RespiratoryPharmacology_Lecture_2ndYear_2o25 2

Pharmacology of the Respiratory System

Bronchopulmonary Diseases

• Includes:
  • Asthma bronchiale
  • Chronic bronchitis
  • Emphysema
• COPD (Chronic Obstructive Pulmonary Disease):
  • Includes chronic bronchitis and emphysema.

Asthma

• Statistics:
  • 23 million patients/year
  • 12.4 million "attacks"
  • 1.8 million ER visits
  • 21 billion in healthcare costs & meds
  • >5000 deaths
• Normal Lung:
  • Efficient gas exchange
• Asthmatic Lung:
  1. Inflammation in the bronchial wall
  2. Airways bronchoconstriction
  3. Airway hyperresponsiveness
  4. Increased mucous secretion (due to edema of the mucosa)
• Consequences of untreated asthma: Reversible airways obstruction with possible chronicism and progressive inflammation.

Immunopathogenesis of Asthma

• Early reaction and late reaction phases.
• Involves various cells and mediators including mast cells, smooth muscle, T lymphocytes, eosinophils, neutrophils, IL4, IL5, PGD2, histamine, LTC4, TNF, tryptase, ECP, MBP, PAF, proteases, TGF, and GM-CSF.
• Allergen triggers release of mediators leading to inflammation and bronchoconstriction.

Pathomechanism of Asthma

1. Immune response to allergen:
   • Genes predisposing to allergies & lack of TH1 stimulation → Increase of TH2 expression→ Secretion of IL4-13 → Activation of B cells→ Releasing of IgE & some of them link to high-affinity IgE receptor.
2. Acute allergic inflammation of the airways:
   • Early stage:
     • Allergen + IgE (attached on mast cells)→ mast degradation with the releasing of:
       • Eosinophils chemotactic factor (ECF)
       • Histamine→ incr. mucous secretion, airways edema and bronchoconstriction
     • Other important factors in bronchoconstriction and mucous secretion are LTB4, LTC4, LTD4, TXA2, PGD2 and PGF2!
   • Late stage response:
     • Due to the cellular infiltrate (eosinophils, mast cells, dentritic cells, basophils and neutrophils) that maintains the response
3. Chronic inflammation of the airways:
   • Main cellular unit in this phase is the eosinophil!
     • The eosinophils → secr. ROS (reactive oxygen species)→ cytotoxic effects on bronchial epithelium
     • The eosinophils → secr. LT => stimulates:
       1. remodelling
       2. edema and mucus production
       3. bronchocostriction (and eos. stimulate it’s maintaining too)

Airway Remodeling

1. Muscular hypertrophy and hyperplasia
2. Mucus gland hypertrophy & Goblet cells hyperplasia
3. Vasodilation of lamina propria

Asthma - Short Pathomechanism

• Allergen → Mast Cell Mediators (Histamine, Leukotrienes, Prostaglandins, Interleukins)
• Inflammatory cell recruitment (Eosinophils, Leukocytes, Macrophages) → Mediators (Cytokines, Interleukins, Leukotrienes) → INFLAMMATION
• Triggers (Cold air, Exercise, Tobacco smoke, Other smoke, Pollutants) → BRONCHOSPASM & Bronchial hyperreactivity
• Inflammation and Bronchospasm lead to Airflow Limitation

Medications Used for Asthma Relief

• Quick Relief (Rescue):
  • Provide relief of acute asthma episodes
  • Bronchodilators
• Long-term Control:
  • Control and prevent asthma symptoms
  • Make airways less sensitive to triggers and prevent inflammation that leads to an acute asthma episode (Immunomodulatory)
  • Taken on a daily basis
  • Includes: Corticosteroids (inhaled, I.V.), Long-acting β2-agonists, Sustained-release methylxanthines, Cromolyns, Anticholinergics, Leukotriene modifiers, Antagonism of IgE.

