Dr. CHANDANE R. D.Dr. CHANDANE R. D.
Assistant ProfessorAssistant Professor
Dept. Of PharmacologyDept. Of Pharmacology
Gov...
HISTORYHISTORY
• Greek- azzein- sharp breathGreek- azzein- sharp breath
• HippocratesHippocrates
• GalenGalen
• Bronchodil...
ASTHMA DEFINATIONASTHMA DEFINATION
““Asthma is defined as a chronicAsthma is defined as a chronic
inflammatory disease of ...
Asthma is characterisedAsthma is characterised
CLINICALLYCLINICALLY- Recurrent bouts of coughing, shortness of
breath,ches...
Edema, cellular infiltration,Edema, cellular infiltration,
hyperplasiahyperplasia
PATHOGENESIS OF ASTHMAPATHOGENESIS OF ASTHMA
ASTHMA AS ANASTHMA AS AN INFLAMMATORY ILLNESSINFLAMMATORY ILLNESS
↑↑ no. of i...
Lymphocyte directedLymphocyte directed
eosinophilic bronchitiseosinophilic bronchitis
INHALED STIMULIINHALED STIMULI
Endothelin-1Endothelin-1
NitrousNitrous
Oxide,Oxide,
PGE2PGE2
CytokinesCytokines
GM-CSFGM-C...
INVESTIGATIONSINVESTIGATIONS
1.1. Pulmonary Function Test – PEFR, FEV1 etc.Pulmonary Function Test – PEFR, FEV1 etc.
2.2. ...
Approaches to treatmentApproaches to treatment
1.1. Prevention of AG:AB reaction- AG avoidancePrevention of AG:AB reaction...
AVOIDANCE OF TRIGGER FACTORSAVOIDANCE OF TRIGGER FACTORS
Feathers, animalFeathers, animal
danger, dust mitedanger, dust mi...
AEROSOL DELIVERY OF DRUGAEROSOL DELIVERY OF DRUG
• High local conc.-↓systemic side effects
• Delivery to Lung- Particle si...
INHALATION DELIVERY SYSTEMINHALATION DELIVERY SYSTEM
• MDI (Pressurized Metered Dose Inhaler) :-
-CFC propellants
- HFA pr...
• DRY POWDER INHALER :- Spinhaler & RotahalerDRY POWDER INHALER :- Spinhaler & Rotahaler
- Lactose or Glucose- Lactose or ...
CLASSIFICATIONCLASSIFICATION
I)I) BRONCHODILATORS :BRONCHODILATORS :
A)A) ββ-2 Sympathomimetics:- Salbutamol, Terbutaline,...
I)I) BRONCHODILATORSBRONCHODILATORS
A}A} ββ-2 SYMPATHOMIMETICS-2 SYMPATHOMIMETICS
► SHORT ACTING - Symptomatic reliefSHORT...
Receptor DesensitizationReceptor Desensitization:-:-
►chronic t/t ,chronic t/t ,
►Receptor on bronchial smooth muscles → r...
SHORT ACTINGSHORT ACTING ββ-2 ADRENERGIC AGONISTS-2 ADRENERGIC AGONISTS
Albuterol(salbutamol), Levoalbuterol,Albuterol(sal...
i]i] ALBUTEROL(SALBUTAMOL):-ALBUTEROL(SALBUTAMOL):-
- Attack of asthma- Attack of asthma
- S/E – Muscle tremors, palpitati...
iv] METOPROTERENOL:-iv] METOPROTERENOL:-
- Less- Less ββ2 selective2 selective
- resistant to methylation by COMT- resista...
LONG ACTINGLONG ACTING ββ-2 ADRENERGIC AGONISTS-2 ADRENERGIC AGONISTS
SALMETEROL, FORMOTEROL, BAMBUTEROL,SALMETEROL, FORMO...
ii) FORMOTEROL:-ii) FORMOTEROL:-
- Fast onset of action, duration 12 hrs- Fast onset of action, duration 12 hrs
- DOSE: 12...
ORAL THERAPY:-ORAL THERAPY:-
- Greater risk of side effects- Tremors, muscle cramps,- Greater risk of side effects- Tremor...
B} METHYL XANTHINESB} METHYL XANTHINES
--Theophylline - first extracted from tea leaves –Theophylline - first extracted fr...
PHARMACOLOGICALACTIONS:PHARMACOLOGICALACTIONS:
1) CNS: Stimulation ↑ performance & motor activity caffeine1) CNS: Stimulat...
MECHANISM OF ACTIONMECHANISM OF ACTION
THREE DISTINCT ACTIONSTHREE DISTINCT ACTIONS
a) Inhibition of phosphodiesterasea) I...
ADVERSE EFFECTSADVERSE EFFECTS
Efficacy Plasma conc.Efficacy Plasma conc. µg/mlµg/ml toxicitytoxicity
BRONCHODILATATIONBRO...
INTERACTIONS:-INTERACTIONS:-
1) Inducer -↑dose – Phenytoin, Rifampicin, Phenobarbitone1) Inducer -↑dose – Phenytoin, Rifam...
Doxophylline:- Long acting,Doxophylline:- Long acting,
- Not interfere- sleep, G I secretion- Not interfere- sleep, G I se...
C} ANTICHOLINERGIC AGENTS
Atropinic drugs – block constrictor tone, large airway
IPRATROPIUM BROMIDE:-
- Muscarinic recept...
II) LEUKOTRIEN ANTAGONISTSII) LEUKOTRIEN ANTAGONISTS
Leukotrien receptor antagonist- Montelukast & ZafirlukastLeukotrien r...
PHARMACOKINETICS & METABOLISMPHARMACOKINETICS & METABOLISM
DRUGDRUG BioavaiBioavai TT1/21/2 MetabolismMetabolism Prot. BPr...
III) MAST CELL STABILIZERSIII) MAST CELL STABILIZERS
1) SODIUM CROMOGLYCATE ( Cromolyn Sod.):-1) SODIUM CROMOGLYCATE ( Cro...
Adverse Effects- bronchospasm, cough, Throat irritation,Adverse Effects- bronchospasm, cough, Throat irritation,
Laryngeal...
IV) CORTICOSTEROIDSIV) CORTICOSTEROIDS
InhaledInhaled ββ2 agonist for 4 or more times wkly - start2 agonist for 4 or more ...
