Exam 3 Second Set of Lecture Slides Flashcards
What are the physiological factors that affect absorption?
- 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
What is the importance and purpose of epithelia?
They are used for external surfaces (epithelial cells are epitheliod) → sits on a layer of extracellular matrix proteins such as collagen and fibronectin which is called the basal lamina → epithelial cells are polarized with directional transport (have transporters on the outer membrane)
What are the different types of epithelia?
- simple squamous
- simple columnar
- translational
- stratified squamous
What is simple squamous epithelium?
A thin layer of flattened cells that are relatively permeable → lines most blood vessels, placenta, endothelial cells (ex. is air sacs in the lungs)
What is simple columnar epithelium?
usually found in the GI tract (ex. intestine)
What is translational epithelium?
comprised of several layers with different shapes → usually required to stretch
What is stratified squamous epithelium?
multiple layers of squamous cells that cover areas subject to wear and tear → skin is an example of a barrier that comes from keratinization (ex. esophagus)
Where are endothelial cells found?
Lines the inside surfaces of body cavities, blood vessels, and lymph → have simple squamous morphology
Where can you find pseudostratified ciliated columnar epithelium?
the respiratory tract
Where can you find simple cuboidal epithelium?
the kidneys
What are tight junctions?
- like a Ziploc seal around the cells and is important for the function of the confluent epithelium and endothelium
- restrict solute movement between the cells (paracellular)
- polarize cells into apical (luminal/blood facing) and basolateral (abluminal/brain facing) areas
- allows for differing functions between the two membranes
- can involve up to 50 proteins
What does sialic acid do?
Makes the glycocalyx more anionic
What defines a cell as a living unit?
Being enclosed by one or more membranes
What is the biological membrane and what is its purpose?
A semi-permeable membrane that permits the rapid passage of some chemicals while preventing the passage of others which isolates cellular contents from the environment (forms a barrier) → lipid composition is polarized and the intracellular membrane lipids are different than the extracellular lipids
What can go through tight junctions?
Tight junctions are anionic in charge so cationic drugs can go through faster and anionic drugs go through slower
How can depolarization of phospholipids lead to cancer therapy?
Phosphatidylserine is normally found in the inner leaflet of the bilayer with other cationic lipids → when cells die, get mutated or infected, the lipid polarization changes which can interfere with drug transport
Does cholesterol only have harmful effects on membranes?
No → provides fluidity at lower levels (which is good) but when it exceeds a certain level in the membrane, the membrane undergoes a phase transition and forms a liquid crystalline state called atherosclerosis in the vasculature
What is the permeability coefficient?
Put into well and grow the cells in which the drug was placed on top of the cells and grow out the cells for 21 days and measured how much drug got to the bottom → called the permeability coefficient (if multiplied by the initial concentration we put in, that would be flux)
Does permeability have units?
It’s a rate → the faster drug crosses the intestinal barrier, the more likely it is to be absorbed (the faster the higher the rate, the better)
What is the importance of PAMPA?
could see the permeability and the lipophilicity
What is the significance of lipid composition varying according to the organ?
Changes in the fatty acid/lipid composition can dramatically influence the passive absorption and function of cells
What are examples of passive (non-saturable) intestinal transport mechanisms?
- paracellular (between cells)
2. transcellular (through cells)
What are examples of carrier-mediated (saturable) intestinal transport mechanisms?
- active (energy dependent)
2. facilitated diffusion (energy independent)
Passive drug transport follows what?
Fick’s first law: donor well → membrane → acceptor well
What affects paracellular transport?
hydrophilicity, molecular size and shape, pKa of ionizable groups
What affects transcellular transport?
lipophilicity (H binding potential, hydrophobicity), molecular size and shape, pKa of the ionizable groups
What do the typical permeability assays tell you?
PAMPA: passive diffusion
PAMPA+Caco-2: mechanistic information
Caco-2: passive, active influx, efflux, and paracellular
What does the typical graph look like for Caco-2 permeability (y axis) vs PAMPA permeability (x axis)
A straight linear line (most transport is passive diffusion) → if it deviates up/positively, it indicates absorptive influx (active uptake) and/or paracellular transport → if it deviates down/negatively, it indicates secretory efflux transport/metabolism or even MDR1/pgp
What are drug transporters?
Membrane bound proteins that are widely distributed throughout the body and is prominently on apical and basolateral surfaces or organs involved in clearance
What is the physiological role of drug transporters?
