DOSAGE I: Exam 2 Flashcards
Why do we use enteric coatings? (5)
1.To prevent acid sensitive APIs from gastric fluids
2. To prevent gastric distress from the API
3. To target API delivery to a site in the intestine
4. To provide a delayed/sustained release.
5. To deliver the API in a higher local concentration in
the intestines where it may be absorbed and have a
higher bioavailability
What is sustained release?
the onset of pharmacologic action is delayed, but its therapeutic effect has a sustained duration
What is controlled release?
-goes beyond sustained release and
implies a reproducibility and predictability in the drug
release kinetics
-Allows us to maintain a narrow drug plasma concentration
Examples of controlled release formulations (4)
- coated beads, granules, microspheres
- multitablets
- microencapsulated
- drug embedded in a slowly eroding or hydrophilic matrix
Define “steady state”
-the rate going into the body must equal the
disposition (the rate distributing early and being metabolized, and/or being excreted from the body)
-allows us to maintain a narrow drug plasma concentration
Characteristics of drugs suited for controlled release formulation (5)
- Exhibit neither slow or fast rates of absorption
and excretion - Uniformly absorbed from the gastrointestinal
tract - Administered in relatively small doses
- Have good safety/therapeutic window
- Chronic therapies better suited than acute
Physiological factors affecting absorption (7)
- Absorbing Surface Area
- Residence Time at Absorption Site
- pH changes in lumen
- Permeability/Perfusion (Functional and molecular characteristics of transporters and metabolism)
- Dietary Fluctuations/Effects
- Complexation/protein binding
- Biliary uptake and clearance
Describe epithelia (3)
- cells predominantly used for external surface + endothelial cells
- sit on a layer of extracellular matrix proteins (cell side = apical, protein side = basal)
- polarized with directional transport
Define endothelial cells
simple squamous cells that line the inside surfaces of body cavities, blood vessels, and lymph
Composition of biological membranes (2)
- The cell membrane is a semi-permeable
membrane, permitting the rapid passage of some
chemicals while preventing the
passage of others - Cellular lipid composition is POLARIZED, and
intracellular membrane lipids are different then
extracellular lipids.
What does cholesterol do in lower levels? In higher levels?
In lower levels, cholesterol provides fluidity. At higher levels, causes membrane to undergo phase transition to liquid crystalline state
Intestinal transport mechanisms
- PASSIVE (non-saturable)
-paracellular: between cells (hydrophilicity)
-transcellular: through cells (lipophilicity) - CARRIER-MEDIATED (saturable)
-active: energy dependent
-facilitated diffusion: energy independent
What is PAMPA?
Parallel artificial membrane permeability assay
SEE PICTURES
Define “influx transporters”
transfer substrates into cells
Define “efflux transporters”
pump substrates out of cells
Define “absorptive transporters”
transfers substrates into the systemic blood circulation
Define “secretory transporters”
transfer substrates from the blood circulation into bile, urine, or GI lumen
Nutrient and xenobiotic transporters
solute carriers (SLC) + ATP-binding cassettes (ABC)
Solute carriers (SLC): types
PepT1, OATs, OATPs
*influx and efflux
ATP-binding cassette (ABC): types
P-glycoprotein, MRPs
*efflux2
GI tract epithelia: oral cavity (buccal + sublingual)
buccal: stratified squamous
sublingual: simple squamous
GI tract epithelia: esophagus
stratified squamous
GI tract epithelia: trachea
pseudo-stratified squamous
GI tract epithelia: stomach
columnar, goblet cells (mucus), parietal cells (acid), enterochromaffin cells (histamine)
GI tract epithelia: small and large intestines
columnar
GI tract epithelia: rectum
upper: simple columnar
lower: stratified squamous non-keratinized to stratified squamous keratinized
Fasting pH of stomach
< 3
Fed pH of stomach
5-7
Function of stomach: fundus
contains gastric acid and produces contractions to move contents
Function of stomach: body
reservoir for ingested foods and fluids
Function of stomach: antrum
lowest part of stomach, pyloric region funnels/controls flow into the small intestine
Where does most absorption occur?
small intestine
Small intestine pH
5.0-6.5
Define “bioavailability”
rate and extent of drug absorption
Define “Paracelsian theory”
a chemical might have no effect, a beneficial effect, or a toxic effect
Define “dose”
-amount of chemical in which the whole organism is treated
-the local concentration of the chemical at the biological response site
What does ADMET stand for?
A= absorption
D= distribution
M= metabolism
E= excretion
T= toxicity
D+M+E = disposition phase
M+E = elimination
Define “therapeutic window”
Plasma level between minimum effective level and minimum toxic level
Sites of first pass metabolism
GI epithelium, liver
Systemic metabolism
can occur in organs and in the blood stream
Phase 1 metabolism
metabolism of the main compound i.e. decarboxylases, oxygenases, deamidation
**cytochrome P450s, especially CYP3A4
Phase 2 metabolism
metabolism through addition, conjugation i.e. glucuronidation, sulfation
Phase 3 metabolism
transport-multidrug resistance
- ABCs and SLCs
Increased surface area leads to…
increased dissolution rate
Rate of dissolution
dM/dT = change in amount of mass that appears in solution over time
What percent of approved drugs have pediatric labeling?
20-30%
Therapeutic equivalence=
pharmaceutical equivalence + bioequivalence
PAMPA = Caco-2
Passive diffusion
PAMPA > Caco-2
Pgp efflux, secretory efflux
PAMPA < Caco-2
Active uptake or paracellular transport
