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Inhaled Drugs beyond Bronchodilators. China 4000 Years Ago.

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Presentation on theme: "Inhaled Drugs beyond Bronchodilators. China 4000 Years Ago."— Presentation transcript:

1 Inhaled Drugs beyond Bronchodilators

2 China 4000 Years Ago

3 Bennet’s inhaler This may be the earliest published image of an inhalation device. In 1654 an English physician, Christopher Bennet, himself suffering with consumption, Bennet experimented on himself with a number of different remedies.

4 First isolation attempts The Plague doctor illustration is from Devils, Drugs & Doctors (Haggard, 1929). It depicts the protective clothing used by doctors treating the plague in Marseilles c1720. The beak was filled with spices to purify the inhaled air. At the time it was believed that plague was contagious by touch, hence the leather gloves and wand.

5 Kirkwood’s inhaler This advertisement from 1874 1888 shows Kirkwood’s inhaler, an apparatus for delivering fuming ammonium chloride. It was used as an antiseptic agent, and was recommended at times of contagion and epidemic.

6 Page's Inhalers Page's Inhalers were smoked "for the temporary relief of the paroxysms of asthma and to aid in the relief of the discomforts dust to excessive secretions in the nasal passage associated with hay fever and simple nasal irritations. Page's Inhalers were produced by the Consolidated Chemical Company of Grand Rapids, Michigan which was established in 1892.

7 Early inhalers

8 Early Home Care The ‘Indispensible’ inhaler was created by Dr Arnold, and was described as permitting the sick to follow the treatment of Dr Arnold at their own homes.

9 Treatments while you sleep

10 First Listed inhaled Medications The first official formulae of inhalation medicines were listed in the British Pharmacopoeia of 1867. The first official formulae of inhalation medicines were listed in the British Pharmacopoeia of 1867. British Pharmacopoeia of 1867British Pharmacopoeia of 1867 Hydrocyanic acid - which was used for the treatment of dry cough, however, in large doses it is lethal as it can paralyze respiration. Hydrocyanic acid - which was used for the treatment of dry cough, however, in large doses it is lethal as it can paralyze respiration. Vapor of hemlock is also described, it was also used as a treatment for cough. Vapor of creosote is also described, this was used as a treatment for tuberculosis and bronchitis. Vapor of creosote is also described, this was used as a treatment for tuberculosis and bronchitis.

11 Getting inhaled drugs to work

12 I Will Make This Work Cost Lack of Knowledge Lack of interest

13 A Guide to Aerosol Delivery Devices For Respiratory Therapists

14 A Guide to Aerosol Delivery Devices for Respiratory Therapists, 2nd Edition

15 3 mechanisms usually cited by which an aerosol particle can deposit Inertial impaction, - occurs with larger, fast-moving particles > 10 μm that are filtered in the nose and/or oropharynx Gravitational settling (sedimentation) is a function of particle size and time, with the rate of settling is proportional to particle size generally 5-10 μm reach the proximal generations of the lower respiratory tract. Diffusion occurs with particles smaller than 1-5 μm reach the lung periphery



18 Medical Marihuana

19 Perception of Marihuana Use

20 The Real Story Responsibility for the Medical Marihuana Program is The Bureau of Health Professions (BHP) within the Michigan Department of Community Health (MDCH) A qualifying patient is a person who has been diagnosed by a physician and have obtain a written certification from a that physician as having a debilitating medical condition such as cancer, HIV, AIDS. A primary caregiver means a person who is at least 21 years old and who has agreed to assist with a patient’s medical use of marihuana and who has never been convicted of a felony involving illegal drugs. The caregiver can assist no more than five patients.

21 ALBUTEROL FOR HYPERKALEMIA Hyperkalemia is classified as mild (5.5 to 6.0), moderate (6.1 to 6.9) and severe (>7.0). Definitive management of severe hyperkalemia is hemodialysis. Temporizing measures for moderate hyperkalemia,and severe hyperkalemia, includes –calcium gluconate –insulin with glucose –kayexalate

22 ALBUTEROL FOR HYPERKALEMIA Guidelines Albuterol can be administered in moderate to severe hyperkalemia. Mechanism of action is an increased cellular uptake of potassium, similar to the actions of insulin Onset of action was within 30 minutes, however the maximum effect was at 90 minutes after nebulization. 12-40% of the patients were unresponsive to albuterol and it was recommended that insulin should always be given in conjunction with the albuterol Nebulized dose of 10 mg was used in most adults studies but 20 mg was shown to be more effective at 120 minutes. Nebulized dose of 10 mg was used in most adults studies but 20 mg was shown to be more effective at 120 minutes. The potassium level should be measured 90-120 minutes after the desired dose is given and compared to the pre-albuterol level;

