Pharmacology of Inhaled Drugs

Pulmonary Drug Delivery

• Pulmonary drug delivery is a method of administering medications to the lungs, commonly used in treating respiratory conditions.
• Inhaled drugs act quickly, minimize the required dose, and are non-invasive.
• Inhaled drugs go directly to the lung, minimizing side effects and avoiding hepatic first-pass metabolism.
• Inhaled drugs are systemically absorbed.

Objectives

• Understanding droplet size and settling velocity effects on drug disposition is crucial.
• Differences between Metered-Dose Inhalers (MDIs) and Dry-Powder Inhalers (DPIs) in terms of ingredients should be understood.
• The 3 USP sections provide guidelines on this topic.
• Patient factors (lung anatomy, disease state, breathing patterns, age) can affect how droplets deposit in the respiratory tract.
• Ophthalmic and intranasal products' viscosity and surface tension influence residence time and drug absorption.
• Understand the acceptable pH and isotonicity ranges for ophthalmic and intranasal products.
• Knowing the advantages, disadvantages, and characteristics of MDI, DPI, nebulizers, and spacers is essential.

Rationale

• Ancient civilizations, current smokers, and drug abusers have long known the effectiveness of inhaled drugs.
• Scientists and physicians later discovered that inhaled drugs deliver medication directly to the lung, minimizing side effects, and avoiding hepatic first-pass metabolism.

Advantages of Respiratory Drug Delivery

• Delivers medication to the site of action.
• Requires lower doses of medication due to the large surface area of the lung.
• Reduces systemic side effects.
• Has a rapid onset.
• Avoids the GI upset.
• Avoids first-pass metabolism (liver).
• Provides a less hostile environment for medication retention. (lung tissue is less hostile to most drugs compared to the GI tract).

Disadvantages of Respiratory Drug Delivery

• Difficulty with dose estimation and reproducibility due to many variables.
• Proper technique and guidance are required for effective use.
• Mucus and infection can hinder drug deposition in the lower airways.
• The physical stability of pharmaceutical aerosols can be problematic.
• Systemic absorption is limited by the mucous layer and mucociliary clearance. (which is not helpful for poorly soluble or slowly absorbed drugs.)

Respiratory Tract

• The lower respiratory tract comprises the trachea, which divides into bronchi.
• Bronchi branch into bronchioles.
• Bronchioles lead to alveoli, where gas exchange with the blood occurs.

Factors Affecting Drug Deposition in the Lung

• Physicochemical properties of aerosolized droplets/particles containing the drug.
• Physiological and anatomical considerations.
• The delivery device.

Physicochemical Factors

• In pulmonary drug delivery, inhaled particles need to settle on lung tissues.
• Diameter and density are important factors.
• Mean Aerodynamic Diameter (MAD) is the diameter of a unit density sphere that has the same settling velocity as another particle.
• A 5-micron irregular shaped particle has the same settling velocity as a 5-micron spherical particle with a density of = 1 g/cm³.
• Stokes diameter is the diameter of a sphere with the same density and settling velocity as the particle.

Aerosol Size and Work Region

• Aerosol sizes, such as >10 µm, 5-10 µm, 2-5 µm, and 0.8-3 µm, relate to different regions of the respiratory tract, such as the nasopharyngeal/oropharyngeal regions, central airways, and terminal airways/alveolar regions.

Settling Velocity

• Settling velocity is adapted from Stokes' law (viscous fluid motion).
• Ae = aerodynamic diameter, D1=volume equivalent diameter, p = particle density.

Additional Formulation Factors

• Humidity of the respiratory tract is 99.5% at 37°C.
• Lipophilic particle MAD is unaffected, but hydrophilic particles increase MAD (hygroscopic).
• Particles sized <1 micron are affected by Brownian motion.
• Stability concerns: drugs should not decompose before reaching the target; should not decompose before reaching the target.
• Electrostatic charge and inertial impact of the airstream affect drug deposition, especially in the upper airways.