INHALED STEROIDS
High topical & Low systemic activity
1) Beclomethasone dipropionate
2) Flunisolide
3) Fluticasone propion...
Fluticasone Budesonide – higher affinityFluticasone Budesonide – higher affinity
-Dose- 100-200 µg BD upto 400 µg QID-Dose...
CICLESONIDE-CICLESONIDE-
- Improved topical:Systemic activity ratio- Improved topical:Systemic activity ratio
- Prodrug- P...
ADVERSE EFFECTS OF INHALED STEROIDADVERSE EFFECTS OF INHALED STEROID
Horseness of voice, dysphonia, sore throat &Horseness...
STEROID RESISTANT ASTHMA
Definition- It is defined as a failure to respond to high
doses of oral glucocorticoids
(2wk cour...
MANAGEMENT OF STEROID RESISTANTMANAGEMENT OF STEROID RESISTANT
ASTHMAASTHMA :-:-
1)1) Methotrexate:Inhibit amidophosphorib...
V) ANTI IgE ANTIBODYV) ANTI IgE ANTIBODY
OMALIZUMABOMALIZUMAB
1921 Prausnitz & Kustner -reagin transfer allergic reaction1...
OMALIZUMAB…..OMALIZUMAB…..
Pharmacokinetics- Single s.c. inj. every 2-4 wksPharmacokinetics- Single s.c. inj. every 2-4 wk...
GUIDELINE FOR TREATMENT OF ASTHMAGUIDELINE FOR TREATMENT OF ASTHMA
1) MILD EPISODIC ASTHMA –1) MILD EPISODIC ASTHMA –
♦♦ S...
3) MODERATE ASTHMA (Frequent exacerbations)3) MODERATE ASTHMA (Frequent exacerbations)
♦♦ SymptomsSymptoms >1/day, attack ...
4) SEVERE ASTHMA -4) SEVERE ASTHMA -
♦ Continuous symptoms Limitation of♦ Continuous symptoms Limitation of
activity . Fre...
STATUS ASTHMATICUSSTATUS ASTHMATICUS (Severe Acute Asthma)(Severe Acute Asthma)
Acute asthmatic attack not responding to r...
MANAGEMENT OF STATUS ASTHMATICUSMANAGEMENT OF STATUS ASTHMATICUS
1.1. Hydrocortisone hemisuccinate 100mg iv statHydrocorti...
COMPLIMENTARY AND ALTERNATIVECOMPLIMENTARY AND ALTERNATIVE
1.1. Acupuncture –Acupuncture –
2.2. Air ioniser - +ve & -ve io...
Pharmacotherapy of Asthma
Pharmacotherapy of Asthma
Pharmacotherapy of Asthma
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Pharmacotherapy of Asthma

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Educational and therapeutic topic on asthma for MBBS and MD pharmacology students. other students like BDS , BHMS, BAMS etc can use for knowledge. and academic purpose.

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Pharmacotherapy of Asthma

  1. 1. Dr. CHANDANE R. D.Dr. CHANDANE R. D. Assistant ProfessorAssistant Professor Dept. Of PharmacologyDept. Of Pharmacology Govt. Medical College, AkolaGovt. Medical College, Akola
  2. 2. HISTORYHISTORY • Greek- azzein- sharp breathGreek- azzein- sharp breath • HippocratesHippocrates • GalenGalen • Bronchodilators- 1901Bronchodilators- 1901 • anti-inflammatory added in 1960anti-inflammatory added in 1960 Incidence- higher in low income populationIncidence- higher in low income population
  3. 3. ASTHMA DEFINATIONASTHMA DEFINATION ““Asthma is defined as a chronicAsthma is defined as a chronic inflammatory disease of airway that isinflammatory disease of airway that is characterized by increase responsiveness ofcharacterized by increase responsiveness of tracheobronchial tree to a multiplicity oftracheobronchial tree to a multiplicity of stimuli .”stimuli .” Extrinsic: episodic, atopyExtrinsic: episodic, atopy Intrinsic : perennial, status asthmaticusIntrinsic : perennial, status asthmaticus
  4. 4. Asthma is characterisedAsthma is characterised CLINICALLYCLINICALLY- Recurrent bouts of coughing, shortness of breath,chest tightness & wheezing PHYSIOGICALLYPHYSIOGICALLY- Narrowing of bronchial airway & increase in bronchial responsiveness PATHOLOGICALLYPATHOLOGICALLY- Lymphocytic eosinophilic inflammation of bronchial mucosa Remodelling of bronchial mucosa & hyperplasia of all structural elements
  5. 5. Edema, cellular infiltration,Edema, cellular infiltration, hyperplasiahyperplasia
  6. 6. PATHOGENESIS OF ASTHMAPATHOGENESIS OF ASTHMA ASTHMA AS ANASTHMA AS AN INFLAMMATORY ILLNESSINFLAMMATORY ILLNESS ↑↑ no. of inflammatory cells (eosinophills)no. of inflammatory cells (eosinophills) These produces mediators asThese produces mediators as • Mediators stored in granules (immediate)- Histamine,Mediators stored in granules (immediate)- Histamine, Protease enzymes, TNF-Protease enzymes, TNF-αα • Membrane phospholipids f/b mediator synthesisMembrane phospholipids f/b mediator synthesis (within minutes) - PGs, LTs, PAF(within minutes) - PGs, LTs, PAF • Gene activation f/b protein synthesis (over hrs)- ILs,Gene activation f/b protein synthesis (over hrs)- ILs, TNF-TNF-αα
  7. 7. Lymphocyte directedLymphocyte directed eosinophilic bronchitiseosinophilic bronchitis
  8. 8. INHALED STIMULIINHALED STIMULI Endothelin-1Endothelin-1 NitrousNitrous Oxide,Oxide, PGE2PGE2 CytokinesCytokines GM-CSFGM-CSF IL-8IL-8 EotaxinEotaxin Growth FactorsGrowth Factors EGFEGF IGF-1IGF-1 PDGFPDGF Broncho-Broncho- constrictionconstriction VasodilationVasodilation InflammationInflammation FibrosisFibrosis Smooth MuscleSmooth Muscle HyperplasiaHyperplasia
  9. 9. INVESTIGATIONSINVESTIGATIONS 1.1. Pulmonary Function Test – PEFR, FEV1 etc.Pulmonary Function Test – PEFR, FEV1 etc. 2.2. Absolute eosinophil countAbsolute eosinophil count 3.3. Chest X-rayChest X-ray 4.4. Allergy testAllergy test
