Absorption Flashcards
How do drugs avoid 1st pass metabolism?
bypass the portal vein and enter systemic circulation
Which enteral routes of admin avoid 1st pass?
- Buccal/sublingual
2. Rectal
T/F Parenteral routes bypass 1st pass
False
T/F intranasal routes bypass 1st pass
true
T/F topical routes bypass 1st pass
true
T/F inhalation routes bypass 1st pass
false
The upper rectum bypass 1st pass
False, upper rectum vasculature is connected to portal vein so drugs are susceptible to 1st pass
For most drugs, the optimum site for drug absorption after oral administration is the ________
upper portion of SI or duodenum region
What is unique about the duodenum that allows the drug to diffuse passively?
immense SA
The duodenal region is highly perfused with a network of capillaries which helps maintain a _________ from the intestinal lumen and plasma circulation
concentration gradient
Where is the most rapid drug absorption?
Duodenal area of SI
- due to villi and microvilli
Why does the colon have limited drug absorption?
- lack of villi
- lack of SA
- lack of blood flow
- more viscous and semisolid nature of lumen contents
Ethanol absorption
- completely miscible with water
- easily crosses cell membranes
- efficiently absorbed from stomach
What kind of drugs can be absorbed from the stomach through passive diffusion?
fat soluble, acid stable
_________ exists for efficient absorption and drugs should be released from dosage form completely during this
anatomic absorption window
What is gastric emptying delayed by?
high fat meals
cold beverages
anticholinergic drugs
What does a delay in gastric emptying cause?
slow rate of drug absorption because it delays drug reaching duodenum
What kind of drugs degrade if gastric emptying is delayed?
unstable drugs (penicillin)
Are liquids or solids digested faster from the stomach?
liquids and small particles
- emptied due to higher basal pressure in stomach over duodenum
Large particles are delayed for ______ by the presence of food in stomach
3-6 hours
Indigestible solids
- empty slowly
- mainly during inter digestive phase when food is not present and stomach is less motile
- periodically empties due to housekeeper wave contraction
Gamma scintigraphy
- label drug dosage with y-emitting radio nucleotide that is NOT absorbed by patient and can be excreted
- Correlates residence time of drug in a given region after the dosage form is broken up to absorption
______ added to dosage form reduces uptake of drugs absorbed exclusively from SI
mannitol
____ slows GI transit, decreases stool water content and decreases drug absorption
Codeine
______ accelerates GI transit, increases stool water content and increases drug absorption
Lactulose
GI perfusion
- study absorption and permeability of drug in various segments of GI tract
- jejunum typical choice because of lower peristaltic activity than duodenum
What is caco-2 cultures used for?
- study permeability of passively transported drugs
- classify BCS classes of drugs
Class I of BCS
- drug dissolves rapidly
- well absorbed
- high solubility
- higher permeability
Class II of BCS
- drug is dissolution limited
- well absorbed
- low solubility
- high permeability
Class I bioavailability
problem not expected for IR drug products (APAP)
Class II bioavailability
controlled by dosage form and rate of release of drug substance (Ibuprofen, Naproxen)
Class III of BCS
- permeability limited
- high solubility
Class III bioavailability
- may be incomplete if drug is not released and dissolved within absorption window (Atenolol, penicillins)
Class IV of BCS
- low solubility
- low permeability
Class IV bioavailability
- difficult in formulating a drug product that will deliver consistent drug bioavailability
- alternate route of admin may be needed (Amphotericin B, Neomycin)
Lipinskis RO5
- MW <500
- H Bond donors <5
- H bond acceptors <10
- LogP <5
What is the 1st barrier to gastric emptying?
pyloric sphincter muscle
How does the presence of food affect drug absorption?
- may delay gastric emptying
- increase blood flow
- changes in pH
- food may interact with drug
- bile flow stimulated
- change in metabolism/excretion within GI tract
Water and drug absorption
- larger volumes of water increase solubility of drug
T/F disintegrating tablet absorption is delayed by presence of food
False
- smaller particles absorbed more consistently regardless of food presence
What is the double-peak phenomenon in drug PK profiles?
delayed gastric emptying due to presence of food can result in lower dissolution –> double peak in Cmax
What molecules can pass through cell membranes?
water, selected small molecules, lipid-soluble
What molecules cannot pass through cell membranes?
highly charged, large
In a cell membrane how can polar molecules and charged ions cross?
