Dr. CHANDANE R. D.Dr. CHANDANE R. D. Assistant ProfessorAssistant Professor Dept. Of PharmacologyDept. Of Pharmacology Govt. Medical College, AkolaGovt. Medical College, Akola

HISTORYHISTORY

• Greek- azzein- sharp breathGreek- azzein- sharp breath

• HippocratesHippocrates

• GalenGalen

• Bronchodilators- 1901 Bronchodilators- 1901

• anti-inflammatory added in 1960anti-inflammatory added in 1960

Incidence- higher in low income populationIncidence- higher in low income population

ASTHMA DEFINATIONASTHMA DEFINATION

““Asthma is defined as a chronic Asthma is defined as a chronic

inflammatory disease of airway that is inflammatory disease of airway that is characterized by increase responsiveness of characterized by increase responsiveness of tracheobronchial tree to a multiplicity of tracheobronchial tree to a multiplicity of stimuli .”stimuli .”

Extrinsic: episodic, atopyExtrinsic: episodic, atopy

Intrinsic : perennial, status asthmaticus Intrinsic : perennial, status asthmaticus

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

Edema, cellular infiltration, Edema, cellular infiltration, hyperplasiahyperplasia

PATHOGENESIS OF ASTHMAPATHOGENESIS OF ASTHMA

ASTHMA AS AN ASTHMA 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 synthesis (within Membrane phospholipids f/b mediator synthesis (within

minutes) - PGs, LTs, PAFminutes) - PGs, LTs, PAF

• Gene activation f/b protein synthesis (over hrs)- ILs, Gene activation f/b protein synthesis (over hrs)- ILs,

TNF-TNF-αα

Lymphocyte directed Lymphocyte directed eosinophilic bronchitiseosinophilic bronchitis

INHALED STIMULIINHALED STIMULI

Endothelin-1Endothelin-1

Nitrous Nitrous

Oxide, Oxide,

PGE2PGE2

CytokinesCytokines

GM-CSFGM-CSF

IL-8IL-8

EotaxinEotaxin

Growth FactorsGrowth Factors

EGFEGF

IGF-1IGF-1

PDGFPDGF

Broncho-Broncho-

constrictionconstrictionVasodilationVasodilation InflammationInflammation

FibrosisFibrosis

Smooth Muscle Smooth Muscle

HyperplasiaHyperplasia

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

Approaches to treatmentApproaches to treatment1.1. Prevention of AG:AB reaction- AG avoidance Prevention 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

AVOIDANCE OF TRIGGER FACTORSAVOIDANCE OF TRIGGER FACTORS

Feathers, animal Feathers, animal danger, dust mitedanger, dust mite

Pollens & air Pollens & air pollutantspollutants

Pharmacological stimuli: Aspirin, colouring Pharmacological stimuli: Aspirin, colouring agents, Beta-blockers, sulfiting agents agents, Beta-blockers, sulfiting agents

Occupational factors- wood laundry Occupational factors- wood laundry detergents, metal salts etcdetergents, metal salts etc

Industrial chemicals & plasticsIndustrial chemicals & plastics

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

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

• 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

CLASSIFICATIONCLASSIFICATIONI) 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

I)I) BRONCHODILATORSBRONCHODILATORSA} A} ββ-2 SYMPATHOMIMETICS-2 SYMPATHOMIMETICS

► SHORT ACTING - Symptomatic reliefSHORT ACTING - Symptomatic relief► LONG ACTING - Prophylactic t/tLONG ACTING - Prophylactic t/tMECHANISM OF ACTIONMECHANISM OF ACTION► Stimulation of Stimulation of ββ-2 receptors -2 receptors →↑→↑c-AMP formation in c-AMP formation in

bronchial smooth muscle → relaxation of smooth bronchial smooth muscle → relaxation of smooth muscle. ↑conductance of large Camuscle. ↑conductance of large Ca+2+2 sensitive K sensitive K++ channels → membrane hyper polarization & channels → membrane hyper polarization & relaxationrelaxation

► Stimulation of Stimulation 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

Receptor DesensitizationReceptor Desensitization:-:-

►chronic t/t , chronic t/t , ►Receptor on bronchial smooth muscles → resistant Receptor 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.

