Respiratory Pharmacology. Manuel Otero Lopez Department of Anaesthetics and Intensive Care Hôpital Européen Georges Pompidou, Paris, France

Transcription

1 Respiratory Pharmacology Manuel Otero Lopez Department of Anaesthetics and Intensive Care Hôpital Européen Georges Pompidou, Paris, France

2 Programme Bronchomotor tone Drugs and factors influencing airway calibre Drugs and factors affecting pulmonary vascular resistance Pulmonary pharmacology of inhaled anaesthetics Drugs stimulating respiratory centre (respiratory analeptics) Surfactant replacement therapy

3 BRONCHOMOTOR TONE

4 Regulation of bronchomotor tone

5 Regulation of bronchomotor tone

6 Bronchoconstriction leads to the following: increased difficulty in breathing inadequate ventilation V/Q mismatch impaired ability to cough hypoxaemia

7 Drugs and Factors Influencing Airway Calibre

8 Drugs and Factors Acting on Airway Calibre Bronchoconstriction Cholinergic drugs β 2 -adrenergic antagonists Inflammatory mediators Allergy and anaphylaxis Bronchodilatation β 2 -adrenergic agonists Methylxanthines Anticholinergics Prevention of bronchoconstriction Membrane stabilizers - sodium cromoglycate Steroids

9 3 types of bronchodilator are in clinical use β 2 -adrenergic agonists Methylxanthines Anticholinergics

10 Effects of -agonists on the airways Specific Increase in intracellular camp and cause bronchodilatation Non-specific but complementary Inhibition of mast cell mediator release Inhibition of plasma exudation and microvascular leakage Prevention of airway oedema Increased mucus secretion and mucociliary clearance Prevention of tissue damage mediated by O 2 free radicals Decreased AcCh release in cholinergic nerves by an action on prejunctional 2 -receptors

11 β 2 - ADRENERGIC AGONISTS Main representatives epinephrine ephedrine isoproterenol β non-selective salbutamol salmeterol formoterol terbutaline β 2 selective

12 β 2 - ADRENERGIC AGONISTS Selectivity of β 2 -agonists is only relative. They produce β 1 effects: in high doses in the presence of predisposing factors (hypoxaemia, hypercapnia)

13 Adverse effects of -agonists 1 effects tachycardia and other tachyarrhythmias hypertension Other effects muscle tremor: a direct effect on 2 receptors in skeletal muscle hypokalaemia: increased uptake of K + by skeletal muscles ( 2 ) metabolic effects: increases in the plasma levels of free fatty acids, insulin, glucose, pyruvate and lactate ( 3 ) anxiety, headache, dizziness nausea and vomiting

14 β 2 - ADRENERGIC AGONISTS Epinephrine remains the drug of choice in anaphylaxis

15 β 2 - ADRENERGIC AGONISTS Ways of administration Inhalation is the method of choice more effective (reaches surface cells) less systemic side-effects pressurized aerosol or nebulization Oral administration no advantage over inhalation is associated with more side-effects Intravenous administration in severe bronchospasm in case of failed inhalation therapy more frequent side-effects

16 Theophylline Aminophylline METHYLXANTHINES Main representatives most commonly used parent compound water-soluble salt, contains >75% theophylline injectable form of theophylline

17 METHYLXANTHINES Mechanisms of bronchodilation phosphodiesterase inhibition increase of intracellular camp nonselective adenosine receptor antagonism: (adenosine, especially in asthmatic subjects, causes mast cell histamine release) endogenous catecholamine release prostaglandin inhibition interference with Ca mobilization potentiation of β 2 -agonists can be combined with β 2 -agonists as second-line agents

18 Factors affecting the plasma concentration of methylxanthines for a given dose Factors lowering the plasma concentration Children Smoking Enzyme induction - rifampicin, ethanol, carbamazepine, barbiturates High protein diet Low carbohydrate diet

19 Factors affecting the plasma concentration of methylxanthines for a given dose Factors increasing plasma concentration by reducing clearance Old age Congestive heart failure Liver failure Enzyme inhibition - cimetidine, erythromycin, omeprazole, valproate, isoniazid, ciprofloxacin Viral infection or vaccination High carbohydrate diet

20 Common adverse effects of methylxanthines Nausea and vomiting Gastro-oesophageal reflux Arrhythmias Increased diuresis Hypokalaemia Headache and restlessness Seizures

21 ANTICHOLINERGIC DRUGS Atropine is not popular because of side effects Ipratropium less soluble synthetic quaternary ammonium compound active topically with little systemic absorption has a safe profile effective in both prevention and treatment of reflex bronchoconstriction max effect in min, duration up to 8 hours second-line bronchodilator Tiotropium longer duration, once daily, not useful in acute cases

22 PREVENTION OF BRONCHOCONSTRICTION Membrane Stabilizers - disodium cromoglycate Anti-inflammatory Agents - Steroids

23 MEMBRANE STABILIZERS no intrinsic bronchodilator effect Disodium cromoglycate stabilizes mast cell membrane mediated by closure of calcium and delayed chloride channels cannot reverse bronchospasm or alter bronchial tone used for prevention of bronchospasm poorly absorbed from intestine delivered topically by inhalation can also be used as a nasal spray to reduce symptoms of allergic rhinitis few side effects (cough, wheeze, pharyngeal discomfort)

24 STEROIDS Some important points second-line treatment in acute asthma delayed onset of action a peak effect in a few hours after iv administration used in acute severe asthma but not for an immediate effect reduce the frequency and severity of acute episodes in chronic asthma for chronic use may administered orally or by inhalation

25 Adverse effects of inhaled steroids hoarseness oral / pharyngeal candidiasis throat irritation and cough Reasons: surface absorption swallowed pharyngeal deposits

26 DRUGS AND FACTORS ACTING ON PULMONARY VASCULAR RESISTANCE

27 Factors increasing pulmonary vascular resistance Hypoxia Acidosis a-adrenergic agonists β-adrenergic antagonists Protamine Histamine Serotonin Angiotensin II Thromboxane

28 Factors and drugs decreasing pulmonary vascular resistance Oxygen Alkalosis a-adrenergic antagonists β-adrenergic agonists Prostaglandins PGI 2 and PGD 2 Calcium channel blockers ACE inhibitors Acetylcholine Aminophylline Nitrates and nitrites Nitric oxide Sodium nitroprusside Hydralazine, Diazoxide

29 The actions of volatile anesthetics on respiratory system

30 Inhaled anesthetics affect every facet of pulmonary physiology control of ventilation airway smooth muscle tone pulmonary blood flow surface tension secretion of mucus lung inflammatory responses

31 Understanding of the multifactorial actions of inhaled anesthetics on the respiratory system is critical to the safe delivery of anesthesia.

32 Thanks to

33 Thank you for attention Manuel Otero Lopez