Pharmacokinetics Flashcards
absorption refers to what kind of drug administration?
oral: most common enteral (via GI tract) route
enteral vs parenteral drug administration and most common types of each
enteral: via GI tract, oral (po) most common
parenteral: bypasses GI tract, intravenous (iv) most common
what is the limit of active transport in drug passage across GI membranes?
active transport is saturable - limits amount of drug that can be transported
*most drug absorption happens via passive diffusion
how are large biologic macromolecules drugs administered?
parenterally (bypass GI tract) because they are too large to diffuse across GI membranes (MW >1,000)
_____ is the best predictor of drug entry into the body
how is it quantitatively measured
hydrophobicity (P)
P = [drug] in lipid phase
—————————
[drug] in water phase
determined via equilibrium experiment
*large P = MORE hydrophobic
describe how ionization state of a drug affects its passage across GI membrane
only non-ionized (uncharged) form of acid (HA) or base (B) can diffuse passively across GI epithelium
many drugs are either weak bases or weak acids
[HA <—> H+ + A-]
[BH+ <—> B + H+]
Only nonionized (uncharged) forms of acidic or basic drugs can diffuse passively across the GI.
What are weak acids and what groups do they have?
What are weak bases and what groups do they have?
weak acid: include carboxylate (COOH) or phenolic group (Aryl-OH), which can lose proton to form anion (COO- or Ar-O-)
weak base: has amine group (R-NH2), which can gain proton to form cation (R-NH3+)
how do you determine the fraction of total acidic or basic drug molecules are in protonated vs unprotonated state?
Hendersen-Hasselbach:
pH = pKa + log[A-]/[HA]
or
pH = pKa + log[B]/[BH+}
pKa = pH at which drug is 50/50 unprotonated vs protonated
what is Hendersen-Hasselbach relationship for both acid and base
acid:
pH = pKa + log[A-]/[HA]
base:
pH = pKa + log[B]/[BH+]
pKa = pH at which drug is 50/50 of protonated vs unprotonated
below an acidic drug’s pKa, which form dominates?
below pKa, protonated and UNIONIZED form (HA) dominates for acid
[above acidic drug’s pKa, unprotonated, ionic form A- dominates]
below a basic drug’s pKa, which form dominates?
protonated and ionic form (BH+)
[above basic drug’s pKa, unprotonated form, B, dominates]
*this is why basic drugs are not absorbed well (no place in body with a high enough pH)
how can you rearrange Hendersen-Hasselbach equation to focus on the ratio of protonated vs unprotonated drug
pH = pKa + log[A-]/[HA]
or
pH = pKa + log[B]/[BH+]
gives
[A-]/[HA] = 10^(pH-pKa)
or
[B]/[BH+] = 10^(pH-pKa)
at equilibrium, the total drug concentration (ionic + non ionic) will be HIGHER in the compartment with GREATER degree of ______
pH-dependent ionization
*whichever compartment makes the drug most ionized, because it will get stuck there (it won’t be able to cross to other compartment again)
pH of gastric juice in stomach is 1.5, while plasma is 7.4.
Acetylsalicylate (aspirin) is a weak acid with pKa of 3.5.
How would you find ratio of total drug in plasma to that in gastric juice at equilibrium?
imaging you have lipid membrane partition between stomach (pH 1.5) and plasma (pH 7.4)
- apply Hendersen-Hasselbach to each side of partition - *set value of nonionic drug (protonated form of acid [HA] in this case) to 1, since this is the only drug that can diffuse (will be equal on both sides!)
- calculate total parts of [ionic drug] + [nonionic drug] on each side
- take total parts of each side and make ratio
after doing this math, you find acidic aspirin is well absorbed from the stomach (way more drug in plasma than in stomach at equilibrium)
in general, are acidic or basic drugs absorbed better?
acidic
basic drugs usually have high pKa and there is nowhere in body with high enough pH for unprotonated (B) form to dominate
*remember that drugs need to be nonionic to pass through lipid membranes
how do plasma proteins (albumin) affect drug absorption and how do you account for this
many weak acids and bases can bind plasma proteins (albumin), which prevents it from crossing back into GI tract from plasma
when drug is bound to albumin, it is pharmacologically inert - not available to have an effect
*when doing HH for both sides of lipid membrane, factor albumin binding to only plasma side AFTER doing the HH equation (because your original number gives you how much would be on that side if there was NO albumin, but actually albumin is holding some of the drug hostage - so divide your number by the present of the total that is actually free - problem will always give you %bound, so subtract from 100% and divide by that number)
how do you quantitatively factor albumin binding into HH equation for drug equilibrium
- do HH for both sides of lipid membrane
- on PLASMA side, the number you get represents how much drug would be on that side if there was NO albumin
- to adjust for albumin binding, divide this number by the percentage of free drug (the problem will give you %bound, so subtract this from 100% and divide by this number)
- use your adjusted plasma number to find lumen to plasma drug concentration ratio
describe how each of these affects drug absorption from GI tract:
1. surface area
2. blood flow
3. contact time
4. food
- surface area: more = better absorption (villi, microvilli of GI)
- blood flow: more = better absorption (blood flow to intestine is greater than stomach)
- contact time: longer = better absorption (ex- diarrhea limits drug absorption)
- food: presence slows the absorption of oral drugs
what makes the intestine the most efficient area of drug absorption from the GI tract? (as compared to stomach)
high surface area (villi, microvilli) and high blood flow
what are the reasons for taking a drug with or without food?