SHORT ACTING SHORT 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 drug Most effective drug → reversing → reversing BronchoconstictionBronchoconstiction

Rapid symptomatic relief; as needed basis Rapid symptomatic relief; as needed basis

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 albuterol Similar to albuterol

- Dose- 5mg oral, 0.25mg sc, 250µg inhalation- Dose- 5mg oral, 0.25mg sc, 250µg inhalation

iv] METOPROTERENOL:- iv] METOPROTERENOL:-

- Less - Less ββ2 selective 2 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 used 2 selective widely used

- resistant to metabolism by MAO - resistant to metabolism by MAO

- Inhalation- Inhalation

vi] FENOTEROL :- vi] FENOTEROL :- Association with increase death Association with increase death

vii] BITOLTEROL:-vii] BITOLTEROL:- Prodrug - esterases hydrolyzes to Prodrug - esterases hydrolyzes to

active Colterol active Colterol

vii] PIRBUTEROL & ix] PROCATEROL :-vii] PIRBUTEROL & ix] PROCATEROL :- Inhalation Inhalation

LONG ACTING LONG 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 agonist 2 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 environment slowly dissociate from receptor environment - DOSE: 50-100 µg BD by inhalation- DOSE: 50-100 µg BD by inhalation

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 inhalationiii) 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 drug More 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-T1/21/2 - 36-39 hrs - Pork meat poisoning - 36-39 hrs - Pork meat poisoning

ORAL THERAPY:-ORAL THERAPY:-

- Greater risk of side effects- Tremors, muscle cramps, - Greater risk of side effects- Tremors, muscle cramps,

cardiac tachyarrhythmia & metabolic disturbances cardiac tachyarrhythmia & metabolic disturbances

- two situations of oral therapy - two situations of oral therapy

1. Young children (syr.) -can not manipulate inhalers 1. Young children (syr.) -can not manipulate inhalers

2. Severe asthma exacerbation - local irritation2. Severe asthma exacerbation - local irritation

COMBINATIONCOMBINATION – –

- - Long acting Long acting ββ2 agonist + Glucocorticoids 2 agonist + Glucocorticoids

- Salmeterol + Fluticasone, Formoterol + Budesonide - Salmeterol + Fluticasone, Formoterol + Budesonide

- More effective than doubling steroid dose - More effective than doubling steroid dose

- Current guideline- medium/low doses of steroids - Current guideline- medium/low doses of steroids

symptom persists symptom persists

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

PHARMACOLOGICAL ACTIONS:PHARMACOLOGICAL ACTIONS:

1) CNS: Stimulation ↑ performance & motor activity caffeine 1) CNS: Stimulation ↑ performance & motor activity caffeine

Higher doses (Theophylline) - nervousness, insomnia,Higher doses (Theophylline) - nervousness, insomnia,

delerium, convulsion vomiting delerium, convulsion vomiting

2) CVS: Stimulation ↑ force of contraction, tachycardia – BP2) CVS: Stimulation ↑ force of contraction, tachycardia – BP

3) Smooth Muscle: Relaxation -Most prominent Bronchial -↑ VC 3) Smooth Muscle: Relaxation -Most prominent Bronchial -↑ VC

4) Kidney: Mild diuretic 4) Kidney: Mild diuretic

5) Stomach : ↑ secretions 5) Stomach : ↑ secretions

6) Skeletal Muscle: ↑ contractile power 6) Skeletal Muscle: ↑ contractile power

7) Mast cells, inflammatory cells:↓release of histamine & mediators 7) Mast cells, inflammatory cells:↓release of histamine & mediators

8) Metabolism: ↑ BMR8) Metabolism: ↑ BMR

MECHANISM OF ACTIONMECHANISM OF ACTIONTHREE DISTINCT ACTIONS THREE DISTINCT ACTIONS a) Inhibition of phosphodiesterase a) Inhibition of phosphodiesterase

- ATP - ATP Adenylyl cyclaseAdenylyl cyclase cAMP cAMP PhosphodiesterasePhosphodiesterase 5AMP 5AMP . or or or . or or or - GTP - GTP Guanylyl cyclaseGuanylyl cyclase cGMP cGMP Inhibited by Inhibited by

