Drugs for Chronic Obstructive Pulmonary Disease

Chronic obstructive Pulmonary disease Syndromes •Asthma acute episodes of reversible bronchoconstriction cause by underlying airway inflammation. • Chronic bronchitis- excessive mucus production due to hyperplasia and secreting goblet cells. • Emphysema - abnormal and permanent enlargement of respiratory air spaces of their walls with fibrosis. hyper functioning of mucus

Asthma statistics
Number of non-institutionalized adults who currently have asthma: 15.7 million
·

Number of children who currently have asthma: 6.5 million Number of hospital emergency department visits: 1.8 million · Number of deaths: 3,780

·

Genetic predisposition

Enviromental exposure

Airway inflammation Airway responsiveness Airway limitation

Asthma symptoms

inhaled allergens are ingested by a type of cell known as antigen presenting cells, or APCs. APCs then "present" pieces of the allergen to other immune system . In asthmatics, IMMUNE CELLS ARE FORMED -(TH2), The resultant TH2 cells activate the humoral immune system which produces antibodies against the inhaled allergen. Later, when an asthmatic inhales the same allergen, these antibodies "recognize" it and activate a humoral response. Inflammation results: chemicals are produced that cause the airways to constrict and release more mucus, and the cell-mediated arm of the immune system is activated.

THE FOLLOWING DRUGS ARE KNOWN TO CAUSE REACTION AMONG ASTHMATICS:

1.  2. 3.  4.  5. 

ASPIRIN aspirin sensitivity – 9 to 44% NSAIDS ACETAMINOPHEN 6 – 8% BETA-BLOCKERS Can exacerbate ACE – INHIBITORS Develop cough

Agents Used to treat COPD
I – Bronchodilators
A. Methylxanthines B.Adrenergic agonists (Sympathomimetics) C. Muscarinic antagonist (Anticholinergics)

II – Mediator Release Inhibitors
A. Cromolyn Sodium (Intal) B. Corticosteroids C. IgE BLOCKER D. Antieukotriene drugs

DRUGS FOR ASTHMA MANAGEMENT A. RELIEVERS 2. SHORT ACTING B2 AGONIST - SALBUTAMOL TERBUTALINE

B. CONTROLLERS

(MAINTENANCE)

2. MEDIATOR RELEASE INHIBITORS - CROMOLYN - INHALED GLUCOCORTICOIDS - LEUKOTRIENE MODIFIERS - MONTELUKAST -ZILEUTON

2. ANTICHOLINERGIC - IPRATROPUIM -ATROPINE

5.ORAL GLUCOCORTICOSTEROIDS
4. LONG ACTING B2 AGONIST -SALMETEROL -FORMETEROL 5. SUSTAINED RELEASE THEOPHYLLINE

Methylxanthines

Methylxanthines Caffeine Theobromine Theophylline Enprofylline

Degree of Bronchodilations

+ +

+++ ++++

(Prototype : Theophylline)

Mechanism of action 1. Inhibits cAMP phosphodiesterase which leads to ↑ cAMP – smooth muscle relaxation bronchodilation. xanthine Cyclic 3’5 AMP 5’ AMP

Cyclic AMP phosphodiesterase

2. Inhibits the re-uptake of catecholamines which can elevate cyclic AMP. Theophylline is an adenosine receptor antagonist Adenosine (endogenous mediator)

Membrane receptors

Theophylline antagonizes Adenosine

Pharmacologic Effects:
A. Respiratory system 1. Rapid relaxation of bronchial sm. Muscle – bronchodilation 2.Decrease histamine release 3.Stimulate ciliary transport of mucus 4. Improve respiratory performances by improving contractility of the diaphragm and by stimulating the medullary respiratory center.