  10. 10. Approaches to treatmentApproaches to treatment 1.1. Prevention of AG:AB reaction- AG avoidancePrevention of AG:AB reaction- AG avoidance HyposensitizationHyposensitization 2.2. Neutralization of IgE- OmalizumabNeutralization of IgE- Omalizumab 3.3. Supression of inflammation & bronchial hyperreactivitivity-Supression of inflammation & bronchial hyperreactivitivity- corticosteroidscorticosteroids 4.4. Prevention of release of mediators- mast cell stabilizersPrevention of release of mediators- mast cell stabilizers 5.5. Antagonism of related mediators- LT antagonist,Antagonism of related mediators- LT antagonist, antihistamines, PAF antagonistantihistamines, PAF antagonist 6.6. Blockade of constrictor NT- AnticholinergicsBlockade of constrictor NT- Anticholinergics 7.7. Mimicking dilator NT- SympathomimeticsMimicking dilator NT- Sympathomimetics 8.8. Directly acting bronchodilator- Methyl xanthinesDirectly acting bronchodilator- Methyl xanthines
  11. 11. AVOIDANCE OF TRIGGER FACTORSAVOIDANCE OF TRIGGER FACTORS Feathers, animalFeathers, animal danger, dust mitedanger, dust mite Pollens & airPollens & air pollutantspollutants Pharmacological stimuli: Aspirin,Pharmacological stimuli: Aspirin, colouring agents, Beta-blockers,colouring agents, Beta-blockers, sulfiting agentssulfiting agents Occupational factors- wood laundryOccupational factors- wood laundry detergents, metal salts etcdetergents, metal salts etc Industrial chemicals & plasticsIndustrial chemicals & plastics
  12. 12. AEROSOL DELIVERY OF DRUGAEROSOL DELIVERY OF DRUG • High local conc.-↓systemic side effects • Delivery to Lung- Particle size 1-5µm • Other factors- Rate of breathing & breath holding • Maneuvers that ↑ drug deposition in lung • Spacer - ↑ inhaled : swallow drug
  13. 13. INHALATION DELIVERY SYSTEMINHALATION DELIVERY SYSTEM • MDI (Pressurized Metered Dose Inhaler) :- -CFC propellants - HFA propellants - Cheap portable – Hand breathing co-ordination • NEBULIZER :- - two types – ultrasonic & jet - not req. handbreathing co-ordination - Severe asthma exacerbation - face mask- children & older pt. - ultrasonic- hypertonic saline
  14. 14. • DRY POWDER INHALER :- Spinhaler & RotahalerDRY POWDER INHALER :- Spinhaler & Rotahaler - Lactose or Glucose- Lactose or Glucose - High air flow req.- High air flow req. - Irritating , Storage –humidity- Irritating , Storage –humidity FATE OF DRUGFATE OF DRUG - Only small % deposited 2-10%Only small % deposited 2-10% - Swallowed drug –First pass metabolismSwallowed drug –First pass metabolism
  15. 15. CLASSIFICATIONCLASSIFICATION I)I) BRONCHODILATORS :BRONCHODILATORS : A)A) ββ-2 Sympathomimetics:- Salbutamol, Terbutaline,-2 Sympathomimetics:- Salbutamol, Terbutaline, Bambuterol, Salmeterol, FormoterolBambuterol, Salmeterol, Formoterol B) Methyl Xanthines:- Theophylline, Aminophylline, Choline-B) Methyl Xanthines:- Theophylline, Aminophylline, Choline- theophyllinate, Hydroxyethyl Theophylline, Doxophyllinetheophyllinate, Hydroxyethyl Theophylline, Doxophylline C) Anticholinergics :– Ipratropium bromide, Tiotropium bromideC) Anticholinergics :– Ipratropium bromide, Tiotropium bromide II)II) LEUKOTRIEN ANTAGONISTS :LEUKOTRIEN ANTAGONISTS : Montelukast, Zafirlukast, ZileutonMontelukast, Zafirlukast, Zileuton III)III) MAST CELL STABILIZERS :MAST CELL STABILIZERS : Na cromoglycate, Nedocromil, KetotifenNa cromoglycate, Nedocromil, Ketotifen IV)IV) CORTICOSTEROIDS :CORTICOSTEROIDS : A) Systemic: Hydrocortisone, Prednisolone etcA) Systemic: Hydrocortisone, Prednisolone etc B) Inhalational: Beclomethasone dipropionate, Budesonide,B) Inhalational: Beclomethasone dipropionate, Budesonide, Fluticasone propionate, Flunisolide, CiclesonideFluticasone propionate, Flunisolide, Ciclesonide V)V) ANTI IgE ANTIBODYANTI IgE ANTIBODY : Omalizumab: Omalizumab
  16. 16. I)I) BRONCHODILATORSBRONCHODILATORS A}A} ββ-2 SYMPATHOMIMETICS-2 SYMPATHOMIMETICS ► SHORT ACTING - Symptomatic reliefSHORT ACTING - Symptomatic relief ► LONG ACTING - Prophylactic t/tLONG ACTING - Prophylactic t/t MECHANISM OF ACTIONMECHANISM OF ACTION ► Stimulation ofStimulation of ββ-2 receptors-2 receptors →↑→↑c-AMP formation inc-AMP formation in bronchial smooth muscle → relaxation of smoothbronchial smooth muscle → relaxation of smooth muscle. ↑conductance of large Camuscle. ↑conductance of large Ca+2+2 sensitive Ksensitive K++ channels → membrane hyper polarization &channels → membrane hyper polarization & relaxationrelaxation ► Stimulation ofStimulation of ββ-2 receptors on inflammatory cells →-2 receptors on inflammatory cells → ↑intracellular c-AMP → inhibit release of mediators↑intracellular c-AMP → inhibit release of mediators & cytokines& cytokines
  17. 17. Receptor DesensitizationReceptor Desensitization:-:- ►chronic t/t ,chronic t/t , ►Receptor on bronchial smooth muscles → resistantReceptor on bronchial smooth muscles → resistant ►Receptor on inflammatory cells → desensitized rapidly.Receptor on inflammatory cells → desensitized rapidly. ► Little effective in inhibiting airway inflammation.Little effective in inhibiting airway inflammation.