TheophyllineTheophylline 5GMP 5GMP - accumulation of cyclic nucleotide- ↑signal transduction - accumulation of cyclic nucleotide- ↑signal transduction - Bronchodilatation, cardiac stimulation - Bronchodilatation, cardiac stimulation & vasodilatation - Inhibition & vasodilatation - Inhibition of PDE4 & PDE5 (PDE4) Bronchodilatation of PDE4 & PDE5 (PDE4) Bronchodilatation

b) Release of Cab) Release of Ca++++ from sarcoplasmic reticulum - skeletal & cardiac. At from sarcoplasmic reticulum - skeletal & cardiac. At higher conc. than therapeutic plasma conc.higher conc. than therapeutic plasma conc.

c) Competitive antagonist at adenosine receptor - c) Competitive antagonist at adenosine receptor - Adenosine – contract smooth muscle, dilate cerebral blood vessel, Adenosine – contract smooth muscle, dilate cerebral blood vessel, depress cardiac pacemaker, inhibit gastric secretiondepress cardiac pacemaker, inhibit gastric secretion

- - Anti-inflammatory action : histone deacetylase activation →Anti-inflammatory action : histone deacetylase activation →

↓ ↓ transcription of proinflammatory gene transcription of proinflammatory gene

ADVERSE EFFECTSADVERSE EFFECTS

Efficacy Plasma conc. Efficacy Plasma conc. µg/mlµg/ml toxicity toxicity

BR

ON

CH

OD

ILA

TA

TIO

NB

RO

NC

HO

DIL

AT

AT

ION

Thera

range

5-

10-

15-

20-

25-

30-

35-

DeathDeath

Convulsion, Shock, Arrhythmia Convulsion, Shock, Arrhythmia Delerium, Extrasystole, worsen CVS Status Delerium, Extrasystole, worsen CVS Status Agitation, Tachypnea, Flushing, Agitation, Tachypnea, Flushing, Hypotension Restlessness, Tremor, Hypotension Restlessness, Tremor, Vomiting, Palpitation, Diuresis Vomiting, 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

INTERACTIONS:-INTERACTIONS:-

1) Inducer -↑dose – Phenytoin, Rifampicin, Phenobarbitone 1) Inducer -↑dose – Phenytoin, Rifampicin, Phenobarbitone

2) Inhibit metabolism- ↓dose- Erythromycin, Ciprofloxacin, 2) Inhibit metabolism- ↓dose- Erythromycin, Ciprofloxacin,

Cimetidine, OC Pills, Allopurinol Cimetidine, OC Pills, Allopurinol

3) Theophylline ↑ effect of – Furosemide, Digitalis, 3) Theophylline ↑ effect of – Furosemide, Digitalis,

Anticoagulants, Sympathomimetics, Hypoglycemics Anticoagulants, 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 iv Aminophylline- 250-500mg slow iv

Hydroxyethyl Theophylline- 250mg im/iv Hydroxyethyl Theophylline- 250mg im/iv

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 & Roflumilast PDE4 Inhibitors- Cilomilast & Roflumilast

In Asthma Theophyllines : In Asthma Theophyllines : -Bronchodilatation, -Bronchodilatation, - ↓ release of inflammatory mediators, - improve mucociliary clearance, - stimulate respiratory drive & - ↑ diaphragmatic contractility

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

II) LEUKOTRIEN ANTAGONISTSII) LEUKOTRIEN ANTAGONISTS

Leukotrien receptor antagonist- Montelukast & ZafirlukastLeukotrien receptor antagonist- Montelukast & Zafirlukast5 Lipoxygenase inhibitor- Zileuton5 Lipoxygenase inhibitor- Zileuton

History- 1930 Kellaway study leukotrien History- 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, LTE4 Cysteinyl 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 5LOX arachidonic acid → Leukotrien by 5LOX Inhibit formation of cys LTsInhibit formation of cys LTs

