Sympathomimetics in Bronchial asthma

1. Sympathomimetics in Bronchial asthma Presented by :Heba Abd El-fattah Sabry

2. Asthma-Treatment What are the treatments? Drugs that reduce inflammation Drugs that reduce bronchoconstriction

3. Asthma - Introduction (Cont.)  Airway Inflammation  Bronchospasm Drug therapy b adrenergic receptor agonist Glucocorticoids Leukotriene inhibitors Methylxanthine Chromones Muscarinic receptor antagonist IgE inhibitors Prophylaxis prevention Long-term (controller medications) Symptomatic relief Short-term

4. BronchodilatorsOpen up the bronchial tubes so that more air can move through Help clear mucus from the lungs. Asthe airways open, the mucus moves more freely and can be coughed out (expelled) more easily.

5. O H O H H O H O N H N H C H 3 Very lipophilic (persistent membrane contact?) H C C H 3 3 O Sympathomimetics- Use in Asthma Short-acting (2-6 hrs) Long-acting (>12 hrs) Adrenoceptor agonists (2-selective agents preferred ) Symptomatic relief Prophylactically in combination with steroid Albuterol (Proventil, etc.) L-albuterol (Xopenex) Metaproterenol (Alupent) Terbutaline (Brethaire) Pirbuterol (Maxair) Salmeterol (Serevent) Formoterol (Foradil)

6. Short-Acting Beta2-Agonists • Most effective medication for relief of acute bronchospasm. • More than one canister per month suggests inadequate asthma control. • Regularly scheduled use is not generally recommended. • May lower effectiveness. • May increase airway hyperresponsiveness.

7. Long-Acting Beta2-Agonists • Not a substitute for anti-inflammatory therapy • Not appropriate for monotherapy (sometimes OK with mild asthma) • Beneficial when added to inhaled corticosteroids • Not for acute symptoms or exacerbations

8. Mechanism of action • Stimulation of ß2-AR causes relaxation of smooth muscle by inducing an increase in intracellular cAMP. This intracellular increase results in activation of protein kinase A, which phosphorylates myosin-light-chain kinase. This produces prolonged bronchodilation by inhibiting the factor involved in smooth muscle contraction.

9. Sympathomimetics- Use in Asthma 2-agonist have two important effects involved in asthma therapy: 1)Relax airway smooth muscle: • Inhibit release of some mast cell bronchoconstrictive mediators. • Inhibit micro vascular leakage may increase mucociliary transport . • Inhibit neutrophil, eosinophil, and lymphocyte functional responses. Increase mucociliary transport, and affect vascular tone and edema formation . • Stimulate adenyl cyclase, increasing cAMP formation in airway tissue Inhibits cell growth. 2)Prevents release of inflammatory mediators and cytokines:

10. Beta adrenergic drugs are the most potent and rapidly acting bronchodilators currently available for clinical use. They can be given in different forms: • Short acting = isoproterenol. • Intermediate acting = albuterol, metaproterenol, pirbuterol, levalbuterol, terbutaline (intravenous preparation only), fenoterol [not available in the US]. • Long acting = salmeterol, formoterol. Used via different delivery systems: • Oral liquids, tablets. • Metered dose inhalers. • Nebulizer solutions. • Dry powder inhalers.

11. Tolerance Decreased sensitivity or tolerance to beta agonists is a potential effect which occurs when these drugs are used on a chronic basis . This effect may be primarily mediated by downregulation of beta-2-adrenergic receptors . Oral routes are more likely to induce tolerance than inhaled methods of delivery. The development of tolerance requires relatively continuous stimulation of the membrane-associated beta receptors. Thus, shorter acting isoproterenol is less likely to produce tolerance than intermediate acting albuterol . The clinical significance of tolerance relates to its potential impact on the overuse of beta agonist inhalers by patients whose disease process involves more than just bronchial smooth muscle constriction and is increasing in severity. It may increase frequancy of administration and reduce sensitivity to receptor

12. Sideeffects of sympathomimetics: 1)Alpha receptor stimulation • Increased blood pressure • Decreased oxygen delivery 2)Beta-1 receptor stimulation : • Tachycardia • Palpitation • Arrhythmia – Increased myocardial oxygen consumption • Dizziness • Headache

13. 3)Beta-2 receptor stimulation : • Tremor (skeletal muscle receptor) • Nausea / vomiting • Nervousness • Anxiety • Insomnia • Hypotension (peripheral vasodilation) • Hypokalemia • Hypoxemia – Worsened  • Increased blood glucose and insulin levels • Independent of receptor stimulation – • Bronchoconstriction due to additives or propellants • Tolerance

14. Intermediate acting B2 agonist

18. Dose of Terbutaline • Premature labor (tocolysis; unlabeled use):   Acute: I.V. 2.5-10 mcg/minute; increased gradually every 10-20 minutes. Effective maximum dosages from 17.5-30 mcg/minute have been use with caution. Duration of infusion is at least 12 hours.   Maintenance: Oral: 2.5-10 mg every 4-6 hours for as long as necessary to prolong pregnancy depending on patient tolerance