  18. 18. SHORT ACTINGSHORT ACTING ββ-2 ADRENERGIC AGONISTS-2 ADRENERGIC AGONISTS Albuterol(salbutamol), Levoalbuterol,Albuterol(salbutamol), Levoalbuterol, Metapreterenol, Terbutaline, Pirbuterol,Metapreterenol, Terbutaline, Pirbuterol, Isoetharine, Bitolterol, Fenoterol, ProcaterolIsoetharine, Bitolterol, Fenoterol, Procaterol Inhalation, onset action within 1-5 min.Inhalation, onset action within 1-5 min. Bronchodilation for 2-6 hrs.Bronchodilation for 2-6 hrs. Most effective drugMost effective drug → reversing→ reversing BronchoconstictionBronchoconstiction Rapid symptomatic relief; as needed basisRapid symptomatic relief; as needed basis
  19. 19. i]i] ALBUTEROL(SALBUTAMOL):-ALBUTEROL(SALBUTAMOL):- - Attack of asthma- Attack of asthma - S/E – Muscle tremors, palpitation restlessness,- S/E – Muscle tremors, palpitation restlessness, nervousness, ankle edema, throat irritationnervousness, ankle edema, throat irritation - Presystemic metabolism in gut wall- Presystemic metabolism in gut wall - Dose- 2-4mg oral, 100-200µg inhalation,- Dose- 2-4mg oral, 100-200µg inhalation, 0.25-0.5mg im/s.c.0.25-0.5mg im/s.c. ii]ii] LEVOALBUTEROL(LEVOSALBUTAMOL):-LEVOALBUTEROL(LEVOSALBUTAMOL):- - R-enantiomer of albuterol- R-enantiomer of albuterol - more potent Bronchodilator- more potent Bronchodilator - less side effects: so used in pt with h/o SVT & other- less side effects: so used in pt with h/o SVT & other arrhythmiasarrhythmias iii]iii] TERBUTALINE:-TERBUTALINE:- Similar to albuterolSimilar to albuterol - Dose- 5mg oral, 0.25mg sc, 250µg inhalation- Dose- 5mg oral, 0.25mg sc, 250µg inhalation
  20. 20. iv] METOPROTERENOL:-iv] METOPROTERENOL:- - Less- Less ββ2 selective2 selective - resistant to methylation by COMT- resistant to methylation by COMT - More prone to cardiac stimulation- More prone to cardiac stimulation v] ISOETHARINE:-v] ISOETHARINE:- - First- First ββ2 selective widely used2 selective widely used - resistant to metabolism by MAO- resistant to metabolism by MAO - Inhalation- Inhalation vi] FENOTEROL :-vi] FENOTEROL :- Association with increase deathAssociation with increase death vii] BITOLTEROL:-vii] BITOLTEROL:- Prodrug - esterases hydrolyzes toProdrug - esterases hydrolyzes to active Colterolactive Colterol vii] PIRBUTEROL & ix] PROCATEROL :-vii] PIRBUTEROL & ix] PROCATEROL :- InhalationInhalation
  21. 21. LONG ACTINGLONG ACTING ββ-2 ADRENERGIC AGONISTS-2 ADRENERGIC AGONISTS SALMETEROL, FORMOTEROL, BAMBUTEROL,SALMETEROL, FORMOTEROL, BAMBUTEROL, CLENBUTEROLCLENBUTEROL i)i) SALMETEROL:-SALMETEROL:- - First long acting- First long acting ββ2 agonist2 agonist - slow onset of action- slow onset of action - duration is 12 hrs bronchodilation- duration is 12 hrs bronchodilation - inhalation twice daily - nocturnal asthma- inhalation twice daily - nocturnal asthma - 10,000 more lipophilic than albuterol- 10,000 more lipophilic than albuterol - unbound salmeterol persist in membrane &- unbound salmeterol persist in membrane & slowly dissociate from receptor environmentslowly dissociate from receptor environment - DOSE: 50-100 µg BD by inhalation- DOSE: 50-100 µg BD by inhalation
  22. 22. ii) FORMOTEROL:-ii) FORMOTEROL:- - Fast onset of action, duration 12 hrs- Fast onset of action, duration 12 hrs - DOSE: 12-24 µg BD by inhalation- DOSE: 12-24 µg BD by inhalation iii) BAMBUTEROL:-iii) BAMBUTEROL:- - Prodrug of terbutaline- Prodrug of terbutaline - Hydrolyzed by pseudo cholinesterase-release active drug- Hydrolyzed by pseudo cholinesterase-release active drug - Chronic bronchial asthma- Chronic bronchial asthma - DOSE: 10-20 mg OD in evening orally- DOSE: 10-20 mg OD in evening orally iv) CLENBUTEROL:-iv) CLENBUTEROL:- -- More potent, long acting & thermogenic drugMore potent, long acting & thermogenic drug - ↑ aerobic capacity, ↑ BP, CNS Stimulation- ↑ aerobic capacity, ↑ BP, CNS Stimulation - ↑ fat & protein use ↓ glycogen storage – wt. loss drug- ↑ fat & protein use ↓ glycogen storage – wt. loss drug - banned for athletes & players- banned for athletes & players - DOSE: 20-60µg/day max. 150µg- DOSE: 20-60µg/day max. 150µg -T-T - 36-39 hrs - Pork meat poisoning- 36-39 hrs - Pork meat poisoning
  23. 23. ORAL THERAPY:-ORAL THERAPY:- - Greater risk of side effects- Tremors, muscle cramps,- Greater risk of side effects- Tremors, muscle cramps, cardiac tachyarrhythmia & metabolic disturbancescardiac tachyarrhythmia & metabolic disturbances - two situations of oral therapy- two situations of oral therapy 1. Young children (syr.) -can not manipulate inhalers1. Young children (syr.) -can not manipulate inhalers 2. Severe asthma exacerbation - local irritation2. Severe asthma exacerbation - local irritation COMBINATIONCOMBINATION –– -- Long actingLong acting ββ2 agonist + Glucocorticoids2 agonist + Glucocorticoids - Salmeterol + Fluticasone, Formoterol + Budesonide- Salmeterol + Fluticasone, Formoterol + Budesonide - More effective than doubling steroid dose- More effective than doubling steroid dose