23 Heliox Helium is a colorless tasteless, non-combustible gas that is biologically inert and insoluble in human tissue It is seven times lighter than air. Combining helium and oxygen (Heliox) results in a gas with a similar viscosity to air but with a substantially lower density. Heliox lowers the resistance of gas flow in the airways and allows for an increase in ventilation due to changing turbulent flow into more efficient laminar flow. It also may decreases the pressure gradient needed to achieve a given level of turbulent flow which may decrease work of breathing. Use of Heliox does not treat the underlying disease, but is used to reduce airways resistance and respiratory muscle work until definitive treatments act.

24 Heliox History In 1930’s BarachIt recommended Heliox as an adjunct therapy for treatment of respiratory failure from obstructions of the larynx, trachea, and airways Use decreased in the 1940s due to the World War II and the loss of helium sources and development of bronchodilators that were more effective. Heliox resurfaced in the early 1980s when asthma deaths began to rise despite advances in medicine

25 Considerations of Heliox Heliox usually comes in a 80/20 mixture. There is little evidence of any severe adverse reactions for patients breathing Heliox since it is an inert gas that has no effect on human metabolism. Helium has a high thermal conductivity and may be associated with a lowering of body temperature when used for prolonged periods. Administration is best via a closed system as this allows the best concentration to be delivered to the patient without any mixing of room air to occur. When using an 80/20 mix FIO2’s >0.45 negate the therapeutic effect of He/O2. With an 80/20 mix when using an oxygen flow meter multiply by 1.8 to calculate the actual system flow. Understanding the effects of heliox on ventilator performance. Heliox cylinders cost about four times as much as oxygen.

26 Use of Heliox Decreases air-trapping in thereby reducing intrinsic positive end-expiratory pressure (PEEP). Decreases dyspnea and work of breathing, Improves distal-airway deposition of aerosol particles. Upper airways obstruction COPDCroupAsthma

27 Evidence of Heliox A prospective study by Gluck showed heliox reduced peak airway pressure and PaCO2 and helped correct respiratory acidosis in 7 intubated patients with status asthmaticus. Schaeffer reported that 11 mechanically ventilated for status asthmaticus receiving heliox had improved oxygenation in adult and pediatric patients. A retrospective study by Abd-Allah heliox was used in 28 mechanically ventilated children with status asthmaticus. Heliox was associated with significantly lower mean peak pressure and mean PaCO2, and a improved arterial pH. Gerbeaux retrospectively studied 81 nonrandomized patients who were admitted for exacerbation of COPD and respiratory acidosis. 39 patients received 70:30 heliox and 42 did not receive heliox. There were no significant differences in age, gender, medicalhistory, Among those who received heliox, the intubation rate was lower (8% vs 50%, p 0.01), mortality was lower (3% vs 24%, p 0.01), and intensive-care-unit (ICU) admissions were lower (46% vs60%, p 0.23). Among the survivors, mean ICU stay was shorter (8 vs 18 d, p 0.01). Gross et al found that in children mechanically ventilated for bronchiolitis, heliox did not improve oxygenation.

28 The White Elephant in the Room Inhaled Vasodilators –The short half-life of inhaled vasodilators minimizes the systemic effects, compared to intravenous, subcutaneous,or oral administration –Vasodilators that have been administered via inhalation, clinically and experimentally, include oxygen, nitric oxide, milrinone, nitroglycerin, prostacyclins, nitroprusside, nitric oxide donors, phosphodiesterase inhibitors, endothelin receptor antagonists, and agonists of soluble guanylate cyclase.

29 Nitric Oxide Nitric oxide was regarded as a pollutant until 1987. NO is a free radical, produced by the endothelium, that relaxes Vascular smooth muscle (via, cGMP) producing vasodilation. Atmospheric concentrations of nitric oxide typically range between 10 and 500 parts per billion but may reach 1.5 parts per million (ppm) in heavy traffic and 1000 ppm in tobacco smoke. In 1991, inhaled nitric oxide was shown to be a selective pulmonary vasodilator in patients with pulmonary hypertension. In 1991, inhaled nitric oxide was shown to be a selective pulmonary vasodilator in patients with pulmonary hypertension. 1992 Nitric Oxide was named molecule 1993, inhaled nitric oxide emerged as a potential therapy for the acute respiratory distress syndrome (ARDS), because it decreased pulmonary vascular resistance without affecting systemic blood pressure and improved oxygenation by redistributing pulmonary blood flow toward ventilated lung units in patients with this condition. Short half life Oxidizes to NO 2 Almost all cells can produce NO