Pharmacologic Effects:
B.Effects on other systems 1. Heart (+) chronotropic and inotropic effect cardiac stimulation Caffeine Theobromine Theophylline Enprofylline - (+) - (++) - (+++) - (++++)

Pharmacologic Effects:
B.Effects on other systems 1. Pulmonary and peripheral vasodilatation (↓ B.P) 2. ↑ alertness and cortical arousal medullary stimulation – can cause severe nervousness and seizures. 3.Stimulation of gastric acid and pepsinogen release. 4. Diuresis

Pharmacokinetics : Prototype drug Theophylline
• rapidly and completely absorb from GIT • metabolize in the demethylation liver by oxidation and

• half life – children – 3.5 hrs ; Adult – 8-9 hrs Bronchodilator effect is achieve at bld levels of 10-20 mg/ml (above this is associated with greater toxicity) * Aminophylline – is a theophylline – ethylene diamine complex

Drug Interactions
A. Drugs that ↑ theophylline effects 1. Cimetidine 2. Erythromycin , troleandomycin 3. Oral contraceptives B. Drugs that ↓ effectiveness of theophylline 1. Lithium 2. blockers 3. Barbiturates 4. Beta 5. Phenytoin Halothane - given with theophylline may result to cardiac dysrhythmias

Adverse Effects
1. Vomiting and GI bleeding 2. Cardiac arrhythmais 3. Nervousness , seizures , behavioral problems in children Clinical Uses 1. COPD 2.Apnea in pre-term infants * Initial loading dose – 5mg/kg – by infusion drip over 30 min. * Maintenance- 0.6 to 0.7 mg/kg/h * Pnts with heart or liver disease – 0.3 mg/kg/h

Beta Receptor Agonist (Sympathomimetics)
- relaxes smooth muscle by ↑ cAMP as a result of activation of adenylate cyclase. ATP

cAMP 
Adenylate cyclase Activated by Beta agonist

Agents
1. Epinephrine- given subcutaneously / aerosol 2. Ephedrine 3. Isoproterenol 4. B2 Selective a.Metaproterenol (Alupent) b.Terbutaline (Bricanyl) c.Fenoterol (Berotec) d.Pirbuterol e.Procasterol (Meptin) f.Bambuterol (Bambec) g.Salmeterol (Serevent)

Comparison of Beta – Receptor agonist on Selectivity
Beta 1 Beta 2 1. Albuterol (Ventolin) + ++++ Remarks
- highly potent - orally active - safe - less cardiac - stimulation

2.Terbutaline (Bricanyl) 3. Procaterol (Meptin)

+

+++

- more side - effects than - albuterol - more potent, - more effective - than albuterol

+

++++

Comparison of Beta – Receptor agonist on Selectivity
Beta 1 Beta 2 4. Fenoterol (Berotec) 5. Pirbuterol (Exirel) + ++++ Remarks - more selective
- for lung tissue 2x - potent than - albuterol by aerosol -long acting

+

++++

- improve cardiac

performances - more selective on lung tissue

-rapid onset more

6.Epirephrine

++++

++++

cardiac side effects ∝ activity +++

Comparison of Beta – Receptor agonist on Selectivity
Beta 1 Beta 2 7.Isoproterenol
8.Metaproterenol /

Remarks

++++

++++

- cardiac side effects
-less effective than albuterol

++

++

Alupent

Long acting beta – receptor agonist , are analogs of albuterol and are long acting(12 hrs) , more affinity to the beta 2 receptor , has slow onset of action . 1. salmeterol 2. formeterol

Adverse Effects

1. Cardiac effects – arrhythmias 2.CNS effect – stimulation 3.Skeletal muscle tremor

Anticholinergics:
Mech. of Action – competitively inhibit the effects of acetylcholine at muscarinic receptors

- block the contraction of airway sm. muscle - block ↑ in secretion of mucus in response to vagal activity. - Very effective in achieving bronchodilation in patients with hyperreactive airway disease due to vagal stimulation.

Ipratropium bromide (Atrovent)
- is a quarternary ammonium deriv of atropine that is given by aerosol. It does not cross BldBrain barrier and is poorly absorb from GIT , thus minimizing Anti-cholinergic side effects. - useful in chronic bronchitis , emphysema and in pnts who cannot tolerate Beta receptors agonist.
Combivent – combination of albuterol + ipratropium bromide

Mediator Release Inhibitors : (MRI)
• Cromolyn Na (Intal) – Mech. of action – it stabilizes Mast cell membranes and prevent release of mediators in response to various stimuli. • It inhibits both early and late Phase rxn to antigen exposure. • It inhibit release of histamine & leukotriene Dose – 20 mg inhaled 4x a day

