pharmacology of respiratory system
TRANSCRIPT
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Chaired by- Dr. Harcharan
Modulated by- Dr. Dhawan
Presented by- Dr. Pratibha
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1) Sympathetic nervous systemneural transmitter substance
nor-epinephrine oradrenaline
adrenergic response ( via and-receptors)- smooth
musclerelaxation
bronchodilationpulmonary vasodilation
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2) Parasympathetic nervoussystem
Neural transmitter substance-Acetylcholine
Cholinergic response -smooth muscle
contraction
bronchoconstriction pulmonary
vasoconstriction
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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.
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Prostaglandins
Derived from arachadonic acid
Causes Bronchoconstriction
Edema
Increases Mucus production
Leukotrienes:
Potent bronchoconstrictors (LT-1) Long durations of action
IgE- familial atopy
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Mucous is produced by gobletcells in the respiratory tractas a protective covering of therespiratory epithelium. It
traps the foreign particleswhich are small enough to betraped by the fine nasal hairs.
Though it is protective but the
collection of dry cough in therespiratory tract may causeobstruction. Excessiveproduction may be anotherproblem.
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Respiratory drugs act via
second messenger andmost important second
messenger is
cyclic AMP
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Action
Smooth Muscle Relaxation
Promotes bronchodilationPulmonary Vasodilation
Structure
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Sympathomimetic Amines
Parasympatholytics
Methyl Xanthines
Mediator Antagonists Inhaled Steroids
Mucolytics, expectorents and antitussives
Anti-Infectives (antibiotics)
Exogenous Surfactants
Respiratory stimulants
Inhalational anaesthetic agents.
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Also Called
Beta agonists/Beta adrenergic
bronchodilators
Alpha agonists
decongestant
vasopressorvasoconstrictor
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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
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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 peractuation, 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
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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
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Indications: Prevention of bronchospasm Treatment of bronchospasmrescue
treatment
Prevention of exercise-induced asthma
Side Effects Cardiovascular (B1) tachycardia Hypertension
Tremor Nausea Insomnia
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Also Called Anticholinergics
Examples Atropine sulfate (Tropine)
Ipratropium bromide ( Atrovent)
Tiotropium
Major Action inhibits acetylcholine release
limits bronchoconstriction
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Marketed as- Tropine, Atreza
MOA-inhibits action of acetylcholine atmuscarinic 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, 0.4mg/ml, 0.6 mg/ml, 1mg/ml) aerosols (vianebulisers)
Indications- Bronchospasm
Doses- 0.025 mg/kg in 2.5ml NS QID
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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%), nasalspray (0.02%)
Indications- maintenance treatment of asthma,chronic bronchitis and emphysema, allergicrhinitis, acute exacerbation of asthma
Doses- 2 puffs QID
2 sprays per nostril BD
2.5 ml in nebuliser TDS
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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 inhalationvia handihaler (18mcg capsules)
Indications- maintanence therapy ofbronchospasm, improving pulmonaryfunction in cystic fibrosis
Doses- 2 oral inhalation of 1 capsule OD
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Routes
inhalation via nebulizer and MDI
Side Effects
Cardiovascular-tachycardia tremors
nausea
allergic reactions (Atrovent)
drying of secretions
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Also Called Xanthines
Phosphodiesterase Inhibitors
Examples Theophylline
Aminophylline
Dyphyllin
Deriphyllin
Pentoxiphyllin
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Marketed as- Theodur
MOA- inhibits phosphodiastrase enzyme which causesdegradation of cAMP to 5AMP, directly relaxessmooth 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 releasetablets 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 infusionor 4.8-7.2 mg/kg oral BD
Therapeutic level- 10-15 mg/l
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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.
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Treatment and management:
Establish airway, breathing and circulation
IV benzodiazepines abort the seizures.
Consider gastric lavage if patient hasrecently taken the drug.
Administer activated charchoal after
effectively controlling nausea and vomiting.
Administer polyethylene glycol electrolyte
solution untill the clear rectal effluent comes
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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
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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 IgEOmalizumab (Xolair)
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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
Omalizumabinjection for subcutaneous administration
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Examples
Dexamethasone sodium phosphate [Decadron,
Respirahaler]
Beclomethasone dipropionate [Beclovent,Vanceril]
Triamcinolone acetonide [Azmacort]
Flunisolide [Aerobid]
Fluticasone propionate [Flovent] Budesonide [Pulmicort]
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Major Actions: interfere with all stages of theinflammation 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
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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]
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Side Effects
Short-Term
anaphylaxis [beclomethoasone]
yeast infections
wheezing a tight feeling in the chest
feeling depressed
feeling restless or nervous
dry mouth
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Side Effects
Long-Term
moon face (Cushingoid)
fluid retention
weight gain
increase in fat pad [dowagers hump]
osteoporosis
pathologic fractures glomerulonephritis
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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
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Also Called Mucolytics
Mucoactive agents
Mucous controlling agents
Examples Mucomyst [n-acetylcysteine]
Pulmozyme [Dornase alfa] Bland aerosol therapy
2% sodium bicarbonate
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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
systeme.g.- Guaifenesin
Antitussives work to suppress coughinge.g.-Codeine or hydrocodone
Dextromethorphan
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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 loosensecretions
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 duringbronchoscopy or suctioning.
