DRUGS OF THE

RESPIRATORY DISEASE

DRUGS OF THE

RESPIRATORY DISEASE

I. Cough preparations.II. Mucolytics.III. Drugs used in

asthma.IV. Respiratory

stimulants.V. Drugs used in

allergies and anaphylaxis.

These categories are:

I. COUGH PREPARATIONS

1.Codein phosphate :Inhibits the cough reflex centrally.Codein is approximately 60% as effectively orally as parenterally, both as an analgesic and as respiratory depressant.

Typical drugs are weak opioids :

Codeine has a high oral to parenteral potency ratio.

The greater oral efficacy of these drugs less first-pass metabolism in the liver.

Codeine is metabolized by the liver, its metabolites are excreted chiefly in the urine, largely in inactive forms.

A small fraction (approximately 10%) of administered codeine is O-demethylated to form morphine, and both free and conjugated morphine found in the urine after therapeutic doses of codeine.

Codeine low affinity for opioid receptors, analgesic effect of codeine due to its conversion to morphine.

Its antitussive actions may involve distinct receptors that bind codeine.

Half-life of codeine in plasma is 2-4 hours.

Conversions of codeine to morphine is effected by the cytochrome P450 enzyme CYP2D6.

Well-characterized genetic polymorphisms in CYP2D6 lead to the inability to convert codeine to morphine, making codeine in effective as an analgesic for about 10% of the Caucasian population.

Other polymorphisms can lead to enhanced metabolism increased, sensitivity to codeine’s effective.

Morphine and related opioids produce a wide spectrum of unwanted effects respiratory depression, nausea, vomiting, dizziness, clouding, dysphoria, pruritus, constipation, increased pressure in the biliary tract, urinary retention and hypotension.

2.DextromethorphanDextromethorphan (d-3-methoxy-N-methylmorphinan) the d isomer of the codeine analog methorphan; no analgesic or addictive properties and does not act through opioid receptors.

The drug acts centrally to elevate the threshold for coughing.

Its potency is nearly equal to that of codeine.

Compared with codeine, dextromethorphan produces subjective and gastrointestinal side effects.

In therapeutic dosages, the drug does not inhibit ciliary activity, its antitussive effects persist for 5-6 hours.

Its toxicity is low, but extremely high doses may produce CNS depression.

Mechanism my which dextromethorphan exerts its antitusive effects is still unclear.

3.NoscapineOccuring opium alkaloid of the except for its antitissive effect, it has no significant actions on the CNS in doses within the therapeutic.

The drug is a potent releaser of histamine, and large doses bronchoconstriction and transient hypotension.

4. Other drugsAs centrally acting antitussives include carbetapetane, caramiphen, chlophedianol, diphenhydramine, and glaucine.

Each is a member of a distinct pharmacological class unrelated to the opioids.

The mechanism of action of diphenhydramine, an antihistamine unclear.

II. MUCOLYTICS

Mucolytics (e.g. carbocisteine and methyl cysteine hydrochloride) are designed to reduce the viscosity of sputum, thereby aiding expectoration.

The indications for use have

been in:•Chronic bronchitis.•Chronic asthma.•Cystic fibrosis.•Bronchiectasis.

The drugs may be of benefit in treating acute exacerbations in COPD.

III. DRUGS USED IN ASTHMA

Two main categories :A.Relievers

(Bronchodilators).B.Preventers

(corticosteroids, sodium cromoglycate, leukotrine receptor antagonist)

Bronchodilators can be split into :

1.-adrenergic receptor agonist.

2.Anticholinergics.3.Xanthines.

A.Relievers (Bronchodilators)

Mechanism of action and use in asthma

The -adrenergic receptor agoints for the treatment of asthma selective for the 2-receptor subtype.

The agonists can be classified as short- and long-acting.

1. -adrenergic receptor agonist.

Short-acting -adrenergic receptor agonists

Drugs in this class include albuterol (Proventil, Ventolin), levalbutel [Xopenex, the (R)-enantiomer of albuterol], metaproterenol (Alupent), terbutaline (Brethaire), and pirbuterol (Maxaair).

These drugs are used for acute inhalation treatment of broncospasm.

Each of the inhaled drugs on onset of action within 1-5 minutes and produces a bronchodilation that lasts for about 2-6 hours.

In oral dosage forms, the duration of action in some what longer (oral terbutaline, for example, has a duration of action of 4-8 hours).

The mechanism of the antiasthmatic action of short-acting -adrenergic receptor agonist is undountedly direct relaxation of airway smooth muscle and consequent bronchodilation.