MDI Inhalers

• Advantages: reliable and consistent dose delivery directly to the action site, faster onset than oral bronchodilators, fewer side effects, portable and low-cost.
• Disadvantages: coordination of actuation and inhalation needed, not very efficient delivery, uncertainty about the remaining amount of medication.

MDI Composition

• Container, metering valve (releases fixed volume), elastomer seal (prevents leakage), actuator (permits discharge), drug (suspension in propellant or solution in cosolvent mix), propellant/excipient mixture.
• How they work: pressure releases drug-propellant mixture in the metering valve that gets sheared and broken into an aerosol.
• Examples of MDI medications mentioned include Albuterol, Ipratropium, Fluticasone, Levabuterol Tartrate, and Pirbuterol.

CFC vs HFA

• In the 1980s, the USA and other countries phased out CFCs (chlorofluorocarbons) due to environmental concerns.
• HFA (hydrofluorocarbons) propellants exhibit better lung deposition performance compared to CFCs..

Dry Powder Inhalers (DPIs)

• Advantages: automatic coordination between dose delivery and inhalation, no propellants needed, potential drug stability and high dose carrying capacity.
• Disadvantages: requires high inspiratory flow rate (from patient), potential for procedural errors.

Dry Powder Inhaler Mechanism

• Micronized medication particles are prepared in 1 -5 µm diameters.
• Air is drawn through a dose of drug powder using a carrier.
• The carrier can also serve as a bulking agent to help with reproducibility.
• Patient inhales, drug dissociates from the carrier.
• The carrier aids the formulation's flow properties and metering uniformity.
• It protects the powder from humidity

Nebulizers

• Nebulizers convert liquid medication into a fine mist form for inhalation.
• Droplet size and deposition depend on factors such as orifice diameter, pressure, density, concentration, viscosity, surface tension, and flow rate.
• Surfactants help lower surface tension, forming fine droplets, and rescue/preventative inhalations are suitable for nebulization.
• Delivery methods include compressed air, oxygen, and ultrasonic power.
• Examples of nebulized solutions mentioned include Albuterol Sulfate, Ipratropium bromide, Budesonide (Pulmicort Respules), Albuterol/Ipratropium (Duoneb), and Levalbuterol (Xopenex).

Nebulizers: Advantages

• Passive breathing, good for pediatric patients, administering any solution in solution form, minimal coordination, works for low inspiratory flows, adjustable drug concentration.

Nebulizers: Disadvantages

• Time-consuming, external/rechargeable power sources needed (cost implications), requires cleaning, low dose delivery (~10%).

Nebulizers: Components

• Air compressor (for jet nebulizers)
• Nebulizer cup
• Mask/mouthpiece
• Medication (unit dose vials/bottles with measuring device)
• Compressor tubing
• Baffle (ultrasonic nebulizers, decreases MAD)

Nebulizers: Concerns

• Contaminated solutions, multi-dose vials, caregivers not washing hands adequately, not cleaning nebulizer parts, drug concentration increasing over time during use.

Spacers/Holding Chambers

• Purpose: deliver medication to the lungs, decreasing particle size, improving delivery.
• Advantages: less/no coordination needed, multiple breaths possible for complete dose, useful for pediatric patients, cheaper than nebulizers, reduces drug deposition in oropharynx.
• Disadvantages: more cumbersome than MDIs, requires cleaning.

Cascade Impactor

• Cascade impactor (machine) separates and sizes aerosol particles.

Nasal Drug Delivery

• The nasal cavities are used to administer medications systemically or locally.
• The nasal cavity's total surface area and volume are relevant to drug delivery.
• The nasal vestibule contains filters.
• Nasal cavity pH is ~7.4; mucus pH is 5.5-6.5.

Nasal Structure

• The nose is divided into three regions: vestibule (first), turbinates, and olfactory regions.
• The vestibule has hairs (vibrissae) filtering particles larger than 10 µm.
• The turbinates are bony structures covered in mucosa, crucial for drug absorption.
• Olfactory regions are the upper nasal areas.