Pharmacotherapy

• Bronchodilators:
  • Adrenergic agonist
  • Selective beta2-R stimulants
  • Methylxanthines
  • Anticholinergics - Muscarinic antagonists
• Anti-inflammatory:
  • Glucocorticoids
  • Cromolyn, nedocromil
  • Leukotriene-antagonists
  • H1 -R antagonists
• Inhalatory therapy = First line

Bronchodilators

1. Adrenergic Agonists

• Older non-selective drugs:
  • Ephedrine
  • Epinephrine (still used for status asthmaticus)
  • Isoproterenol
• Newer selective Beta-2 adrenergic Agonist:
  • Fewer systemic side effects
  • Promote bronchodilation
  • Suppress lung histamine
  • Increase ciliary motility

Clinical Use of Adrenergic Agonists

• Relievers: Short-acting (SABAs)
  • Adrenaline (epinephrine), ephedrine: α, β1,β2
    • Stimulates cAMP production
  • Terbutaline, albuterol, pirbuterol, bitolterol, levalbuterol (R-albuterol): β2 > β1 (220- 400 x)
• Controllers: Long-acting (LABAs); selective β2 agonists
  • Formoterol
  • Salmeterol
  • Indacaterol
  • Olodaerol
  • Warning: increased chance of serious or fatal asthma

MoA of Beta-2 Agonists

• Beta-2 agonists act as ligands to adrenergic receptors with increased selectivity towards beta-2 adrenergic receptors.
• Activation initiates a transmembrane signal cascade involving Gs and adenylyl cyclase (AC).
• Adenylyl cyclase increases intracellular cAMP.
• cAMP activates cAMP-dependent protein kinase A (PKA).
• PKA phosphorylates Gq-coupled receptors, reducing intracellular Ca^{2+} or decreasing the sensitivity of Ca^{2+}.
• Changes in Ca^{2+} inhibit myosin light chain phosphorylation, preventing airway smooth muscle contraction.

Side Effects of Adrenergic Agonists

• Tachycardia
• Nervousness, Irritability, Tremor
• Angina
• Inhaled preparations: Less common side effects
• Oral preparations: More common side effects
• Tachydysrhythmias
• Usually dose-related; may be related to additives.

Pharmacokinetics of Adrenergic Agonists

• Duration:
  • Short acting (begin immediately, 3-5 hour dur) = SABA
  • Long acting (begin 2-30 min, 10-12 hour dur) = LABA
• Routes:
  • Inhaled
  • Oral
• Use:
  • Short acting: PRN for symptoms
  • Long acting: Fixed schedule (NOT PRN EVER)

Drugs

• Short acting:
  • Albuterol (Proventil, Ventolin): Metered Dose Inhaler(MDI), nebulization
  • Levalbuterol (Xopenex): neb only
  • Bitolterol (Tornalate): neb only
  • Pirbuterol (Maxair): neb only
• Long Acting:
  • Salmeterol (available only in combination)
  • Formoterol (Foradil Aerolizer): DPI
• Oral:
  • Albuterol: Tablets, Extended tabs, syrup
  • Terbutaline: Tablets
• INN - salbutamol
• USAN - albuterol

Dosing of Albuterol

• MDI:
  • Usually 1-2 puffs Q 4-6 hrs
  • Deep exhale
  • Inhale and puff
  • Hold breath for slow ten count
  • Exhale slowly
  • Wait one minute before second puff
  • Use spacer
• Dry Powder:
  • Usually one inhalation, not a puff
  • One smooth continuous inhalation

Black Box Warning

• FDA Panel: Restrict Some Top Asthma Drugs (DECEMBER 11, 2008)
• Salmeterol xinafoate (SEREVENT)
• Formoterol (FORADIL)
• Government health advisers called for restrictions on some long-acting asthma drugs, but spared Advair, a top-selling medication.
• News source:
  • https://www.cbsnews.com/news/fda-panel-restrict-some-top-asthma-

Summary Table – β agonists

2. Methylxanthines

• Mechanism:
  • Inhibits PDE (phosphodiesterase)
  • High levels cAMP
  • Smooth muscle relaxation
  • Inhibits IgE release of mast cell mediators
  • Competitive antagonist at adenosine (A2) receptors
  • Adenosine leads to:
    • Bronchoconstriction
    • Potentiate inflammatory mediator release
• Forms:
  • Theophylline, Caffeine (>)
  • Synthetic: Aminophylline (>theophylline) , Dyphylline, Oxtriphylline

Methylxanthines - Use, Administration, and Pharmacokinetics

• Use: Very limited (CNS stimulants)
• Administration: Oral, Inhaled, (rectal, IV)
• Pharmacokinetics:
  • Onset: Unknown
  • Effect: 1-2 h
  • Duration: Varies
• Side Effects:
  • Nausea, vomiting, anorexia
  • Cardiac effects: sinus tachycardia, extrasystole, palpitations, arrhythmia
  • Kidney: weak diuretic
  • Skeletal Muscle: increase contractions

Primary vs Other Actions

• Primary actions:
  • CNS excitation
  • Bronchodilation
• Other actions:
  • Cardiac stimulation
  • Vasodilation
  • Diuresis
• Usually considered third line.
• High side effect profile.
• Narrow therapeutic range.