  24. 24. B} METHYL XANTHINESB} METHYL XANTHINES --Theophylline - first extracted from tea leaves –Theophylline - first extracted from tea leaves – 1888 by German biologist Albrecht Kossel.1888 by German biologist Albrecht Kossel. - Synthesized by another German scientist,- Synthesized by another German scientist, Wilhelm Traube.Wilhelm Traube. - First clinical use in asthma t/t in 1950s.- First clinical use in asthma t/t in 1950s. - Among Least expensive- Among Least expensive - Three xanthine alkaloids: Caffeine, Theophylline &- Three xanthine alkaloids: Caffeine, Theophylline & TheobromineTheobromine
  25. 25. PHARMACOLOGICALACTIONS:PHARMACOLOGICALACTIONS: 1) CNS: Stimulation ↑ performance & motor activity caffeine1) CNS: Stimulation ↑ performance & motor activity caffeine Higher doses (Theophylline) - nervousness, insomnia,Higher doses (Theophylline) - nervousness, insomnia, delerium, convulsion vomitingdelerium, convulsion vomiting 2) CVS: Stimulation ↑ force of contraction, tachycardia – BP2) CVS: Stimulation ↑ force of contraction, tachycardia – BP 3) Smooth Muscle: Relaxation -Most prominent Bronchial -↑ VC3) Smooth Muscle: Relaxation -Most prominent Bronchial -↑ VC 4) Kidney: Mild diuretic4) Kidney: Mild diuretic 5) Stomach : ↑ secretions5) Stomach : ↑ secretions 6) Skeletal Muscle: ↑ contractile power6) Skeletal Muscle: ↑ contractile power 7) Mast cells, inflammatory cells:↓release of histamine & mediators7) Mast cells, inflammatory cells:↓release of histamine & mediators 8) Metabolism: ↑ BMR8) Metabolism: ↑ BMR
  26. 26. MECHANISM OF ACTIONMECHANISM OF ACTION THREE DISTINCT ACTIONSTHREE DISTINCT ACTIONS a) Inhibition of phosphodiesterasea) Inhibition of phosphodiesterase - ATP- ATP Adenylyl cyclaseAdenylyl cyclase cAMPcAMP PhosphodiesterasePhosphodiesterase 5AMP5AMP . or or. or or or - GTPor - GTP Guanylyl cyclaseGuanylyl cyclase cGMPcGMP Inhibited by TheophyllineInhibited by Theophylline 5GMP5GMP - accumulation of cyclic nucleotide- ↑signal- accumulation of cyclic nucleotide- ↑signal transduction -transduction - Bronchodilatation, cardiac stimulation & vasodilatationBronchodilatation, cardiac stimulation & vasodilatation - Inhibition of PDE4 & PDE5- Inhibition of PDE4 & PDE5 (PDE4) Bronchodilatation(PDE4) Bronchodilatation b) Release of Cab) Release of Ca++++ from sarcoplasmic reticulum - skeletal & cardiac.from sarcoplasmic reticulum - skeletal & cardiac. At higher conc. than therapeutic plasma conc.At higher conc. than therapeutic plasma conc. c) Competitive antagonist at adenosine receptor -c) Competitive antagonist at adenosine receptor - Adenosine – contract smooth muscle, dilate cerebral bloodAdenosine – contract smooth muscle, dilate cerebral blood vessel, depress cardiac pacemaker, inhibit gastric secretionvessel, depress cardiac pacemaker, inhibit gastric secretion -- Anti-inflammatory action : histone deacetylase activation →Anti-inflammatory action : histone deacetylase activation →
  27. 27. ADVERSE EFFECTSADVERSE EFFECTS Efficacy Plasma conc.Efficacy Plasma conc. µg/mlµg/ml toxicitytoxicity BRONCHODILATATIONBRONCHODILATATION Thera range 5- 10- 15- 20- 25- 30- 35- DeathDeath Convulsion, Shock, ArrhythmiaConvulsion, Shock, Arrhythmia Delerium, Extrasystole, worsen CVS StatusDelerium, Extrasystole, worsen CVS Status Agitation, Tachypnea, Flushing,Agitation, Tachypnea, Flushing, Hypotension Restlessness, Tremor,Hypotension Restlessness, Tremor, Vomiting, Palpitation, DiuresisVomiting, Palpitation, Diuresis Headache, Nervousness,Headache, Nervousness, Insomnia Minimal side effectsInsomnia Minimal side effects PHARMACOKINETICS- cross placenta, secret in milk T1/2 – Adult-7-12hrs Children- 3-5hrs premature infant-24-36hrs & with higher doses up to 60 hrs
  28. 28. INTERACTIONS:-INTERACTIONS:- 1) Inducer -↑dose – Phenytoin, Rifampicin, Phenobarbitone1) Inducer -↑dose – Phenytoin, Rifampicin, Phenobarbitone 2) Inhibit metabolism- ↓dose- Erythromycin, Ciprofloxacin,2) Inhibit metabolism- ↓dose- Erythromycin, Ciprofloxacin, Cimetidine, OC Pills, AllopurinolCimetidine, OC Pills, Allopurinol 3) Theophylline ↑ effect of – Furosemide, Digitalis,3) Theophylline ↑ effect of – Furosemide, Digitalis, Anticoagulants, Sympathomimetics, HypoglycemicsAnticoagulants, Sympathomimetics, Hypoglycemics 4) Theophylline - ↓ effect of Phenytoin, Lithium4) Theophylline - ↓ effect of Phenytoin, Lithium DOSE:- Theophylline – 100-300mg TDS (15 mg/kg/day)DOSE:- Theophylline – 100-300mg TDS (15 mg/kg/day) Aminophylline- 250-500mg slow ivAminophylline- 250-500mg slow iv
  29. 29. Doxophylline:- Long acting,Doxophylline:- Long acting, - Not interfere- sleep, G I secretion- Not interfere- sleep, G I secretion - 400mg OD in evening- 400mg OD in evening PDE4 Inhibitors- Cilomilast & RoflumilastPDE4 Inhibitors- Cilomilast & Roflumilast In Asthma Theophyllines :In Asthma Theophyllines : -Bronchodilatation,-Bronchodilatation, - ↓ release of inflammatory mediators, - improve mucociliary clearance, - stimulate respiratory drive & - ↑ diaphragmatic contractility