20. Drug-Drug interaction • MAO (monoamine oxidase) inhibitors (e.g. phenelzine, tranylcypromine) • tricyclic antidepressants (e.g. amitriptyline) • some beta-blockers (e.g. propranolol) • epinephrine • other bronchodilators (e.g. salbutamol)

21. It was a long-acting beta-agonist widely used in New Zealand in the early 1990s but withdrawn because of its association with an excess number of deaths. • This was due to its additional effects on the B1 receptors that lead to cardiovascular adverse effects, notably dysrhythmia and cardiac hypoxia. Fenoterol increased the risk of death because it was typically used in excessively large doses for severe asthma attacks in the absence of medical assistance. Instances were known of patients who had used up to 80 puffs before seeking medical attention. • Polymorphisms affecting amino acids 16 and 27 of the beta2-adrenoceptor alter receptor regulation in vitro. Whether these polymorphisms alter the response to beta2-agonist therapy in asthma is unknown.

22. B2 Agonist(Long acting)

23. Mechanism for long duration: high lipid solubility-- (creates a depot effect) • Routes of administration: oral inhalation-- greatest airway effect • Salmetrol was a subsidiary drug of salbutamol, where the task was to create a drug with the required affects of salbutamol but with a longer duration of action. • Salbutamol gives immediate affect to asthma; it forms hydrogen bonding with the receptor and can avoid catalysis of the enzyme catechol O-methyl transferase due to a methanol substitute in the molecule. Salmetrol has a longer duration of action because of its increased lipophilicity; this was achieved by replacing the    t-butyl group of salbutamol with the highly lipophilic N(CH2)6O(CH2)4Ph group.

26. USEs • Maintenance treatment of asthma. • Prevention of bronchospasm with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma. • Prevention of exercise-induced bronchospasm. • Maintenance treatment of bronchospasm associated with COPD.

27. Asthma inhaler • An asthma inhaler is a handheld device that delivers asthma medication straight into the airways. While asthma medications can be taken orally and intravenously, with an asthma inhaler the medication goes directly into the lungs to help relieve asthma symptoms faster and with fewer side effects.

28. Criteria for an ideal inhaler

29. Metered dose inhalers (MDIs):A metered dose inhaler (MDI) delivers asthma medication through a small, handheld aerosol canister. The metered dose inhaler gently puffs the medicine into your mouth when you press down on the inhaler, and you breathe the medicine in. • Dry powder inhalers (DPIs): Dry powder asthma inhalers require you to breathe in deeply as the medication enters your lungs. These asthma inhalers may be difficult to use, especially during an asthma attack when you cannot fully catch a deep breath. Read the instructions carefully for each dry powder inhaler because they vary considerably. The technique you learned for one type of inhaler often does not apply to others • Medications used in asthma inhalers are anti-inflammatory (steroids such as prednisone), bronchodilators (beta-2 agonist medications), or both (a combination inhaler

30. Three principal types of devices are used to generate therapeutic aerosols: nebulizers, metered dose inhalers, and dry powder inhalers. All three generate aerosols using different mechanisms. In many cases, clinicians must choose the most appropriate device for drug delivery as well as the appropriate therapeutic agent. • All three types of devices can be used to efficiently deliver medication to spontaneously breathing patients. Only nebulizer systems and metered dose inhalers can be used in intubated patients; dry powder inhalers should not be used in intubated patients.

31. NEBULIZERS • The basic design and performance of pneumatic (or jet) nebulizers have changed little over the past 25 years. • This may be less important for inhaled bronchodilators, although newer nebulizer designs should be considered for more expensive formulations where precise dosing is required . • Performance of nebulizers is influenced by several common factors including: • Mechanism. • Use of mouthpiece or facemask. • Drug formulation.

32. A jet flow of driving gas creates an area of low pressure above the medication reservoir, generating an aerosol. The baffle helps insure the formation of respirable particles, and prevents inhalation of oversized droplets of medication. Most nebulizers require a flow rate of 8 liters per minute for optimum performance

33. Mechanism • The operation of a pneumatic nebulizer requires a pressurized gas supply, which acts as the driving force for liquid atomization. Compressed gas is delivered as a jet through a small orifice, generating a region of negative pressure above the medication reservoir. The solution to be aerosolized is first entrained, or pulled into the gas stream and then sheared into a liquid film. This film is unstable, and rapidly breaks into droplets due to surface tension forces.

34. Factors determine the efficiency of a nebulizer system • The respirable dose: Droplet size should be 2 to 5 µm for airway deposition and 1 to 2 µm or smaller for parenchymal deposition. . • Nebulization time: The time required to deliver a dose of medication, is an important determinant of patient compliance in the outpatient setting. . • Dead volume of the device: Increasing the flow rate of the driving gas results in an increase in nebulized output and a reduction in particle size . • The gas used to drive the nebulizer: The density of the gas powering the nebulizer affects nebulizer performance. For example, the inhaled mass of albuterol is significantly reduced when a nebulizer is powered with a mixture of helium and oxygen (heliox). Accordingly, the flow to the nebulizer should be increased by 50 percent if it is powered with heliox [ 14]. Heliox may improve aerosol delivery to the lower respiratory tract, because the decrease in density results in the creation of smaller particles .

