Pharmacokinetics

Question 1

pharmacokinetics

Answer 1

• time course of drug action as it relates to the concentration of drug in the plasma
• ADME = Absorption, Distribution, Metabolism, and Excretion

Question 2

rational therapeutic regimens

Answer 2

• dose
• absorption
• first pass metabolism
• area under the curve
• elimination clearance
• patient compliance

Question 3

measurement of drug concentration in plasma

Answer 3

-for most drugs, the concentration of drug at its site of action will be related to the concentration of the drug in the systemic circulation. Therefore it can be used to predict therapeutic and/or toxic effects of drugs

Question 4

Area under the curve clinical significance

Answer 4

• used to compare the amount of drug that reaches the systemic circulation by different routs of administration: bioavailability (F)
• used to compare clearance (CL) of a drug in different individuals after administration of the same dose
• AUC= dose iv/CL or AUC= dose p.o./ (CL/F)
• CLx/CLy = AUCy/AUCx

Question 5

drug absorption

Answer 5

-the processes by which drugs move from their site of administration to the plasma

Question 6

processes following oral drug administration

Answer 6

• disintegration of solids and dissolution of drug in fluids of GI tract
• passage of drug across or between cells to reach the systemic circulation
• stomach and small intestine have large surface area for absorption and the drug leaves that area via passive diffusion and drug transporters to the systemic circulation

Question 7

factors affecting drug absorption

Answer 7

• chemical composition of drug and delivery formulation
• regional differences in blood flow
• transport mechanisms
• permeability characteristics (lipid solubility)
• ion trapping
• non-specific binding
• surface area

Question 8

types of passive transport

Answer 8

• paracellular transport
• diffusion
• facilitated diffusion

Question 9

aqueous diffusion

Answer 9

• small molecules
• passive movement driven by concentration gradient
• route may be paracellular or via aqueous pores

Question 10

lipid diffusion

Answer 10

• passive process
• driven by concentration gradient
• the rate of absorption increases with increasing drug concentration
• the more lipid-soluble, the faster the rate of transport
• lipid soluble drugs cross mbs readily, but they may be poorly soluble in aqueous gut fluids which may limit their absorption
• lipid solubility is affected by the degree of ionization- henderson hasselbach equation

Question 11

Henderson Hasselbach equation

Answer 11

pKa = pH + log ([AH]/[A-]) or ([BH+]/[B])

-the ionized form is less lipid soluble– A- or BH+

Question 12

Where in the body are acids/bases best absorbed?

Answer 12

• weak acids- bet in stomach (lower pH)
• weak bases - best at higher pH
• both are well absorbed in the small intestine

Question 13

Degree of ionization depends on difference between pH and pKa how?

Answer 13

-pH- pKa = -3, Acids = .1, Bases = 99.9
-pH-pKa= -2, acids =1, bases = 99
-pH-pKa = -1, acids = 10, bases =90
-pH-pKa =0, acids =50, bases =50
etc.

Question 14

ion trapping

Answer 14

• non-ionized forms can diffuse across lipid membranes, so it equilibrates between blood and urine. Then more of the substance can be trapped on one side or the other based on the pH of the compartment

Question 15

First pass metabolism

Answer 15

some drugs are highly metabolized when they pass through the liver- only a fraction (F) of the absorbed drug reaches the systemic circulation
-intestinal and hepatic

Question 16

enterohepatic circulation

Answer 16

Drug may be secreted into the bile and reabsorbed via the intestine. This can delay delivery to the systemic circulation and may reduce bioavailability

Question 17

Stomach contents and absorption

Answer 17

stomach contents and gastric emptying can affect the rates of drug absorption
ex. Ca2+ from food in the stomach tends to bind drugs and decrease absorption

Question 18

bioavailability

Answer 18

-fraction of the administered dose that reaches the systemic circulation in its active form
-a drug can have less than 100% bioavailability if it is incompletely absorbed or if it undergoes metabolism
Foral= AUCp.o/AUCi.v.