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Side Effects n-acetylcysteine [Mucomyst]
may precipitate wheezing; a bronchodilatorshould be added to the aerosol
airway obstruction due to liquefaction ofsecretions
nausea and rhinorrheao odor [hydrogen sulfide]
Dornase alfa [Pulmozyme] pharyngitis, laryngitis rash chest pain weight loss
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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 pulmonarydiseases
Doses- 5-10 ml of 10/20 % solution by nebuliserQID
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Also Called
Antimicrobials
Examples
Pentamidine isethionate (Pentam,
NebuPent]
Ribavirin - virazole
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Aerosolized antibiotics
Gentamicin
Carbenicillin
Colomycin
Ceftazidime
Tobramycin
Garamycin
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Major Action
Pentamidine - treatment of
pneumocystis carinii pneumonia [PCP] -
a protozoan. Ribavirin - treatment of respiratory
syncytial virus [RSV]
Aerosolized antibiotics -specific
bacterial organism
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Routes of Administration
Pentamidine - oral or aerosolized every
two weeks
Ribavirin - aerosolized via small particle
aerosol generator [SPAG]
Aerosolized antibiotics - SVN
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Side Effects
Pentamidine
cough, bronchial irritation,
bronchospasm and wheezing, shortnessof breath, fatigue, bad or metallic
taste, pharyngitis.
Decreased appetite, dizziness, rash,
nausea, night sweats, chills.
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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
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Examples
Survanta [beractant] - natural bovine
extract
Exosurf [colfosceril palmitate withcetyl alcohol and tyloxapol] -a synthetic
mixture
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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 respiratorydistress
Routes of Administration Instilled directly into endotracheal tube
Side Effects Procedural- during instillation or during
endotracheal intubation
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Marketed as- SurvantaMOA- similar to naturally occuring
surfactant i.e. to prevent collapse
of alveoli
Onset of action- within minutes
Metabolism- unknownExcretion- 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 birthas circumstances arises.
Prevention of RDS- if birth weight is
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Administration of surfactant-
Instill through 5 french endholecatheter 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 ventilationbetween positions
Store in fridge, warm to room temperature,
swirl to mix (no shaking)
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a) Naloxone-
Marketed 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 narcosisRoutes 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 uptomaximum 10 mg.
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b) Doxapram-Marketed as- Dopram
MOA- centrally acting drug. Directly
act over medullary respiratory centre
to stimulate respiration.
Onset of action- 20-40 secDuration 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 inducedCNS depression
Doses 0.5-1 mg/kg iv infusion no more than 3mg/min or 2hours.
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c) Flumazenil-
Marketed as Romazicon
MOA- competitive benzodiazepine
receptor antagonistOnset 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.
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Ether
Nitrous oxide
Halothane Isoflurane
Sevoflurane
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History- Ether was prepared by Valeuscordus in 1540 AD known as sweetoil of vitriol. At that time firstpublic demonstration of etheranaesthesia was given by Williamthomas green (WTG) Mortan onoctober 16th 1846.
Characteristics-
pungent smelling
highly inflammable
explosive
decomposes in presence of light (so
stored in amber coloured bottles)
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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 completeanaesthetic agent
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Also called laughing gasFirst synthesised by Pristley in 1774and its first clinical use was done byHorace Wells in a tooth extraction.
Physical properties
-Colourless-Odorless
-Non inflammable but supportscombustion
- gas in room temp and liquid underpressure
-Cylinder- colour- bluepressure- 760psi
pipeline pressure- 45-55 psi
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Effects
- direct myocardial depressants
- But stimulant of sympathetic systemso pulse rate and blood pressureremains stable
- Causes hypovolumia
- Pulmonary vasoconstriction soincreases resistance
- Tachypnea and decrease in tidalvolume
- Good analgesic
- increases cerebral blood flow and itsoxygen consumption
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Second gas effect- During induction of generalanesthesia when a large volume of nitrous oxide istaken up from alveoli into pulmonary capillaryblood, the concentration of gases remaining in thealveoli is increased. This results in effectsknown as the concentration effect and the"second gas effect.
Diffusion hypoxia(or Fink effect or third gaseffect)-When a patient is recovering fromN2O anaesthesia, large quantities of this gas crossfrom the blood into the alveolus (down itsconcentration gradient) and so for a short period
of time, the oxygen and carbon dioxide in thealveolus are diluted by this gas. This couldpotentially cause the partial pressure of oxygen todecrease and could temporarily lead to hypoxia.
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Introduced in 1956, most cost-effectiveinhalational agent
Properties-
-Halogenated agent
-Spontaneous oxidative decomposition which is
retarded by thymol preservative
-Stored in amber coloured bottles-MAC- 0.75
Effects :
Cardiac effects-
Direct myocardial depressants and coronary artery dilator. Decreasescardiac output and lowers arterial blood pressure. Decreases myocardial
demands. Causes bradycardiaRespiratory effects-
Causes fast and shallow breathing
Potent bronchodilator
Depresses mucocilliary function
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CNS effects:
Cerebral vasodilatorIncreases cerebral blood flow
No analgesic effect
Other effects:
Powerful uterine relaxant hence used for manualremoval of placenta
Halothane shakes- it may sometimes causeshivering. Best antidote is pethidine > tramadol
Halothane hepatitis-
it causes centrilobularnecrosis of liver due to decrease hepatic bloodflow.
It may also precipitate malignant hyperthermia
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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 andliver transplant surgeries.
May also precipitate malignant hyperthermia
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Introduced in 1971 butused clinically only after
1990.
Properties :
Nonpungent smell (so agentof choice to induce children)
Cardio supressant
Bronchodilator
Increases cerebral blood flow and ICP
MAC- 2.0
Forms compound A with soda lime in closed circuitventilation
May precipitate malignant hyperthermia
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Indications for Respiratory Drugs
bronchodilation
secretion control
anti-infection prophylaxis
rescue
maintenance
anti-inflammatory General anaesthesia
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