Respiratory Diseases-Pharmacotherapy (Asthma and COPD)

Summary Diagrams:

Asthma and COPD drugs 3Asthma and COPD drugs 2Asthma and COPD drugs

(SABA, LABA and AMA)                                                    (Steroids)                                                                        (Other prophylatic agents)

Refer to them!!!

Class 1 and 2: SABA and LABA

SABA (selective short acting beta-2 receptor agonist)

SalbutamolSalbutamol

-Indicated for management of astham exacerbations or other Chronic obstructive airway diseases.

-Very similar in structure to terbutaline (+ Unlike terbutaline, salbutamol exhibits less cardiac stimulation and more prolongefd bronchodilation than isoproterenol or metaproterenol).

 

(a) Salbutamol

Mechanism of action: Stimulates B2 receptors found in uterus, blood vessels, and lungs–>Bronchodilation (Reduced airway resistance and facilitates mucous drainage). Prevents mast cell degranulation

*Use as an adjunct for the treatment of hyperkalemia (Stimulates Na+/K+ ATPase pump and thus K+ excretion via kidneys).

-Levabuterol/R-Salbutamol is commonly administered, Similar to Terbutaline structure (but exhibits less cardiac stimulation)

-Comes in the form of oral tabs and oral inhalation [More common form] (90% swallowed and goes into GIT)]

*Onset of action (oral inhalation)-5-15 mins and DOA: 2-6 hours

-If SABA is required more than 2 days a week or if significant symptoms reoccur, then start to treat persistant asthma with ICS

-ACUTE SYMPTOM CONTROL!!!

 

(b) Terbutaline

*Indications: (a) Bronchospasm in asthma, COPD (b) Premature labour

 

Note: More than 12 months use will lead to tolerance and decreased lung function

-May stimulate B2 receptors found on the heart (Affect Cardiac-Causes stimulation)

-Terbutaline is less cardiostimulatory than other B2 agonists

Note: May cause hyperglycemia, stimulate uterine relaxation and dilation of arterioles

 

2. LABA (Long acting B-agonists)

 

(a) Salmeterol (Sell me to all)

Mechanism of action: Lipophilic side chain increases hydrophobicity and side chain appears to only bind to exosite (site near B2 receptor). Binding to this exosite allows the the continuous engagement and disengagement with the receptor, thus increasing duration of action. Exosite binding contributes to salmeterol’s inhibition of late phase antigens.

Highly selective to B2

*Indications: Maintenance treatment of asthma, Prevention of bronchospasm in COPD

-Long DOA, thus twice a day dosing is possible. However OAA of salmeterol is prolonged, thus therapeutic effect is limited.

*Never use Salmeterol for Acute asthma attacks (OAA too long). Useful for prophylatic therapy.

-Administered by oral inhalation.

-Onset of therapeutic effects is measured by 15% improvement in FEV1 within 14 mins.

 

(b) Eformoterol

(c) Indacaterol

 

3. Anti-muscarinic agents

(a) Ipratropium

-Synthetic quaternary compound that is similar in structure to atropine

-Administration via nasal spray or oral inhalation (most commonly used as a bronchodilator for cholinergic mediated bronchospasm associated with COPD)

*Much less effective than B2 agonists in reducing exercise induced asthma.

Mechanism of action: Antagonises the action of Acetylcholine on muscarinic receptors in the cholinergic neurons. In airways, this ultimately reduces contractility of smooth muscle. It is not muscarinic selective!!!

Intranasal adminstration of ipratropium produces a localised parasympatholytic effect which reduces watery hypersecretion from mucosal glands (Alleviates rinnorrhea associated with rhinitis or common cold)

(BAD) *Since it is quaternary (charged), it is not readily absorbed into systematic circulation. After intranasal dosing, less than 20% ipratropium dose is absorbed from the nasal mucosa into systemic circulation.

 

(b) Tiotropium

-Long acting N-quaternary structure, selective anti-muscarinic agent (Highly SELECTIVE TO M3 receptors in smooth muscles)

-Very slow dissociation from receptors, long DOA, long half life

-improved lung function (FEV1 and FVC) significantly within 30 mins after first dose administered and improvement was maintained for 24 hours.

 

4. Inhaled Corticosteroids (ICS)

-Anti-inflammation effect. MOST POTENT AND EFFECTIVE CLASS FOR ASTHMA TREATMENT!


