Chaired by- Dr. Harcharan Modulated by- Dr. Dhawan Presented by- Dr.

Pratibha

1) Sympathetic nervous system

neural

transmitter substance nor-epinephrine or adrenaline

adrenergic response ( via and -receptors)- smooth muscle relaxation bronchodilation pulmonary vasodilation

2) Parasympathetic nervous system

Neural

transmitter substanceAcetylcholine

Cholinergic response smooth muscle contraction bronchoconstriction pulmonary vasoconstriction

During the inflammatory process chemical mediators are released:

Histamine:

Causes bronchoconstriction and mucosal edema

Eosinophilic chemotatic factor of anaphylaxis (ECF-A):

Attracts eosinophils to site of irritation Prolongs and worsens inflammation.

Prostaglandins Derived from arachadonic acid Causes Bronchoconstriction Edema Increases Mucus production Leukotrienes: Potent bronchoconstrictors (LT-1) Long durations of action IgE- familial atopy

Mucous is produced by goblet cells in the respiratory tract as a protective covering of the respiratory epithelium. It traps the foreign particles which are small enough to be traped by the fine nasal hairs. Though it is protective but the collection of dry cough in the respiratory tract may cause obstruction. Excessive production may be another problem.

Respiratory drugs act via second messenger and most important second messenger is cyclic AMP

Action Smooth Muscle Relaxation Promotes bronchodilation Pulmonary Vasodilation Structure

 Sympathomimetic

Amines Parasympatholytics Methyl Xanthines Mediator Antagonists Inhaled Steroids Mucolytics, expectorents and antitussives Anti-Infectives (antibiotics) Exogenous Surfactants Respiratory stimulants Inhalational anaesthetic agents.

 Also

Called

Beta

agonists/Beta adrenergic bronchodilators agonists decongestant vasopressor vasoconstrictor

Alpha

Examples: Non selective beta agonists-Epinephrine Isoproterenol Selective beta-2 drugs Albuterol -immediate action, 4-6 hour duration Pirbuterol -immediate action, 4-6 hour Formoterol -10-20 min onset, 12+ duration Levalbuterol -immediate action, 4-6 hour Metaproterenol -immediate action, 4-6 hour Salmeterol - 10-20 min onset, 12+ duration Terbutaline -immediate action, 4-6 hour

Marketed as- Proventil MOA- selective beta-2 agonist Onset of action- 5-15 min Duration of action- 3-5 hrs Protein bindng- 10 % Metabolised by- liver Excreted by- kidney Routes of administration- aerosols ( inhalors or nebulisers) 90mcg per actuation, oral (tablet 4mg/8mg or syrup 2mg/5ml) Indication- acute severe bronchospasm, exercise induced bronchospasm. Dose 2-4 mg TDS 2 puffs inhaled 4-6 hrly

Marketed as- Serevent diskus MOA- beta 2 agonist (long acting) Onset of action- 20 min Duration of action- 12 hrs Protein binding- 96 % Metabolised by- liver Excreted mainly in feces Routes of administration-aerosoles (inhalors 50 mcg/actuation) Indication- prevention of exercise induced bronchospasm, maintenance treatment of asthma Doses 1 puff BD

Indications:

Prevention of bronchospasm Treatment of bronchospasmrescue treatment Prevention of exercise-induced asthma

Side Effects Cardiovascular (B1) tachycardia Hypertension Tremor Nausea Insomnia

 Also

Called

Anticholinergics

Examples

Atropine sulfate (Tropine) Ipratropium bromide ( Atrovent) Tiotropium

Major

Action

inhibits acetylcholine release limits bronchoconstriction

Marketed as- Tropine, Atreza MOA-inhibits action of acetylcholine at muscarinic receptors (anti-muscarinic) Onset of action- 1-3min (rapid onset) Duration of action- 4 hrs Protein binding- 18% Metabolised by- liver Excreted by- kidney Routes of administration- oral (tablet 0.4mg), IV/IM (solutions 0.05mg/ml,0.1 mg/ml, 0.4 mg/ml, 0.6 mg/ml, 1mg/ml) aerosols (via nebulisers) Indications- Bronchospasm Doses- 0.025 mg/kg in 2.5ml NS QID

Marketed as- Atrovent MOA- anticholinergic Onset of action-15 min Duration of action- 3-4 hrs Protein binding- 0-9 % Metabolised by- liver Excreted by- kidney Routes of administration- Metered dose inhalors (17 mcg/actuation, nebulisers 0.03%), nasal spray (0.02%) Indications- maintenance treatment of asthma, chronic bronchitis and emphysema, allergic rhinitis, acute exacerbation of asthma Doses- 2 puffs QID 2 sprays per nostril BD 2.5 ml in nebuliser TDS

