Inhaled Drugs beyond Bronchodilators

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.   • 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.  

11. Getting inhaled drugs to work

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

13. A Guide to Aerosol Delivery Devices For Respiratory Therapists

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

15. 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 3 mechanisms usually cited by which an aerosol particle can deposit

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. • 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 • COPD • Croup • Asthma

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. • 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 NO2 • Almost all cells can produce NO

30. 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 How does INO Work

31. NO Action • 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. Pulmonary Hypertension Treatment Options Inhaled Nitric vs.Iloprost and Flolan

36. Ventavis (iloprost) • Synthetic analogue of prostacyclin PGI2 • 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 Hoeper et al. JACC Vol. 35, No. 1, 2000

40. Aeroneb Pro-X

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

42. 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. Possibility of Combined Therapy 2007;42:1048-1056 Carlo Dani, MD

43. Inhaled Opioids

44. Look at me Now

45. 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 Reason for Inhaled Opioids

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.