PHARMACOKINETICS & METABOLISMPHARMACOKINETICS & METABOLISMDRUGDRUG 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 ↑PT Zafirlukast - warfarin ↑PT • Zileuton- ↑Liver Enzymes, ↑plasma conc. Theophylline &Zileuton- ↑Liver Enzymes, ↑plasma conc. Theophylline &

warfarin warfarin

DOSE:- Montelukast- 10 mg OD Children 5 mg OD DOSE:- Montelukast- 10 mg OD Children 5 mg OD

Zafirlukast- 20 mg BD Children 10 mg BDZafirlukast- 20 mg BD Children 10 mg BD

Prophylactic mild to mod. Asthma, Aspirin induced asthmaProphylactic mild to mod. Asthma, Aspirin induced asthma

III) MAST CELL STABILIZERSIII) MAST CELL STABILIZERS1) 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 chemotaxis inflammatory 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 & bile in urine & bile - T- T1/2 1/2 – 45-100min – 45-100min

Adverse Effects- bronchospasm, cough, Throat irritation, Adverse Effects- bronchospasm, cough, Throat irritation, Laryngeal edema, Headache, Bad tasteLaryngeal edema, Headache, Bad tasteDose- 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

approved approved > > 12 yrs 12 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 inhibited Realease 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

IV) CORTICOSTEROIDSIV) CORTICOSTEROIDSInhaled Inhaled ββ2 agonist for 4 or more times wkly - start 2 agonist for 4 or more times wkly - start

inhaled glucocorticoidsinhaled glucocorticoidsMechanism 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

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

Fluticasone Budesonide – higher affinity Fluticasone Budesonide – higher affinity -Dose- 100-200 µg BD upto 400 µg QID-Dose- 100-200 µg BD upto 400 µg QIDCompliance- highly potent Fluticasone, Compliance- highly potent Fluticasone, -Budesonide-BD/OD improve pt compliance-Budesonide-BD/OD improve pt compliance

BUDESONIDE - High topical:systemic activity BUDESONIDE - High topical:systemic activity

- Dose – 200-400 µg BD-QiD inhalation- Dose – 200-400 µg BD-QiD inhalation

FLUTICASONE PROPIONATE- High potent long acting FLUTICASONE 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

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 bind oral bioavailability <1% Extensively bind

to plasma protein to 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

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, gargling Oropharyngeal 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

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

MANAGEMENT OF STEROID RESISTANT MANAGEMENT OF STEROID RESISTANT ASTHMA ASTHMA :-:-

1)1) Methotrexate:Inhibit amidophosphoribosyltransferase- Methotrexate:Inhibit amidophosphoribosyltransferase- inhibit T cell proliferation, ↓dose ↑sensitivity to inhibit T cell proliferation, ↓dose ↑sensitivity to prednisolone prednisolone

2)2) Cyclosporin: inhibit T cell proliferation, IL2 & other Cyclosporin: inhibit T cell proliferation, IL2 & other cytokine production cytokine production

3)3) Leflunomide: DMARDs Th cytokine expression Leflunomide: DMARDs Th cytokine expression suppress suppress

4)4) Rapamycin: inhibit T cell proliferation, cytokine synth Rapamycin: inhibit T cell proliferation, cytokine synth

5)5) IV Immunoglobulin: Steroid sparing, costly IV Immunoglobulin: Steroid sparing, costly

6)6) Gold: ↓ steroid use Gold: ↓ steroid use

V) ANTI IgE ANTIBODYV) ANTI IgE ANTIBODY

OMALIZUMABOMALIZUMAB1921 Prausnitz & Kustner -reagin transfer allergic reaction 1921 Prausnitz & Kustner -reagin transfer allergic reaction

1971 Ishizaka –IgE1971 Ishizaka –IgEOmalizumab – DNA derived humanized monoclonal Omalizumab – DNA derived humanized monoclonal

antibody of IgG1k subclass. Cell culture (Chinese antibody of IgG1k subclass. Cell culture (Chinese hamster ovary cells)hamster ovary cells)

Mechanism of Action:-Mechanism of Action:-Fc-IgE ↔FcFc-IgE ↔FcεεRIRIAG AG ↔ IgE ↔ Fc↔ IgE ↔ FcεεRIRI → activate mast cell.→ → activate mast cell.→ LTC4, PGD2, cytokinesLTC4, PGD2, cytokinesOmalizumab- 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 Complexcomplex- no affinity to Fccomplex- no affinity to FcεεRI RI ↓ ↓ FcFcεεRI expression on mast cells..RI expression on mast cells..

