L6. Drug Administration & TransportOnly by Fluid Motion Use
April 19, 2018Course 207
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NANO Only Use
Part I: Drug AdministrationCourse 207
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NANO Routes of Drug Administration
Only
Topical: local effect, substanceUse is applied directly where its action is desired.
EnteralCourse: systemic effect, substance is 207given via the gastrointestinal (GI) tract.
Parenteral: systemic effect, substance is given by routes other than the gastrointestinal (GI) tract. 243/CENG
NANO Topical Drug Delivery
Epicutaneous – directly onto the surface of the skin Only allergy testing local anesthesia… Use
Eye drops antibiotics for conjunctivitis … Course
Inhalational207 asthma medications acute infection in upper airway …
243/CENG Intranasal route decongestant nasal sprays … NANO Enteral Drug Delivery
Any form of administration that involves any part of the gastrointestinalOnly tract Use
Course 207 Oral: Rectal: Gastric feeding tube: many drugs as tablets, various drugs in many drugs, enteral capsules, drops… suppository or enema nutrition… form… 243/CENG
NANO Parenteral Drug Delivery
Intravenous: into a vein (many drugs, total parenteral nutrition…) Only Intramuscular: into a muscle (many vaccines, antibiotics…) Use Subcutaneous: under the skin (insulin…)
Intraarterial: into an artery (vasodilator drugs in the treatment of vasospasm…) Course Intradermal: into the skin itself (skin testing some allergens, tattoos…) 207 Transdermal: diffusion through the intact skin (transdermal opioid patches in pain management, nicotine patches for treatment of addiction…) Transmucosal:243/CENG diffusion through a mucous membrane (insufflation of cocaine)
Inhalational: e.g. inhalational anesthetics NANO Drug Administration Routes - Summary
Topical: Epicutaneous (allergy testing, local anesthesia…) Inhalational (asthma medications…) Only Eye drops (antibiotics for conjunctivitis…) Intranasal route (decongestant nasal sprays…) Use
Enteral: any form of administration that involves any part of the gastrointestinal tract Oral (many drugs as tablets, capsules, drops…) Rectal (various drugs in suppository or enemaCourse form…) Gastric feeding tube (many drugs, enteral nutrition…) 207 Parenteral: Intravenous: into a vein (many drugs, total parenteral nutrition…) Intramuscular: into a muscle (many vaccines, antibiotic…) Subcutaneous: under the skin (insulin…) Intraarterial: into an artery (vasodilator drugs in the treatment of vasospasm…) Intradermal: into the skin itself (skin testing some allergens, tattoos…) Transdermal:243/CENG diffusion through the intact skin (transdermal opioid patches in pain therapy, nicotine patches for treatment of addiction…) Transmucosal: diffusion through a mucous membrane (insufflation of cocaine, NANOInhalational, e.g. inhalational anesthetics Novel Administration Routes
Only Use
Contact lenses for eye delivery Course 207
Controlled-release microchip Drug eluting stent 243/CENG
Micro-needle patch NANO And many many more... Oral Administration
stomach Advantages: Only duodenum Convenient - portable, no pain, easy to take. Use jejunum Cheap - no need to sterilize, compact, multi-dose bottles, produced in large quantities. ileum Variety - fast release tablets, capsules, enteric coated,Course layered tablets, slow release, suspensions, et al. 207 Disadvantages:
Sometimes inefficient - high dose or low solubility drugs may suffer poor bioavailability.
First-pass effect - drugs will be metabolized in the liver during absorption. Food - Food and GI243/CENG motility can effect drug absorption. Local effect - Antibiotics may kill normal gut flora and allow overgrowth of fungal varieties. UnconsciousNANO patient - Patient must be able to swallow solid dosage forms. Intravenous Injection
Advantages:
Rapid - A quick response is possible Only Total dose - The whole dose is delivered to the blood Use stream. Large doses can be given by extending the time of infusion. Veins insensitive - irritation by irritant drugs at higherCourse concentration in dosage forms. 207 Disadvantages: First intravenous injection (1667) Suitable vein - It may be difficult to find a suitable vein.
Maybe toxic - Because of the rapid response, toxicity can be a problem.
Requires trained243/CENG personnel - Trained personnel are required to give intravenous injections.
Expensive - Sterility, pyrogen testing and large volume of solvent means great cost for NANOpreparation, transport and storage. Subcutaneous Injection
Advantages: Only • Can be given by patient, e.g. in the case of insulin. Use • Absorption is slow but usually complete. Improved by massage or heat. Course Disadvantages: • Can be painful 207 • Irritant drugs can cause local tissue damage • Maximum of 2 mL injection thus often small doses limit use. 243/CENG
Advantages: Only • Larger volume, than SC, can be given by IM. Use • A depot or sustained release effect is possible with IM injections. Course Disadvantages:
• The site of injection will influence the absorption,207 generally the deltoid muscle is the best site.