Theophylline and Aminophylline

• Oral
• IV (dangerous, usually aminophylline)
• Longer duration
• Metabolized in liver, variable half-life
• Requires periodic blood level monitoring
• Toxicity: NVD, restlessness, dysrhythmias, seizures
• Interactions: caffeine, cimetidine, fluoroquinolones, other CNS drugs

3. Anticholinergics

• 1896: Asthma cigarettes
• Datura Stramonium (Jimsonweed, Weiße Stechapfel)
• Atropine, Ipratropium, and Tiotropium
• MoA: Competitive antagonists of muscarinic Ach receptors
• Clinical indications:
  • Asthma
    • Not responsive to inhaled β2 -adrenergic agonists
    • Inhaled β agonists are contraindicated (i.e. cardiac ischemia or arrhythmia)
  • Chronic bronchitis
  • Emphysema
  • COPD
  • Exercise-induced bronchospasm

Anticholinergics - Administration, Pharmacokinetics, Side Effects

• Administration:
  • A: IV, I, T: inhalation, T: oral
• Pharmacokinetics:
  • Onset: 5-15 m
  • Effect: 1-2 h
  • Duration: 4-5 h
• Side Effects:
  • Dryness of mouth and airway, headache
  • Rarely: tachycardia, dry eyes/blurred vision, urinary retention

Anticholinergic Effects

• Anticholinergic (atropine derivative)
• Approved only for COPD bronchospasm but used in asthma too
• Decrease secretions from nose, mouth, pharynx and bronchi
• Provoke a relaxing state in bronchi and bronchioles muscles
• Decrease airways resistance
• Provoke bronchodilation
• Few systemic side effects

Anticholinergic Drugs

• Ipratropium (Atrovent)
  • Onset 30 minutes; lasts 6 hours
  • MDI, Neb
  • Combivent MDI: combo with Albuterol
  • Also available intranasally for allergic rhinitis
• Tiotropium (Spiriva)
  • Newer, lasts longer
  • Dry Powder Inhaler (Handi-haler)

Antiinflammators

1. GCS (Glucocorticosteroids)

MoA: Gene regulation

• Anti-inflammatory
• Immunosuppression

GCS - Administration and Side Effects

• Administration
  • Inhaled: beclomethasone, triamcinolone, fluticasone, budesonide, flunisolide, mometasone
    • Side Effects: Oropharyngeal candidiasis, dysphonia
  • Oral (most potent): dexamethasone, prednisone
    • Side Effects: mood disturbances, increased appetite, impaired glucose control in diabetics, and candidiasis
    • Long -term use: bone resorption
  • Inhaled Prednisone
• Pharmacokinetics (inhaled):
  • Onset: unknown
  • Effect: unknown
  • Duration: 24 h
  • Warning: Poor compliance!

Discovery of Corticosteroids

• First patient with RA to be treated with Cs was 29-yrs old woman who lay bedridden following 4 yrs (widespread synovitis, severe progressive disease)
• After 3 daily i.m. injections of 100 mg hydrocortisone she was symptomless and fully ambulant with dramatic response (21-st of September 1949)
• It was a fitting conclusion to 20 years of clinical and laboratory effort by Hench et al. which earned them Nobel Prize in Medicine and Physiology (1950)
• The introduction of Cs for RA treatment was greeted with widespread enthusiasm

GCS - PK

• Rapidly absorbed from the GI tract and reversibly bound to plasma proteins
• At normal or low plasma concentration binding is largely to globulins - corticosteroid binding globuline
• At higher concentrations, there is an increase in albumin-bound and free Cs
• In hypoalbumineamic patients' highs dosages leads to high levels of free-CS and increases side-effects
• Rapidly metabolized in the liver and conjugated and excreted in the urine.
• It disappears from the blood within 1.5-3 hours, having a half-life of 1 hour

GCSs - PD

| | |
| :-------------------- | :---------------------------------------------------------------- | |
| Inhibition | PhLA2
Release of lytic enzymes
Synthesis of IL1, IL6, TNF, IF | | |
| Classification | GC/MC effect
GC and MC: Hydroc, Prednisone
GC and no MC: Dexa, Betamethasone | GC and no MC: Dexa, Betamethasone |
| Half-life | 12h: Hydro | 12-36h: Predni
36-72h: Dexa, Beta |
| Strength | Mild: Hydro | Medium: Predni
Strong: Methylpredni, Dexa |

GCS – effects. Inflammatory pathways.