presence of food slows/decreases drug absorption
some drugs need to be taken without food so enough is absorbed
some drugs cause stomach discomfort that can be relieved by taking them with food - must be potent enough to work with less absorption
bioavailability always refers to what drug route
oral, because IV drugs are 100% bioavailable
refers to % of orally administered drug that gains access to systemic circulation in chemically unaltered form
what is the most limiting factor of drug bioavailability
first-pass hepatic transformation (metabolism)
*most important factor unrelated to drug formulation itself
drug in GI tract is brought to liver via portal circulation, and many drugs chemically altered (metabolized) in liver —> significant portion of drug is inactivated (only some drug makes it through unaffected)
*certain drugs are more resistant to metabolism so a larger portion can make it through
how do hydrophilicity, metabolic and pH instability, and physical properties of drug preparation affect oral bioavailability?
- too hydrophilic = poor absorption, decreased bioavailability
- metabolic and pH instability - drugs can be altered by enzymes or acidic pH in GI, decreasing bioavailability
- physical properties - different drug preparations may differ in dissolution properties, so bioavailabilities also differ (bioinequivalence)
bioinequivalence vs therapeutic inequivalence
bioinequivalence: different drugs differ in bioavailability (how much oral drug is absorbed)
therapeutic inequivalence: arises when bioinequivalence of different drug preparations leads to difference in therapeutic outcome
below pKa, this form ALWAYS dominants for both acids and bases
protonated form
above acidic pKa, acid is ionic (A-)
above basic pKa, base is nonionic (B)
what is drug distribution and how does if affect plasma concentration
distribution: drug moving beyond plasma to other areas of body
decreases plasma concentration of drug
how do graphs of plasma concentration of drug vs time look for po (oral) vs iv (intravenous) administration?
po (oral): absorption phases causes concentration to rise, then distribution leads to sharp drop and elimination follows gradually until no drug is left
iv: [no absorption face because it is directly administered to blood stream] concentration begins high and is lowered sharply by distribution followed gradually by elimination
what are the distinct compartments of the body in which drugs can distribute?
ECF (plasma or interstitial fluid/IF)
or
intracelular fluid (ICF)
how do drug MW and hydrophobicity affect drug distribution
heavy MW (HMW) drugs are trapped in plasma
smaller/light MW (LMW) drugs can distribute more widely, extent depending on hydrophobicity:
- hydrophobic LMW can enter plasma, IF, and ICF (most wide distribute, can go anywhere)
- hydrophilic LMW can enter plasma and IF but cannot passively cross membranes to enter ICF
compare distribution properties of hydrophilic and hydrophobic LMW drugs
LMW = light molecular weight
hydrophilic LMW: can enter plasma and IF, but not passively enter ICF
hydrophobic LMW: can enter plasma, IF, and ICF
how does albumin (and other plasma protein) binding affect drug distribution
plasma protein-bound drugs distribute ONLY in plasma (protein complexes cannot enter IF or ICF)
*drug molecules bound to albumin are inert and useless - only free drug is pharmacologically active
how does volume of distribution affect drug distribution and how is it calculated
many drugs do not exclusively distribute into fluid compartments - can enter bone or other tissues
volume of distribution (Vd): volume into which a drug an partition (can be more than body’s water compartments)
Vd = total amount of drug in body
——————————————
plasma concentration of drug
Vd = Ab / Cpl
*Vd of a drug is a volume constant that relates to amount of drug in body (Ab) and plasma concentration (Cpl) generated by that amount
how is volume of distribution (Vd) determined?
- administer standard iv dose of drug
- draw plasma samples over time, plot [drug] vs time
- take mg of drug administered (Ab) over plasma concentration of the drug at distribution equilibrium (Cpl)
*magnitude of Vd is indicative of drug’s tendency to distribute beyond vascular space into tissues
what is volume of distribution (Vd) indicative of?
magnitude of Vd indicates a drug’s tendency to distribute beyond the vascular space into tissues
*Vd must be normalized to body weight, or expressed as a certain volume in a patient weighting a certain amount
*expressed in units of L/kg
