respiratory drugs

1. Doctor RESPIRATORY DRUGS Florencia D. Munsayac, MD, MBA, RMT

A disease of the airways

characterized by hyper-responsiveness of the tracheo-bronchial tree to a multiplicity of stimuli

Manifested: physiologically bywidespread reversible narrowing of the air passages

: clinically by paroxysm of coughing, dyspnea, and wheezes

Exposure to allergensynthesis of IgE: binds to mast cells in the airway mucosa

Re-exposure to allergen/antigenAg-Ab interaction on the surfaces of themast cell triggers:

mediators of anaphylaxis: other mediators or a variety of histamine, tryptase, PGD 2 ,cytokines:

leukotriene C 4 , PAF interleukines 4 & 5, GMCSF,

TNF, TGF

contraction of the airwaysmooth muscleeosinophils & neutrophils

ECP, MBP, Protease, PAF

edema, mucus hypersecretion

increase in bronchial reactivity

smooth muscle contraction

Inhaled irritantsafferent pathways in the vagus nerves travel to the CNSefferent pathways from the CNS travel to efferent gangliapostganglionic fibersrelease acetylcholinebinds to muscarinic receptors on airway smooth musclebronchoconstriction

inhaled materialsstimulate afferent receptors to initiate reflex bronchoconstriction or release of tachynins (substance P)directly stimulate smooth muscle contraction

Aerosol delivery of drugs

Should produce a high local concentration in the lungs with a low systemic delivery-> minimizing side effects

Size of the particles: critical determinant

>10 um deposited in the mouth & oropharynx

0.5 um inhaled, subsequently exhaled

1-5 um allow deposition & most effective

Recommendation: slow, deep breath & held for 5-10 seconds

2-10%: deposited in the lung

To minimize systemic effects:

poorly absorbed from the GIT

Rapidly inactivated via first-pass hepatic metabolism

Use of a large-volume spacer

2 types of devices:

Metered dose inhalers

Advantage: cheaper & portable

Disadvantage: most contain hydroflourocarbons

Nebulizers

preferred for severe asthma exacerbations with poor inspiratory ability

Advantage: not requiring hand-breathing coordination

Can be delivered by face-mask to young children & elderly

Oral administration: Beta Adrenergic Receptor Agonists

Has not gained wide acceptance

Side Effects: tremulousness, muscle cramps, cardiac tachyarrhythmias, metabolic disturbances

2 primary situations in which oral B adrenergic agonists are used:

Brief courses of oral therapy are well tolerated & effective in young children who cannot manipulate metered-dose inhalers

Local irritation with the use of aerosol preparations

Parenteral administration

Indication:

Severe asthma requiring emergency treatment (when aerosolized therapy is not available or has been ineffective)

Directly relax airway smooth muscle by activating G sadenylyl cyclase-cAMP in the airway tissues that results in bronchodilatation

Increase the conductance of large Ca+2-sensitive K+ channels in airway smooth muscle -> hyperpolarization & relaxation

Inhibit release of inflammatory mediators & cytokines from the mast cells, basophils, eosinophils, neutrophils, & lymphocytes

Increase mucociliary transport

Short-acting:

Used only for symptomatic relief of asthma

Terbutaline, albuterol, levalbuterol, metaproterenol, pirbuterol

inhaled drugs:

onset of action: 1-5 min.,

Peak effects: 15-30 min.,

Duration of action: 2 6 hours

Terbutaline, albuterol, metaproterenol

oral form:

DOA: 4-8 hrs.

