8/9/16 Pharmacokinetics: Drug Absorption, Distribution, Elimination - Pilch

Question 1

drug absorption

types and examples

Answer 1

1. enteral : via GI tract

• oral (most common)
• sublingual
• rectal

2. parenteral : GI tract bypassed

• IV (most common)
• intramuscular (IM)
• subcutaneous (subQ)
• transdermal
• inhalation

Question 2

oral route of drug admin

• what is it
• types of transport involved

Answer 2

most common route of enteric admin

absorption from aqueous solution in stomach lumen → plasma [need to cross GI membranes!]

1. active transport

• drugs bind specifically to protein carriers → carriers are present in finite number, therefore, this system can be SATURATED → limits amt of drug that can move across
• often linked to ATP consumption → can move against conc gradient

2. passive transport

• more common than active transport bc system is less selective/specific than active
• doesn’t saturate
• CAN’T move against conc gradient

Question 3

what classes of drugs can be transported passively?

Answer 3

1. hydrophilic drugs

• polarities/charges that allow them to H bond with water → don’t pass through bilayer easily
• however, if small enough (MW < 100), can pass through protein pores in bilayer passively

2. lipophilic drugs

• hydrophobic; interact via van der Waals forces
• no net charge at physiological pH → can move through bilayers more easily

**remember: ONLY MOVES DOWN CONC GRADIENT

Question 4

how can you quantify lipophilicity / the level to which a drug will be absorbed?

Answer 4

Lipid-to-Water Partition Coefficient (P)

• uses two phase mixture of water and hydrophobic solvent (ex. hexane), allows drug to equilibrate between phases

P = [drug] in lipid phase / [drug] in water phase

*higher value of P → drug passes more easily through GI epithelial membranes

Question 5

drugs that are not lipophiles…

what are they?

Answer 5

weak acids : any drug that has a carboxylic acid group

weak bases : any drug that has an amino group

depending on physio pH, WA and WB can be protonated or unprotonated

• imp because…ONLY UNCHARGED FORM CAN MOVE PASSIVELY ACROSS MEMBRANES!
  
  • protonated form of WA
  • deprotonated form of WB

useful to predict fraction of total drug in each state → only uncharged fraction can be absorbed!

Question 6

pKa definition

protonation/deprotonation on either end of pKa

Answer 6

pKa = pH at which amt of protonated and deprotonated molecule is exactly the same

if pH > pKa, amount of deprotonated > protonated

if pH < pKa, amount of protonated > deprotonated

Question 7

predictors for absorption for…

lipophiles

acids/bases

Answer 7

lipophiles : P

acids/bases : pKa

Question 8

pH partition hypothesis

Answer 8

relevant for acids/bases that are being distributed between two compartments that are separated by membranes AND that differ in pH

ex. stomach, plasma

at equilibrium, uncharged form of drug will have equal concentration in both compartments

• THEREFORE, at equilibrium, total drug concentration will be greater in the compartment with greater pH-dep ionization!

Question 9

pH partition hypothesis

sample calc

Answer 9

Question 10

implications of pH partition hypothesis (in stomach) for…

acids

bases

Answer 10

acids : fantastic drugs for oral absorption!

• differential between stomach and plasma pH (1 vs 7.4) pulls the vast majority of drug out into plasma

bases : horrible drugs for oral absorption

• differential between stomach and plasma pH means vast majority stays in stomach and is excreted, NOT absorbed to bloodstream

Question 11

absorption from intestine into plasma

Answer 11

follows principles of pH partition EXCEPT behaves as though pH approx 5.3-5.4

implications for drugs NOT absorbed in stomach :

Question 12

where does the majority of drug absorption take place? why?

• factors that affect absorption

Answer 12

INTESTINE

1. blood flow : blood is the carrier

• blood flow to stomach < blood flow to int
• stomach flow is increased when eating, but always pretty high in intestine

2. surface area : where drugs can be absorbed
   * villi present approx 500x absorptive surface area of the stomach
3. time of contact : drug needs to be present long enough to be absorbed

• things that delay movement through stomach → lowers absorption
• things that speed movement through int (ex. diarrhea) → lowers absorption

4. food : presence of food can slow abs

Question 13

oral bioavailability

what is it?

what limits it? 5 things

Answer 13

fraction of orally administered drug that makes it into circulation IN CHEMICALLY UNALTERED FORM (and stays there)

limited by…

• absorption
• first-pass metabolism (liver) : can often be a “death sentence” for oral drugs bc it can inactivate a significant fraction
• hydrophilicity : too polar/charged means it’ll never make it
  
  • solution : IV admin!
• metabolic and pH instability : altered/inactivated by exposure to enzymes​​
• physical properties of drug prep : drug prep can affect dissolution in aq compartments
  
  • if drug prep alters absorption to the point that the bioavailability is altered: bioinequivalent
  • ​​common in hydrophobic drugs that are not water sol

Question 14

therapeutic inequivalence/index

Answer 14

when bioinequivalence b/w two drug preps is so severe that you have diffs in therapeutic outcomes, you get THERAPEUTIC INEQUIVALENCE

key indicator: therapeutic index

toxic dose (TD50) / effective dose (ED50)

Question 15

when is generic drug substitution problematic?