Marketed as- Spiriva Handihaler MOA- long acting antimuscarinic agent (inhibits M3- receptors) Onset of action-30 min Duration of action- >24 hrs Protein binding- 72% Metabolised by- liver Excreted by- kidney Routes of administration- oral inhalation via handihaler (18mcg capsules) Indications- maintanence therapy of bronchospasm, improving pulmonary function in cystic fibrosis Doses- 2 oral inhalation of 1 capsule OD

 Routes

inhalation
Side

via nebulizer and MDI

Effects Cardiovascular-tachycardia tremors nausea allergic reactions (Atrovent) drying of secretions

 Also

Called

Xanthines Phosphodiesterase Inhibitors

Examples

Theophylline Aminophylline Dyphyllin Deriphyllin Pentoxiphyllin

Marketed as- Theodur MOA- inhibits phosphodiastrase enzyme which causes degradation of cAMP to 5AMP, directly relaxes smooth muscles of respiratory tract Onset of action- variable Duration of action- variable Protein binding- 40-55% Metabolised by- liver Excreted by- kidney Modes of administration- oral (extended release tablets 100mcg,200mcg,300mcg), IV Indications- acute bronchospasm, chronic bronchitis, emphysema Doses- loading dose of 5-7 mg/kg iv and oral maintenance dose of 0.4-0.6 mg/kg/hr iv infusion or 4.8-7.2 mg/kg oral BD Therapeutic level- 10-15 mg/l

It

can indirectly stimulate both 1 and 2 receptors through release of endogenous catecholamines. Signs and symptoms include nausea, vomiting, abdominal pain, hypokalemia, hypocalcemia, hyperglycemia, tachycardia, seizures (in acute toxicity), dysrhythmias (in chronic toxicity) Differential diagnosis includes alcoholic ketoacidosis, diabetic ketoacidosis, delirium tremens, cyanide toxicity, iron toxicity etc.

Treatment and management: Establish airway, breathing and circulation IV benzodiazepines abort the seizures. Consider gastric lavage if patient has recently taken the drug. Administer activated charchoal after effectively controlling nausea and vomiting. Administer polyethylene glycol electrolyte solution untill the clear rectal effluent comes

Mechanism of Action Inhibits the breakdown of cyclic AMP into 5 AMP maximizes cyclic AMP Routes IV Oral Cannot aerosolize Indications:chronic bronchitis and COPD Side Effects nausea tachycardia CNS stimulation insomnia bad taste in mouth

Also Called Prophylactic bronchodilators

Examples Anti histamines Hydroxyzine,cyclizine,promethazine (first generation H1 receptor antagonist) cetrizine, levocetrizine,Ebastine (second generation) Mast cell stabilisers cromolyn sodium (Intal) nedocromil (Tilade) Leukotriene inhibitor montelukast (Singulaire) zafirlukast (Accolate) zileuton (Zyflo) Anti IgE Omalizumab (Xolair)

 Routes Anti- histamines- oral Mast cell stabiliser

Cromolyn sodium (Intal) MDI, SVN Intranasal spray Nedocromil (Tilade) MDI Leucotriene inhibitor Zafirlukast, montelukast,zileuton oral tablets Anti IgE Omalizumab injection for subcutaneous administration

 Examples

Dexamethasone sodium phosphate [Decadron, Respirahaler] Beclomethasone dipropionate [Beclovent, Vanceril] Triamcinolone acetonide [Azmacort] Flunisolide [Aerobid] Fluticasone propionate [Flovent] Budesonide [Pulmicort]

 Major

Actions: interfere with all stages of the

inflammation and allergic response (inhibits inflammatory mediators from mast cells) anti-inflammatory modification of cell transcription peak action or effectiveness from hours to days depending on the cellular metabolism not for acute relief

 Routes

MDI (metered dose inhalor) 2 puffs 5 to 10 second breath hold 1 minute rest between puff rinse mouth after treatment SVN (small volume nebuliser) Pulmocort [0.5 ml undiluted]

Side Effects Short-Term anaphylaxis [beclomethoasone] yeast infections wheezing a tight feeling in the chest feeling depressed feeling restless or nervous dry mouth

Side Effects Long-Term moon face (Cushingoid) fluid retention weight gain increase in fat pad [dowagers hump] osteoporosis pathologic fractures glomerulonephritis

