isolating a drug into a certain environment where its ionization status is favored.  this will prevent drugs from going back into cell compartments where they are no longer needed

fetal plasma is slightly more acidic than a mothers, therefore, ion trapping can happen across the placenta

patient is combatitive, you absolutely need the drug delivered in active for and cannot have the body perform that task for you., you need to deliver a large volume

IV administration delivers 100% bioavailability, but can cause infections and pain.  intramuscular and subQ can be delivered almost anywhere, but transfer of drug is limited to capillary permeability vs. the size of the drug

allthought capillaries in most endothelial tissue are highly permeable, the blood brain barrier is formed by tight juctions between capillary cells thus restricting the passage of substances to the CNS.

sinusoidal capillaries of the liver and spleen have larger openings that allow passage of red blood cells adn seum proteins

it first quickly enteres vessel rich groups of organs (first phase), then muscles, skin, and fat (second phase).

a final redistribution of the drugs is possible following initial distribution, but this usually dignifies the begining of termination of effect (i.e., anesthesia, where maximum effect on brain has been reached, the effect was short lived, and not the drug is being redirected to start clearing it from the system)

only free unbound drugs and produce effects, but some being plasma proteins specifically, but reversibly.  this takes these drugs out of bioavailability.

these extent of bound and unbound drugs is usually help pretty constant (known as steady state.)  is bound plasma-protein drug complexes began being eliminated from the system, circulating plasma-protein drug complexes will start dissociating to maintain the steady state.

albumin mainly sequesters acidic drugs

a-1 acid glycoprotein mainly sequesters basic drugs

bones often can obsorb heavy metals and tetracycline and incorperate them into their crystal lattice.

fat hoards lipid soluble drugs

many enzymes exist that transform drugs into metabolites.  these metabolites may be the active form of the drug, may make a hydrophobic molecule hydrophilic so that it can be excreted, and have been transformed into a percursor before becoming another metabolite

the liver is the primary organ for biotransformation bc:

-has large blood flow

-high conc of enzymes

-high conc of transporters including SLC type and ABC type and MRP2 type

phase 1:  CYPS, FMOs, EHs

phase 2:  UGT (UDP-gluconyltransferase)

all are located in ER of the cell (often hepatocyte) and this is good because the ER is a distinct lipid-bilayer in the cell so when lipid soluble molecules enter the cytosol through the PM, they become embedded in the ER to be acted on by phase 1 enzymes.  once a phase one enzyme acts, another molecule like a phase 2  (UGT)  can modify the metabolite

a transferase (like all phase 2s) which adds a functional group to a metabolite (usually leading to hydrophilicity and are excrete in urine and feces)

urudine diphsophate-glucosyntransferases (UGT) is the most common of the phase  2 enzymes and has highest concentration in GI tract and liver

addes glucuronic acid leading to excretion.  normal flora in ileum can cleave off this acid and cause the substrate metabolite to go back into circulation.

can lead to drug-drug interactions bc UGTs are inducible and can be inhibited

phase two enzymes

SULT makes a metabolite a reactive electrophile

GST addes a glutathione to reactive electrophiles therefore protecting it from reaction

Glutathione (usually stored as GSH) can cause oxidative damage to a cell if its conc falls too low.  Falling levels of GSH has been associated with cancer, AIDS, spsis, trauma, and burns 

a certain percentage of absorbed drugs taken orally will end up in the liver during the first pass, become metabolized, and not be biologically available.  This will happen a few more times until all the agents have been eliminated.

IV drug administration ensures 100% bioavailability

acidify or make alkaline a patient's urine.  The more drug you can ionize, the fast it will clear.

ie. alkalation with sodium bicarbonate to rid of weak acids

acidification with ammonium chloride to rid of weak bases

only drugs that are not bound to plasma proteins can be filtered with water by the glomerulus.  High plasma protein binding means low filtration and excretion of the drug.  as more unbound drugs are  passively diffused into the proximal tubule for elimination, more bound drugs unbind to maintain the steady state.

nonionized drugs are capabably of being reabsorbed if reabsorption of Na ions is causing a gradient.  The nonionized drugs will be carried back to circulation in the water.