- globular proteins embedded in matrix
Transcellular transport
- determined by ease of drug permeability across lipid molecules
Is transcellular or paracellular transport best for small lipophilic drugs?
transcellular
Paracellular transport
- through water filled junctions between cells
T/f active and passive transport are saturable processes
False
- only AT because there is only so many transporters availabilt
Flux units
mass/unit area (mg/cm2)
Flux
rate of transfer
Ficks law of diffusion
molecules diffuse from a region of high concentration to a region of low concentration (Flux)
Ficks law equation
dQ/dt = (DAK/h)(Cgi-Cp)
dQ/dt = P(Cgi)
K in fick’s law
- higher K favors absorption
- more lipid soluble have larger K
A in ficks law
- higher A favors absorption
What order process is extravascular absorption usually?
1st order
Passive transport
- ionization of weak electrolytes
- unequal concentration of ionizable drugs on either side of membrane if pH is different
pH partition hypothesis (if pH on one side of a barrier differs)
- drugs will ionize to different degrees on either side
- total drug concentrations on two sides will be unequal
- the side where the drug is more ionized will contain greater portion of drug
Weak acid/weak base absorption
- WA (salicylic acid): rapidly absorbed from stomach
- WB (ephedrine): poorly absorbed from stomach
How can drugs be absorbed through carrier-mediated transport?
drugs structurally resemble natural substrates in body to allow for carriers to recognize them for transport
Active transport at higher concentrations, the rate of drug absorption remains ______
constant, zero order
What is the function of efflux drug transporters?
protect body from undesirable compounds by pumping drugs out of body (pgp, MDR)
______ are intestinal epithelial absorptive cells the express transporters
enterocytes
What is multi drug resistance in cancers caused by?
efflux transporter proteins such as pgp
How do disintegrates affect absorption?
a. Ka (absorption rate constant)
b. tmax
c. AUC
a. promote disintegration = more SA for absorption
b. decreases (faster)
c. increase due to more drug into circulation (better bioavailability)
How do lubricants affect absorption?
a. Ka (absorption rate constant)
b. tmax
c. AUC
a. decrease absorption by decreasing disintegration due to more lipophilic
b. increases
c. decreases due to slower rate
How do coating agents affect absorption?
a. Ka (absorption rate constant)
b. tmax
c. AUC
NO effect
How does enteric coating affect absorption?
a. Ka (absorption rate constant)
b. tmax
c. AUC
a. decrease (delayed disintegration)
b. increases
c. decreases due to slower rate
How do sustained release agents affect absorption?
a. Ka (absorption rate constant)
b. tmax
c. AUC
a. decrease (delayed disintegration)
b. increases
c. decreases due to slower rate
When is food effect most pronounced on absorption?
when drug is taken shortly after meal
What is most likely to affect GI physiology and absorption?
high calorie
high fat
What can you use to study the effect of food on bioavailability?
high calorie and high fat meals
Food increases absorption of __ drugs
lipid soluble
Food stimulates production of _____, which increases solubility of fat-soluble drugs
bile acids
Basic drugs and absorption
- benefit from presence of food in stomach because it stimulates HCL acid secretion
- lowers pH
- more rapid dissolution of drug and better absorption
Grapefruit juice and absorption
- inhibits CYPS (involved in drug metabolism)
- increases absorption of a drug
Pregnancy and absorption
- delayed gastric emptying and SI motility result in
1. increase Tmax
2. decreased Cmax
3. AUC decreased
CHF and absorption
- decreased rate of drug removal from SI = lower bioavailability due to concentration gradient altered
- increased tmax
- decreased cmax
- decreased rate = lower AUC
Achlorhydria and absorption
- acid production = low
- decreased absorption of weak base drugs
- co admin of acidic beverages can enhance absorption
Crohn’s disease and absorption
- decreased SI transit time
- lower SA available due to inflammation
- erratic and unpredictable effects on absorption
PPI and absorption
- decrease gastric acid production
- increase gastric pH
- may interfere with BA of drugs with gastric absorption
What may cause premature drug release from enteric coated tablets due to early dissolution at higher pH (dose dumping)
PPIs
Celiac disease and absorption
- increased gastric emptying
- increased permeability of SI
- unpredictable effects
cholesyramine effects on absorption
binds to drugs to remove them from the body
Drugs with decreased bioavailability with food
- doxycycline
- atorvastatin
- plavix
- alendronate
- flomax
drugs with increased bioavailability with food
- oxycodone
- metaxalone
- spironolactone
What is the rate limiting step of drug dissolution?
solubility