Long-acting -adrenergic receptor agonists

Salmeterol xinafoate long-lasting adrenergic agonists with very selectivity for the 2-receptor subtype.

Inhalation of salmeterol provides persistent bronchodilation lasting over 12 hours.

The mechanism underlying the therapeutic effect of salmeterol not yet fully.

Extended side chain on salmeterol renders it 10,000 times more lipophilic than albuterol.

Long-acting -adrenergic receptor agonists relax airway smooth muscle and cause bronchodilation by the same mechanisms as do short-duration agonists.

2-adrenergic receptors inhibits the function of numerous inflammatory cells including mast cells, basophils, eosinophils, neutrophils, and lymphocytes.

Chronic treatment with long-acting 2-adrenergic receptor agonists shown to improve lung function, decrease asthma symptoms, decrease use of short-acting inhaled 2-adrenergic agonists, and decrease nocturnal asthma.

Toxicity

Higher doses increased heart rate, and central nervous system effects.

Oral therapy with 2-adrenergic receptor agonists

Use of orally administered adrenergic agonists for bronchodilation has not gained wide acceptance, largely because of the greater risk of producing side effects, especially tremulousness, muscle cramps, cardiac tachyarrhythmias and metabolic disturbances.

Anticholinergic are competitive antagonists of muscarinic acetylcholine receptors.

They therefore block the vagal control of bronchial smooth muscle tone in response to irritants and reduce the reflex bronchocontriction.

2. Anticholinergics.

Ipratropium bromide and oxitropium bromide are both anticholinergics; they have two mechanisms of action :

•Reduction of reflex bronchocontriction (e.g. from dust or pollen).

•Reduction of mucous secretions.

These drugs reach their maximum effect within 60-90 minutes and act for between 4-6 hours.

They are poorly absorbed orally; they must, therefore, be given by aerosol.

As anticholinergics only affect the vagally mediated element of bronchoconstriction, they are bot the first choice bronchodilator in asthma treatment.

There is some evidence that these drugs are effective when given together with a 2 agonist in severe asthma.

However, their main use is in COPD that does not respond to 2 agonists.

Side effecst are rare, but include :

•Dry mouth.•Urinary retention.•Constipation.

Theophylline, caffeine and theobromie methylated xanthines.

Xanthines itself a dioxypurine and structurally related to uric acid.

3. Xanthines.

Caffeine 1,3,6 trimethyl-xanthine.

Theophylline 1,3 dimethyl-xanthine.

Theobromine 3,7 dimethyl-xanthine.

Mechanisme of action :Xanthines appear to work by inhibiting phosphadiesterase, thereby preventing the breakdown of cAMP.

The amount of cAMP within the bronchial smooth muscle cells is therefore increased, which causes bronchodilation in similar way to 2 agonists.

There drugs are metabolized in the liver and there is considerable variation in half life between individuals.

This has important implications because there is a small therapeutic window.

Factors altering theophylline clearance are shown in :

Factor altering theophylline clearance----------------------------------------------------------------------------Increased clearance Decrease clearance----------------------------------------------------------------------------Smoking Liver diseaseAlcohol PneumoniaRifampicin Cimetidine

Clarythromycin (erythromycin etc.)

Childhood Old agei.e.P450 enzyme i.e.P450 enzyme inhibition

induction

Theophylline can be given intravenously in the form of aminophylline (theophylline with ethylenediamine), but must be administrated very slowly (over 20 minutes to administer dose).

Attack that do not respond to 2 agonists and in acute asthma.

Use in asthma :

Theophylline has proven efficacy as a bronchodilator is asthma and formerly was considered fisrt-line therapy.

Therapy initiated by the administration of 12-16 mg/kg/d of theophylline up to a maximum of 400 mg/d for at least 3 days.

Children <1 y.o. require considerably less; dose in mg/kg/d may be calculated as 0,3 X (age in weeks) + 5,0.

Starting with these low doses minimizes the early side effects of nausea, vomiting, nervousness, and insomnia, which often subside with continued therapy, and virtually eliminated the possibility of exceeding concentrations of 20 g/ml in the plasma of patients over the age of 1 year.

Dosage is increased in two successive stages to between 16-20 and, subsequently, 18-22 mg/kd/d (up to a maximum of 800 mg/d), depending on the age and clinical response of the patient, allowing at least 3 days between adjustments.

Steroid reduce the formation, release, and action of many different chemicals involved in inflammation.

B. Preventers (corticosteroids, sodium cromoglycate,

leukotrine receptor antagonist)

1. Corticosteroid

Their mode of action is complex and involves genemodulation after binding to steroid receptors in the cytoplasm of cells.