their phenotype is such that they have pharmacogenetic differences in the expression of xenobiotic metabolizing enzymes.  the difference has to appear in >1% of the population

often this is the case of SNPs

-a drug interacting with receptors that serve functions common to most cells - widespread effects

-a drug working on receptors that are only unique to a few cell types

-a drug interacting with a receptor that serve a vital function may be difficult to dangerous to use

constant and chronic administration of a receptor antagoist

the denervation of a preganglionic fiber that indices postganglionic neuronal supersensitivity

What is:

EC50

Emax

Kd

Bmax

EC50=conc at which 50% of the maximal response is seens

Emax=the dose at which no futher increase in response can be seen

Kd=conc of free drug at which 50% of all binding sites are filled 

Bmax=the total conc of binding sites

an agonist and an antagonist acting at two independent sites and inducing independent, but opposite, effects

i.e. insulin lowers blood glucose by stimulating cells to take up glucose, glucoagon increases blood glucose by promoting hepatic glycogenolysis and gluconeogenesis

CL= rate of elimination

       drug conc in fluid measured

Vd= dose/Cp  <--conc in plasma.

therefore, if the concentration in plasma is very low, we make an apparent assumption that most of the dose is taken up into the extravascular tissues

operates under an assumption of first order kinetics where any drug that has been eliminated from the plasma per unit time depended on the conc of drug remaining in the plasma

rate of drug elimination must be equal to the rate of drug adminstration

dosing rate = CL x Css

by the 4-5th half life, steady state will be achieved

bioavailability is abbreviated by F (the fraction reaching systemic circulation). 

it is effected by inital dose and the amount of first pass hepatic metabolism

the efficiency of first pass hepatic clearance is determined by its intrinsic value, CL, and the flow rate of the blood to it, Q

if the extraction rate of the liver is .33, then the bioavailability is .67 right off the bat

increased blood flow will slow down the liver intrinsic metabolism

calculate the absolute and variable bioactivites of the drugs they were taking.

the formula is set up like is

F = 100 x AUCa x doseb

               AUCb x dose a

a and b can be brand vs. generic, or IV vs. oral

looking for bioequivalence

explain saturable elimination

what does it assimilate graphically

it seems to follow michaelis-menten kinetics (ie. Km is equal to 50% of receptor binding, a definate Vmax exists)

it is risky to increase a dose in a saturation index is near.  even increasing it a small bit could lead to a large jump in plasma conc.  if dosing rate exceeds elimination capacity, toxicity can ensue

these are ZERO-ORDER kinetics and include ethanol, aspirin, and phenytoin

stay low and go slow

increase no more than 50%, and don't do it until 4-5 halflives

an adjusted formula which allows for the state-state dose to factor in the rate of loss

dosing rate = CL x Css

                   F

(F doesn't matter for IV infusions)

-patient's compliance might be low

-patient could have organ impairments

-plasma protein binding could be fluxuating

     -if it (Cp) goes up, Vd does down and vice versa

-patient may be obese

-skeletal muscle mass differences

unpredictable, manifested as ultra sensitivity to a low dose, or extreme insensitivity to high doses

can result from genetic polymorphisms

alteration of gastic pH what they swallow their pill with.  ginger ale is acidic, milk is basic, this could have good or bad consequences

sequestration of drug tetracycline binds to antacids, so if they're taken at the same time, you're going to get poor absorption

alteration of gastic motility slowing it down slows down reabsorption

inhibition or induction of Pgp transporters  they are meant to keep out absorption 

Strong inducers of CYP3A4 and Pgp: 

Induction of CYP1A can?

 potentially lead to carcinogenicity - cigarette smoke and other  hydocarbons are inducers of this family

Moderate-to-strong CYP3A4 inhibitors 

 Cimetidine (reduces stomach acidity)  Erythromycin and Clarithromycin (macrolide antibiotics)  Ketoconazole and Itraconazole (antifungals)  Ritonavir (protease inhibitor; one of the most potent CYP3A4 inhibitors)  Atazanavir (protease inhibitor); also inhibits UGT1A1  Grapefruit juice