ANTILEUKOTRIENE DRUGS
1. ZAFIRLUEKAST , MONTELEUKAST (singulair) -are selective reversible inhibitor of the cysteinyl leukotriene 1 receptor ,thereby blocking the effects of cysteinyl leukotrienes dose : ADULT -10mgs , children -5 mgs Once a day at 6 pm 2. ZILEUTON- is a selective and specific inhibitor of 5 lipoxygenase ,preventing the formation of LTB4 and the cysteinyl leukotriene Adverse effects :  Elevation of hepatic enzymes zileuton and zafirlukast are inhibitors of cytochrome P450 both drugs increases levels of warfarin 2. Headache and dyspepsia 3 . Eosinophilic vasculitis ( CHURG- STRAUSS SYNDROME )

(SEE FIG 27.6 pg 319 LIPPINCOT )

Corticosteroids
MECHANISM OF ACTION: -REDUCE THE SYNTHESIS OF ARACHIDONIC ACID BY PHOSPHOLIPASE A2 AND INHIBIT THE EXPERSSION OF CYCLOOXEGENASE 2 ( COX 2) - no direct effect on airway -decreases the number and activity of inflammatory cells . Inhaled corticosteroids  Budesonide  Fluticasone 3. flunisolide 4. beclomethasone

SIDE EFFECTS : CANDIDIASIS ; SORE THROAT Systemic corticosteroid - prednisone -methylprednisone

Action of steroids on lungs 1. reduces hyperresposiveness of airways to a variety of bronchoconstrictor stimuli ( such as allergens , cold air , and exercise ) 2 . Reverses mucosal edema 3. decreases the permeability of capillaries 4. inhibit the release of leukotrienes Advantages of using inhaled steroids Better asthma control ( fewer symptoms and flare –ups ) Decrease use of beta agonist and systemic steroids Improve lung function Reduce the need for hospitalization

Monoclonal antibodies OMALIZUMAB - IS A RECOMBINANT DNA – DERIVED MONOCLONAL ANTIBODIES THAT SELECTIVELY BINDS TO HUMAN IgE . - REDUCES BINDING OF IgE TO RECEPTORS IN MAST CELLS AND BASOPHILS - GIVEN PARENTERALY TWICE WEEKLY

EXPOSURE TO ANTIGEN AVOIDANCE ANTIGEN AND IgE on MAST CELLS CROMOLYN, STEROIDS ZILEUTON MEDIATORS ( LEUKOTRIENES , CYTOKINES,etc ) BRONCHODILATORS EARLY RESPONSE BRONCHOCONSTICTION
STEROIDS , CROMOLYN, LEUKOTRIENE ANTAGONIST

LATE RESPONSE INFLAMMATION

ACUTE SYMPTOMS

BRONCHIAL HYREPREACTIVITY

Severity of asthma exacerbations mild breathless talk alertness
Use of accessory muscle

moderate

severe
At rest , hunched forward

Respiratory arrest

Walking, can talking , lie down prefers sitting sentences
phrases

words agitated usually loud More than 60 mm Hg Less than 45 mmHg agitated usually loud
Less than 60mmHg More than 45 mmHg
Paradoxical breathing

agitated none
Moderate ,end expiratory

wheezes

absent
Cyanosis

paO2 paCO2

Normal less than 45 mm Hg

More than 45 mm Hg

intermittent Exacerbation Daytime symptom n Nighttime i symptom g h t PEFR

mild

moderate

severe
Limits activity/ sleep

brief Once a week

Affects daily activity and sleep
More than once a week

Daily

Daily
More than once a week

More than Less than 2x a month 2x a month
MORE THAN 80%

Less than once a week

MORE THAN 80%

60- 80 %

LESS THAN 60%

CLASSIFICATION OF ASTHMA BASED ON SEVERITY

Clinical (Mngt) Pharmacology
Home or OPD Mngt of Asthma A. Mild asthma ( attacks less than 2 per week) – inhaled Beta
agonist (e.g albuteral) on an “as needed basis”

B. M ILD PERSISTENCE (more than two attacks per week) 1. Acute attacks Inhaled short Beta agonist 3- 4x 2. Long term control inhaled antiflammatory – Cromolyn or inhaled
Corticosteroid – 200 – 400 mcg/day. May use a combination of inhaled long actging beta 2 agonist + corticosteroid . SERETIDE 250 DISKUS ONCE A DAY

