof non-productive cough which increases discomfort tothe patients.the patients.

Centrally Acting AntitussivesCentrally Acting Antitussives(supress the cough center that mediates the cough reflex)(supress the cough center that mediates the cough reflex)• Codeine (methylmorphine)Codeine (methylmorphine)• DihydrocodeineDihydrocodeine• DextrometorphanDextrometorphan• Glaucin (GlauventGlaucin (Glauvent®®))

Perpheral Acting AntitussivesPerpheral Acting Antitussives• Prenoxidiazine (LibexinPrenoxidiazine (Libexin®® – tabl. 100 mg) – tabl. 100 mg)

Poppy

2. ExpectorantsThese drugs increase the volume or/and decrease the viscosity of the respiratory secretions and facilitate theirremoval by ciliary action and coughing.Mucokinetic Expectorants stimulate the flow ofrespiratory tract secretions by stimulating the bronchialsecretory cells (to increase the volume) and theciliary movement (to facilitate their removal). •Essential oils (oil anise, oil eucalyptus)•Syrup of Ipecacauanha (in sub-emetic doses)•Infusum of Radix Primulae•Ammonium chloride, Sodium citrate•Guaiacol and Guaifenasin (obtained from creosote wood)

Mucolytic Expectorants decrease the viscosity of mucusby splitting the disulfide (–S–S–) bonds of mucoproteins. This action is further facilitated by alkaline pH (7–9).

•Ambroxol•Acetylcystene (used also for the treatment of paracetamol intoxication)•Bromhexine•Dornase-alfa•Mesna (used also for protection of cancerogenic activity of cyclophosphamide and ifosphamide too)