-Administration as a MDI with spacer (Metered dose inhaler+Spacer). *Remember to wash and rinse mouth with water, gargle and spit out after each inhalation. *Oral candidasis is a common side fungal infection due to prolonged ICS use. 

Mechanism of action: Inhibits PLA2 which prevents the conversion of Arachidonic Acid to Prostaglandins, Leukotrienes, PAF etc. Thus inflammatory mediators are reduced and downstream effects inhibited.

-Inhibits both late phase (Recruitment of eosinophils, inflammatory cells) and intermediate phases (Bronchospasm, Production of leukotrienes, chemotaxins by mast cells) of asthma.

 

Glucocorticoid comparion table (DOA, minero-effects) (Refer to slide 21 of notes)

(a) Beclomethasone

-Synthetic halogenated glucocorticosteroid

Indications: Treatment of steroid-dependent asthma, Relieves symptoms associated with asthma and non-asthma rhinitis, Prevention of nasal polyps after surgical removal

-When used intranasally, the anti-inflammatory and vasoconstrictive effects are 5000x more potent than hydrocortisone

Mechanism of action:

1. Naturally occuring hormones that suppress inflammation and immune responses when administered at pharmacological doses.

2. At the molecular level, unbound glucocorticoids readily cross into cell (lipid soluble) and binds to nuclear receptors present on the nuclear membrane. Steroid-Receptor complex taken into nucleus and gene transcription is altered. New proteins are formed and released into systemic circulation. [TIME CONSUMING-SLOW PROCESS]

3. Protein alteration: Inhibition of leukocyte infiltration at the site of inflammation (less adhesion molecules made), Less inflammatory mediators made, Suppression of humoral response (Innate)

 

*Oral inhaled corticosteroid hormones reduce the intermediate and late phase allergic response associated with chronic bronchial asthma.

4. Decreased IgE synthesis

5. Increased number of B-adrenergic receptors on leukocytes

6. Decreased Arachidonic Acid production, Downstream effects of prostaglandin and leukotriene production inhibited (Refer to top)

 

Pharmacokinetics:

-Nasal inhalation absorption. Minimal amounts absorbed systematically.

-Oral inhalation absorption. After oral inhalation, drug is absorbed rapidly from the lungs and GIT. Some absorbed into systemic circulation but not sufficient to exert systemic effects.

OAA:  Occurs in a few days but may take 1-4 weeks to reach full, maximum effect

-Without spacer, approx 10-25% of orally administered dose enters the respiratory tract. The rest is deposited into mouth and is swallowed. Thus the use of spacer increases the amount of drugs that is deposited into the lungs.

 

(b) Budesonide

-Administered either intranasally or oral inhalation. Oral dosage form (tablets) usually for symptom management in Crohn’s diasease, allergic rhinitis and asthma

-Potent glucocorticoid and weak mineralocorticoid activity.

-Intranasal budesonide allows 1x daily dosage but has a less desirable side effect profile than the other intranasal steroids

*High anti-inflammatory effect when applied topically and has low systemic effect!

Pharmacokinetics:

-After nasal inhalation, approx 20% of the dose reaches systemic circulation

-After oral inhalation or nebulisation, approximately 6-13% and 6% of dose respectively reaches systemic circulation.

 

(c) Fluticasone

-Might cause a significant decrease in adrenal cortex production of glucocorticoid.

-Medium-potency corticosteroid

Indications: Used topically to relieve the inflammatory and pruritic (itching) symptoms of dermatoses and psoriasis. Used intranasally for symptom management of allergic and non-allergic rhinitis. Oral inhalation for asthma. Used clinically in some patients for COPD.

 

Pharmacokinetics:

-Administered by intranasal inhalation.

-Most of a dose following intranasal administration of fluticasone is swallowed with metabolism in gut and partial absorption with extensive first pass-metabolism in the liver. Thus, the systemic effect is negligible.

-Absorption following topical administration is minimal.

-Oral inhalation aerosol has a systemic bioavailability of about 3% of delivered dose. Bioavailability of the oral inhalation is roughly 14%.

 

 

(d) Ciclesonide

-Non-halogenated corticosteroid

*Beneficial in treating inflammatory conditions allergic rhinitis and asthma. May be beneficial in treatment of COPD.

-Low systemic bioavailability (Intranasal and oral inhalation). This limits systemic effects such as cortisol suppression.

