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Flashcards in Pharmacokinetics I Deck (51):

What is pharmacokinetics?

how the body deals with the drug
the quantitative description of the rates of the various steps of drug disposition


What are the paths of drug absorption?

fill in


How does a drug move across cellular barriers?

Passive transport:
- paracellular transport
- diffusion

Active transport:
- facilitated diffusion
- drug transporters


What are the paths of drug absorption?

- enteral (sublingual, oral, rectal)
- parenteral (subcutaenous, intramuscular, IV, spinal)
- topical (percutaenous (i.e., skin), inhalation)


What are drug characteristics affecting drug absorption?

- lipid solubility
- molecular size & weight (larger, not going to be absorbed as well)
- pKa


What are tissue characteristics affecting drug absorption?

- membrane permeability (charged substance won't cross, uncharged will)
- pH
- membrane thickness
- local blood flow
- local anatomy (i.e., surface area)
- transport mechanisms


What are four methods of permeation movement of drugs through body?

- aqueous diffusion (passive process governed by Fick's law)
- lipid diffusion (passive process governed by Fick's law)
- transport by special carriers (NOT governed by Fick's law and is capacity limited)
- endocytosis, pinocytosis (NOT governed by Fick's law)


What is Fick's Law of Diffusion?

predicts the rate of movement of molecules across a barrier

Rate = (C1 - C2) * (Permeability Coefficient/Thickness) * Area
C1 = concentration on side of administration
C2 = concentration on other side


What is bioavailability?

the fraction of drug absorbed into the systemic circulation

Intravenous better than oral

Bioavailability (F) = AUC(route)/AUC(i.v.) * 100


Passive diffusion

drugs move down their concentration gradient

J = -D*A*deltaC/deltax

J = net flux
D = diffusion coefficient
A = area available for diffusion
deltaC = concentration gradient
deltax = membrane thickness


What can affect drug absorption?

- alteration of pH
- complexation
- alteration of GI motility
- interference with absorption


Drug pKa - most drugs are what types of acids/bases?

most drugs are either weak acids, weak bases, or are amphoteric


Aspirin is a weak acid (pKa = 3.5); is it readily absorbed?



What does a drug's pKa indicate?

a drug's pKa value represents the pH at which 50% of the molecules in solution are ionized
- acids are increasingly ionized in a basic environment
- bases are increasingly ionized in an acid environment


What is pharmacodynamics?

How a drug acts on the body to produce biological changes


What must be considered in pharmacokinetics?

- dose given
- route of administration
- how well drug distributes throughout body
- how drug can be chemically altered by enzymes
- how drug is eliminated


What are the two principal organs of elimination?

- liver
- kidneys

*other organs play a more minor role including lungs, skin, GI tract, etc.


What organ is most often responsible for drug metabolism?


*after metabolism, the modified drugs can return to the blood to be excreted by the kidneys, or can be secreted into the bile and eliminated by the GI tract


What organ is the primary site for excretion of a drug?



What organ is an important route for eliminating volatile chemicals?

the lungs

*ex: gaseous anesthetics


What are the six routes of drug administration?

- oral
- intravenous
- intramuscular
- subcutaneous
- transmucosal
- transdermal


Describe the pathway of drug after oral administration

- medication taken by mouth
- absorbed from GI tract into portal circulation
- after passing through liver, they enter systemic circulation


Describe the pathway of drug after intravenous administration

- drugs injected directly into systemic circulation on venous side


Describe the pathway of drug after intramuscular administration

- medications injected into muscle
- absorbed through muscle capillaries into blood and pass into venous circulation


Describe the pathway of drug after subcutaneous administration

- drugs injected into subcutaneous tissue (tissue beneath skin)
- absorbed through capillaries into blood and pass into venous circulation


Describe the pathway of drug after transmucosal administration

- medications placed in mouth and absorbed through oral mucosa into capillaries and into bloodstream and pass into venous circulation


Describe the pathway of drug after transdermal administration

- medications placed on skin diffuse through skin and are absorbed through subcutaneous capillaries into the venous circulation


What is the goal (desired location) of absorption?

reaching the systemic circulation (from which the drug has access to its site of action)


What is the time of onset of a drug?

minimal amount of drug that needs to be in circulation that results in a therapeutic effect


What is the therapeutic range?

the minimum of drug in circulation to produce an effect and the maximum amount needed in which there is no more effect no matter how high the dose


What is the duration of action?

how long does the drug produce therapeutic effects


For what routes of administration does a drug need to move across one or more biological membranes to gain access to the circulation?

all but for IV

*in some cases drugs travel across membranes by facilitated transport processes mediated by drug transport enzymes
*more often, they cross membranes by passive diffusion down a concentration gradient


Are drugs that cross membranes by transport carriers or by endocytosis or pinocytosis governed by Fick's Law?