Move important molecules across membranes that wouldn’t normally go across → includes moving drug molecules across membranes
Drug transporters are a crucial determinant of what?
Tissue and cellular distribution of drugs for drug clearance and also sanctuary organs
Variations in drug transporter activity are major determinants of what?
Drug response and drug safety
What are the the 2 nutrient and xenobiotic transporters?
- solute carrier (SLC)
2. ATP binding cassette (ABC)
What are solute carriers?
has 43 subfamilies, more than 300 members identified, generally influx or secretory efflux transporters, examples include PepT1, OATs, OATPs
What are ATP binding cassettes?
catalyze ATP to ADP, has 7 subfamilies, 50 identified members, generally efflux-multidrug resistant transporters, examples include pgp, MRPs
What is the nomenclature of transporters?
transporter type → family number → species variant
example: human PepT1 is SLC15A1
What is concerted metabolism?
phase I and phase II metabolism which is also known as conjugation
What are the 6 routes of permeability?
- influx transporter mediated
- passive transcellular
- passive transcellular and efflux
- passive paracellular
- metabolism
- efflux of the metabolites
What do influx transporters do?
Transfers substrates into cells
What do efflux transporters do?
Pumps substrates out of cells
What do absorptive transporters do?
Transfers substrates into the systemic blood circulation → 2 transporters on both sides of the membrane to pump the drug in (example is endothelial and placental)
What do secretory transporters do?
Transfers their substrates from the blood circulation into bile, urine, and/or GI lumen
What affects passive paracellular permeation?
- hydrophilicity
- molecular size and shape
- pKa of the ionizable groups
- linear increase in permeability with increasing concentration
- adjuvants can open tight junctions and increase transport
What affects passive transcellular permeation?
- lipophilicity
- molecular size and shape
- pKa of ionizable groups
- linear increase in permeability with increasing concentration
- dissolution/solubility limited with high lipophilicity
What affects facilitative/active transcellular permeation?
- affinity (Km) and capacity (Vmax/Jmax)
- concentration dependent saturation
- expression level (constitutive, induced)
- function (drug-drug interactions, inhibition)
- excipients like surfactants that can limit the effects of efflux like pgp or BCRP
What is the equation of Pbarrier?
Pbarrier = Ppara + Ppassive,trans + Pactive,trans ± Pactive,trans
What can affect the net absorption of drug?
efflux and metabolism
What is the difference between affinity and capacity?
Affinity is how tight the drug binds to the transporter while capacity is the rate driving the transport in
What is the importance of COX-2?
COX-2 is involved in inflammation and COX-2 inhibitors are needed for headaches and the inflammatory response
Where does all drug absorption occur?
ascending colon (colon is great for water absorption)
What type of epithelium is in the oral cavity (buccal) and sublingual?
oral cavity (buccal) → stratified squamous sublingual → simple squamous
What type of epithelium is located in the esophagus and the trachea?
esophagus → stratified squamous
trachea → pseudostratified squamous
What type of epithelium is the stomach composed of?
predominantly columnar epithelium mixed with other cell types like mucus producing goblet cells, parietal (acid secreting), and enterochromaffin-like (histamine secreting) cells
The small and large intestines are lined with what type of epithelium?
columnar epithelium (in addition to many different cell types)
The rectum has what kind of epithelium?
the upper part is composed of simple columnar and lower part is composed of stratified squamous non-keratinized transitioning to stratified squamous keratinized near the anal sphincter half
Keratinization sometimes happens due to what?
exposure to air
Why does the stomach and jejunum have more surface area than the cecum?
The cecum region is not as well folded so there is not as much absorption compared to the stomach and jejunum.
What is the role of the stomach?
To digest food and control the flow of its contents into the intestine → acts as a food reservoir, processes food into fluid chyme for nutrient absorption, regulates food delivery to intestine, pH protects against most bacteria which allows pepsin to function
What is the normal stomach pH?
Fasted pH in normal healthy adults is less than 3 and fed pH is in the range of 5-7
How long is gastric emptying half-time?
30 minutes
What is the difference between the fasted emptying cycle and the fed state cycle?
The fasted emptying cycles through 4 phases that culminates with a “housekeeper” wave meanwhile there is no defined cycle for the fed state
What are the 3 primary regions of the stomach?
- fundus
- body
- antrum
What is the fundus of the stomach?
contains gas and produces contractions to move the stomach contents (top part of the stomach)
What is the body of the stomach?
reservoir for ingested food and fluids (the middle part of the stomach)
What is the antrum of the stomach?
the lowest part of the stomach that is funnel shaped and contains the pyloric region and control the flow into the small intestine
What do the parietal cells of the stomach secrete?