30 How does INO Work Fast acting INO produces Selective Pulmonary Vasodilatation Does not Cause Systemic Vasodilatation Increases cGMP which causes Vasodilatation Decrease intrapulmonary shunt Pulmonary Effects –Increased Oxygenation –Decreased PVR

31 NO Action Mark J.D. Griffiths, M.R.C.P., Ph.D., and Timothy W. Evans, M.D., Ph.D Mark J.D. Griffiths, M.R.C.P., Ph.D., and Timothy W. Evans, M.D., Ph.D

32 NO Effects Mark J.D. Griffiths, M.R.C.P., Ph.D., and Timothy W. Evans, M.D., Ph.D

33 Indications

34 Inhaled Nitric Oxide

35 Iloprost and Flolan Pulmonary Hypertension Treatment Options Inhaled Nitric vs. Iloprost and Flolan

36 Ventavis (iloprost) Synthetic analogue of prostacyclin PGI 2 Dilates systemic and pulmonary vascular beds –5 mcg @ mouthpiece (10mcg@ chamber) 6-9 times a day while awake Affects platelet aggregation 10 mcg/ml Must use 1 of 2 (AAD) Adaptive Aerosol Systems Side effects COMMON Cardiovascular: Vasodilatation (27%) Dermatologic: Flushing Musculoskeletal: Trismus (12%) Neurologic: Headache (30%) Respiratory: Increasing frequency of cough (39%) SERIOUS Cardiovascular: Hypotension (11%) Respiratory: Pulmonary edema

37 I-neb

38 Prodose

39 NO vs. ILoprost Before NONO(40 ppm)Baseline 2(Before Iloprost) Iloprost(14– 17mg) CO (liter/ min) 3.4 +1.13.7 6 + 1.23.5 +1.24.2 +1.2 PVR (dyn eszs zcm2 5) 1,342 + 518 1,159 + 587 1,367 + 492920 + 387 SvO2 (%) 58 + 14 60 + 1359 + 1566 + 13 Hoeper et al. JACC Vol. 35, No. 1, 2000

40 Aeroneb Pro-X

41 nebulizer Normal saline Prostacyclin Solution (20,000ng/mL) 12 in. aerosol hose Exp filter Ventilator Infusion pump 24 in. aerosol hose Stop cocks Connector IV extension ValvedTee Flow meter AEROSOLIZED PROSTACYCLIN (EPOPROSTENOL, FLOLAN  ) AEROSOLIZED PROSTACYCLIN (EPOPROSTENOL, FLOLAN  ) Needs experienced Caregivers

42 Possibility of Combined Therapy The treatment with nitric oxide alone or combined with prostacyclin or adrenomedullin (ADM) were effective in decreasing mean PAP and improving oxygenation in a piglet model of PH. However, nitric oxide plus prostacyclin and nitric oxide plus ADM were more effective than nitric oxide alone. The combination of aerosolized prostacyclin and ADM with nitric oxide might have a role in the treatment of infants with PH refractory to nitric oxide alone. The combination of aerosolized prostacyclin and ADM with nitric oxide might have a role in the treatment of infants with PH refractory to nitric oxide alone. 2007;42:1048-1056 Carlo Dani, MD

43 Inhaled Opioids

44 Look at me Now

45 Reason for Inhaled Opioids Dyspnea due to Chronic pulmonary disorders –Pros Rapid Absorption Minimal Systemic effects –Cons Mixed results Small sample sizes Possible Respiratory Depression Legal issues of administration may produce bronchospasm Recommendations Not recommended as a standard treatment option May be helpful with refractory cases on patient by patient use Pain management –Pros Rapid Absorption Minimal Systemic effects –Cons Lack of experience in US

46 Inhaled Insulin FDA approved 2006 Rapid Acting No injections Works best with type 2 Cost more than injections Possible pulmonary effects Dosing can be complicated Dropped by Pfizer Several new drugs in pipeline

47 PENTAMIDINE TREATMENT ADMINISTRATION Brand name Pentam 300 Indication: prophylaxis of Pneumoncystis carinii pneumonia in immune- suppressed patients Dosage 300 mg every 4 weeks 150 mg every 2 weeks 30 mg every 2 weeks To prevent possible bronchospasm, patients should be given 2.5 mg of albuterol via MDI prior to pentamidine NMT. Filtered Neb, protection of others