Question 19

salt factor

Answer 19

in rare cases, a drug may be prepared in a formulation that provides a fraction of the total weight of drug as active drug and the remainder as an inactive salt
-the fraction of total drug that will be delivered as active drug to the systemic circulation is called the salt factor (S)

Question 20

sublingual/buccal dose administration

Answer 20

• bypasses portal circulation and therefore avoids first pass metabolism
• higher pH may be beneficial for absorption of more basic drugs
• can have a bad taste or be uncomfortable

Question 21

rectal dose administration

Answer 21

• about 50-60% of the absorbed drug by-passes the portal circulation and therefore avoids the first pass metabolism
• useful in cases of nausea and vomiting
• inconvenient and uncomfortable

Question 22

inhalation of drugs

Answer 22

• absorption is via passive diffusion and is facilitated by a large surface area
• can be volatile gases or aerosol preps
• drug absorption varies with depth and duration of inspiration so in the hospital would titrate to desired effect or us a metered inhaler

Question 23

topical drug administration

Answer 23

• usually for local therapy

- highly lipid-soluble forms may reach the systemic circulaion

Question 24

transdermal drug administration

Answer 24

• passive diffusion of drugs across the skin driven by a concentration gradient
• controlled release of drug into the patient enables a steady blood level profile
• user friendly= improved patient compliance
• avoids GI system so no GI irritation and no first pass metabolism
• skin barrier limits the number of drugs that can be delivered by passive diffusion from an adhesive patch

Question 25

injection of drugs

Answer 25

- blood flow to the area maintains that conc gradient - drug absorption is faster in highly vascularized tissues - greater degree of reliability and precision of administered dose - fewer problems with absorption (no metabolism or GI) - disadvantages- needles, pain, tissue irritation, limited volume, drugs must be in solution

Question 26

subcuatneous administration

Answer 26

- slow,even absorption - rate of absorption may be modified by altering blood flow (heat/cold) - may be used as a depot - not effective when peripheral circulation is impaired - limited volume

Question 27

intramuscular absorption

Answer 27

- more rapid absorption than subQ because it is more vascularized - can modify rate of absorption by modifying blood flow (heat) - potential for infection/nerve damage - risk of inadvertent IV administration

Question 28

IV administration

Answer 28

- fastest and most reliable means of achieving a defined blood level - risk of overdose by bolus effect, so give drug slowly

Question 29

factors influencing distribution

Answer 29

- regional differences in blood flow - tissue mass - transport mechanisms - permeability characteristics (ex BBB) - ion trapping - protein binding

Question 30

proetin binding to drugs

Answer 30

- many drugs bind to plasma proteins-- albumin binds acidic drugs, and alpha-1 acid glycoprotein binds basic drugs - protein bound drugs are retained in the plasma

Question 31

one compartment distribution

Answer 31

- a rapid equilibrium is achieved between plasma and tissue distribution following drug administration - plasma concentration-time profile declines mono-exponentially

Question 32

two-compartment distribution

Answer 32

- rapid distribution to a central compartment (plasma) is followed by slow distribution ot other tissues/binding sites (second compartment) - this results in a bi-exponential plasma concentratio-time profile (distribution phase and then elimination phase)

Question 33

Volume of distribution

Answer 33

- measure of how evenly distributed a drug is in the body - theoretical volume of fluid into which the total drug administered would have to be diluted to produce the concentration in plasma - relates dose to plasma concentration of drug (dose/Co)=Vd - an increase in unbound fraction of total drug (like in hypoalbuminemia) will result in an increase in the apparent volume of distribution

Question 34

fluid compartments in the body

Answer 34

- plasma = 5% - interstitial fluid = 16% - intracellular fluid 35% - transcellular fluid 2% - fat 20% - extracellular fluid = plasma+interstitial fluid+lymph (1%) - transcellular fluid = cerebrospinal, intraocular, perioneal, pleural, and synovial fluids and digestive secretions

Question 35

drug distribution to compartments based on lipid solubility

Answer 35

- lipid insoluble drugs = confined to plasma and interstitial fluids and most don't enter the brain - lipid soluble drugs reach all compartments, and they may accumulate in fat which can cause Vd to exceed total body volume (because the drug accumulates outside of the plasma)

Question 36

drug reservoirs

Answer 36

- fat and muscle especially can act as drug reservoirs - gradual release of drug from these sites can prolong the therapeutic effect or result in toxicity - plasma proteins can also serve as a drug reservoir (ex. sulfonamides may compete for protein binding and increase the unbound fraction of other drugs)