Acronym for kinetics
Absorption - any process by which drug first enters blood
Distribution - how it moves between compartments
Elimination - any process by which drug leaves the body
Passive transport
Drug diffuses across membrane with gradients
Often lipophilic or gas
Active transport
Protein transports against gradient using ATP
Facilitated fissuion
Protein transports across but only in favor of gradient
Receptor-mediated endocytosis
Drug and receptor enter cell by endocytosis of a clathrin coated protein
All capillary beds are
Highly permeable to lipid souble drugs
Most capillary beds
Water soluble move through fenestrations and lipid solbule diffuse through membrane
Capillary beds in CNS and other tissues
Few fenestrations and lipid soluble drugs and gasses move through
Paracellular movement
Movement between fenestrations
High drug permeability
Liver and kidney
Major drug elimination organs
Average drug permeability
Placenta - assume all drugs taken will get to fetus
Low drug permeabiloty
CNS - complicates development of these drugs…prostate is also
Blood brain barrier
tight junctions between endothelial cells AND P-glycoprotein actively transport drugs out of the CNS
Gases and lipid soluble can get in, but few water soluble
pH effects
Weak base more effective at BBB at a higher pH because it will be neutral
Opposite for bases
MDR - where, what does it move
MDR1 (P-glycoprotein) Most important transporter Found in intestine, liver, kidney, and CNS Active transporter Moves organic cations and neutral drugs
Tubules of nephron transport
Contain OATs (- organic trasnporters) that transport out of blood and into the cell…then move by transporting across brush border and into the lumen
Can move drugs out of or into the lumen
Enteral
GI tract (duodenum or stomach)
Parenteral
All other sites
Inhalation
Used for local admin or systemic
Smaller aerosolized particles penetrate depper into the lungs
Transdermal
Only limited number
Must be potent, lipid solbule, and low molecular weight
IV
Fastest and most accurate
Immedaite peak
Preferred for hard to absorb or easy to degrade
IM
Better tolerated, but slower absorption than IV
Good for long-lasting depot for lipophilic drugs
Must diffuse across cap bed
Subq
Easier to administer, more variable and slower absorption
Oral
Most convenient but most variable
Subject to 1st pass effect
Sublingual or buccal
Rapid absorption
Avoid first pass
Rectal
Useful when can’t cooperate
Reduced first pass effect
First pass effect
Seen when rapidly metabolized drugs are absorbed by stomach or duodenum…drug goes straight to portal circulation to liver
Decrease in bioavailability
How to measure bioavailability
Meausre plasma drug conc
Inject IV of same drug in separate exp
Integrate plasma drug concentration from steps 1 and 2
Controlled release
Slower absorption phase means smaller peak and allows less frequent dosing
Albumin
Binds weak acids and is most abundant and important
alpha 1 acid glycoprotein
Binds basic (+ charged) drugs
Lipoproteins
Bind lipophilic drugs
If concentration of albumin decreases
Then there will be more unbound weak acids to have effect
Most clinical tests measure
Total concentration
Pharmaco effect determined by
Free drug concentation
When drug is protein bound,
It cannot be eliminated by kidney or liver…also cannot have its effect…basically acts as a buffer
Volume of distribution equation
Co=X/Vd
Co = plasma drug concent at T0
X = amount of drug in body
Vd = volume of distribution
Larger Vd means
Need higher dose to achieve the same effect
Vd of Lipophilic vs hydrophilic
Hydrophilic will have smaller Vd because it will stay in the plasma while lipophilic prefers fat
Instantaneous absorp
IV bolus
Zero order absorption
Constant rate
IV drip or controlled release
First order of absorption
Rate varies in proportion to drug concentration at absorption site
Most other routes of admin
Liver and kidney role in elimination
Only metabolites of lipophilic drugs are eliminated in urine or bile
Lipophilic drugs are not eliminated by the kidney but diuffuse across renal epithelium and back into blood
Liver must break down the lipophilic drug into something that is more hydrophilic
Steps in the kidney
Passive drug diffusion into the nephron
active drug transport into the nephron
Either active transport or diffusion out of the nephron
Final elimination
Eliminates hydrophilic drugs
Kidney becomes more important with
Smaller drugs
Biliary excretion is main elimination for
Large hydrophilic drugs
Biliary excretion process
If drug is hydrophilic, may enter bile as uncharged drug
Other drugs must be made hydrophilic via added polar side group like glucuronide
Liver has active transport proteins to pull drug into kidney
Enterohepatic recirculation
Something glucuronated and sent into the bile…intestinal bacteria cleave the glucuronide…more lipophilic molecule reabsorbed into the blood
Zero order elimination
Constant rate
First order elimination
Variable rate proportional to plasma concentration
Most drugs eliminated by
First order process
Zero order elimination occurs when
Drug eliminated at its Vmax
Drug clearance
Describes rate of first order elimination from body but can also be used to describe clearance from an organ
How to measure drug clearance
Sample blood from portal and hepatic veins
Measure blood flow into liver
Calculate organ clearance
Interprettion of clearance
2mL/min means liver is eliminating every minute that same amount you would find in 2mL of blood
Single compartment model useful when
Additional compartments are small or unimportant
2 compartment model
Central and peripheral compartments
Central compartment includes the plasma…absorption and elimination only occur with this compartment which carries to liver and kidneys
How to recognize 2 compartment model
Injected and undergoes distribution so plasma concentration drops rapidly…then, equilibrium attained and curve will flatten out as elimination process dominates
IV infusion order
Zero order
Oral administation order
first order
Intermittent administration order
Instantaneous if IV
First order if oral
IV infusion
Exponential rise to Css
Time to Css determined by T1/2
After one T1/2, it will be at 50% of Css
Css equation
Css=infusion rate/CI
Cs = plasma drug concentration
Infusion rate = units of amount/time
Cltotal = Total drug clearance
If drug has long T1/2
use a loading does to get up to Css
Use C=X/Vd to get htis
Single dose oral admin
Rising and falling phases
Aborption dominantes rising while elimination dominates falling phase
IM injection will follow same thing as will any 1st order
Variables that increase drug conc
Dose, absorp rate, and elimin rate
If you increase dose
Peak concentration higher but takes place at same time
AUC increases
If absorption slows (use a different route)
Peak concentration is lower and delayed
No change in AUC
If elimination slows (renal failure)
Peak concentration is higher and delayed
AUC increases
intermittent IV injections
Sawtooth pattern iwht peaks and troughs
Peaks and troughs undergo exponential rise to maximumu values
Intermittent Oral or IM injections
Css after about 4 halftimes
Time to plateau independent of dosage
Rounded sawteeth
T1/2 determines how long it takes to reach maximum
Non-linear kinetics
Drug concentration and AUC can change drastically with dose…increasing dose can produce unexpectedly large and toxic increases in concentration
Elimination saturation
Blood levels higher than expected with high doses
Oral absorption saturation
Blood levels are lower than expected with high doses
Example of non-linear pharmacokinetics
Zero-order elimination
Therapeutic window
Less than toxic but greater than minimum
Sample right after the peak effect
When is therapeutic monitoring helpful?
Narrow window, Effect can’t be observed, complex kinetics
Cmeasured/Cdesired=original dose/adjusted dose
Why does T1/2 determine time course of IV infusion
Absorption constant during IV infusion…first order elimination is proportional to drug concentration and changes with it…more efficient elimination (smaller T1/2) means elimination rate will increase faster and catch up to absorption sooner