• The main anti-inflammatory effect is achieved by controlling the rate of synthesis of mRNA and proteins
• Increased of lipocortin synthesis and subsequent inhibition of phospholipase A2
• Reduced production of cytokines
• Reduced activation, proliferation differentiation and migration of inflammatory cells
• Reduced inflammatory enzymes (collagenases, elastase and plasminogen activator)
• Alteration in T and B cell function (IL-1, IL-2, lL-4, IL-5, IL-6, INF-gamma)

GCS – effects. Inflammatory pathways.

• Reduction of Fc and C3 receptor expression
• Changes in white cell traffic (in 4-6 hours and return to normal by 24 hours) due to large intravenous doses, the mechanism of basopenia is not known
  • ↑ neutrophils
  • ↓lymphocytes, eosinophlis and monocytes
• Stabilization of neutrophil lysosomal membranes
• Reduced NO synthesis in macrophages

GCS – effects on different organs and systems

• MUSCULOSKELETAL – cortisone myopathy, osteoporosis - vertebral compression, fractures, aseptic necrosis of bone
• GASTROINTESTINAL – peptic ulceration (often gastric), gastric hemorrhage, intestinal perforation, pancreatitis
• CENTRAL NERVOUS SYSTEM – psychiatric disorders, pseudocereberal tumor – Decreased GABA => cortisone psychosis
• OPHTALMOLOGICAL – Glaucoma, posterior subcapsular cataracts

GCS– effects on different organs and systems

• CARDIOVASCULAR AND RENAL – hypertension, sodium and water retention-edema, hypokalemic alkalosis
• ENDOCRINE – growth failure, secondary amenorrhea, suppression of hypothalamic-pituitary adrenal system
• INHIBITION OF FIBROPLASIA – impaired wound healing, subcutaneous tissue atrophy
• BLOOD – lymphopenia, increased number and lifespan of erythrocytes

GCS– effects on different organs and systems

• METABOLISM
  • Glucose => hyperglycemia
  • Lipids => adipose tissue redistribution
  • Proteins => negative azote balance
    • Stimulation of protein catabolism
    • Myopathy, osteoporosis
  • Electrolytes => negative Ca-balance

GCS– effects on different organs and systems

• SUPRESSION OF THE IMMUNE RESPONSE – superimposition of a variety of bacterial, fungal, viral and parastic infections in steroid treated patients
  • Inhibition of release of IL1, IL2, TNF
  • Decreased release of HIS
  • Decreased antibody production
• During long treatment every patient should practice osteoporosis prophylaxis: a daily calcium intake of 1500 mg, vitamin D of 1000 IU, physical exercise, in postmenopausal women hormone replacement therapy (HRT), bisphosphonates in high risk fractures patients

GCS – effects in asthma

• Decrease release of inflammatory mediator
• Decrease infiltration and action of WBCs
• Decrease complement components
• Decrease the Histamine-mediated reaction
• Decrease airway edema
• Decrease airway mucus production
• Increase number of beta-2 receptors
• Increase sensitivity of beta-2 receptors

GSC - doses

• RA patients – 7.5 – 10 mg/daily of prednisone or metylprednisolone oral (low doses) – 20-40 mg of metylprednisolone intra-articular injections
• SLE, PAN (vasculitis) and PM/DM patients (high doses) – 1-2 mg/per kg/daily oral or pulses therapy (500-1000 mg of methylprednisolone intravenous for 3-5 consecutive days)

GCS ClinInd (Substitution)

• Addison's

GCS ClinInd (Diagnose)

• Cushing's (Dexa stimulation)

GCS ClinInd (Anti-inflammatory)

• Rheumatoid and autoimmune diseases
• Dermatological disorders: psoriasis, dermatitis
• Acute cerebral edema

GCS - ClinInd (Anti-inflammatory and antiallergic)