  30. 30. C} ANTICHOLINERGIC AGENTS Atropinic drugs – block constrictor tone, large airway IPRATROPIUM BROMIDE:- - Muscarinic receptor antagonist - M3 receptor – Bronchoconstriction - Block all type of receptors - Slow and less intense bronchodilatation - Dose – 20-40 µg 6hrly inhalation TIOTROPIUM BROMIDE:- - Slow dissociation from muscarinic receptors - High affinity - OD doses
  31. 31. II) LEUKOTRIEN ANTAGONISTSII) LEUKOTRIEN ANTAGONISTS Leukotrien receptor antagonist- Montelukast & ZafirlukastLeukotrien receptor antagonist- Montelukast & Zafirlukast 5 Lipoxygenase inhibitor- Zileuton5 Lipoxygenase inhibitor- Zileuton History- 1930 Kellaway study leukotrienHistory- 1930 Kellaway study leukotrien - 1990s three drugs released- 1990s three drugs released Mechanism of Action-Mechanism of Action- - Leukotrien receptor antagonist-- Leukotrien receptor antagonist- Cysteinyl LT –bronchoconstrictor LTC4, LTD4, LTE4Cysteinyl LT –bronchoconstrictor LTC4, LTD4, LTE4 & LT1& LT1 Montelukast & Zafirlukast Pranlukast - high affinity competitiveMontelukast & Zafirlukast Pranlukast - high affinity competitive antagonist - cys LT1 Receptor -antagonist - cys LT1 Receptor - Leukotrien synthesis inhibitor- 5LOX InhibitedLeukotrien synthesis inhibitor- 5LOX Inhibited arachidonic acid → Leukotrien by 5LOXarachidonic acid → Leukotrien by 5LOX Inhibit formation of cys LTsInhibit formation of cys LTs
  32. 32. PHARMACOKINETICS & METABOLISMPHARMACOKINETICS & METABOLISM DRUGDRUG BioavaiBioavai TT1/21/2 MetabolismMetabolism Prot. BProt. B ZafirlukastZafirlukast 90%90% 10hrs10hrs CYP2C9CYP2C9 >99%>99% MontelukastMontelukast 60-70%60-70% 3-6hrs3-6hrs CYP3A4 & CYP2C9CYP3A4 & CYP2C9 99%99% ZileutonZileuton -- 2.5hrs2.5hrs CYPs & UDP-GTCYPs & UDP-GT 93%93% Adverse Effects:-Adverse Effects:- • Zafirlukast & Montelukast- Systemic eosinophilia,Zafirlukast & Montelukast- Systemic eosinophilia, Vasculitis, Neuropathy.Vasculitis, Neuropathy. • Zafirlukast - warfarin ↑PTZafirlukast - warfarin ↑PT • Zileuton- ↑Liver Enzymes, ↑plasma conc. Theophylline &Zileuton- ↑Liver Enzymes, ↑plasma conc. Theophylline & warfarinwarfarin DOSE:- Montelukast- 10 mg OD Children 5 mg ODDOSE:- Montelukast- 10 mg OD Children 5 mg OD Zafirlukast- 20 mg BD Children 10 mg BDZafirlukast- 20 mg BD Children 10 mg BD
  33. 33. III) MAST CELL STABILIZERSIII) MAST CELL STABILIZERS 1) SODIUM CROMOGLYCATE ( Cromolyn Sod.):-1) SODIUM CROMOGLYCATE ( Cromolyn Sod.):- - Synthesize-1965 , plant Amni visnaga ,- Synthesize-1965 , plant Amni visnaga , - use asthma 1973- use asthma 1973 Mechanism of Action:-Mechanism of Action:- - Inhibit degranulation of mast cells and other- Inhibit degranulation of mast cells and other inflammatory cells. Inhibit chemotaxisinflammatory cells. Inhibit chemotaxis - ↓Bronchial hyperreactivity- ↓Bronchial hyperreactivity Pharmacokinetics-Pharmacokinetics- - not absorbed orally- not absorbed orally - Inhalation Fraction absorbed excreted unchanged- Inhalation Fraction absorbed excreted unchanged in urine & bilein urine & bile - T- T1/21/2 – 45-100min– 45-100min
  34. 34. Adverse Effects- bronchospasm, cough, Throat irritation,Adverse Effects- bronchospasm, cough, Throat irritation, Laryngeal edema, Headache, Bad tasteLaryngeal edema, Headache, Bad taste Dose- 1 mg 4 times dailyDose- 1 mg 4 times daily 2) NEDOCROMIL:-2) NEDOCROMIL:- 1992 , similar to Cromolyn Sod. More effective1992 , similar to Cromolyn Sod. More effective approvedapproved >> 12 yrs12 yrs Dose - 4 mg qidDose - 4 mg qid 3) KETOTIFEN :-3) KETOTIFEN :- Antihistaminic H1 with cromoglycate like actionAntihistaminic H1 with cromoglycate like action Realease of mediator inhibitedRealease of mediator inhibited orally absorbed Bioavai. 50% Torally absorbed Bioavai. 50% T1/21/2 – 22hrs– 22hrs Adverse Effects:- Sedation, dry mouth, dizziness, wt gainAdverse Effects:- Sedation, dry mouth, dizziness, wt gain Dose:- 1-2 mg BD Children 0.5 mg BDDose:- 1-2 mg BD Children 0.5 mg BD
  35. 35. IV) CORTICOSTEROIDSIV) CORTICOSTEROIDS InhaledInhaled ββ2 agonist for 4 or more times wkly - start2 agonist for 4 or more times wkly - start inhaled glucocorticoidsinhaled glucocorticoids Mechanism of Action in Asthma:- -Mechanism of Action in Asthma:- - inhibit airway inflammation -inhibit airway inflammation - Anti-inflammatory effect-Anti-inflammatory effect- *Modulation of cytokine chemokine production,*Modulation of cytokine chemokine production, *Inhibition of eicosanoid production,*Inhibition of eicosanoid production, *Inhibition of accumulation of inflammatory cells in*Inhibition of accumulation of inflammatory cells in Lung tissue &Lung tissue & *↓Vascular permeability*↓Vascular permeability - ↓bronchial hyperreactivity, mucosal edema &- ↓bronchial hyperreactivity, mucosal edema & supress inflammatory response by AG:AB reactionsupress inflammatory response by AG:AB reaction