Seretide 250 diskus –contains salmeterol xinafoate 50mcgs and fluticasone propionate 250mcgs

C. Moderate persistence ( daily attacks , PF =60- 80 % of normal ) 1. acute attacks – short acting beta2 agonist 2. long term control medium dose corticosteroid 400-800mcgs /day+ long acting beta2 agonist combination OR Seretide 250 diskus twice a day D. SEVERE PERSISTENCE ( CONTIUOUS ATTACK AND PF of less than 60% of normal ) 1. acute attacks – short acting beta 2 agonist 2. long term control high dose corticosteroid 800mcg to 1,600 mcg per day + long acting beta2 agonist combination Seretide 500 diskus –contains salmeterol xinafoate 50mcgs and fluticasone propionate 500mcgs 3. sustained release theophylline

Theophylline should be reserved for patients in whom symptoms remain poorly controlled despite combination treatment. • If above regimen is not enough to control symptoms – add an oral conticosteroid – PREDNISONE 40-50 mgs /day for 5 days - Or methylprednisolone 16 mgs every other day

Hopitalized patients if : 2. No improvement within 2-6 hrs after corticosteroid treatment 2. High risk patient (hospitalization within one year) 3. Exacerbation is severe 4. There is further deterioration despite all medications

Treatment of STABLE COPD
MILD COPD
SHORT ACTING BRONCHODILATOR

MODERATE COPD
-REGULAR USE OF MORE THAN ONE BRONCHODILATOR - INHALED GLUCOCORTICOSTEROIDS

SEVERE COPD
-REGULAR USE OF MORE THAN ONE BRONCHODILATOR INHALED GLUCOCORTICOSTEROIDS -ANTIBIOTICS -LONG TERM OXYGEN THERAPY

Other drugs for COPD Alpha1 – proteinase inhibitors (Prolastine) – use to treat emphysema caused by a deficiency in alpha1 – proteinase a peptide that inhibits elastase, in patients with the deficiency, elastase destroys lung parenchyma. Other Agents affecting the Respiratory Tract Drugs Used to treat Rhinitis 1. Antihistaminics (Hi- receptors antagonist) a. chlorpheniramine b. diphenhydramine c.loratidine
secretion and parasympathetic activity

Drugs Used to treat Rhinitis 2. µ (alpha) receptor agonist A. Nasal aerosols 1.Epinephrine 2.Oxymetazoline 3.Phenylephrine B. Administered orally 1.Phenylpropanolamine 2.Pseudoephedrine 3.Xylometazoline 4.Phenylephrine 3. Topical corticosteroids 1 .Beclomethasone (Beconase) 2. Fluticasone (Flixotide) 3. Flunisolide (Nasalide) 4. Cromolyn Na

Constrict dilated arterials in nasal mucosa

EXPECTORANTS
A. VAGAL STIMULANTS 1. GLYCERYL GUIACOLATE 2. SALT SOLUTIONS B. DIRECT STIMULANTS 1. POTASSIUM IODIDE SATURATED SOLUTION (KISS) 2. BROMHEXINE 3. CARBOCISTEINE 4. AMBROXOL

ANTITUSIVES
I. NARCOTIC ANTITUSSIVES
• • HEROIN / MORPHINE CODEINE

II. NON-NARCOTIC ANTITUSSIVES A. MORPHINAN DERIVATIVES DEXTROMETHORPHAN B. BENZYLISOQUINOLINES NOSCAPINE/ NORCEINE HYDRASTINE / HOMARYLAMINE

ANTITUSIVES
II. NON-NARCOTIC ANTITUSSIVES
C. DIPHENYLAKYLAMINES CHLOPHENDIANOL LEVOPROPXYPHENE D. PHENYLCYCLOPENTALKYLAMINES CARAMIPHEN CARBETAPENTANE E. MISCELLANEOUS BENZONATATE CLOBUTINOL DIBUNATES

CODEINE
- PHENATHRENE DERIVATIVE OPIATE AGONIST - PPC: 1 TO 2 HOURS; DURATION: 4 HRS ACTION: DIRECT EFFECT ON THE CENTER DRYING EFFECT DECREASE VISCOSITY ANALGESIC & SEDATIVE EFFECT ADVERSE EFFECT:  NAUSEA & VOMITING  CONSTIPATION  DIZZINESS  PRURITUS  TOLERANCE & PHYSICAL DEPENDENCE

