8/9/16 Pharmacokinetics: Drug Absorption, Distribution, Elimination - Pilch Flashcards
drug absorption
types and examples
- enteral : via GI tract
- oral (most common)
- sublingual
- rectal
- parenteral : GI tract bypassed
- IV (most common)
- intramuscular (IM)
- subcutaneous (subQ)
- transdermal
- inhalation
oral route of drug admin
- what is it
- types of transport involved
most common route of enteric admin
absorption from aqueous solution in stomach lumen → plasma [need to cross GI membranes!]
- 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
- passive transport
- more common than active transport bc system is less selective/specific than active
- doesn’t saturate
- CAN’T move against conc gradient
what classes of drugs can be transported passively?
- 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
- 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
how can you quantify lipophilicity / the level to which a drug will be absorbed?
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
drugs that are not lipophiles…
what are they?
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!
pKa definition
protonation/deprotonation on either end of pKa
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
predictors for absorption for…
lipophiles
acids/bases
lipophiles : P
acids/bases : pKa
pH partition hypothesis
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!
pH partition hypothesis
sample calc
implications of pH partition hypothesis (in stomach) for…
acids
bases
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
absorption from intestine into plasma
follows principles of pH partition EXCEPT behaves as though pH approx 5.3-5.4
implications for drugs NOT absorbed in stomach :
where does the majority of drug absorption take place? why?
- factors that affect absorption
INTESTINE
- 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
-
surface area : where drugs can be absorbed
* villi present approx 500x absorptive surface area of the stomach - 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
- food : presence of food can slow abs
oral bioavailability
what is it?
what limits it? 5 things
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
therapeutic inequivalence/index
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)
when is generic drug substitution problematic?
- if original and generic preps are BIOINEQUIVALENT
- if prescribed drug has a NARROW THERAPEUTIC INDEX
* if toxicity is an issue, stick with what you know
IV route
type of admin
reasons for using it
most common type of parenteral administration
- drugs are hydrophilic, poorly absorbed
- drugs are metabolically labile and would be degraded by stomach enzymes
- IV admin gives you increased speed of action
- 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
drug distribution
fluid compartments in body
drugs can distribute to any of 3 functionally distinct fluid compartments
- ICF (intracellular fluid)
- ECF (extracellular fluid)
- interstitial fluid (IF)
- plasma
physical props of drugs affecting distribution
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
drug binding to plasma proteins : albumin
what binds?
significance of albumin binding
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)
factors that affect total body water and drug distribution
- gender : 60% of males, 50% of females water
- age : 80% of infants, decreasing % in old age
-
body composition : higher % lipid → lower % water
* obesity affects dosage!
volume of distribution (Vd)
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:
- body is a single compartment into which drug distributes uniformly
- drug concentration in that compartment is equivalent to plasma concentration
indicative of tendency of drug to distribute beyond vascular space into tissues
things that affect plasma concentration of drugs
DISTRIBUTION (always being distributed OUT of plasma)
ELIMINATION (from plasma)
factors affecting Vd
- body composition - lipid contact can affect distribution
* lipophilic drugs can have higher Vd in obese person! - pathological hemodynamics
* higher dosage at well perfused areas due to preferential distribution - polypharmacy
* competition for albumin binding sites can affect distribution
drug elimination
2 paths
1. drug metabolism
- liver metabolism reduces lipid solubility → promotes biliary/renal elim
2. renal elimination
- unmetabolized drugs pass through, hit 3 partitioning events
- glomerular filtration (out)
- tubular secretion (out)
- tubular reabsorption (in)
renal elim
- glomerular filtration
- ~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
renal elim
- secretion
- 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!
renal elim
- tubular reabsorption
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
clearance (CL)
how do you alter clearance?
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)
kd
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
CL(body)
CL(body) = CL(liver) + CL(kidney)
clearance at an organ
equation
implication (disease)
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
half-life (t 1/2)
formula?
why useful?
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
fluid compartments in body
breakdown by volume
ECF (IF + plasma) = 14 (11 + 3)
ICF = 28
total body water = 42 L
