Respiration

GASES & VAPOURS

Types of gases:

1- Therapeutic: Oxygen (O2) – Ozone (O3) – Carbon dioxide (CO2) – Helium 2- Noxious: Carbon monoxide (CO) – Hydrocyanic acid

OXYGEN THERAPY

Uses of O2: 1- Treatment of (as in bronchial asthma , COPD & anemia) 2- As a diluent for inhalation anesthesia

Side effects of O2: 1. Oxygen apnea 2. Retrolental fibroplasias in preterm neonates 3. Pulmonary atelectasis due to bronchial obstruction. ------Uses of Hyperbaric O2: 1- Anaerobic infections 2- Air embolism & Decompression sickness 3- Burns 4- Bone infections 5- CO poisoning 6- poisoning ------

Ozone (O3) Therapy: - Ozone Therapy is the most powerful of the oxygen therapies as ozone is more strongly oxidizing - Uses of Ozone: 1- Anti-infective against bacteria, fungi & viruses 2- Antineoplastic

3- Ozonated olive oil (Topical) is used in: dry skin, Wrinkles & sunburns 4- Ozonated lemon juice (Topical or Drinking) is used in: cancer skin, psoriasis & ulcer 5- Ozonated water is used in (Drinking): Alzheimer disease, allergy & cancer

6- Oxidizes toxins & chelates heavy metals

- Methods of application: 1- Injection 2- Insuflation into ear, vagina or rectum 3- Inhalation: bubbled through olive oil 4- Ingestion of ozonated water 5- Topical through bagging, body suit, ozonated olive oil or steam sauna

102 Respiration

Cyanide poisoning

- Sources of cyanide: Cyanide is found in insecticides, rodenticides, metal cleaners (silver polish) & photographic solutions and may be released from combustion of nitrogen-containing plastics

- Effect & toxicity of Cyanide: Cyanide has high affinity to bind with F+++ of cyto-chrome oxidase enz. (mitochondrial enz. responsible for tissue respiration) leading to histotoxic hypoxia & death within 5 min.

- Treatment of Cyanide posoning:

-Na Nitrite IV Na Thiosulphate IV -Methylene blue IV Treatment - Inhal. (Tissue rodenase) -Ascorbi a. IV

Blood Hb Met-Hb Cyan-Met-Hb Met- Hb Hb ++ +++ +++ ++ (Fe ) (Fe ) (Fe ) (Fe )

Cytochrome oxidase Tissues +++ (Fe ) + Cyanide

÷ Treatment 1) Long method: 1. Na Nitrite (IV) or Amyl Nitrite (inhalation): convert haemoglobin (Fe++) to met – Hb [Fe+++] – met. Hb + cynide Ï non-toxic cyan–met - Hb Rhodenase 2. Na thiosulphate (I.V) + cyan- met- Hb e n z Na thiocyanate (excreted in urine) + met. Hb. 3. Methlyne blue or vit. C (I.V): reduce met Hb to Hb.

2) Short method 1. Hydroxocobalamine (I.V): chelate cyanide Ï Cyanocobalamine (Vit B12) 2. Dicobalt edetate (I.V): chelate cyanide

103 Respiration

COUGH THERAPY Types of cough: 1- Dry [Un productive – Useless] cough: ttt by Ï Antitussives 2- Productive cough: which may be: • Effective (secretion easily expelled) • Ineffective (secretion present but difficult to expel) ttt by Ï Expectorants ± Mucolytics

(1) Anti- tussives [Cough supressors]

A) Peripheral anti- tussive: B) Central anti- tussives: 1. Demulcents [Liquorice] 1) Narcotic 2. Water steam inhalation ± Tr. Benzoin 1- Highly addicitive Ï h secr. a-Morophine 3. Drugs with local anesthetic activity b-Dihydromorphin Ï [Benzonatate]: c-Heroin It has dual mechanism d-Methadone • Centrally Ï i cough center 2- Less addictive • Peripherally Ïi cough [stretch] a-Codeine receptors b-Dihydrcodeinone c-Pholcodine 2) Non- narcotic 1- Opiate derivative: a- Narcotine b- Dextromethorphan 2- Non- opiate derivative: a- Benzonatate b-Carmiphen [antiparkinsonian] c- Diphenhydramine [H blocker] 1 d- Oxeladine