DEXTROMETHORPHAN
- METHYL ETHER OR DEXTROROTATORY FORM OF LEVORPHANOL - PPC: 15 – 30 MINS; DURATION: 6 - 8 HRS - USEFUL FOR CHRONIC NON-PRODUCTIVE COUGH SIDE EFFECTS: * NAUSEA * DRYING EFFECT * DIZZINESS DRUG INTERACTIONS: * PENICILLIN *TETRACYCLINES *SALICYLATES * PHENOBARBITAL

* KISS

BROMHEXINE - SYSTEMICALLY ACTIVE MUCOLYTIC AGENT

ACTION:  Depolymerization of Mucopolysaccharide  Direct Effect on Bronchial Glands  Liberation of Lysosomal Enzymes producing cells which digest mucopolysaccharide fibers INDICATIONS:  ALL forms of TRACHEOBRONCHITIS  Emphysema with Bronchitis  Pneumoconiosis  Chronic Inflammatory Pulmonary Conditions  Bronchitis with Bronchospasm  Asthma

BROMHEXINE
SIDE EFFECT: EPIGASTRIC DISTRESS DRUG INTERACTIONS: INCREASE ANTIBIOTIC CONCENTRATION

AMBROXOL
- MUCOKINETIC & SECRETOLYTIC ACTION:  INCREASE RESP. TRACT SECRETIONS  ENHANCE PULM. SURFACTANT PRODUCTION  STIMULATES CILIA ACTIVITY IMPROVED MUCUS FLOW & TRANSPORT (CILIARY CLEARANCE FACILITATES EXPECTORATION)

AMBROXOL
USE:  SECRETOLYTIC THERAPHY IN ACUTE & CHRONIC BRONCHO-PULMONARY DISEASES ASSTD WITH ABNORMAL SECRETIONS & IMPAIRED MUCUS TRANSPORT. SIDE EFFECT:  NAUSEA & VOMITING  RASHES  CAN INCREASE ANTIBIOTIC CONC.

CARBOCISTEINE
(S-CARBOXYMETHYLCYSTEINE) - MUCOREGULATOR IN RESP. TRACT DISORDERS CHARS BY EXCESSIVE OR VISCOUS MUCUS - ACT BY REGULATING AND NORMALIZING THE VISCOSITY OF SECRETION FROM THE MUCUS CELLS OF RESP. TRACT - STIMULATES THE LESS VISCOUC SIALOGLYCOPEPTIDES AND SULFOGLYCOPEPTIDES

CARBOCISTEINE
- STIMULATES THE LESS VISCOUS NEUTRAL GLUCOPEPTIDES DUE TO ACTIVATION OF SIALYLTRANSFERASE OR INHIBITON OF NEURAMIDASE - DECREASE THE SIZE AND NUMBER OF MUCUS PRODUCING CELLS. SIDE EFFECT: GIT BLEEDING, NAUSEA, DIARRHEA, RASH, DIZZINESS, HEADACHE, PALPITATIONS

MUCOLYTIC AGENTS
ACETYLCYSTEINE: (MUCOMYST)  REDUCES THE THICKNESS & STICKINESS OF PURULENT & NONPURULENT PULMONARY SECRETIONS  BREAKS DISULFIDE LINDAGES OR BONDS OF MUCOPROTEIN MOLECULES OF RESP. SECRETIONS INTO SMALLER, MORE SOLUBLE & LESS VISCOUS STRANDS  ANTIDOTE FOR PARACETAMOL POISONING

MUCOLYTIC AGENTS
ACETYLCYSTEINE (con’t..)  BRONCHOPULMONARY DSES. i.e. CYSTIC FIBROSIS  DXs AID IN BRONCHIAL STUDIES (bronchospirometry/ bronchograms) GIVEN: INHALATION/ INSTILLATION ADVERSE EFFECTS: Hemoptysis, resp. irritation & difficulty N & V, inc temp, throat irritation

Clinical case scenario Two year ago , a 31 year old female came to your clinic complaining of paroxysmal cough accommpanied by chest tightness and shortness of breath . This occur when her family moved into a new house 4 weeks PTC. This happened 2-3 x per week and affected her sleep .