Terbutaline

parenteral form (0.25mg SC)

Long acting:

Salmeterol, formoterol

Given by inhalation

DOA: 12 hours or more

Interact with corticosteroids to improve asthma control

Salmeterol-fluticasone

Formoterol-budesonide

Not recommended as the sole therapy for asthma

Used prophylactically in the treatment of asthma

Epinephrine

Rapid acting

Injected SC or inhalation

Onset: 15 minutes

DOA: 60-90 minutes

SE: tachycardia, arrhythmias, worsening of the angina pectoris

Ephedrine

Longer duration of action

Orally/parenterally administered

Lower potency

More pronounced central effects

Isoproterenol

Onset: 5 minutes

DOA: 60-90 minutes

SE: cardiac arrhythmias

Caffeine (1,3,7-trimethyxanthine)

Theobromide (3,7-dimethylxanthene)

Theophylline (1,3-dimethylxanthine)

Most commonly used

Derivatives:

Aminophylline

Dyphylline

oxtriptylline

Mechanisms of action:

inhibit cyclic nucleotide phosphodiesterases-> high

concentration of IC cAMP & cGMP-> smooth muscle relaxation

= Cilomilast, Roflumilast, Tofimilast: Selective PDE4 inhibitors

inhibition of cell surface receptors for adenosine

= Enprofylline: xanthine derivative devoid of adenosine antagonism

anti-inflammatory effect : inhibit synthesis & secretionof inflammatory mediators from mast cells & basophils

Pharmacodynamics:

mild cortical arousal w/ increased alertness & deferral of fatigue

nervousness; insomnia

in high doses: medullary stimulation and convulsions

primary SE: nervousness and tremor

have positive inotropic and chronotropic effects

Arrhythmia

sinus tachycardia and increased cardiac output

rises the PVR and BP slightly

decrease blood viscosity and may improve blood flow(pentoxifylline)

Pharmacodymanics:

stimulate secretion of gastric acid and digestive enzymes

Kidneys :

weak diuretics

Skeletal muscles :

have potent effects in improving contractility and in reversing fatigue of diaphragm in patient with COPD

Smooth muscle :

inhibit antigen-induced release of histamine from lung tissue

Pharmacokinetics:

Absorbed readily & completely

Food slows the absorption of theophylline

40% protein bound

Distributed into all body compartments

Cross the placenta & pass into breast milk

Metabolism: liver by CYP 1A2 enzyme

10% excreted unchanged

Half-life: 3.5 hrs children; 8 or 9 hrs adult

Usual dose: 3-4 mg/kg every 6 hours

Drug Interactions:

Erythromycin, cimetidine, cirrhosis, CHF, acute pulmonary edema - half-life

Phenytoin, barbiturates, cigarette smoking, rifampicin, oral contraceptives -clearance

Toxicities:

Sudden death

Headache, palpitation, dizziness, nausea, hypotension, precordial pain

Tachycardia, severe restlessness, agitation, emesis plasma concentration of > 20 ug/ml

Focal & generalized seizures 40 ug/ml

Bronchodilators Anti-Muscarinic Agents

Competitively inhibits the effect of acetylcholine at muscarinic receptors-> effectively block the contraction of the airway smooth muscle and increase in secretion of mucus

Ipratropium bromide a quarternary ammonium derivative of atropine

Tiotropium structural analog of ipratropium, approved for COPD, permits once daily dosing

Delivered by aerosol (metered dose inhaler/nebulizer)

Slightly less effective than beta agonist

Effective in COPD

Improving all indices of asthma: severity of symptoms, tests of airway caliber, bronchial reactivity, frequency of exacerbation and quality of life

Inhibiting airway inflammation:

modulation of cytokine & chemokine production,

(-) of eicosanoid synthesis,

(-) of accumulation of basophils, eosinophils & other leukocytes in lung tissue,

decrease vascular permeability

Preparations:

a. oral: prednisone

b. IV: methylprednisolone

c. aerosol: beclomethasone, flunisolide, budesonide, triamcinolone, fluticasone, mometasone

SE : oral candidiasis, hoarseness, slow the rate of growth in children, decrease bone mineral density, cataract, mood disturbances, appetite, & impaired glucose control in diabetics

