RESPIRATORY PHARMACOLOGY

Transcription

1 Yerevan State Medical University Department of Anaesthesiology and Intensive Care Yerevan, Armenia RESPIRATORY PHARMACOLOGY Dr. Armen VAROSYAN Associate Professor, DEAA, PhD

2 Lecture Outline Drugs stimulating respiratory centre Bronchomotor tone Drugs and factors influencing airway calibre Drugs and Factors affecting pulmonary vascular resistance Surfactant replacement therapy Pulmonary pharmacology of inhaled anaesthetics 2 Dr. Armen Varosyan, DEAA, PhD

3 SOURCES OF INFORMATION 3 Dr. Armen Varosyan, DEAA, PhD

4 Fundamental Textbooks of Anaesthesiology Dr. Armen Varosyan, DEAA, PhD 4

5 A highly recommended textbook Sue Hill

6 Drugs stimulating respiratory centre (Respirtaory analeptics) Dr. Armen Varosyan, DEAA, PhD 6

7 Some clinical indications for the use of respiratory stimulants include: overdose with sedatives post-anaesthetic respiratory depression opioid overdose idiopathic hypoventilation facilitation of blind nasal intubation treatment of apnoea in premature neonates Dr. Armen Varosyan, DEAA, PhD 7

8 Assisted ventilation is the best option for respiratory management in most of these cases and respiratory stimulants should be used only as a short-term measure or when facilities for assisted ventilation are not immediately available Dr. Armen Varosyan, DEAA, PhD 8

9 Respiratory stimulants should not be used if respiratory failure is caused by muscle exhaustion Dr. Armen Varosyan, DEAA, PhD 9

10 Examples of still commercialized respiratory stimulants Doxapram Caffeine Nikethamide (Cordiamin) Crotetamide (Micorene) Dr. Armen Varosyan, DEAA, PhD 10

11 Bronchomotor Tone Dr. Armen Varosyan, DEAA, PhD 11

12 Regulation of bronchomotor tone Dr. Armen Varosyan, DEAA, PhD 12

13 Drugs and Factors Influencing Airway Calibre Dr. Armen Varosyan, DEAA, PhD 13

14 Bronchoconstriction leads to the following: increased difficulty in breathing inadequate ventilation V/Q mismatch impaired ability to cough hypoxaemia Dr. Armen Varosyan, DEAA, PhD 14

15 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 Dr. Armen Varosyan, DEAA, PhD 15

16 3 types of bronchodilator are in clinical use β 2 -adrenergic agonists Methylxanthines Anticholinergics Dr. Armen Varosyan, DEAA, PhD 16

17 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 Dr. Armen Varosyan, DEAA, PhD 17

18 β 2 - ADRENERGIC AGONISTS Main representatives epinephrine ephedrine isoproterenol β non-selective salbutamol salmeterol terbutaline β 2 selective Dr. Armen Varosyan, DEAA, PhD 18

19 Selectivity of β 2 -agonists is only relative. They may produce β 1 effects: in high doses in the presence of predisposing factors (hypoxaemia, hypercapnia) Dr. Armen Varosyan, DEAA, PhD 19

20 1 effects Adverse effects of -agonists anxiety headache dizziness tachycardia and other tachyarrhythmias hypertension nausea and vomiting Other effects muscle tremor resulting from a direct effect on 2 receptors in skeletal muscle hypokalaemia caused by increased uptake of K + by skeletal muscles (mediated by 2 receptors) metabolic effects: increases in the plasma levels of free fatty acids, insulin, glucose, pyruvate and lactate Dr. Armen Varosyan, DEAA, PhD 20

21 Epinephrine remains the drug of choice in anaphylaxis Dr. Armen Varosyan, DEAA, PhD 21

22 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 last resort in severe bronchospasm more frequent side-effects Dr. Armen Varosyan, DEAA, PhD 22

23 METHYLXANTHINES Main representatives Theophylline most commonly used parent compound Aminophylline water-soluble salt, contains >75% theophylline injectable form of theophylline Dr. Armen Varosyan, DEAA, PhD 23