  36. 36. INHALED STEROIDS High topical & Low systemic activity 1) Beclomethasone dipropionate 2) Flunisolide 3) Fluticasone propionate 4) Budesonide 5) Triamcinolone acetonide 6) Mometasone Newer steroids- a) on site activated – Ciclesonide, Rofleponide b) Soft steroids – improved local topical selectivity Lactone GCS conjugate, Loteprednol etabonate
  37. 37. Fluticasone Budesonide – higher affinityFluticasone Budesonide – higher affinity -Dose- 100-200 µg BD upto 400 µg QID-Dose- 100-200 µg BD upto 400 µg QID Compliance- highly potent Fluticasone,Compliance- highly potent Fluticasone, -Budesonide-BD/OD improve pt compliance-Budesonide-BD/OD improve pt compliance BUDESONIDE - High topical:systemic activityBUDESONIDE - High topical:systemic activity - Dose – 200-400 µg BD-QiD inhalation- Dose – 200-400 µg BD-QiD inhalation FLUTICASONE PROPIONATE- High potent long actingFLUTICASONE PROPIONATE- High potent long acting - Dose- 100-250 µg OD (max. 1000 µg/day)- Dose- 100-250 µg OD (max. 1000 µg/day) FLUNISOLIDE - 25 µg TDSFLUNISOLIDE - 25 µg TDS
  38. 38. CICLESONIDE-CICLESONIDE- - Improved topical:Systemic activity ratio- Improved topical:Systemic activity ratio - Prodrug- Prodrug - esterases in bronchial epithelium- esterases in bronchial epithelium - oral bioavailability <1% Extensively bindoral bioavailability <1% Extensively bind to plasma proteinto plasma protein - Dose- 80-160 µgOD in evening inhalation- Dose- 80-160 µgOD in evening inhalation SYSTEMIC THERAPY-SYSTEMIC THERAPY- Use – Chronic sever asthma & Acute asthma exacerbation.Use – Chronic sever asthma & Acute asthma exacerbation. - Prednisolone 20-60 mg/day (1-2mg/kg) Taper- Prednisolone 20-60 mg/day (1-2mg/kg) Taper & start inhalation& start inhalation - Acute asthma exacerbation- iv steroid then shift to- Acute asthma exacerbation- iv steroid then shift to oral & tapperoral & tapper
  39. 39. ADVERSE EFFECTS OF INHALED STEROIDADVERSE EFFECTS OF INHALED STEROID Horseness of voice, dysphonia, sore throat &Horseness of voice, dysphonia, sore throat & Oropharyngeal candiasis- minimized by spacer, garglingOropharyngeal candiasis- minimized by spacer, gargling & topical nystatin /clotrimazole& topical nystatin /clotrimazole Hypothalamic adrenal supression-no risk ↑ with >1500Hypothalamic adrenal supression-no risk ↑ with >1500µgµg Osteoporosis- female 500Osteoporosis- female 500 µg /dayµg /day CHO & Lip[id metabolism - >1000µg /dayCHO & Lip[id metabolism - >1000µg /day Cataract –Cataract – Skin thinning- dose related 400-2000µg/day purpureaSkin thinning- dose related 400-2000µg/day purpurea Growth retardation- no significant riskGrowth retardation- no significant risk
  40. 40. STEROID RESISTANT ASTHMA Definition- It is defined as a failure to respond to high doses of oral glucocorticoids (2wk course of 40mg prednisolone/day) Two types :- • Type I:- 90% ↓binding affinity of GCS to T cell receptor • Type II:- primary inactivity of steroid receptor / abnormally low no. of GCS receptor binding sites
  41. 41. MANAGEMENT OF STEROID RESISTANTMANAGEMENT OF STEROID RESISTANT ASTHMAASTHMA :-:- 1)1) Methotrexate:Inhibit amidophosphoribosyltransferase-Methotrexate:Inhibit amidophosphoribosyltransferase- inhibit T cell proliferation, ↓dose ↑sensitivity toinhibit T cell proliferation, ↓dose ↑sensitivity to prednisoloneprednisolone 2)2) Cyclosporin: inhibit T cell proliferation, IL2 & otherCyclosporin: inhibit T cell proliferation, IL2 & other cytokine productioncytokine production 3)3) Leflunomide: DMARDs Th cytokine expressionLeflunomide: DMARDs Th cytokine expression suppresssuppress 4)4) Rapamycin: inhibit T cell proliferation, cytokine synthRapamycin: inhibit T cell proliferation, cytokine synth 5)5) IV Immunoglobulin: Steroid sparing, costlyIV Immunoglobulin: Steroid sparing, costly 6)6) Gold: ↓ steroid useGold: ↓ steroid use
  42. 42. V) ANTI IgE ANTIBODYV) ANTI IgE ANTIBODY OMALIZUMABOMALIZUMAB 1921 Prausnitz & Kustner -reagin transfer allergic reaction1921 Prausnitz & Kustner -reagin transfer allergic reaction 1971 Ishizaka –IgE1971 Ishizaka –IgE Omalizumab – DNA derived humanized monoclonalOmalizumab – DNA derived humanized monoclonal antibody of IgG1k subclass. Cell culture (Chineseantibody of IgG1k subclass. Cell culture (Chinese hamster ovary cells)hamster ovary cells) Mechanism of Action:-Mechanism of Action:- Fc-IgE ↔FcFc-IgE ↔FcεεRIRI AGAG ↔ IgE ↔ Fc↔ IgE ↔ FcεεRIRI → activate mast cell.→→ activate mast cell.→ LTC4, PGD2, cytokinesLTC4, PGD2, cytokines Omalizumab- IgG AB – AG is Fc-IgE (Anti- AB AB)Omalizumab- IgG AB – AG is Fc-IgE (Anti- AB AB) Omalizumab + Free IgE → Omalizumab – IgE ComplexOmalizumab + Free IgE → Omalizumab – IgE Complex complex- no affinity to Fccomplex- no affinity to FcεεRIRI ↓↓ FcFcεεRI expression on mast cells..RI expression on mast cells..