*Administered by intranasal or oral inhalation. Oral bioavailability is negligible.

 

Pharmacokinetics:

-Ciclesonide is a produg drug with an active metabolite des-ciclesonide (100x-120x more potent)

-Esterases in the nasal mucosa hydrolyse ciclesonide to a biologically active des-ciclesonide

-Des-ciclesonide undergoes furthur metabolism in the liver via CYP3YP (MAJOR) and CYP2D6 (Minor)

-OAA: (Intranasal) 24-48 hours, with additional effects observed in 1-2 weeks for those with seasonal allergic rhinitis and 5 weeks in those with perennial allergic rhinitis.

 

 

(e) Hydrocortisone/Cortisol

(f) Prednisolone (Active metabolite), Prednisone (Prodrug)

-Prednisolone, including derivatives, are synthetic glucocorticoids used as an anti-inflammatory or immunosuppressive agent.

-(Opthalmic solutions) Can be used to treat allergic various inflammatory eye conditions.

*Can be administered with systemic corticosteroids for the maintainence treatment of uncontrolled persistant asthma

-Once stablisation of asthma is achieved, dose should be reduced or eliminated due to side effects associated with chronic use.

 

 

 

5. Cromones

(a) Sodium cromoglycate

Mechanism of action: Inhibits antigen induced bronchospasm. Prophylatic agent in the treatment of mild to moderate asthma. Intranasal inhalation to treat seasonal allergic rhinitis. Opthalmic solution to treat allergic and vernal conjunctivits.

Oral treatment for mastocytosis (too many mast cells in the body) and ulcerative collitis.

*Approved for use in adults and children as young as 2 years of age.

*An alternative to ICS in the treatment of mild persistent asthma.

  • Mechanism of action: Cromolyn works at the surface of the mast cell to inhibit its degranulation (Mast cell stabilisation occurs). This prevents release of histamine, slow reacting substance of anaphylaxis (SPS-A) and mediators of Type 1 allergic reactions.

-May reduce the release of inflammatory leukotrienes. However, it does not interfere with the binding of IgE to the mast cells or antigen to IgE.

-They can reduce hypersensitivity of the bronchi and asthmatic responses to environmental triggers.

-It is not a bronchodilator. Largely prophylatic actions.

 

  • Pharmacokinetics:

-Systemic bioavailability of oral cromolyn is 1%. However, it is still administered orally to treat systemic mastocytosis and ulcerative collitis. 

-Minimal systemic absorption occurs after intranasal and opthalmic use.

-Roughly 5%-10% of an inhaled dose reaches lungs [Amount that reaches lungs depends on extent of bronchoconstriction present]

-Several weeks of therapy may be required before improvement is obvious (hence 1 month wait to see improvements when administered ocularly)

 

 

(b) Nedocromil Sodium

*Mast cell stabiliser

-Available as opthalmic solution (For allergic conjunctivis). Available as oral inhalational aerosol (Respiratory anti-inflammatory agent for the long-term treatment of mild-moderate asthma).

*Nedocromil is an alternative to ICS in the treatment of mild persistent asthma in children 5 years of old.

-Actions similar to cromoglycate.

  • Mechanism of action:

-Although both nedocromil and cromoglycate works similarly (inhibits mast cell degranulation), nedocromil PREVENTS BRONCHOCONSTRICTION primarily (at lower doses than cromoglycate)

-Interferes with mast cell degranulation thus histamine not released. However it does not inhibit chemotaxis of eosinophils by PAF and LTB4.

-Inhibits the activation and release of PAF, leukotriene B4 and histamine from mast cells.  ***NOTE: PAF and Leukotriene B4 causes acute bronchoconstriction and increased vascular permeability (late phase of allergen-induced asthma).

-Prevents migration and recruitment of eosinophils, neutrophils, macrophages and platelets that causes airway inflammatory changes.

Does not interfere with binding of antigen to IgE or IgE to mast cells.

 

  • Pharmacokinetics

-Administered via oral inhalation or by ocular administration.

-Systemic bioavailability of inhaled nedocromil is approximately 6% to 9%

-After ocular administration, less than 4% of the total dose of 2% is systemically absorbed [Absorption is mainly through the nasolacrimal duct]

 

 

6. Leukotriene antagonists

(a) Montelukast (Prophylatic agent)

-Prophylatic agent and chronic treatment of asthma and allergic rhinitis.