HCl
What is prefeed?
the pH rises before we even eat (could be because we’re thinking about food and salivating)
How can different foods affect gastric emptying?
cold-carbonated drinks can rapidly induce gastric emptying while a Big Mac can virtually halt gastric motility
The lower the pH…
the more bioavailability of the compound
What is the transit time from the mouth to the anus?
24-32 hours
What is the transit time through the small intestine?
3 hours
Where does most absorption occur?
small intestine! where pH ranges from 5-6.5
Where does most colon drug absorption occur?
in the ascending region nearest to the small intestine
What are the characteristics of the intestine?
- most transporters are located in the small intestine
- upper small intestine is for mixing
- lower small intestine is for electrolyte absorption
- colon is for fluid and electrolyte absorption
What are the characteristics of the small intestine?
5-6 m in length, has 3 regions: duodenum (shortest and widest 20-30 cm), jejunum (proximal 2/5), ileum (distal 3/5), composed of serosa, muscles, submucosa, mucosa (with villi and crypts), have villi
What are the increases in surface area in the small intestine due to folding?
area of cylinder (1) → folds of Kerckring (х3) → villi (х30) → microvilli (х600)
Why is the relative size of micro vs nanoparticles important?
Micro particles are unable to fit through the microvilli and even 480 nm particles cannot squeeze through → 120 nm particles are more able to squeeze through (but still fairly large) → nothing is absolute in science!!
What are the different columnar epithelial cells?
- crypt cells: progenitor cells
- goblet cells: secrete mucus
- M cells: absorbs intact polypeptides and proteins, has a high metabolic capacity/rapid membrane turnover
What type of epithelium covers each villus?
columnar epithelial cells form a single continuous layer over the villus → separated from lamina propria by the basal lamina which is comprised of glycoproteins and penetrable by lymphocytes
What is the crypt region?
comprised of undifferentiated cells that proliferate and contains goblet cells that secrete mucus, Paneth cells that regulate microflora, and argentaffin cells that secrete mucus component
What is the villus region?
Contains absorptive enterocytes, has a few goblet cells and M cells that overlay the Peyer’s patch, cells from the crypt migrate to the villus tip and are sloughed off every 2-3 days which is the lifetime of an enterocyte → the entire lining of the GI tract turns over every 2-4 days
What does the basolateral membrane consist of?
located below the tight junction, no microvilli or glycocalyx, has desmosomes
What are the characteristics of the apical membrane?
microvilli and brush border, protein to lipid ratio of 1.7 to 1, is a dynamic membrane, the brush border turns over more rapidly than renewal rate of cells
What do the membrane proteins do?
Participate in both transport and metabolism to facilitate nutrient absorption and to prevent xenobiotic toxicity
Lymphatic flow does not go where?
the liver
About what % of cardiac output goes to the GI tract (aka digestive process)?
25-30%
How many liters of blood flow to the intestinal wall?
40 liters/hour → 30 L/h flow to the mucosa → 19 L/h flow to the epithelial layer → only about 50% make it to the site of absorption
Where does drug absorption and metabolism predominantly occur?
epithelial layer/villus enterocytes
Where do the principal enzymes and transporters (CYP3A and pgp) reside?
villus enterocytes
The muscle layer can affect what?
intestinal integrity and absorption
Diseases such as IBS, IBD, Crohn’s, and camping can cause what?
Changes in muscle contractility which will alter GI transit time and absorption
What is the length of the colon?
125 cm from the caecum to the anus (transport is much slower compared to small intestine): ascending colon is 20 cm, traverse colon is 45 cm long, and descending colon is 30 cm long → the rest is the sigmoid region
What is the thickness of the colon?
Varies in thickness from 2.5 cm in the sigmoid region to 8.5 cm in the caecum
What is the importance of the colon?
it is responsible for water and electrolyte absorption (caecum, ascending colon) which prevents dehydration and leads to formation of solid fecal matter
What does the ileocaecal valve?
it limits food flow from the ileum into the caecum and vice versa
What is the structure of the colon?
- consists of serosa-squamous epithelium covered with adipose tissue
- has a muscularis externa which consists of an inner circular muscle layer and an incomplete outer longitudinal layer
- has a submucosa and mucosa
What are the three layers of colonic mucosa?