  43. 43. OMALIZUMAB…..OMALIZUMAB….. Pharmacokinetics- Single s.c. inj. every 2-4 wksPharmacokinetics- Single s.c. inj. every 2-4 wks - Bioavai- 60%,- Bioavai- 60%, - T- T1/21/2- 26 days- 26 days Adverse Effects- well toleratedAdverse Effects- well tolerated - Inj. Site reaction- redness, stinging, induration- Inj. Site reaction- redness, stinging, induration - Anaphylaxis 0.1%- Anaphylaxis 0.1% In Asthma- >12yrs allergy & mod to severe AsthmaIn Asthma- >12yrs allergy & mod to severe Asthma - ↓ exacerbations & steroid req- ↓ exacerbations & steroid req PAF ANTAGONIST-PAF ANTAGONIST- - Gingkgolide & structural analogue of PAF- Gingkgolide & structural analogue of PAF - PAF – bronchoconstriction & edema- PAF – bronchoconstriction & edema
  44. 44. GUIDELINE FOR TREATMENT OF ASTHMAGUIDELINE FOR TREATMENT OF ASTHMA 1) MILD EPISODIC ASTHMA –1) MILD EPISODIC ASTHMA – ♦♦ Symptoms < 1 daily & Normal between attacksSymptoms < 1 daily & Normal between attacks ♦♦ STEP 1:- Inhaled short actingSTEP 1:- Inhaled short acting ββ2 agonist - onset of2 agonist - onset of attack. No prophylactic t/t.attack. No prophylactic t/t. 2) MILD CHRONIC ASTHMA –2) MILD CHRONIC ASTHMA – ♦♦ Symptoms once daily or soSymptoms once daily or so ♦♦ STEP 2:- Regular inhaled low dose steroids & episodeSTEP 2:- Regular inhaled low dose steroids & episode t/t witht/t with Inhaled short actingInhaled short acting ββ2 agonist2 agonist
  45. 45. 3) MODERATE ASTHMA (Frequent exacerbations)3) MODERATE ASTHMA (Frequent exacerbations) ♦♦ SymptomsSymptoms >1/day, attack affect activity & sleep>1/day, attack affect activity & sleep ♦♦ STEP 3:- ↑ dose ofSTEP 3:- ↑ dose of inhaled steroids (upto 800inhaled steroids (upto 800µg/day)µg/day) ++ Inhaled long actingInhaled long acting ββ2 agonist2 agonist (alternative leukotrien antagonist, Theophylline)(alternative leukotrien antagonist, Theophylline) episode t/t withepisode t/t with Inhaled short actingInhaled short acting ββ2 agonist2 agonist
  46. 46. 4) SEVERE ASTHMA -4) SEVERE ASTHMA - ♦ Continuous symptoms Limitation of♦ Continuous symptoms Limitation of activity . Frequentactivity . Frequent exacerbations/Hospitalisationexacerbations/Hospitalisation ♦♦ STEP 4:- Regular inhaled High dose steroidsSTEP 4:- Regular inhaled High dose steroids (800-2000µg/day) large vol spacer + Inhaled(800-2000µg/day) large vol spacer + Inhaled long actinglong acting ββ2 agonist2 agonist twice dailytwice daily - Additional t/t with 1 or more -- Additional t/t with 1 or more - i) Leukotrien antagonist/ SR theophylline/ Orali) Leukotrien antagonist/ SR theophylline/ Oral ββ2 agonist /2 agonist / Inhaled ipratropium bromideInhaled ipratropium bromide ii) episode t/t with Inhaled short actingepisode t/t with Inhaled short acting ββ2 agonist2 agonist ♦♦ STEP 5:- pt not adequately controlled or needing frequentSTEP 5:- pt not adequately controlled or needing frequent emergency careemergency care - Oral steroid therapy- Oral steroid therapy
  47. 47. STATUS ASTHMATICUSSTATUS ASTHMATICUS (Severe Acute Asthma)(Severe Acute Asthma) Acute asthmatic attack not responding to routine t/t &Acute asthmatic attack not responding to routine t/t & ββ22 agonist life threateningagonist life threatening Precipitated byPrecipitated by i) Acute respiratory infectioni) Acute respiratory infection ii) Abrupt cessation of steroid therapyii) Abrupt cessation of steroid therapy iii) Pharmacological stimuli/Allergensiii) Pharmacological stimuli/Allergens iv) Acute emotional stressiv) Acute emotional stress
  48. 48. MANAGEMENT OF STATUS ASTHMATICUSMANAGEMENT OF STATUS ASTHMATICUS 1.1. Hydrocortisone hemisuccinate 100mg iv statHydrocortisone hemisuccinate 100mg iv stat f/b 100-200mg 4-8hrly infusion ( take 6hrs to act)f/b 100-200mg 4-8hrly infusion ( take 6hrs to act) 2.2. Nebulized Salbutamol (2.5-5mg) + IpratropiumNebulized Salbutamol (2.5-5mg) + Ipratropium bromide (0.5mg)bromide (0.5mg) 3.3. High flow humidified OHigh flow humidified O22 4.4. Salbutamol /Terbutaline 0.4mg s.c.Salbutamol /Terbutaline 0.4mg s.c. 5.5. Intubation & mechanical ventilationIntubation & mechanical ventilation 6.6. AntibioticsAntibiotics 7.7. Saline + Sod. BicarbonateSaline + Sod. Bicarbonate Aminophylline 250-500mg dil in 20-30mlAminophylline 250-500mg dil in 20-30ml 5% Glucose iv over 20-30min5% Glucose iv over 20-30min
  49. 49. COMPLIMENTARY AND ALTERNATIVECOMPLIMENTARY AND ALTERNATIVE 1.1. Acupuncture –Acupuncture – 2.2. Air ioniser - +ve & -ve ion generatorAir ioniser - +ve & -ve ion generator 3.3. Osteopathic, Physiotherapeutic, Chiropractic,Osteopathic, Physiotherapeutic, Chiropractic, Respiratory therapeutic maneuvers –Respiratory therapeutic maneuvers – 4.4. Homeopathy – mild benefit. Arsenic, Album, aconite,Homeopathy – mild benefit. Arsenic, Album, aconite, kalicarbonicum, Natrum etc.kalicarbonicum, Natrum etc. 5.5. Yoga, Pranayam, Meditation etc.Yoga, Pranayam, Meditation etc. 6.6. Buteyko Method – Russian therapy-Breathing exerciseButeyko Method – Russian therapy-Breathing exercise 7.7. Helminthic therapy – -ve associationHelminthic therapy – -ve association 8.8. Guaifenesin – expectorant-thick mucusGuaifenesin – expectorant-thick mucus 9.9. Aroma Therapy – Eucalyptus, Lavender, Rosemary –Aroma Therapy – Eucalyptus, Lavender, Rosemary – Free breathing fragranceFree breathing fragrance
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