Marketed as- Pulmicort MOA- anti-inflammatory Onset of action- 24hrs to 2 wks Duration of action- long acting Protein binding- 85-90 % Metabolised by- liver Excreted by- kidney (60%), feces(40%) Routes of administration- inhalers (90mcg/actuation) and nebulisers (0.25 mg/2ml, 0.5mg/2ml, 1mg/2ml solution) Indication- maintenance therapy of asthma Doses- 180 mcg (2 puffs) inhaled BD

 Also

Called

Mucolytics Mucoactive agents Mucous controlling agents

Examples

Mucomyst [n-acetylcysteine] Pulmozyme [Dornase alfa] Bland aerosol therapy 2% sodium bicarbonate

Mucolytics: Liquefy bronchial mucus Enable mucus to be removed by coughing or suction apparatus e.g.-Acetylcysteine

Expectorants

facilitate the removal of mucous from the respiratory system e.g.- Guaifenesin work to suppress coughing e.g.-Codeine or hydrocodone Dextromethorphan

Antitussives

Major Actions[s] Mucomyst breaks down di-sulfide bonds Pulmozyme is a proteolytic used primarily for the treatment of cystic fibrosis patients Bland aerosols mechanically hydrate and loosen secretions 2% sodium bicarbonate may hydrate or affect mucous bonding Routes of Administration primarily via SVN bland aerosols may be administered via large volume nebulizers (LVN) may be instilled into endotracheal tubes during bronchoscopy or suctioning.

Side Effects
n-acetylcysteine [Mucomyst] may precipitate wheezing; a bronchodilator should be added to the aerosol airway obstruction due to liquefaction of secretions nausea and rhinorrhea o odor [hydrogen sulfide] Dornase alfa [Pulmozyme] pharyngitis, laryngitis rash chest pain weight loss

Marketed as- Mucomyst MOA- open up disulphide bonds in mucoproteins Onset of action- 5-10 min Duration of action- varies but approx.1 hr Protein binding- 80% Metabolised by- liver Excreted by- kidney Routes of administration- nebuliser (10% and 20% solutions) Indications- as mucolytic in all pulmonary diseases Doses- 5-10 ml of 10/20 % solution by nebuliser QID

 Also

Called Antimicrobials

Examples

Pentamidine

isethionate (Pentam,

NebuPent] Ribavirin - virazole

 Aerosolized

antibiotics Gentamicin Carbenicillin Colomycin Ceftazidime Tobramycin Garamycin

 Major

Action Pentamidine - treatment of pneumocystis carinii pneumonia [PCP] a protozoan. Ribavirin - treatment of respiratory syncytial virus [RSV] Aerosolized antibiotics -specific bacterial organism

 Routes

of Administration Pentamidine - oral or aerosolized every two weeks

Ribavirin

- aerosolized via small particle aerosol generator [SPAG] antibiotics - SVN

Aerosolized

 Side

Effects Pentamidine cough, bronchial irritation, bronchospasm and wheezing, shortness of breath, fatigue, bad or metallic taste, pharyngitis. Decreased appetite, dizziness, rash, nausea, night sweats, chills.

Side Effects Ribavirin skin rash, eyelid erythema. When used in conjunction with mechanical ventilators may cause sticking of exhalation valve and other sensors. Pulmonary function may deteriorate Aerosolized Antibiotics bronchospasm Anaphylaxis

 Examples

Survanta

[beractant] - natural bovine

extract Exosurf [colfosceril palmitate with cetyl alcohol and tyloxapol] -a synthetic mixture

Major Action Replacement therapy for premature babies with low Lecithin:Sphingomyline ratio Rescue for RDS (respiratory distress syndrome) infants. Prophylactic in infants less than 1350 grams or larger infants who show signs of respiratory distress Routes of Administration Instilled directly into endotracheal tube

Side Effects Procedural- during instillation or during endotracheal intubation

Marketed as- Survanta MOA- similar to naturally occuring surfactant i.e. to prevent collapse of alveoli Onset of action- within minutes Metabolism- unknown Excretion- unknown Routes of administration- intratracheal suspension (25mg/ml) Indications- respiratory distress syndrome and respiratory failure in neonates. Doses- 100 mg surfactant (4 ml/kg) within 16 hrs of birth as circumstances arises. Prevention of RDS- if birth weight is <1250 g or with evidence of surfactant deficiency, give within 15 min of birth.