- muscularis mucosae
- lamina propria
- epithelium
What is the difference between the proximal and distal colon and what formulations it targets?
The proximal colon is where enteric coated formulations target by oral administration. The distal colon is where rectal administration target such as suppositories.
Where do you see the most microbiome?
ileum and colon (example is fecal transplants)
Where is residence time the longest?
colon (while esophagus is the shortest)
Out of children, young adults, and elderly people, which age group has the longest transit time?
Elderly people (in all 4 regions) → and then children except for the right colon) → young adults usually had the shortest transit time
What is the relationship between stomach emptying rates and colonic retention of the contents?
As stomach emptying rates decrease as time passes, the colonic retention time of the contents increase (stomach lines go downward and colonic retention increases)
What all affects how much gets absorbed?
Things like the time of day and the types of meals
What type of epithelium is the rectum composed of?
has an upper (simple columnar) and lower (stratified squamous non-keratinized region transitioning to stratified squamous keratinized region near anal sphincter) half → highly folded
What is the significance of the stratified squamous, non-keratinized epithelium?
allows high drug absorption → there are a number of high potency drugs that can be delivered rectally
What is the significance of delivering drugs rectally?
many young and old patients cannot swallow pills so then extemporaneous compounding of the drug in suppositories is used → also has a low residence time
What are the 3 sources of variability in drug response?
- genetic factors → drug targets, drug transporters, drug metabolizing enzymes
- environmental factors → induction and inhibition
- physiological factors → age and disease
Once a drug breaks down into smaller particles, the smaller the particle, the more likely it will be…
wet → more surface area to be wet, the more likely to get more drug into the solution
After the dissolution process, what are the 2 forms?
- crystalline form → low solubility
2. amorphous → increased solubility
What will eventually get through the membrane?
the free API (active pharmaceutical ingredient)
What are some examples of potential confounders?
food, pH, protein binding
What is the mean residence time?
3.45 hours (but varies from 0.87 hours to 9.5 hours)
What does biorelevant mean?
how closely do we mimic biology/physiology
For the same batch of non-disintegrating pellets, is there significant variation?
Yes → there is a significant variation of intra-individual small intestinal transit times
What is the importance of the study of the plasma levels of 4-amino-salicylic acid (4-ASA) in 2 different patients after ingestion of an enteric coated capsule?
- gastric residence differs dramatically
- gastric emptying controls colonic absorption where greater GI residence leads to higher absorption
- Patient 2 had a significantly faster GI transit-capsule voided in less than 6 hours (compared to patient 1 that took longer)
Where does the fed state pH stay around?
pH of 3-4
What is the pH difference between the jejunum, ileum, and colon?
jejunum (7.08), ileum (7.8), colon (8.1)
Where is bile salt content found when there’s a problem?
jejunum
When sequestered in a micelle, what happens?
Can be taken up as a lipid droplet so that not only the free drug is sequestered (gets across)
The amount of buffer capacity can change what?
pH and the fraction of ionized/unionized
More unionized is likely to get through the membrane using what process?
Passive transcellular diffusion
More ionized means what?
Less likely to get through the membrane and less likely to get absorbed
What are the 5 factors that can influence drug solubility?
- buffer capacity
- bile salts
- regional fluids
- other drugs
- potential issues from endogenous substrates
The GI tract can be divided into what smaller areas?
duodenum → jejunum I → jejunum II → ileum I → ileum II → ileum III → ileum IV → colon
Why do one size formulations do not fit all?
- transporters and enzymes vary along the GI tract
- variability in GI fluid composition
- diet and chemical exposure varies
- drug-drug and drug-nutrient interactions occur
- pharmacogentics and genomics are big issues
Disposition consists of what?
distribution and elimination
Elimination includes both what?
metabolism and excretion
Toxicity results from what?
exposure
ADME can be defined by what?
Plasma vs. time curves → can also be used for bioequivalence
What is the major role of metabolism?
To make the compound more polar so it can be more easily excreted in the bile or urine (making lipophilic compounds more polar)
Once a drug is ingested, what can happen?
dissolution, degradation, or absorption
Humans are treated as what?
one compartment model → individual organs can be separated and modeled based on kinetics
How is the nature of pharmacokinetic processes described by?
Concentration time profiles in which the shape of the profiles depends on point of observation → compartments represent kinetically similar tissues or spaces in which processes can be reversible/irreversible or linear/nonlinear → fast and slow processes disappear
What is the Tmax?
the time to reach the maximum blood/plasma concentration from a dosage form
What is Cmax?
the maximum blood/plasma concentration from a dosage form
What is bioavailability?
refers to the rate and extent of drug absorption
What is absolute bioavailability?