• Trained personnel required for injections. • Absorption is sometimes243/CENG erratic, especially for poorly soluble drugs. • The solvent maybe absorbed faster than the drug causing precipitation of the drug at the site of injection. NANO Inhalation
Advantages: Only • By-passing the liver Use • Fastest method, 7-10 seconds for the drug to reach the brain
• User can titrate (regulate the amount of drug they are receiving) Course Disadvantages:
• Most addictive route of administration because207 it hits the brain so
quickly
• Difficulties in regulating the exact amount of dosage • Absorption of243/CENG gases is relatively efficient, but not solids or liquids
NANO A Comparison of Different Administration Routes
Administration of Human Immunoglobulin G (IgG) Only Use
Course 207
IgG, ~150 kDa 243/CENG
NANO Adapted from Lancet 1972, i, 1208 Drug Administered via Different Routes Will Have Different Consequences Only The route and method of drug administration will influence:
Pharmacokinetics: what the body does to the drugUse
Absorption Distribution Course Metabolism Excretion 207 Pharmacodynamics: what a drug does to the body
Effectiveness of the drug 243/CENG
NANO Intravenous Injection for Systemic Drug Delivery
Only Use Notorious and fatal diseases usually require direct
treatments with fast response and large dosage. Course 207
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NANO Only Use
Part II: Drug TransportCourse by Fluid Motion 207
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NANO Basic Concept
Diffusion: molecular movement within 100 µm; driven by Only concentration gradient Use Bulk flow & convection: long distance movement in the body; driven by hydrostatic and osmotic pressure Course 207 How blood flow is regulated?
How to measure molecule concentration in blood? 243/CENG
NANO 1. Blood Movement in the Circulating System
Cylindrical vessel model Only Use r
θ Course z 207
P: hydrostatic pressure V : fluid velocity along the z axis (function of radial distance from the tube centerline) z 243/CENG
NANO 1. Blood Movement in the Circulating System
Hagen-Poiseuille flow Only Use
Course 207
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NANO 1. Blood Movement in the Circulating System
Equation for conservation of momentum: Only Use
Course 207
243/CENG Parabolic dependence of local NANOvelocity on radical position. 1. Blood Movement in the Circulating System
Overall rate of blood flow Vessel cross sectionOnly
Use dr dθ r Course Overall resistance of a cylindrical vessel to flow 207
When blood vessel243/CENG becomes smaller, the resistance to flow increases dramatically.
The majority of the overall resistance to blood flow resides in the smallest vessels. NANO 1. Blood Movement in the Circulating System
Blood supply to tissue Only Local blood flow to tissue is controlled by constriction and dilation of the arterioles delivering blood to the tissue. Use
Individual arterioles have muscular walls which allow them to adjust their diameter, and hence resistance. Course 207
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NANO 1. Blood Movement in the Circulating System
Flow distribution in branching networks can be regulated by resistance Only If one branch changes its resistance: Use
R → ½ R Course
One arteriole size drops by a factor of ½,207
Flow rate in the large artery drops to 81.25 mL/min 243/CENG
NANO 1. Blood Movement in the Circulating System
Efficient mixing Only For highly toxic drug (e.g., chemotherapy drug), they need to be injected to large vein/artery. Use - High flow velocity (15~20 cm/s) - Extensive branching of the cardiovascularCourse circuit 207
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NANO 2. Monitoring Drug/Nanoparticle Concentration in Blood
(1) Radioisotope labeling Only e.g., docetaxel-loaded PLGA nanoparticles Use Docetaxel-14C (half-life: 5730 years) PLGA-3H (half-life: 12 years)
e.g., liposomal nanoparticles CourseScience , 1994, 263, 160.
lipid-chelated 111In (indium, 2.8 days)207 153Gd (gadolinium, 240 days) 45Ca (calcium, 163 days) 51Cr (chromium, 27 days) 32P (phosphorus, 14 days) 243/CENG109Cd (cadmium, 464 days)
Advantages: trace amount; very accurate NANODisadvantages: dangerous; trained person 2. Monitoring Drug/Nanoparticle Concentration in Blood
(2) Fluorescence labeling Only Challenge: interference from blood
Solutions: (1) high loading of blue, green, or red probes Use (2) using far red fluorescent probes: Alexa 647, Cys 5.5, etc
(3) No labeling Course
Chemical characterization of drug/material207 itself.
- high performance liquid chromatography (HPLC): UV absorbance - mass spectroscopy: elemental composition - electrochemical analysis: Redox reaction 243/CENG
NANO