-Alternative but not preferred substitute for ICS in treating mild persistent asthma.

-Efficacy shown in children as young as 12 months old and infants as young as 6 months old for allergic rhinitis.

*Available in tablet form (chewable tablet) and oral granule formulations.

 

  • Mechanism of action: Potent and selective antagonist of the receptor CYSLT1 receptor found in airways.

-Mast cells and eosinophils release LTD4, LT4, LTE4 (Bronchoconstrictors). Montelukast inhibits LTD4 from binding.

-Leukotrienes cause increased endothelial membrane permeability, peripheral edema, smooth muscle contraction and hypersecretion of viscous mucus

.-They are also associated with symptoms of allergic rhinitis (e.g. sneezing, nasal itching, rhinitis and late-stage congestion)

Montelukast inhibits both early and late-phase bronchoconstriction due to antigen challenge. Also helps in alleviating the above symptoms.

 

  • Pharmacokinetics

-Administered orally. Chewable tablet has an oral bioavailability of 63% (after being reduced by food). However, the clinical efficacy is not affected!

*ALL ORAL FORMS OF MONTELUKAST MAY BE TAKEN WITHOUT REGARD TO FOOD (i.e. taking after, before, during food is allowed)

-It is 99% bound to serum albumin.

-Undergoes extensive first pass metabolism in the liver via CYP3A4 and CYP2C9. Half life is 2.7-5.5 hours in average healthy, young adults.

(b) Zirfirlukast

 

 

7. Anti-IgE antibodies

 

Omalizumab

-First monoclonal humanised (chimaeric) antibody directed against IgE. Treats moderate to severe allergic asthma (i.e. due to allergens)

-Addition of this drug to patient’s drug regimen reduced the frequency of allergic asthma exacerbations. More patients can also discontinue or reduce dosage of corticosteroids.

*Anaphylatic shock may/may not develop after first dose or during ongoing treatment.

  • Mechanism of action:

-Binds to human IgE antibody (Fc-Constant region). This prevents the binding of IgE to various cells (BUT NOT ANTIGEN). Antigen can still bind to IgE.

-Omalizumab thus lowers free serum IgE concentrations (more than 90% decrease)

-Avoiding the bridging between IgE and cells prevents Ag-Ab induced cross-linking or receptors. No degranulation of mast cells occur, no inflammatory mediators produced.

-Suppresses eosinophil induced sputum and blunt both early and late phase allergic responses.

 

  • Pharmacokinetics:

-Administered by subcutaneous (SC) injection. Every 3 weeks, 1 injection.

-Serum free IgE levels are reduced in a dose-dependent manner within 1 hour of the first dose of omalizumab and are maintained between doses.

 

Pros: The IgE levels do not return to pre-treatment levels after discontinuation of Omalizumab (up to 1 year)

-Slow elimination t1/2 is 22+/- 9 days

 

 

8. Methylxanthine derivatives

(a) Theophylline

-Used both orally and IV to treat asthma and bronchospasm.

*Narrow therapeutic range-Thus careful monitoring of serum levels is required!

  • Mechanism of action:

1. Believed to inhibit PDE 3 and PDE 5 in smooth muscle cells. Thus, cAMP levels increase and less Ca2+ is formed–>Vasodilation.  However, other PDE inhibitors (e.g. dipyridamole, papaverine) don’t have a bronchodilating effect…(suggests an alternative mechanism)

2. Adenosine antagonism. Adenosine is a CNS stimulant, thus antagonising it will stimulate the medullary respiratory centre (increases sensitivity to carbon dioxide)

3. Inhibition of histamine release

4. Can stimulate cardiac and skeletal muscle (Opposite effect to smooth muscles)

 

  • Pharamokinetics:

-Children more than 1 years of age and adults metabolise theophylline hepatically via CYP1A2, 2E1 and 3A4

-Forms active metabolites (caffeine and 3-methylxanthine)

 

***Monitoring Parameters

-Monitor heart rate, CNS effects (insomnia and irritability), respiratory rate

-Patients often have elevated respiratory rates (due to increased sensitivity to Carbon dioxide)

 

Reference Range– Asthma (5-15 mcg/ml)–>Therapeutic Range                   >20mcg/ml–>Toxic

(b) Aminophylline

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