35. METERED DOSE INHALERS • Consists of a pressurized canister, a metering valve and stem, and a mouthpiece actuator . • The canister contains the drug suspended in a mixture of propellants, surfactants, preservatives, flavoring agents, and dispersal agents. The propellant has traditionally been a chlorofluorocarbon (CFC). • CFC-free propellants such as hydrofluoroalkane (HFA) have become available . Patients should be informed that the plume emitted from an HFA-MDI is warmer and softer than the CFC plume. • The mixture is released from the MDI canister through a metering valve and stem into an actuator boot. After volatilization of the propellant, the final volume emitted from the MDI is 15 to 20 mL per dose . The MDI can be actuated as frequently as every 15 seconds

36. Pressurised metered dose inhaler • Used for administration of corticosteroida and bronchodilators. • Advantages: • Cheap . • Simple to manufacture on a large commercial scale . • Availability of a range of drugs that can be formulated for pMDIs.

37. DRY POWDER INHALERS • Create aerosols by drawing air through a dose of powdered medication. • The release of respirable particles of the drug requires inspiration at relatively high inspiratory flow rates , which results in pharyngeal impaction of the larger carrier particles that comprise the bulk of the aerosol. • The oropharyngeal impaction of carrier particles gives the patient the sensation of having inhaled a dose. DPIs produce aerosols in which most of the drug particles are in the respirable range

38. DPIs can be single- or multi-dose devices. The multi-dose devices contain a month's worth of medication or more. With single-dose devices, the patient places a capsule into the device immediately before each treatment. Because these capsules are similar in appearance to oral medications, it is important to instruct patients not to ingest the capsules.

39. Single dose inhaler: • 1)Spinhaler™ (Aventis( : • First introduced for the delivery of sodium cromoglycate. • To deliver a dose of such magnitude, this aerosol delivery system comprised an inhaler which was supplied with separate capsules. Each gelatin capsule contained a single dose of drug, which was placed inside the inhaler before each use and the empty capsule was discarded. Presentation of the formulation in a capsule also provided protection from moisture . • Advantage: • Accommodate the large (20 mg) required dose of sodium cromoglycate.

40. Disadvantage: • Inconvenient to use because of the number of steps required to administer each dose. • It required inspiratory effort to draw the medication from the device, so drug was only released while the patient inhaled. This applies to all DPIs, but for some the effect is minimal, whereas other DPIs show significant flow-dependent dose emission. • Concurrent with the introduction of DPIs was a growing environmental concern that the chlorofluorocarbon propellants used in pMDIs were causing irreparable damage to the ozone layer. The pharmaceutical industry was therefore committed to the development of non-chlorofluorocarbons (CFC) propellants for use in pMDIs and also DPIs that required no propellant at all. The reformulation to change the propellant used in pMDIs to those based on hydrofluoroalkanes, in place of CFC was not easy and some difficulties still remain.

41. Multi-dose reservoir devices • Contain more than one dose of drug. There are two types of multi-dose DPI, reservoir and multi-unit dose devices. Multi-dose reservoir devices contain a bulk supply of drug from which individual doses are released with each actuation. • 1) Turbuhaler™ : • which is used to deliver β2-agonists and corticosteroids separately and in combination. The drug located within this inhaler is formulated as a pellet of a soft aggregate of micronised drug which may be formulated with or without any additional lactose excipient.

42. To release a dose of drug, the patient twists the base of the device resulting in a dose of drug being shaved off the pellet while holding the inhaler in a vertical position. It is essential that this orientation is used when dose metering all reservoir DPIs, because they rely on gravity to fill the dose metering cup. The dose is then dispersed by turbulent airflow as the patient inhales through the device. This turbulent airflow creates the energy to disperse particles in the emitted dose that are small enough to have a high possibility of depositing in the conducting airways.

43. Easyhaler™ , Clickhaler,™ and Twisthaler™ • The design of new multi-dose reservoir DPIs has focussed on minimising the flow-dependent dose emission that occurs with the Turbuhaler. • Protection of the formulation from moisture ingress during routine storage and patient use

44. Aerohaler™ • Contained six unit dose capsules as a magazine, each delivering one dose of drug. The device was used to deliver fenoterol and ipratropium bromide and was very similar in design to single-unit dose inhalers.

45. Diskhaler™ • Used in conjunction with refill Rotadisks™ which house four or eight sealed blisters containing drug and lactose excipient. • Excipients such as lactose improve dose uniformity by increasing the mass of powder for each dose thereby improving the accuracy of dose metering and minimising the effect of inhalation flow-dependent dose emission. • The sealed blisters offer a high degree of protection against humidity and because the premetered doses of drug are factory prepared and separately packaged, dose uniformity is assured. • It designed to simplify use by providing up to 1 month's medication in one device without the need to manually replace spent cartridges or capsules. • incorporates a dose counter, which enables the patient to monitor the number of doses remaining in the device,

46. Factors affecting dry powder inhaler use