• Asthma
• Anaphylactic reactions
• Quincke edema, Larynx edema
• Herxheimer reaction
• Allergic rhinitis
• Allergic skin reactions
• Insect bites
• Drug induced allergy

GCS - ClinInd (Immunosuppresive)

• Autoimmune diseases
  • Autoimmune hemolytic anemia
  • Tromocytopenic purpura
  • Chronic autoimmune hepatitis
• Organ transplant
• Nephrotic syndrome

GCS - ClinInd (Lympholytic)

• Lymphomas
  Hodgkin
  Non-Hodgkin
• Acute lymphoblastic leukemia

GCS indications – extra-adrenal. Summary

• Allergic reactions
• Collagen-vascular disorders
• Eye diseases
• GiT diseases
• Systemic inflammation
• Infections
• Inflammatory conditions of joints and bones
• Nausea and vomiting
• Organ transplantation
• Pulmonary diseases
• Renal diseases
• Skin disorders
• Thyroid disorders

GCS – short half-life (Hydrocortisone)

• PK
  • Fast oral absorption, slow im absorption
  • Plasma half-life 1,5 h, tissue half-life 12h
• PD
  • anti-inflammatory, antiallergic, immunosuppressant
• ClinInd
  • Substitution
  • Emergency
  • Locally

GCS – medium half-life

• t1/2 tissue 12-36h
• GC and MC effect except Triamcinolone (no MC)
• Stronger anti-inflammatory effect as Hydrocortisone
• Prednisone – locally inactive
• Prednisolone
• Methylprednisolone (Medrol) – very potent
• Triamcinolone – very potent

GCS – long half-life

• t1/2 tissue 36-72h
• Very potent anti-inflammatory effect
• No MC effect – no salt-water retention
• Strong inhibition of the Hypoth-hypoph-corticosuprarenal axis
• High risk of cortico-dependency
• Dose high then tapered down
• Dexamethasone
• Betamethasone

GCS - Systemic vs Inhaled

• Systemic
  • Stronger effects
  • Action unaffected by lung restriction
  • More side effects, especially with long term therapy
• Inhaled
  • Localized action
  • Fewer side effects: some absorption occurs
  • Disease may prevent penetration of drug to affected areas

GCS - Inhaled Corticosteroids

• Fluticasone (Flovent) MDI
• Advair Diskus DPI (combo with salmeterol)
• Flunisolide (Aerobid) MDI
• Budesonide (Pulmicor Turbohaler) DPI,neb
• Beclomethasone QVAR (MDI)
• Triamcinolone (Azmacort) MDI
• Almost all of these also have intranasal preparations for allergic rhinitis

GCS - SE

• Hypercorticism: exogenic, endogenic
• Steroid diabetes
• Osteoporosis
• Cortisone myopathy
• Disseminated infections
• Delayed growth
• Skin atrophy
• GiT ulcer
• Psychosis
• Glaucoma, cataract
• Teratogenity
• …

GCS - Side effects

• Inhaled (gargle and use spacer):
  1. Oral candidiasis
  2. Dysphonia
  3. Thrush
  4. Cough and throat irritation accompanied by reflex bronchoconstriction
  5. Unusual local complication (ex. Perioral dermatitis, gum hypertrophy, increased thirst)
• General
  1. Adrenal suppression
  2. Gastritis
  3. Pancreatitis
  4. Visceral perforation
  5. PUD
  6. Hypokalemia
  7. Infertility
  8. Myopathy
  9. Euphoria
  10. Depression
  11. Psychosis
  12. Bone loss and avascular necrosis
  13. Slow growth in children, but not ultimate height
  14. Posterior subcapsular cataracts
  15. glaucoma
  16. Exophtalmos
  17. PUD

GCS - ContraInd

• GiT ulcer
• Heart failure
• HBP
• Osteoporosis
• Muscular dystrophy
• DM
• Psychosis
• Pregnancy
• Infection without specific therapy

Airway Changes - Before and After Treatment

• Untreated:
  • Narrowed airways
  • Constricted muscles
  • Damaged airway wall
  • Inflammation
• After treatment:
  • Widened airways
  • Relaxed muscles
  • Further damage prevented
  • Reduced inflammation