Many drugs are week acids or weak bases - the uncharged forms diffuse across membranes, since charged compounds are very insoluble in the hydrophobic lipid core of the membrane. The ionization of a drug depends on what?

the Henderson-Hasselbalch Equation

pH = pKa + log (unprotonated/protonated)

unprotonated: A- or B
protoanted: HA or HB+

*note: HB+ cannot cross the membrane because it is charged; deprotonated B will cross the membrane, form HB+ on the opposite side


Low pH favors absorption of _____ (acids or bases?) from stomach and opposes absorption of ____ (acids or bases?).

Low pH favors absorption of acids from stomach and opposes absorption of bases.


The weaker the acid (higher pKa), the _____ the fraction of drug that is uncharged.

* the lower the pH, the higher the fraction of drug that is unchraged


Basic environment on one side of the membrane will tend to shift the equilibrium toward the ____ (dissociated or protonated?) form of a weak acid?

dissociated - by reducing the concentration of free protons

more basic, less protons, favors deprotonation

therefore, rate of movement from that side will be low, compared to movement form opposite, more acidic side

this 'traps' a weak acid on the alkaline side


to treat overdose of a weak base, _____ urine using ______.

acidifcy; NH4Cl


To treat overdose of a weak acid, _____ urine using ______.

alkaline; NaHCO3


What are the four forms of oral dosage?

- tablet
- capsule
- suspension
- elixir


The major cause of differences in absorption of a drug from various forms is the need for _____.


* a drug needs to be released from a solid form and dissolved in GI fluids before it is capable of crossing the gut membrane and reaching the blood stream


Describe the passage of a drug (oral)

through GI lumen, through gut wall, through liver, then to general circulation

*blood perfusing nearly all GI tissues drains into the liver via the portal vein (with exception of within the mouth and the rectum)


Drugs cross GI membranes by what two methods?

- passive diffusion (large or polar drugs)
- carrier-mediated transport


What are the possible sites of loss for drug after oral administration?

- GI lumen: decomposition of a drug may occur due to chemical instability or metabolism by luminal enzymes (CYP3A4) or bacteria; or if poorly absorbed, remain in lumen and pass into the stool
- GI wall: metabolism by enzymes located in the gut wall (CYP3A4) OR PGP excretion into GI lumen
- liver: metabolism (many CYPs) or biliary excretion


Intestinal epithelial cells contain various proteins that lower drug uptake by pumping a wide range of xenobiotics (compounds, like medications, which come from outside the body) out of the cell and back into the intestinal lumen vi an energy dependent process.
The most important of these efflux pumps is ______.

-an ATP-dependent transporter that limits bioavailability and tissue penetration of hundreds of drugs

*active drug efflux contributes to the low and variable absorption of a variety of drugs


What is pre-systemic, or first-pass, metabolism

when a drug (typically orally administered) passes through the liver via the hepatic portal system before reaching systemic circulation

*orally administered drug gets metabolized in liver
*important mechanism of loss
*drugs which are subject to a large first-pass effect are typically administered by other, non-oral, routes


What is the path of drug in the hepatic portal system?

- small intestine absorbs products of digestion
- nutrient molecules travel in hepatic portal vein to liver
- liver monitors blood content
- blood enters general circulation by way of hepatic vein


What is bioavailability?

the fraction of drug absorbed into the systemic circulation

Bioavailability (F) = (AUC)oral/(AUC)iv

0 < F < 1
0 = does not reach systemic circulation
1 = completely absorbed into systemic circulation


The total area under the plasma concentration-time curve (area under the curve, AUC) can be used to evaluate what?

the extent of absorption


Comparing teh AUC after oral administration to that after IV administration allows us to determine what?

the oral bioavailability (F), an index of the fraction of drug which gets absorbed into the bloodstream


Do sublingual drugs pass through liver (first-pass)?

no, they get absorbed through oral mucosa directly into systemic circulation