Medications for Nasal Delivery

• Medications can be used for localized effects (nasal congestion/infection, allergic rhinitis), systemic effects (pain, migraines), emergency situations (naloxone, overdose), and vaccine deliveries.
• Medications used in nasal delivery can be delivered as creams, ointments, or drops.

Nasal Drug Delivery: Examples

• Local: Flonase (allergic rhinitis), Mupirocin (antibacterial), Azelastine HCL (allergic rhinitis).
• Systemic: Sumatriptan (migraine), Salmon Calcitonin (osteoporosis), Fentanyl Citrate (pain), vaccines.

Nasal Drug Delivery: Advantages

• No swallowing required (high compliance), avoids GI/hepatic metabolism, can use lower production costs (no sterility needed), use for chronic diseases without irritation, higher bioavailability (55-100%), faster delivery.

Nasal Drug Delivery: Disadvantages

• Limited medication types suitable for intranasal delivery, concentrating the drug to achieve an ideal dosing volume can be a problem, nasal mucosa varies by individual (limiting dosing volumes), enzymatic activity of nasal fluid (cytochrome P450s).

Systemic Delivery Advantages & Disadvantages

• Advantages: Larger surface area & good blood supply for absorption.
• Disadvantages: Limited to smaller delivery volumes (~25-200 µL), mucus barrier/mucociliary clearance, enzymatic activity, low epithelial permeability for hydrophilic drugs.

Systemic Delivery and Absorption

• Drugs must be absorbed across the nasal epithelium to circulate systemically.
• Absorption can take place via passive diffusion: transcellular (lipophilic molecules) and paracellular (small hydrophobic molecules).

Physicochemical Properties Affecting Intranasal Delivery

• Drug solubility (hydrophilicity/lipoplilicity and molecular size); a drug's rate and extent of absorption is inversely proportional to its molecular weight (hydrophilic drugs).
• Degree of ionization (unionized drugs absorbed better).

Formulation Factors Affecting Bioavailability

• Low aqueous solubility, rapid/extensive enzymatic degradation in nasal cavity, short contact time between drug and epithelium, poor permeability of drug (affect formulations negatively).
• Strategies to improve bioavailability include increasing aqueous solubility, viscosity, and using prodrugs.

Patient Factors for Nasal Delivery

• Patient compliance and nasal pathology/disease can influence nasal delivery (nasal structure may change, cold, surgery, cocaine abuse).

Other Important Information for Intranasal Delivery

• Intranasal solutions are isotonic.
• Pediatric strength may be half of adult strength.
• Typical nasal volume is 15-30 ml.
• Dosing volumes should be less than 1ml/nostril (lower if for systemic use).
• Packaging must be tightly closed
• Avoid precipitated matter
• Ideal pH = 5.0 to 8.0

Warnings/Precautions for Nasal Delivery

• Hypo- and hyperosmotic solutions can cause bronchoconstriction.
• Make sure excipients are safe for respiratory epithelium.
• Antioxidants can trigger bronchospasm.

Ocular Drug Delivery

• Medications for ocular ailments can be topical, systemic or intraocular/periocular (oral/injection/injection/implant).
• Ocular medications include solutions, suspensions, ointments, gels, and emulsions.

Ocular Routes & Barriers

• Cornea is the primary route.
• Intravitreal is delivery directly behind the eye.
• The blood-retina barrier restricts drug entry into the eye from systemic circulation.

Topical Ophthalmic Preparations

• Includes solutions, suspensions, ointments, and gels.
• Used for eye disorders like infection, inflammation, allergy, dry eye, glaucoma, corneal ulceration, anesthetics, and diagnostics.

Ophthalmic Preparations: Additional Info

• Eyeball can hold 30µL fluid if it doesn't blink, eye drops should be administered several minutes apart, 1 drop is ~50 µL (based on 20 drops/mL).
• Tears are more acidic for contact lens wearers.