2. Cromolyns: Mast Cell Stabilizers (Cromolyn, nedocromil)

• MoA:
  • Alter activity of delayed Cl- channels (inhibiting their activation)
  • Blocks release of inflammatory mediators: mast, eosinophil, basophil, lymphocyte
  • Use:
  • Prophylactic therapy for mild- moderate allergic asthma
  • Allergic rhinitis (C)
  • Administration: Inhalation
  • Pharmacokinetics:
  • Effect: Weeks (takes weeks to see whether it is efficient or not)
  • Side Effects:
  • C: safest of all
  • Increased coughing, wheezing
  • Age matters:
  • Cromolyn: Children, adolescents
  • Nedocromil: ≥12 years

Cromolyns - Use

• Used for prophylaxis, not acute treatment
• Seasonal allergy
• Exercise induced asthma
• Can be used intranasally for allergic rhinitis
• Stabilizes mast cells
• Prevents release of histamine, inflammatory mediators
• Inhibits eosinophils, macrophages
• MDI
  • Cromolyn
  • Nedocromil

Drug Delivery & Metabolism After Inhalation

• Mouth deposition (∼90% is swallowed).
• 21% absorbed in lung (pulmonary absorption + topical effect).
• Drug goes through liver first pass metabolism.
• Drug is converted to inactive metabolite.
• Drug absorbed via GI tract absorption.

Monotherapy - Acute vs Chronic Inflammation

• Acute inflammation: Steroid provides response (treatment timeline)
• Chronic inflammation: Structural changes persist despite steroid use.

Combi-therapies

• Budesonide + Formeterol fumerate
  • Refer to each component
  • Moderate-severe uncontrolled asthma
• Fluticasone proprionate + Salmeterol xinofate
  • Refer to each component
  • Moderate-severe uncontrolled asthma

Potential New Therapies for Asthma

• Vaccines (DNA vaccine; Mycobacterium, CpG)
• Desensitization (allergen-specific immunotherapy including recombinant gene-manipulated antigens and peptides)
• Cytokine modulators (gene, protein)
  • Anti IL-4, IL-5, IL-13
  • IL-12
  • IL-10
• Selective phosphodiesterase inhibitors
• Selective tryptase inhibitors
• Potassium channel activators
• Adhesion molecule inhibitors
• Gene therapy
  • Targeting susceptibility genes
  • Targeting polymorphism of receptors for drugs
• Others

Step-wise Approach to Asthma Therapy

• Intermittent Asthma: SABA
• Persistent asthma (daily medication):
  • Low dose ICS
  • Or
  • Medium dose ICS
    • Alternatively:
      • Cromolyn
      • LTRA
      • Nedocromil
      • Theophylline
      • or Zileuton
  • Low dose ICS + LABA
    • Or
    • Medium-dose ICS + LABA
      • Alternative:
        • Medium-dose ICS + LTRA, Theophylline or Zileuton
  • High-dose ICS + LABA
    • And
    • Omalizumab for patients with allergies(?)
    • High-dose ICS + LABA + Oral corticosteroid
      • And
      • Omalizumab for patients with allergies(?)
• If a SABA is used > 2 days a week that means the treatment is not controlled properly! → Treatment escalation

COPD- Therapy

COPD

• 12 million
• 4th leading cause of death
• Year
• 26 billion / year
• >127,000 deaths
• DEFINITION: Chronic inflammatory lung disease that leads to an irreversible obstructive respiratory dysfunction

ASTHMA vs COPD

Staging COPD – GOLD (made by spirometry)

COPD Treatment

• Similar to asthma, difference is the damage that here is progressive and irreversible
• Ipratropium
• O2 in advanced disease

Cough - therapy

• Cough: Complex reflex mechanism
• Cough: Cleans airways from mucous and external agents
• R: In the bronchi
• Afferent nerve/fibre: N.Vagus, N.Laryngeus sup., N.Glossopharyngeus, N.Trigeminus
• Cough center: truncus cerebri (brain stem)
• Efferent nerve/fiber: larynx, diaphragm, intercostal muscles

Cough Mechanism

• Appears after a short, deep inhalation
• = Forced expiration with closed glottis
• Result: increased pressure in the airways, forced dilation of the glottis
• The air drifts mucus out
• The negative thoracic pressure ceases
• The filling of the right heart is inhibited

1. Cough Suppressants (Antitussives)

• Opioid – centrally acting
  • Codeine and Hydrocodone
  • Reduces cough reflex centrally
• Non-opioid
  *