Administration of surfactantInstill through 5 french endhole catheter inserted into endotracheal tube just above carina (not into bronchus). Inject each dose into the catheter over 2-3 sec Each dose instilled as 4 quarter doses, with body in different positions to assure adequate distribution, allow 30 seconds ventilation between positions Store in fridge, warm to room temperature, swirl to mix (no shaking)

NaloxoneMarketed as Narcan MOA-competitive opioid antagonist Onset of action- 1-2 min (iv), 2-5 min (im/sc) Duration of action- 1-4 hrs Metabolised by- liver Excreted by- kidney Indication- opioid overdose, carbon dioxide narcosis Routes of administration- IV/IM/SC/ET injectable solution 0.4mg/ml, 1mg/ml. Doses- 0.4- 2mg iv/im/sc repeated every 2-3 min upto maximum 10 mg.
a)

b) DoxapramMarketed as- Dopram MOA- centrally acting drug. Directly act over medullary respiratory centre to stimulate respiration. Onset of action- 20-40 sec Duration of action- 5-12 min Metabolism- unknown Excreted in- Urine and feces Routes of administration- intravenous (solution of 20mg/ml) Indications- COPD associated with hypercapnia, drug induced CNS depression Doses 0.5-1 mg/kg iv infusion no more than 3mg/min or 2 hours.

c) FlumazenilMarketed as Romazicon MOA- competitive benzodiazepine

receptor antagonist

Onset of acton- rapid onset Duration of action- 30-60 min Routes of administration- intravenous (injectable solution 0.1 mg/ml) Doses- 0.2 mg iv over 15-30 sec.

Ether Nitrous oxide Halothane Isoflurane Sevoflurane

History- Ether was prepared by Valeus cordus in 1540 AD known as sweet oil of vitriol. At that time first public demonstration of ether anaesthesia was given by William thomas green (WTG) Mortan on october 16th 1846. Characteristics pungent smelling highly inflammable explosive decomposes in presence of light (so stored in amber coloured bottles)

Clinical effects - Slow induction - good analgesic - Muscle relaxant - Does not depress myocardium - Does not depress respiration - Potent bronchodilator - Preserves ciliary activity - Increases secretions markedly - High incidence of nausea and vomiting - Crosses placental barrier - Causes hyperglycemia - Due to above features it is also called complete anaesthetic agent

Also called laughing gas First synthesised by Pristley in 1774 and its first clinical use was done by Horace Wells in a tooth extraction. Physical properties -Colourless -Odorless -Non inflammable but supports combustion - gas in room temp and liquid under pressure -Cylinder- colour- blue pressure- 760psi pipeline pressure- 45-55 psi

Effects - direct myocardial depressants - But stimulant of sympathetic system so pulse rate and blood pressure remains stable - Causes hypovolumia - Pulmonary vasoconstriction so increases resistance - Tachypnea and decrease in tidal volume - Good analgesic - increases cerebral blood flow and its oxygen consumption

Second

gas effect- During induction of general anesthesia when a large volume of nitrous oxide is taken up from alveoli into pulmonary capillary blood, the concentration of gases remaining in the alveoli is increased. This results in effects known as the concentration effect and the "second gas effect. Diffusion hypoxia(or Fink effect or third gas effect)-When a patient is recovering from N2O anaesthesia, large quantities of this gas cross from the blood into the alveolus (down its concentration gradient) and so for a short period of time, the oxygen and carbon dioxide in the alveolus are diluted by this gas. This could potentially cause the partial pressure of oxygen to decrease and could temporarily lead to hypoxia.

Introduced in 1956, most cost-effective inhalational agent Properties-Halogenated agent -Spontaneous oxidative decomposition which is retarded by thymol preservative -Stored in amber coloured bottles -MAC- 0.75 Effects : Cardiac effectsDirect myocardial depressants and coronary artery dilator. Decreases cardiac output and lowers arterial blood pressure. Decreases myocardial demands. Causes bradycardia Respiratory effectsCauses fast and shallow breathing Potent bronchodilator Depresses mucocilliary function

CNS effects: Cerebral vasodilator Increases cerebral blood flow No analgesic effect Other effects: Powerful uterine relaxant hence used for manual removal of placenta Halothane shakes- it may sometimes cause shivering. Best antidote is pethidine > tramadol Halothane hepatitis- it causes centrilobular necrosis of liver due to decrease hepatic blood flow. It may also precipitate malignant hyperthermia

Introduced in 1981.
Most commonly used agent at present

Properties: Pungent ethereal odor. Cardio protective. Bronchodilator MAC- 1.2 Agent of choice for cardiovascular, neuro and liver transplant surgeries. May also precipitate malignant hyperthermia

Introduced in 1971 but used clinically only after 1990. Properties : Nonpungent smell (so agent of choice to induce children) Cardio supressant Bronchodilator Increases cerebral blood flow and ICP MAC- 2.0 Forms compound A with soda lime in closed circuit ventilation May precipitate malignant hyperthermia

 Indications

for Respiratory Drugs

bronchodilation secretion control anti-infection prophylaxis rescue maintenance anti-inflammatory General anaesthesia