AUC of a given dosage form compared with the AUC of the same dose injected intravenously
What is relative bioavailability?
refers to the AUC of a given dosage form compared to an arbitrary reference standard
Bioequivalent does not mean what?
that the therapeutic effect of two dosage forms are equivalent → so not therapeutically equivalent!!
What is the Paracelsian theory?
A chemical might have no effect on an organism, a beneficial effect, or a toxic effect
What is the most important factor in pharma and toxicology?
The dose-response relationship
What 2 aspects does dose cover?
- the amount of chemical in which the whole organism is treated
- the local concentration of the chemical at the biological response site
What is a function of ADME?
The relationship between dose and receptor concentration
What goes into consideration for the dose?
- physicochemical properties of the compound
- physiological factors
- formulation factors
- will lead to being safe and efficacious
The absorption rate is controlled by what?
formulation parameters that are optimized to provide a Cmax and Tmax associated with a safe and efficacious response in the patient
What is the difference between MTL and MEL?
MTL = minimum toxic level MEL = minimum effective level
Prolonged exposure to subtherapeutic doses or ineffective drugs can lead to what?
the development of the disease becoming worse → above the MTC can be harmful
For multiple dosing and accumulation, what do we want to do?
Want frequency near the value between MTC and MEC near the Cpss value (plasma concentration at steady state)
What happens when AUC is above MTC, in the TW, and below the MEC?
Above MTC = toxic response
In TW = safe and efficacious
Below MEC = not efficacious
What do coatings do?
Control diffusion rates and modify the release properties of the drug from the interior
What do disintegrants do?
Control regions of release based on physicochemical properties
What do lubricants do?
Slow dissolution based on properties
How do internal excipients modify release rates?
swellable matrices, non-swelling matrices, inert plastics
Coatings are applied to the outside of solid dosage forms to do what?
- protection of agent from air and/or humidity
- mask taste
- provide special drug release
- aesthetics
- prevent inadvertent contact with the drug (ex. proscar and pregnant women)
Aqueous film coatings contain the following:
- film-forming polymer
- plasticizer to produce flexibility and elasticity of coating
- colorant and opafier
- vehicle
Non-aqueous film coatings usually contain the following:
- film-forming polymer to produce smooth films
- provide water solubility or permeability to the film
- plasticizer to produce flexibility and elasticity
- surfactants to enhance film coat spreading
- colorant and opafier to improve appearance
- sweeteners, flavors, and aromas
- glossant to provide luster
- volatile solvent to allow spreading and evaporation
What is the purpose of enteric coatings?
added to dosage forms to prevent the early release of an API in a region where it may undergo chemical or metabolic breakdown
What are the primary reasons for enteric coatings?
- prevent acid sensitive APIs from gastric fluids
- to prevent gastric distress from the API
- to target API delivery to a site in the intestine
- to provide a delayed/sustained release
- to deliver the API in a higher local concentration in the intestines where it may be absorbed and have higher bioavailability
What is sustained release?
slow the release of a therapeutic agent so that its appearance in the systemic circulation is delayed/prolonged and is plasma profile is sustained in duration → onset of pharmacologic action is delayed but its therapeutic effect has a sustained duration
What is controlled release?
implies a reproducibility and predictability in the drug release kinetics → allows us to maintain a narrow drug plasma concentration steady state
What are examples of coated beads, granules, or microspheres?
coating on the beads controls release by programmed erosion → an example would be contact
What is an example of the multitablet system?
small tablets placed in a gelatin capsule
What is an example of a microencapsulated formulation?
solids, liquids, or gases that are encapsulated into walled material which allows spreading of microparticles across absorbing surfaces
What does drug embedding in a slowly eroding or hydrophilic matrix mean?
the drug is homogenously dispersed in the eroding matrix and its release is controlled by erosion rate
At steady state, the levels achieved depend on what?
- clearance
- volume of distribution
- dose
- dosing interval
A drug with a lower K has what?
longer t 1/2 → so a drug with a higher K has a shorter t 1/2
At steady state, the rate doing into the body must equal what?
the disposition (the rate distributing early and being metabolized and/or being excreted from the body throughout)
What are the characteristics of drugs that are best suited for oral controlled release formulations?
- 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 are better suited than acute