48 Inhaled CHEMOTHERAPY (Doxorubicin, Cisplatin ) chemotherapy so it goes directly into the lungs. The goal is to maximize the delivery to the area needing treatment and minimize the toxicity to the rest of the body. Furthermore, researchers found there was a 25-fold increase in the amount of chemotherapy found in the lungs compared with the level obtained with traditional intravenous delivery. Cisplatin Childhood bone cancer

49 Inhaled Alteplase Dissolve clots Given to stroke patients Same safety issues of other Blood thinners Used as an inhaled drug to treat fibrin cast in the lungs

50 Nose to Brain OptiNose has developed innovative nasal drug delivery devices that enable nasal administration of CNS (nose to brain), systemic and topical nasal formulations. OptiNose’s unique breath actuated devices deliver intranasal drugs to targeted regions of the nasal cavity, including the sinuses and the olfactory region, without lung deposition, unlike traditional nasal inhalers, nasal sprays or nebulizers. The Company offers both single and multi-use intranasal delivery devices for liquid and powder formulations. Founded in 2000, OptiNose has extensively tested the technology in both in- vitro and in-vivo deposition studies and concluded Phase I studies. The Company has recently completed Phase II clinical studies with rhinosinusitis and migraine therapies.

51 Surfactant Replacement Therapy Composed of lipids (90%) and proteins (10%). Instillation directly into the lung possibly more effective at this time than aerosolized (Ex-osurf). Cost for responders may be to high.

52 Hypertonic Saline CF airways lack enough salt and water, researchers thought a hypertonic saline mist would help clear the thick mucus from the lungs. 7% hypertonic saline Presented at the 2004 North American Cystic Fibrosis Conference published in the New England Journal of Medicine and University of North Carolina at Chapel Hill. 0.9% vs 7% Both groups had increased lung function However the hypertonic group had even better lung function also, the hypertonic saline group had fewer lung infections. Average dose 4 mL You should not mix any other medications with hypertonic saline. Side effects that were noted included coughing more, sore throat and chest tightness. (It is known that hypertonic saline can irritate the airways.)

53 Pulmozyme ( Pulmozyme (DNase) Pulmozyme is a man-made form of naturally occurring DNase. It works by "cutting up" the DNA left by neutrophils. Standard dose 2.5 mg Launched in 1994, Pulmozyme was the first new therapeutic drug for the management of CF in more than 30 years. Take every day, whether they have cystic fibrosis symptoms or not. This may help break the cycle of cystic fibrosis progression. Must be stored in the refrigerator at 2-8°C (36-46°F) and protected from strong light. Pulmozyme should not be diluted or mixed with other drugs,.mixing with other drugs could lead to adverse physiochemical and/or functional changes in Pulmozyme or the combined products. Daily administration of Pulmozyme has also been shown to reduce the risk of respiratory tract infections requiring less antibiotics. Pulmozyme should not be used in patients with known allergies to dornase alfa, Chinese Hamster Ovary cell products, or any component of the product.

54 Pulmozyme Action

55 Administering Aerosolized Ribavirin Clinical Indications Documented symptomatic RSV infection Recipients of allogeneic stem cell transplant Recipients of autologenous stem cell transplant Contraindications Hypersensitivity to Drug Pregnant or planning to become pregnant within two weeks of exposure Requiring mechanical ventilation Recommended Dosage 33.3 mL of 60 mg ribavirin/mL aerosolized for 2 hrs every 8 hrs Total of 6 g/day (100 mL divided into 3 doses) Given for 5–10 days NOTE: Administer a Bronchodilator Pre-treatment C. Haas

56 Setup Use Blender, if supplemental O 2 is required Assemble SPAG unit –Set Drive Pressure to 26 psi –Set Nebulizer Flowmeter to max (6-10 L/min) –Set Drying Chamber Flow to 8 L/min (range 3-8) Attach aerosol tubing to patient face/trach mask –Not to be used on vent pts Place a blue pad under the SPAG

57 Employee Precautions The treatment should be given in the Demistifier 2000B HEPA filtration scavenging hood ‘Droplet Precautions’ should be followed for all patients with RSV (gloves, gown, isolation mask, face shield/goggles when w/i 3 feet of patient) –During therapy, wear an N-95 mask or the PAPR unit Pregnant women should avoid contact Those wearing contact lenses should avoid contact (wear goggles or take out)