This has a number of effects

including :•Down-regulation of pro-

inflammatory cytokine.•Production of anti-

inflammatory proteins.

One of these anti-inflammatory proteins is thought to reduce the activity of phospholipase A2 which itself plays a role in the production of arachidonic acid.

Steroid in treatment of asthma may be topical (inhaled) or systemic (oral parenteral).

Inhaled steroids

These include:•Beclomethasone.•budesonide.•Fluticasone.

Side effects of inhaled steroids in adults are relatively minor (primarily hoarseness and oral candidiasis).

They may have a short-term effect on growth in children.

Oral steroids

The primary oral steroid is prednisolone.

Side effects of systemicsteroids include :•Adrenal suppression.•Effects on bones

(including growth retardation)

•DM.

• Increased susceptibility to infecton.

•Weight gain.•Effects on skin (e.g.

bruising and atrophy).•Mood changes.

Cromolyn synthesized in 1965 as part of an attempt to improve on the bronchodilator activity.

Nedocromil, a compound with similar chemical and biological properties.

2. Sodium cromoglycate & Nedocromil sodium

Mechanism of action

Cromolyn & nedocromil have been reported to have a variety of activities that may relate to their therapeutic effect in asthma inhibiting mediator release from bronchial mast cells to reverse increase functional activation in leukocytes obtained from to blood of asthmatic patients.

Pharmacokinetics

For asthma, cromolyn is given by inhalation, using either solutions (delivered by aerosol spray or nebulizer), powdered drug.

The pharmacological effects are from the topical deposition of the drug in the lung.

Only about 1% of an oral dose of cromolyn absorbed.

Once absorbed, the drug is excreted unchanged in the urine and bile in about equal proportions.

Peak concentrations in plasma occur within 15 minutes of inhalation, and excretion begins after some delay, such that the biological half-life range from 45-100 minutes.

The terminal half-time of elimination following intravenous administration is about 20 minutes.

Toxicty

Cromolyn and nedocromil generally well tolerated by patients.

Adverse reactions are infrequent and minor; bronchospasm, cough or wheezing, laryngeal edema, joint swelling & pain, angioedema, headache, rash, & nausea.

Use in asthma

The main use of cromolyn and nedocromil treatment to mild to moderate bronchial asthma to prevent asthmatic attacks.

Inhaled several times daily, cromolyn will inhibit both the immediate and the late asthmatic responses to antigenic challenge or to exercise.

With regular use for more than 2-3 months, there is evidence of reduced bronchial hyperreactivity.

IV. RESPIRATORY STIMULANTS

A respiratory stimulant (analeptic) such as doxapram can be used for patients with chronic obstructive pulmonary disease in type II respiratory failure.

However, mechanical ventilation and a high incidence of side effects have reduced their use.

Doxapram stimulates carotid body chemoreceptors and must be given intravenously.

Side effects of doxapram are:

•Tachycardia.•Palpitations.•Nausea.•Sweating.•Tremor.

Contraindications of doxapram are:

• Epilepsy.• Hypertension.• Hyperthyroidism.

V. DRUGS USED IN ALLERGIES & ANAPHYLAXIS

These drugs are used in the treatment of allergies, such as hayfever.

Examples of these drugs are :• Promethazine.• Trimeprazine.

The mechanism of action is to block H1 receptors.

The drugs cross the blood-brain barrier and have a general depressant action (sedative); in high doses, this actions can cause respiratory depression.

Newer drugs such as terfenadine do not readily cross the blood-brain barrier and therefore do not cause respiratory depression.

Anaphylaxis

Anaphylactic shock is a systemic allergic reaction which is a life-threatening condition.

The features of anaphylactic shock are:

• Severe hypotension.• Laryngeal spasm.• Bronchoconstriction.

The treatment of anaphylaxis must therefore be rapid:

•Secure the airway.•Maintain blood

pressure by lying the patient flat and raising his or her legs.

Drug therapy is a follows:• Intramuscular adrenaline

(epinephrine) (0.5 - 1.0 mg, 0.5 - 1.0 mL of adrenaline injection 1:1000), repeated at 10-minute intervals depending on the blood pressure.

•100% oxygen.

•Chlorpheniramine (antihistamine) 10-20 mg intravenously, continued 24-48 hours.

•Salbutamol can be given intravenously for those patients not responsive to adrenaline.

•Hydrocorticosteroid 200-300 mg intravenously may be given as a second-line drug to reduce further deterioration.