Answer 15

1. if original and generic preps are BIOINEQUIVALENT
2. if prescribed drug has a NARROW THERAPEUTIC INDEX
   * if toxicity is an issue, stick with what you know

Question 16

IV route

type of admin

reasons for using it

Answer 16

most common type of parenteral administration

1. drugs are hydrophilic, poorly absorbed
2. drugs are metabolically labile and would be degraded by stomach enzymes
3. IV admin gives you increased speed of action
4. confers max control of plasma concentration bc allows you to reach/maintain peak pl conc
   * esp imp in cases of narrow TI, toxicity, need to maintain efficacy

Question 17

drug distribution

fluid compartments in body

Answer 17

drugs can distribute to any of 3 functionally distinct fluid compartments

1. ICF (intracellular fluid)
2. ECF (extracellular fluid)

• interstitial fluid (IF)
• plasma

Question 18

physical props of drugs affecting distribution

Answer 18

1. high molecular weight drugs

• HMW drugs are trapped in plasma, can’t get out bc of size

2. low molecular weight drugs

• LMW hydrophilic : can enter IF (size), but can’t diffuse into ICF (charge)
• LMW hydrophobic : can enter ECF, IF, and ICF

3. drugs binding to plasma proteins

• plasma only (bc drug-protein complexes can’t move out)
• ex. albumin (loves hydrophobic drugs) makes drugs pharmacologically inert and traps them in plasma → only the fraction of drug that is UNBOUND IN PLASMA is pharmacologically active

Question 19

drug binding to plasma proteins : albumin

what binds?

significance of albumin binding

Answer 19

anionic hydrophobic drugs bind strongly to albumin, hydrophilic drugs don’t

• free form is the active form of drugs → drugs that bind albumin are INERT
• since stock of albumin (and albumin binding sites) is ltd, competition for binding sites can lead to unexpected drug-drug interactions in multiple drug therapy (bc youre expecting both to be bound, but the number of sites is ltd)

Question 20

factors that affect total body water and drug distribution

Answer 20

1. gender : 60% of males, 50% of females water
2. age : 80% of infants, decreasing % in old age
3. body composition : higher % lipid → lower % water
   * obesity affects dosage!

Question 21

volume of distribution (Vd)

Answer 21

most drugs don’t distribute solely in the water compartments → can preferentially dist to bone/lipids/proteins, etc

Vd gives an idea of how much fluid volume the drug is actually distributed to

based on 2 (flawed) assumptions:

1. body is a single compartment into which drug distributes uniformly
2. drug concentration in that compartment is equivalent to plasma concentration

indicative of tendency of drug to distribute beyond vascular space into tissues

Question 22

things that affect plasma concentration of drugs

Answer 22

DISTRIBUTION (always being distributed OUT of plasma)

ELIMINATION (from plasma)

Question 23

factors affecting Vd

Answer 23

1. body composition - lipid contact can affect distribution
   * lipophilic drugs can have higher Vd in obese person!
2. pathological hemodynamics
   * higher dosage at well perfused areas due to preferential distribution
3. polypharmacy
   * competition for albumin binding sites can affect distribution

Question 24

drug elimination

2 paths

Answer 24

1. drug metabolism

• liver metabolism reduces lipid solubility → promotes biliary/renal elim

2. renal elimination

• unmetabolized drugs pass through, hit 3 partitioning events

1. glomerular filtration (out)
2. tubular secretion (out)
3. tubular reabsorption (in)

Question 25

renal elim

1. glomerular filtration

Answer 25

• ~125 mL/min
• non saturable process
• filters ONLY non-protein bound drug, but doesn’t discriminate based on pKa or lipophilicity → unfiltered drug is filtered and contributes to concentration in cortex

Question 26

renal elim

2. secretion

Answer 26

• active transport carrier system moving free or protein-bound drug from blood into nephron prox tubule
  
  • diff systems for cations, anions
• SATURABLE carriers, v little specificity for drug structure
  
  • competition for carriers within cation and anion groups
• can secrete both free and protein-bound drug!

Question 27

renal elim

3. tubular reabsorption

Answer 27

only occurs if solute is DIFFUSIBLE

• only free, unionized drug (pH partitioning occurs!)

concentration in distal tubule is high → passive diffusion from nephron lumen into blood

*bicarbonate alkalinizes urine → increases anionic (acidic) clearance

*ammonium chloride acidifies urine → increases cationic (basic) clearance

Question 28

clearance (CL)

how do you alter clearance?

Answer 28

primary parameter for elimination

volume of biological fluid from which (over specified interval of time) all drug present is removed

CL = rate of elimination / C

ONLY WAY TO CHANGE CLEARANCE? alter the kidney (filtration, secretion, reabs)

Question 29

kd

Answer 29

kd : fractional rate of drug loss from the body

kd = CL / Vd

implication : CL and Vd are directly proportional

• if CL goes up, Vd goes up and vice versa

Question 30

CL(body)

Answer 30

CL(body) = CL(liver) + CL(kidney)

Question 31

clearance at an organ

equation

implication (disease)

Answer 31

CL = OPF x ER

OPF : organ plasma flow

ER : extraction ratio

implication : disease states can impact clearance, esp when affect organs involved in drug elim

Question 32

half-life (t 1/2)

formula?

why useful?

Answer 32

time it takes for plasma concentration to reach 1/2 level

t 1/2 = .693/kd = .693(Vd) / CL

useful because…

• indication of time taken for drug level to reach steady state
• indication of time taken for drug to be removed from body
• indication of approp dosing for an individ

Question 33

fluid compartments in body

breakdown by volume

Answer 33

ECF (IF + plasma) = 14 (11 + 3)

ICF = 28

total body water = 42 L