OMALIZUMAB…..OMALIZUMAB…..

Pharmacokinetics- Single s.c. inj. every 2-4 wks Pharmacokinetics- Single s.c. inj. every 2-4 wks

- Bioavai- 60%, - Bioavai- 60%,

- T- T1/21/2- 26 days - 26 days

Adverse Effects- well tolerated Adverse 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 Asthma In 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

GUIDELINE FOR TREATMENT OF ASTHMAGUIDELINE FOR TREATMENT OF ASTHMA

1) MILD EPISODIC ASTHMA – 1) MILD EPISODIC ASTHMA –

♦♦ Symptoms < 1 daily & Normal between attacks Symptoms < 1 daily & Normal between attacks

♦♦ STEP 1:- Inhaled short acting STEP 1:- Inhaled short acting ββ2 agonist - onset of 2 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 so Symptoms 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 acting Inhaled short acting ββ2 agonist 2 agonist

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 of STEP 3:- ↑ dose of inhaled steroids (upto 800inhaled steroids (upto 800µg/day)µg/day)

+ + Inhaled long acting Inhaled long acting ββ2 agonist2 agonist

(alternative leukotrien antagonist, Theophylline)(alternative leukotrien antagonist, Theophylline)

episode t/t withepisode t/t with Inhaled short acting Inhaled short acting ββ2 agonist2 agonist

4) SEVERE ASTHMA - 4) SEVERE ASTHMA - ♦ Continuous symptoms Limitation of ♦ Continuous symptoms Limitation of activity . Frequent activity . Frequent exacerbations/Hospitalisation exacerbations/Hospitalisation

♦ ♦ STEP 4:- Regular inhaled High dose steroids STEP 4:- Regular inhaled High dose steroids

(800-2000µg/day) large vol spacer + Inhaled (800-2000µg/day) large vol spacer + Inhaled

long acting long 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/ Oral i) Leukotrien antagonist/ SR theophylline/ Oral ββ2 agonist / 2 agonist / Inhaled ipratropium bromideInhaled ipratropium bromide ii) episode t/t with Inhaled short acting episode 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 care emergency care

- Oral steroid therapy- Oral steroid therapy

STATUS ASTHMATICUS STATUS 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 & ββ2 2 agonist life threatening agonist life threatening

Precipitated by Precipitated by i) Acute respiratory infection i) Acute respiratory infection ii) Abrupt cessation of steroid therapy ii) Abrupt cessation of steroid therapy iii) Pharmacological stimuli/Allergens iii) Pharmacological stimuli/Allergens iv) Acute emotional stressiv) Acute emotional stress

MANAGEMENT OF STATUS ASTHMATICUSMANAGEMENT OF STATUS ASTHMATICUS

1.1. Hydrocortisone hemisuccinate 100mg iv stat Hydrocortisone 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) + Ipratropium Nebulized 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 ventilation Intubation & mechanical ventilation 6.6. AntibioticsAntibiotics7.7. Saline + Sod. Bicarbonate Saline + Sod. Bicarbonate Aminophylline 250-500mg dil in 20-30ml Aminophylline 250-500mg dil in 20-30ml

5% Glucose iv over 20-30min 5% Glucose iv over 20-30min

COMPLIMENTARY AND ALTERNATIVECOMPLIMENTARY AND ALTERNATIVE

1.1. Acupuncture – Acupuncture – 2.2. Air ioniser - +ve & -ve ion generatorAir ioniser - +ve & -ve ion generator3.3. 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 exercise7.7. Helminthic therapy – -ve associationHelminthic therapy – -ve association8.8. Guaifenesin – expectorant-thick mucus Guaifenesin – expectorant-thick mucus 9.9. Aroma Therapy – Eucalyptus, Lavender, Rosemary – Aroma Therapy – Eucalyptus, Lavender, Rosemary –

Free breathing fragranceFree breathing fragrance