Sympathomimetics in Bronchial asthma

Presented by :Heba Abd El-fattah Sabry

Asthma-Treatment

What are the treatments?Drugs that reduce inflammation

Drugs that reduce bronchoconstriction

Asthma - Introduction (Cont.)Drug therapy

Airway Inflammation Bronchospasm

Glucocorticoids

Leukotriene inhibitors

Chromones

IgE inhibitors

adrenergic receptor agonist

Methylxanthine

Muscarinic receptor antagonist

Prophylaxis preventionLong-term (controller medications)

Symptomatic reliefShort-term

Bronchodilators

Open up the bronchial tubes so that more air can move through Help

clear mucus from the lungs. As the airways open, the mucus moves

more freely and can be coughed out (expelled) more easily.

Short-acting bronchodilators

Long-acting bronchodilators

called "quick acting," "reliever," or "rescue

relieve asthma symptoms very quickly by opening the airways

used to provide control -- not quick relief -- of asthma

The action starts within minutes after inhalation and lasts for 2 to 4 hours .

Used 15-20 minutes before exercise to prevent exercise-induced asthma.

last for at least 12 hours.

Those containing formoterol begin their action within a few minutes, while those containing salmeterol take up to 45 minutes to begin their action.

Sympathomimetics- Use in AsthmaAdrenoceptor agonists (2-selective agents preferred )

Short-acting(2-6 hrs)

Long-acting(>12 hrs)

Symptomatic relief Prophylactically in combination with steroid

Salmeterol (Serevent)Formoterol (Foradil)

Albuterol (Proventil, etc.)L-albuterol (Xopenex)Metaproterenol (Alupent)Terbutaline (Brethaire)Pirbuterol (Maxair)

OH

OH

NH

O

Very lipophilic (persistent membrane contact?)CH3CH3

OH

OH

NH

CH3

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.

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

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.

Sympathomimetics- Use in Asthma2-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:

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.

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

Side effects 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

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

Intermediate acting B2 agonist

Albuterol (Salbutamol)

Ventolin®(HFA , Syp., tab. , Inhalr.)

DoseAcute bronchospasm:   Inhalation: MDI 90 mcg/puff: 4-8 puffs every 20 minutes for up to 4 hours, then every 1-4 h.as needed   Nebulization: 2.5 mg, diluted to 3ml, 3-4 times/day over 5-15 m.Oral:   Regular release: 2-4 mg/dose 3-4 times/day; maximum dose not to exceed 32 mg/day (divided doses)     Extended release: 8 mg every12h

PKOnset : Peak effect:   Nebulization/oral inhalation: 0.5-2h.

   Ventolin® HFA: 25 minutes    Oral: 2-3 hours

Duration: Nebulization/oral inhalation: 3-4 hours; Oral: 4-6 hours

Albuterol

Metabolism:Hepatic to an inactive sulfate

Half-life elimination: Inhalation: 3.8 h.

Oral: 3.7-5 h.

Excretion:Urine (30% as unchanged drug

Drug interaction:

Beta-adrenergic blockers antagonize albuterol's effects;CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of albuterol. As carbamazepine, phenobarbital, phenytoin, and rifamycins. Inhaled ipratropium ↑ duration of bronchodilation.MAO inhibitors, TCAs may increase side effects.Sympathomimetics may increase side effects; monitor heart rate and blood pressure.

Terbutaline

Bricanyl ® tab., syp. , Inhaler.

Dose  Oral: 5 mg/dose every 6 h.; not to exceed 15 mg in 24 h.   SubQ: 0.25 mg/dose; may repeat in 15-30 minutes (maximum: 0.5 mg/4-hour period)

Oral: Children:    <12 years: Initial: 0.05 mg/kg/dose 3 times/day, increased gradually as required; maximum: 0.15 mg/kg/dose 3-4 times/day . DOSING: RENAL IMPAIRMENT Clcr 10-50 mL/minute: Administer 50% of normal dose. Clcr <10 mL/minute: Avoid.

PKOnset of action: Oral: 30-45 minutes;

SubQ: 6-15 minutes

Protein binding: 25%.

Metabolism: Hepatic to inactive sulfate cong.

Half-life elimination: 11-16 hours

Excretion: Urine

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

Fenoterol Berotec®

DoseMetered dose inhaler (MDI):     Acute treatment: 1 puff initially; may repeat in 5m. if relief is not evident, additional doses and/or other therapy may be necessary     Intermittent/long-term treatment: 1-2 puffs 3-4 times/day (maximum of 8 puffs/24 hours)

  Inhalation solution: 0.5-1 mg (up to 2.5 mg)

PKOnset of action: 5 minutes   Peak effect: 30-60 minutes

Duration: 3-4 hours (up to 6-8 hours)

D-D interaction

Beta-adrenergic blockers : Antagonize bronchodilatory effects. Diuretics: Concurrent use may increase risk of hypokalemia.Ipratropium (inhaled): May increase duration of bronchodilation.MAO inhibitors, TCAs: May increase adverse effects of fenoterol.Sympathomimetics: May increase adverse effects of fenoterol;

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)

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.

B2 Agonist(Long acting)

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.

Formeterol

Foradil® Aerolizer

Salmeterol

Serevent®Diskus

DoseAsthma (maintenance): Inhalation: 12 mcg capsule every 12 hours

maintenance:

Inhalation:One inhalation (50 mcg) every 12 hours.

PKOnset: Within 3 minutes Peak effect: 80% of peak effect within 15 minutes.

Duration: Improvement in FEV1 observed for 12 hours in most patients

Onset : Asthma: 30-48 m., COPD: 2h.

Peak : 2-4 h, COPD: 3h. Duration: 12 hours

Absorption: Rapidly into plasma.

Protein binding: 61% to 64% in vitro at higher concentrations than achieved with usual dosing

Protein binding: 96%

FormeterolSalmeterol

MetabolismHepatic via direct glucuronidation and O-demethylation.

Half-life elimination: ~10-14h.

Time to peak: Maximum improvement in FEV1 in 1-3h.

Hepatically hydroxylated.

Half-life elimination: 5.5h.

Excretion Children : Urine (7% to 9% as direct glucuronide metabolites, 6% as unchanged drug)   Adults: Urine (15% to 18% as direct glucuronide metabolites, 10% as unchanged drug)

Feces (60%), urine (25%)

Drug-Drug interaction

Beta2-agonists: May diminish the bradycardic effect of beta-blockers (beta1 selective).Beta-blockers (nonselective): May diminish the bronchodilatory effect of beta2-agonists.Sympathomimetics: May enhance the adverse/toxic effect.

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.

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.

Criteria for an ideal inhaler

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

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.

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:

1. Mechanism.2. Use of mouthpiece or facemask.3. Drug formulation.

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

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.

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 .

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

Pressurised metered dose inhaler

Used for administration of corticosteroida and bronchodilators.

Advantages:1. Cheap .

2. Simple to manufacture on a large commercial scale .

3. Availability of a range of drugs that can be formulated for pMDIs.

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

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.

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 .

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.

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.

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.

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

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.

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,

Factors affecting dry powder inhaler use

Drug delivery

Consistent dose delivery throughout device lifeDose reproducibility across range of temperatures and humiditiesHigh proportion of dose available for inhalation over a range of inspiratory flow ratesLarge fine particle mass in relation to total emitted dose (see section Drug delivery)Low resistance of device to airflow during inhalation

Ease of use Small number of steps required to actuate deviceLow inhaler technique training requirementsLow degree of manual dexterity required to use device

Patient preference

Appropriate size and low o btrusivenessIncorporation of a dose counterPositive reinforcement of dose delivery