Pharmacology of Respiratory System

7/30/2019 Pharmacology of Respiratory System

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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%


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 %


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%


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 %


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


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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Pharmacology of Respiratory System

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