- Ciclesonide

MOA: alteration in the function of delayed chloride channels in the cell membrane, inhibiting cell activation

Inhibiting parasympathetic and cough reflexes

Inhibition of the early response to Ag challenge

Inhibition of the inflammatory response

inhibiting mediator release from bronchial mast cells

Suppressing the activating effects of chemotactic peptides on neutrophils, basophils & monocytes

Taken prophylactically

Used as aerosol

Effectively inhibit both antigen-and exercise-induced asthma & reducing symptoms of allergic rhinoconjunctivitis

throat irritation, cough, mouth dryness,

chest tightness and wheezing,

reversible dermatitis,

myositis,

gastroenteritis,

pulmonary infiltration with eosinophils and anaphylaxis

Block the action of leukotrienes by :

- inhibition of 5-lipoxygenase, thereby preventing leukotriene synthesis

- inhibition of the binding of leukotriene C4, D4, E4 to its cys-LT1 receptor ontarget tissues, thereby preventing its action

Drug categories

a. Zileuton a 5-lipoxygenase inhibitor

- 600 mg QID

- may cause hepatotoxicity

- inhibits the formation of LTB4

b. Zafirlukast 20mg BID

Montelukast 10mg OD

- are Leukotriene D4-receptor antagonists

Zileuton : absorbed rapidly

metabolized extensively by CYPs & by UDP- glucuronosyltransferases

short-acting drug

half-life: 2.5 hrs

93% protein-bound

Zafirlukast : absorbed rapidly

90% bioavailability

99% protein-bound

metabolized extensively by hepatic CYP2C9

half-life: 10 hrs

Montelukast : absorbed rapidly

60 - 70% bioavailability

99% protein-bound

metabolized extensively by CYP3A4 & CYP2C9

half-life: 3 6 hrs

Other Effects:

Have demonstrated an important role for leukotrienes in aspirin-induced asthma

Their effect on symptoms, airway caliber, bronchial reactivity and airway inflammation are less marked than the effects of inhaled corticosteroids, but they are almost equally effective in reducing the frequency of exacerbations

1. Anti-IgE Antibodies

- drugs that reduce the amount of IgE-bound to mast cells

- inhibits synthesis of IgE by B-lymphocytes

- Omalizumab(anti-IgE MAb)

= most important effect : reduction of the frequency & severity of asthma exacerbations

= delivered as a single SC injection q 2 4weeks

= 60% bioavailability

= peak serum levels: 7 8 days

= half-life: 26 days

= elimination: liver reticuloendothelial system, bile

2. Calcium channel Blockers

- inhibit airway narrowing induced by variety of stimuli

3. Nitric Oxide Donors

- relaxation of smooth muscle and vasculature

- very lipophilic drug, can be inhaled as a gas

- more useful in pulmonary hypertension

Monoclonal antibodies directed against cytokines

Antagonist of cell adhesion molecules

Protease inhibitors

Immunomodulators

Mucolytic Agents

1. Acetylcysteine (mucomyst)

- reduce the thickness and stickiness of purulent and non-purulent pulmonary secretions

- antidote for paracetamol poisoning

2. Carbocysteine (SCMC)

- act by regulating and normalizing the viscosity of secretion from the mucus cell of respiratory tract

- decrease the size and number of mucus producing cells

3. Bromhexine

- depolymerization of mucopolysaccharides, direct effect on bronchial glands

- liberation of lysosomal enzymes producing cells which digest mucopolysaccharide fibers

Mucokinetic & Secretolytic

1. Ambroxol

- increase respiratory tract secretions

- enhance pulmonary surfactant production

- stimulates cilia activity

Expectorant

1. Vagal stimulants: glyceryl guiacolate, salt solution

2. Direct stimulants: KISS, bromhexine, SCMC, ambroxol

Antitussives

1. Narcotic antitussives: heroin, codeine, morphine

2. Non-narcotic antitussive: Dextromethorphan

respiratory drugs

Education