Formulation Factors for Ophthalmic Preparations

• Short residence time: may cause systemic effects, softening point near body temp, sterile, low preservatives (no preservatives in surgery), isotonic (0.6% - 1.8% NaCl), lacrimal fluid is isotonic (~0.9% NaCl).

Formulation Factors (Cont'd)

• Tears' low buffer capacity means pH should range from 4.5-11.5, ideally 6.5-8.5 for neutral pH.
• Drug ionization can be pH-dependent for hydrolytic degradation (e.g. pilocarpine). A weak buffer can help maintain pH.
• Surface tension and viscosity can improve drug absorption.

Ophthalmic Solutions

• Advantages: easy manufacture, relative ease of administration, rapid onset, no dissolution required.
• Disadvantages: rapid drainage from the eye.

Ophthalmic Suspensions

• Advantages: can prolong drug release.
• Disadvantages: prone to stability issues (e.g., cake formation, dissolution changes). Needs to be shaken well.

Sub-micron Emulsion

• Common for drugs with poor aqueous solubility.
• Example: Restasis® (cyclosporine oil-in-water emulsion).

Ophthalmic Ointments

• Advantages: reduces drug drainage/clearance, improves residence time, allows sustained release (2-4 hrs), improves drug solubility, greater bioavailability,
• Disadvantages: difficulty in administration, causes blurry vision, reduces patient compliance.

Ophthalmic Gels

• Semisolid, water-soluble bases
• Incorporate water-soluble drugs
• Gel activation: ions, pH, temperature.
• Example: Timolol (glaucoma treatment) forms a gel in the eye.

Systemic Drug Delivery

• IV administration needs to cross the blood-retina barrier.
• High systemic doses are required.
• Example: Visudyne® (AMD treatment).

Intravitreal Injections

• Most effective technique for delivering drugs to the eye.
• Bypasses blood-ocular barriers.
• Minimizes systemic side effects.
• Better for low molecular weight drugs and monoclonal antibodies.
• Repeated injections may be needed every few weeks.
• Examples: Lucentis®️, treating wet macular degeneration; Triamcinolone acetonide (steroid), treating inflammation).

Intraocular Implants

• Classified as non-biodegradable or biodegradable.
• Drug release depends on the polymer type and drug properties.
• Required biocompatibility, no interaction with surrounding tissue or immune responses.

Non-Biodegradable Implants

• Drug coated with semi-permeable polymer.
• Ex: Vitrasert® (CMV treatment), Retisert® (uveitis treatment)

Biodegradable Implants

• Polymer is metabolized by enzymes (or non-enzymatic, e.g. hydrolysis)—no removal typically needed.
• Ex: Ozurdex® (dexamethasone ocular implant).

Counseling Points for Ophthalmic Medications

• Ophthalmic ointments can cause temporary blurry vision (better applied at night.)
• Contact lenses may need to be removed.
• Eye drops should be administered several minutes apart.
• Some products have a short shelf-life and should not be reused.

USP Guidelines and Sections

• USP 797: Pharmaceutical compounding for sterile preparations.
• USP 795: Pharmaceutical compounding for non-sterile preparations.
• USP 800: USP guideline for handling hazardous drugs.

Types of Plastic Containers

• Polyethylene, polypropylene, polyvinyl chloride, polystyrene, polycarbonate.

Properties of Plastic Containers

• Polyethylene (widely used, good water barrier, poor oxygen barrier, odors and gases permeate)
• Polypropylene (very popular, excellent water and gas barrier)
• Polyvinyl chloride (good oxygen barrier, yellows with heat/UV light, used for parenteral solutions, permeable to water)
• Polystyrene (rigid, crystal clear, used for solid dosage forms).
• Polycarbonate (rigid, possible replacement for glass, expensive)

Test your knowledge on the pharmacological principles behind respiratory drug delivery. This quiz covers advantages, disadvantages, and the structure of the lower respiratory tract related to inhaled medications. Assess your understanding of inhalation therapy's rationale and effectiveness.