Physiologic Factors consider systemic delivery routes of administration oral (peroral parenteral (s.c., i.v., i.m.) transdermal buccal and sublingual nasal rectal pulmonary

Oral

Oral Absorption

Oral gastric emptying volume of gastric contents determines [drug] time dosage form/drug spends in stomach influences absorption liquids emptied faster than solids acids slow gastric emptying natural triglycerides inhibit gastric motility eating influences transit

Oral intestinal transit blood flow material moved by peristalsis presence of food retards absorption transit time is consistent among individuals blood flow GIT is well vascularized hepatic first-pass effect

Parenteral i.v., i.m., s.c. bypass hepatic first-pass

Parenteral i.m. and s.c. not all drugs fully absorbed tissue more acidic than most tissues blood flow is important good supply of capillaries drug absorption function of diffusion rate

Transdermal rate limiting step is diffusion through stratum corneum

Transdermal EPIDERMIS - divided into 4 layers; all cells attached by protein fibres called desmosomes - cell division occurs only in basal layer - these cells are round - upon division one cell moves upward while other remains - as cell migrates upwards and matures, its shape changes to flat, it extrudes lipids into the extracellular space, organelles and nucleus degraded, cytoplasm becomes almost completely filled with dense, crystalline filamentous proteins (keratin and keratohyalin); finally become keratinocytes stratum corneum - outermost layer; between 15-20 cells thick; primarily lipids (20%) and protein (40%) and water (15%) -cells are organized into a tight fitting interdigitating structure cemented together with extracellular lipids; this structure gives the skin its large resistance to movement through it - at surface, physiologically inactive, are shedded

Transdermal Factors Affecting Transport rate of transport is dependent on solubility and diffusivity of component through SC

Transdermal Lag Time

Transdermal Optimum Ko/w K measures lipo/hydro balance - usually K given in terms of octanol - optimum K exists (between 100 and 1000)

Transdermal Limitations qualifications drug must be potent drug must be effective when delivered slowly over a long period of time benefits over existing methods? qualifications narrow therapeutic window subject to extensive first-pass degradation taken many times/day unpleasant side-effects

Transdermals - recall that drugs need to be of small size, lipophilic, effective at low doses, generally have a narrow therapuetic window, nasty side-effects, required to be taken several times daily - low melting point is a reflection of tendency of drug to partition into crystalline, ordered structure. - lower Tm means more ready transport through SC - these are the 7 drugs that are currently marketed as transdermals

Buccal and Sublingual avoids exposure to GIT

Nasal frontal sinus external naris sinus nasal cavity (20ml capacity) large surface area (180 cm2) hair at entrance act as filters covered with richly vascularized mucous membrane mucus constantly being secreted and moved toward pharynx by action of cilia cilium - approximatetly 5 µm in length and moves at 20 beats/s microvilli along epithelium provide large surface area function is to warm and filter air that is entering the lungs sinus

Nasal mucus moderately viscous, glycoprotein protects nasal mucosa and traps particulate matter contains many enzymes pH 5.5-6.5, low buffering capacity advantageous for drugs poorly absorbed orally for some peptides and small molecules bioavailability comparable to injections drugs lypressin, desmopressin, vitamin B-12, progesterone, insulin, calcitonin, propanolol foreign bodies such as dust, pollen, bacteria, carried out to pharynx where the mass is swallowed or expectorated effective ciliary movement depends on the viscosity of the mucus, if too viscous then cilia cannot move it and becomes uncomfortable some drugs can affect cilia movement as well - 0.2-0.3% NaCl found to stop ciliary movement - an effect that was difficult to revers - 0.9% NaCl had no effect - cocaine - paralyzes cilia

Rectal, Vaginal, Urethral lined with one or more layers of epithelial cells luminal side covered with mucus layer contains a small amount (1-3 ml) of fluid fluid has low buffering capacity abundantly vascularized drug absorption primarily by passive diffusion avoids some first pass clearance useful alternative to oral route (unconscious,pediatric or geriatric) avoid some first pass metabolism (50%) preferred for drugs destroyed or upsetting to G.I. tract when oral route precluded by vomiting DISADVANTAGES compliance erratic and unpredictable absorption inconvenient

Pulmonary large contact surface (surface area > 30 m2 ) extensive blood supply (2000 km of capillaries) thin membrane separating air from blood disadvantages small proportion of the drug reaches the site e.g., disodium cromoglycate: 8% Variability in dose Lack of Compliance

Pulmonary

Summary