58 Patient Preparation Explain therapy goals and procedure Administer bronchodilator Ask if patient needs to use the restroom If wearing contact lens, ask to take out or apply goggles Place a drape sheet over patient

59 Spag-2 Setup Drying Chamber Driving Pressure (26 psi) Nebulizer Nebulizer Flow 6 to 10 Lpm Drying Chamber flow 3 to 8 Lpm (Output is 12.5-15 mL/hr)

60 Fightting the Flu RELENZA (ruh-LENS-uh) is a medicine that can both treat influenza (flu, infection caused by influenza virus) and help to prevent getting the flu. While some antiviral medicines only protect against influenza A, RELENZA is effective against both influenza A and B. RELENZA belongs to a group of medicines called neuraminidase inhibitors. These medications target the influenza virus and prevent it from spreading inside your body. RELENZA treats the cause of influenza at its source, rather than simply treating the symptoms. Some patients have had bronchospasm (wheezing) or serious breathing problems when they used RELENZA. Many but not all of these patients had previous asthma or chronic obstructive pulmonary disease.

61 The green Movement

62 Others That Benefit form Inhaled Drugs

63 Inhaled Anesthetics In the ICU Pro –May provide better sedation –Cost –Ability to avoid Hypotension – Used as last ditch tx. Cons –Untrained personal –Environment

64 A Gaze Into The Future

65 Advanced delivery Technology SPIONS- Superparamagnetic iron oxide nanoparticles Nanobytes

66 ORBIT-1 Treatment for Bronchiectasis First Patient February Phase 2b study 96 Patients randomized 100 – 150 mg of Liposomal Ciprofloxacin

67 Carbon Monoxide Carbon monoxide is lethal at certain doses that kills thousands of Americans every year "The therapeutic window for carbon monoxide is very small, it's equivalent to the amount you'd receive sitting in a traffic jam in Mexico City May improve transplant out comes-- Hmox expression goes up, it reduces iNOS expression and suppresses a key signaling pathway involved in the immune response Research team focuses on the relationship between carbon monoxide and nitric oxide.

68 Love Hormone University of Haifa has found that the hormone oxytocin, the “love hormone", which affects behaviors such as trust, empathy and generosity, also affects opposite behaviors, such as jealousy and gloating. "Subsequent to these findings, we assume that the hormone is an overall trigger for social sentiments: when the person's association is positive, oxytocin bolsters pro-social behaviors; when the association is negative, the hormone increases negative sentiments. Previous studies have shown that the oxytocin hormone has a positive effect on positive feelings. The hormone is released in the body naturally during childbirth and when engaging in sexual relations. Participants in an experiment who inhaled the synthetic form of the hormone displayed higher levels of altruistic feelings, and it is supposed that the hormone plays an important role in the formation of relationships between people. However, in earlier studies carried out by other investigators with rodents, it was found that the hormone is also related to higher levels of aggression. Therefore, it was decided to examine whether the hormone also affects negative social sentiments. The present study, which was published in the journal Biological Psychiatry, included 56 participants. Half of the participants inhaled the synthetic form of the hormone in the first session and were given a placebo in the second session; the others were given a placebo in the first session and oxytocin in the second session. Following drug administration each participant was asked to play a game of luck along with another competitor, who was in fact - and without their knowledge - a computer. Each of the participants was asked to choose one of three doors and was awarded the sum of money that was hidden behind that door. Sometimes the participant gained less money than the other player, and sometimes more, creating conditions in which a person might well develop feelings of envy and gloating. The findings show that those participants who inhaled the oxytocin displayed higher levels of envy when the opponent won more money and of gloating when they were ahead. Another interesting result was that as soon as the game was over, no differences between the participants were evident with regards to these sentiments. This indicates that the negative feelings were empowered only in the course of the game itself. Possible use of the hormone as a medication for various disorders, such as autism but the hormone's undesirable effects must be examined.

69 New Inhaled Vasodilator inhaled Treprostinil for the treatment of pulmonary arterial hypertension. The NDA will be subject to a standard review period of 10 months, with a targeted user fee deadline of April 30, 2009. United Therapeutics Corporation is a biotechnology company focused on the development and commercialization of unique products to address the unmet medical needs of patients with chronic and life-threatening cardiovascular and infectious diseases and cancer. Lung Rx, Inc. is a biotechnology company focused on unmet medical needs in pulmonary medicine and pulmonary delivery of innovative therapeutic products.




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