24 METHYLXANTHINES Mechanisms of bronchodilation phosphodiesterase inhibition increase of intracellular camp 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 Dr. Armen Varosyan, DEAA, PhD 24

25 Factors affecting the plasma concentration of methylxanthines for a given dose Factors lowering the plasma concentration Children Smoking Acidosis Enzyme induction - rifampicin, ethanol, phenobarbital Increased protein diet Reduced carbohydrate diet Dr. Armen Varosyan, DEAA, PhD 25

26 Factors affecting the plasma concentration of methylxanthines for a given dose Factors increasing plasma concentration by reducing clearance Old age Congestive heart failure Liver disease - cirrhosis Enzyme inhibition - cimetidine, erythromycin Viral infection or vaccination Increased carbohydrate diet Dr. Armen Varosyan, DEAA, PhD 26

27 Common adverse effects of methylxanthines Nausea and vomiting Gastro-oesophageal reflux Headache and restlessness Diuresis Arrhythmias Seizures Hypokalaemia Dr. Armen Varosyan, DEAA, PhD 27

28 ANTICHOLINERGIC DRUGS Atropine is not popular because of side effects Ipratropium less soluble ammonia 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 Dr. Armen Varosyan, DEAA, PhD 28

29 Prevention of bronchoconstriction Membrane Stabilizers - disodium cromoglycate Anti-inflammatory Agents - Steroids Dr. Armen Varosyan, DEAA, PhD 29

30 MEMBRANE STABILIZERS Disodium cromoglycate has no intrinsic bronchodilator effect stabilization of the 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) Dr. Armen Varosyan, DEAA, PhD 30

31 STEROIDS Sites of action and mechanisms of anti-inflammatory effects Intracellular steroid receptors Lipocortin Eosinophils T-lymphocytes Macrophages Endothelial cells Airway smooth muscle β 2 -adrenoceptors Dr. Armen Varosyan, DEAA, PhD 31

32 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 Dr. Armen Varosyan, DEAA, PhD 32

33 Adverse effects of inhaled steroids hoarseness oral pharyngeal candidiasis throat irritation and cough + systemic side-effects (less frequently) surface absorption swallowed pharyngeal deposits Dr. Armen Varosyan, DEAA, PhD 33

34 Drugs and Factors Acting on Pulmonary Vascular Resistance Dr. Armen Varosyan, DEAA, PhD 34

35 Factors increasing pulmonary vascular resistance Hypoxia Acidosis a-adrenergic agonists β-adrenergic antagonists Protamine Histamine Serotonin Angiotensin II Thromboxane Dr. Armen Varosyan, DEAA, PhD 35

36 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 Dr. Armen Varosyan, DEAA, PhD 36

37 Surfactant Replacement Therapy Dr. Armen Varosyan, DEAA, PhD 37

38 Exogenous surfactant preparations reported in scientific literature Chemical name Trade name Source Protein-free synthetic surfactants Pumactant ALEC Colfosceril Exosurf Turfsurf, Aposurf Animal derived surfactants (a) minced lung extracts Poractant alfa Curosurf porcine Surfactant TA Surfacten porcine Beractant Survanta bovine Surfactant CK, HL-10, Butantan, Newfactan, Surfactant BL (b) lung lavage surfactant extracts Bovactant bovine Calfactant bovine Surfacen porcine Human surfactant Amniotic fluid-derived Surfactants with synthetic / recombinant proteins Lucinactant (sinapultide) etc. Surfaxin

39 The actions of volatile anesthetics on respiratory system Dr. Armen Varosyan, DEAA, PhD 39

40 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 Dr. Armen Varosyan, DEAA, PhD 40

41 Understanding of the multifactorial actions of inhaled anesthetics on the respiratory system is critical to the safe delivery of anesthesia Dr. Armen Varosyan, DEAA, PhD 41

42 Further investigations are needed to determine the precise role of inhalational agents as friend or foe. Dr. Armen Varosyan, DEAA, PhD 42

43 Thank you for your patience and attention Dr. Armen VAROSYAN