(2) Mucolytic agents

÷ They liquefy viscid secretions & facilitate the action of expectorants [they are not expectorants] ÷ Used in acute & chronic bronchitis. ÷ Examples: 1. Bromhexine (Bisolvon): deploymerization of mucopolysaccharides of ground substance of sputum. MP S S MP 2. Ambroxol: is an active metabolite of Bromhexine 3. Carboxymethylcysteine: break the disulphide bonds (s-s) in mucus Ïi surface tension 4. Acetyl cysteine: MP MP • As carboxmethylcysteine S S • Uses: - Inhalation in bronchitis - orally to ttt hepatotoxicity induced by Paracetamol. 104 Respiration

(3) Expectorants (Protussives) ÷ Example: Guaiacol (Guaifensin) ÷ Uses: acute ineffective productive cough ÷ Side effects: GIT disturbances – Drowsiness

BRONCHIAL ASTHMA Definition: “ Hypersensitivity & Hyper- responsiveness of the bronchi associated with inflammatory changes leading to wide spread narrowing of them” symptoms: - Episodes of triad: Cough – Dyspnea - Wheezes - Between the attacks the pt. may be asymptomatic

Physiology: 1) Para symp. nerve Ï A.ch Ï M2,3 Ï Broncho-spasm & hsecretions 2) Symp: Ï nerve Ï N.A Ï α Ï V.C & i secretions Ï Adrenal medulla Ï adrenaline Ï Non- innervated B2 Ï Bronchodilatation 3) Most autacoids Ï Broncho-spasmp except: PGE2 & V.I.P 4)

ATP

Bronchodilatation A.C + B-agonist

+ c.AMP

Bronchial Tone Theophyllin PDE -

A.ch. + + Adenosine AMP - - Bronchoconstriction

M-antagonist Theophyllin

105 Respiration

Pathogenesis Rexposure

YY Exposure to Allergen

Mast cells Ig.E Lymphocyte

Release of preformed mediators Synth. & release of newly formed mediators

- Histamine - PGs - Esinophil chemotactic factor - Leucotreins (LTC4 & LTD4 ) - Neutrophil chemotactic factor - Platelet activating factor (P.A.F)

Bronchoconstriction Chemotaxis (Early Reaction)

Esinophils Neutrophils

+ Other mediators

1- Bronchoconstriction 2- Edema & Cellular infiltration 3- Mucous secretion (Late Reaction)

106 Respiration

Management of Bronchial asthma 1-General: 1) Advice Ï change the jop 2) Avoid 1. Antigen exposure – smoking - stress & emotions 2.severe excercises 3.the following drugs: * N.S.A.I.Ds allow only paracetamol * Non- selective  blockers allow only selective 1 blockers * Parasympathomimetics Ï Bronchospasm * Parasympatholytic: Atropine Ï Dry secretions allow only Ipratropium. * Histamine & histamine releasers * Anti histaminics (1st generation as they have atropine like effect) * Brabiturates Ï i Respiratory center (R.C) * Morphine Ï i R.C, i cough center & it is a histamine releaser * Ether, thiopentone & cyclopropane general anesthesia allow only Halothane 3) ttt: 1.Any chest infection 2.Immunotherapy: hyposensitization

2-Drug therapy of B.A 1) Broncho – dilators: 1- Sympathomimetic: B2 agonist (short acting [SABA] & long acting [LABA]) 2- Parasympatholytic (Anticholinergics): Ipratropium - Tiotropium 3- Methyl xanthines: Aminophylline 4. Other drugs: 1- PGE2 2- (NO) Nitric oxide donors 3-K+ channal openers as (cromokalim) 4-Ca++ channal blockers 2) Anti- inflammatory: 1- Mast cell stabilizers: Disodium cromoglycate (Cromolyn) (Intal) - Ketotifen 2- Cocticosteroids. 3- Anti leukotriene drugs: 1- Zileluten Ï 5- lipo – oxygenase enz. inhibitor 2- Zafirlukast & montelukast Ï leukotriene [LTD4] receptor antagonist • given orally in prophylaxis of B.A • S.E: h serum liver enz. – HME inhibitor - vasculitis – Headache 3) Immunoglobulin antagonists: Anti- IgE monocolonal antibodies Omalizumab (Xolair) 4) Adjuvant drugs: 1. Mucolytic & Expectorants 2. O2

NB.: Anti-asthmatic drugs, now, are clasified into: 1. Quick-relief (rescue) medications: SABA - Systemic steroids - Anticholinergics - Aminophylline 2. Long-term (controller) medications: LABA – Long acting methylxanthines – Antiinflamatory drugs - Anti- IgE 107 Respiration

Sympathomimetics

Mechanism of action: 1) h B2- receptors : (it is a Gs-receptor) Ï h A.C Ï h c.A.M.P Ï 1.Broncho dilatation 2.i Bronchial secretion 3.Mast cell stabilization 2) h α receptors Ï V.C Ï Decongestion & i edema

Members: Ï (see before)

1) Non – selective: Ï serious cardiac side effects - Adrenaline : (S.C & inhal.) - Isoprenaline : (S.C & inhal.) - Ephedrine : (orally)

2) Partially selective B2- agonist: Ï some cardiac side effects - Orciprenaline (Metaproterenol) Ï inhal.& oral.

3) Selective B2 agonist: a- Salbutamol(Albuterol) (ventolin): Oral -I.V- Inhalation (1-2 puffs / 4h [100 g / puff]) b- Levalbuterol, Terbutaline, Salmetrol (servent), Formoterol (foradel), Fenoterol (berotec) • Side effects of selective B2 agonist: Ï Nervous Tension / Tachycardia /Tremors / Tolenance/ Locked lung syndrome

Muscarinic Antagonists [Ipratropium & Tiotropium]

Mechanism of action: competetive block of muscarinic receptors Ï prevent bronchospasm induced by A.ch as aresult of vagal stimulation.

Advantages over atropine: 1. Does not cause dryness of bronchial secretions. 2. Dose not i mucociliary clearance of bronchial secrection 3. No C.N.S action or systemic anticholinergic effect (as it’s a quaternary ammonium)

Clinical use: by inhalation 1. In patients with Chronic obstructive pulmonary disease (C.O.P.D) esp. eldery patient 2. Adjuvant to B2 agonist in acute severe asthma 3. When B2 agonist & Theophylline are contraindicated as in thyrotoxicosis

NB.: Tiotropium: as Ipratropium, but long acting used once daily

108 Respiration

Methyl-xanthines

Mechansim of action: 1) i [P.D.E] enz Ï h c.A.M.PÏ • Broncho dilatation • i bronchial secretion • mast cell stabilization 2) competetive block of adenosine receptors Ï • Broncho dilatation • i release of histamine • h release of catecholamines: [due to block of presynaptic receptor] 3) improve diaphragmatic contractions.

Uses in Bronchial asthma 1. Acute attack (250 – 500 mg slow I.V) as 2nd line drug in addition to steroids afte r failure of B2 agonist 2. Status asthmaticus: - slow I.V or I.V infusion 6 mg / kg over 30 min. as loading dose, then 0.7 mg / kg / h as maintenance. 3. Prophylaxis: - oral slow release [SR] 200 mg / 12h. - rectal suppository every night 500 mg.

Side effects: 1) Narrow safety margin: - therapeutic plasma level Ï 10-20 g / ml - toxic plasma level Ï >20 g/ ml 2) G.I.T - anorexia – nausia – vomiting - proctitis in childern when used rectally 3) C.V.S - Tachycardia – Arrhythmia- Hypotension – Arrest 4) C.N.S - Nervousness – Insomnia – Headache – Convulsions

Drug inter actions: It is important as it has narrow safety margin

1) Its metabolism i by: 2) Its metabolism h by: [enzyme inhibitors] [enzyme inducers] 1. Anti microbial : 1. Anti epileptics: Erythromycin & Quinolones phenobarb. & phenytoin 2. Cimitidine 2. Rifampicin 3. Disease of the liver & heart 3. Tobacco & alcohol

Preparations: 1) Theophyllin: - S.R tablet Or Capsule 200 mg / 12 h 2) Aminophyllin: - I.V slowly 250 – 500 mg - Rectally 500 mg

N.B. Enprofylline Ï more potent – No block of adenosine receptors. 109 Respiration

Mast cell stabilizers

1) Sodium cromoglycate [intal] & Nedocromil Na+

Mechanism of action: i [P.D.E] enz. In mast cells Ï stabilization & i Degranulation ** No broncho dilatation , so ineffective in acute altack Uses: prophylaxis in children 1) Bronchial asthma: Ï inhalation of powder by spinhaler Ï inhalation of soluation by nebulizer or metered dose inhaler [M.D.I] 2) Allergic rhinitis Ï nasal spray (Rynacrom) 3) Allergic conjunctivitis Ï ophthalmic solution (Optocrom) Side effects: Bronchospasm – Cough – Dermatitis- Myositis ------(2) Ketotifen [Zaditen] similar to intal but: 1) Effective orally 1mg / 12h 2) Mechanism of action: - No i [P.D.E] enz - Up-regulation of B2 receptors - Antihistamin & antiserotonin 3) Side effects Ï Drowsiness & Dry mouth

Corticosteroids

- They are the most effective class of drug in the treatment of chronic asthma Mechansim of action: 1) Anti- inflamatory effect: 1. i phospho lipase A2 Ï i arachidonic acid Ï i PGs & LTs 2. i capillary permeability Ï i edema 2) Anti – allergic effect: 1. i antibody formation 2. i antigen / antibody reaction 3) Potentiale the effect of B2 agonists as they cause upregulation of B2 receptors.

NB.: Inhaled corticosteroids produce some improvement in asthmatic symptoms after 24 h and a maximum response after 1-2 weeks.

Preparations: 1) oral Prednisolone 2) I.V Hydrocortisone sodium succinatc 3) Inhaled - Beclomethasone - Budesonide (Pulmicort) - Fluticasone - Flunisolide -Triamcinolone (azmacort)

110 Respiration

* side effects of inhaled steroids: 1- Oropharyngeal candidiasis 2- Dysphonia (candidiasis on vocal cords & Myopathy of laryngeal muscle)

Treatment Of Acute Attack

1) S tart by inhaled B2 agonist: * salbutamol 100 g / puff 1-2 puffs 2) I f response is inadequate, add ipratropium inhalation 3) I f response is inadequate, add inhaled steroid 4) I f response is inadequate, add Aminophylline 250 – 500 mg slow I.V ------

Treatment of status asthmaticus 1) H ospitalization 2) O 2 3) S ystemic steroids: a- Hydrocortisone sodium succinate [ drug of choice] b- Prednisolone 15 mg / 6 h. orally for 1-2 days, then gradually withdrawal 4) B ronchodilators a- Selective B2 agonist: nebulizer – I.M, or slow I.V b- Aminophylline I.V infusion - Loading dose 6 mg / kg for 30 min for persons not using theophyllin - Maintenance dose 0.7 mg / kg / h 5) G lucose 5% to correct dehydration 6) A ntimicrobial to treat infection ------Long term prophylaxis 1) General measures: 2) Drug therapy: 1. Selective B2 agonists e.g: Salmetrol 2. Long acting theophylline 200mg / 12h SR. tab. Or caps. 3. Mast cell stabilizer: - inhaled Intal - oral Ketotifen 4. Steroids: - Inhaled Beclomethazone [50 g / puff 2-3 puffs / 3-4 time daily] - Oral Prednisolone, only if all measures fail 5. Leukotriene inhibitors

N.B: Magnesium sulphate IV magnesium sulphate can be given in severe asthma if life-threatening features are present. It acts by reducing Ca++ influx by blocking Ca channels. SE.: A-V block – N-M block - Hypotension

111 Respiration

Stepwise Management of Asthma (According to British guideline management of asthma (2007)

* Beclomethasone dose - In children: the dose of inhaled steroid: 200-400 mcgm/day with maximum dose 800 mcgm/d - Consider step down on improvement

112 Respiration

TREATMENT OF RHINITIS

1- Antihistaminics: use sedating ones (Chlorpheniramine & Cyproheptadine) as the have atropine like effect, causing dryness of secretion 2- -adrenoceptor agonist (nasal decongestants): see before 3- Topical steroids: as Prednisone, Dexamethasone, Beclomethasone & Fluticasone 4- Disodium cromoglycate may be used in prophylaxis in allergic rhinitis

113