Pharmacokinetics Introduction

Question 1

What is pharmacokinetics?

Answer 1

Movement and modification of drug throughout body.

Question 2

What is pharmacodynamics?

Answer 2

Mechanism of action of drug on target tissue.

Question 3

What are the four main aspects of pharmacokinetics?

Answer 3

Absorption (drug getting into body), distribution (drug getting to target tissue), metabolism (drug modified by liver, lungs, kidneys, gut), clearance (drug removed from body)

Question 4

What must happen to a drug before it can be utilized?

Answer 4

It must cross epithelial cell layers to get into the body (except topical treatments)

Question 5

In what ways can a drug pass through the plasma membrane of a cell?

Answer 5

Facilitated passive transport - movement along concentration gradient assisted by ion channels or carrier proteins
passive transport - diffusion across concentration gradient
active transport - movement against concentration gradient that takes energy and a carrier protein.

Question 6

What is bioavailability?

Answer 6

Bioavailability is “how much” of the drug actually gets absorbed and can be readily accessed for use.

Question 7

What is the method of distribution for most drugs?

Answer 7

Through the circulatory system

Question 8

How does pH affect drug absorption?

Answer 8

Ionized drugs will not be able to pass through the plasma membrane. A drug will most readily pass through the membrane when it is uncharged. If the drug is an acid, you would want the tissue environment to be super acidic for the drug to pass through. If the drug was basic, you would want to have a more basic environment for optimized transport.

Question 9

Why do drugs need to be neutrally charged to pass into cells?

Answer 9

Most drugs use passive transport to get into their target tissue. To passively get across a cell membrane requires a hydrophobic molecule (the lipid bilayer will resist any polar molecules trying to get in)

Question 10

What are key considerations for drug absorption?

Answer 10

Time of exposure to tissue, surface area of tissue, pH of tissue. Hardly any drug gets absorbed in the mouth/esophagus because it’s only exposed to tissue for seconds. The stomach is extremely acidic so many drugs will donate hydrogens and will be charged so they won’t be absorbed. But some acidic drugs will be absorbed best in the stomach. The small intestine has the slowest movement of material and has the most surface area, so most absorption occurs there.

Question 11

What is drug recycling?

Answer 11

Sometimes bacteria in the gut can actually undo the modifications made in the liver on a drug. This means that the drug is passed again through tissue as an active molecule, able to act on its targets. It’s important to know if this occurs in regulating dosages. If a patient was ever taking an antibiotic they could potentially underdose (if bacteria recycles drug) or overdose (if bacteria breaks down drug)

Question 12

What barriers to orally administered drugs need to overcome to enter the body? What about inhaled, intravenous, or subcutaneous?

Answer 12

Orally administered drugs have to get out of the lumen, into the interstitial space, and ultimately into the intravenous space (blood vessel). Inhaled drugs are often used to act on the lungs, so they can often just interact with the epithelium of the alveoli. Intravenous drugs are immediately stuck in the blood stream, so they have perfect absorption/bioavailability. Subcutaneous drugs have skipped the outer lumen but need to get through the walls of the endothelial blood vessel cells.

Question 13

What is drug transit time?

Answer 13

How long the drug is exposed to a given tissue before being moved along (especially important in oral administration. the drug will be in the stomach and esophagus for much less time than the intestines)

Question 14

What is the pH ranges of the mouth, stomach, small intestine, and large intestine?

Answer 14

mouth is 5.5-8. Stomach is 1.5-3.5. small intestine is 6-7.5. large intestine is 5.7-6.7

Question 15

How many plasma membranes does an orally administered drug need to pass through before entering the blood?

Answer 15

4! 2 (apical and basal) in the lumen wall and 2 (basal and apical) in the endothelium wall (plus the interstitial space in between)

Question 16

How do the rates of facilitated, passive, and active transport differ?

Answer 16

Facilitated and active transport can be saturated, meaning each protein carrier has a maximal velocity. Passive diffusion cannot be saturated. If you add molecules you will just keep on linearly increasing the rate at which molecules diffuse. The graph for a passive diffusion rate v. concentration of substrate is a sloped line. the graph for active or facilitated transport is an asymptotic line.

Question 17

If your drug is acidic, what do you want the environment to be like for maximal absorption?

Answer 17

You want the environment to be more acidic (so lower pH) than the PkA of the drug, so it does not donate its hydrogen ions. Opposite for basic drugs.

Question 18

Why doesn’t pKa tell you if something is acidic or basic?

Answer 18

It’s not the definition! A base donates electrons (accepts hydrogens), an acid accepts electrons (donates hydrogens)

Question 19

What is the henderson hasselbach equation for an acidic drug? A basic drug? What is a key assumption for these equations?

Answer 19

Henderson Hasslebach only works for passive diffusion. it’s always unprotonated/protonated
A-/HA = 10^pH-pka
B/HB+=10^pH-pka

Question 20

Why is bioavailability for all non-intravenous drugs less than 100%?

Answer 20

Some drug will be broken down in the stomach, or lost in translation, or peed out, before it’s able to act on the target tissue.

Question 21

What is the bioavailability curve?

Answer 21

A curve that shows the concentration of drug in the body over time (of a given drug through IV administration), and second curve that shows THE SAME DRUG through a different application mechanism. The curve is only valuable because the IV of each drug is used as a standard. The area under the curve (integrals :) woo!) represents total “exposure” to the drug. bioavailability is calculated as Area under tested method/ Area under IV injection

Question 22

What is the first pass effect?

Answer 22

The drug, immediately upon entry into the blood, is pulled out by the liver. So the concentration in systemic circulation is way less than what was first put into the blood.

Question 23

Where is bioavailability measured?

Answer 23

It needs to be measured AFTER the liver. The liver picks up a ton of drug and sometimes keeps it from moving on. Measuring ahead of the liver would give you an overestimated concentration in the body.

Question 24

What is a parenteral injection?

Answer 24

Administration of drug not in the mouth.

Question 25

What role do gut bacteria play in drug pharmacokinetics?

Answer 25

Gut bacteria can breakdown drugs before they enter systemic circulation, OR they can actually recycle drugs by removing modifications made to the drug in the liver. Bacterial recycling increases exposure to drug. Bacterial degradation decreases exposure to drug.

Question 26

What is volume of distribution?

Answer 26

The degree to which a drug “spreads” in the body’s three water compartments (intracellular, plasma, and interstitial). Calculated as total dose/concentration in plasma

Question 27

What is the standard “perfect” VoD per kilogram in humans?

Answer 27

0.6 L/kg means even concentration of drug throughout the body, all tissue types.

Question 28

How could VoD be above 0.6 L/kg?

Answer 28

If a drug was preferentially pulled into intracellular fluid

Question 29

How could VoD be significantly beneath 0.6 L/kg?

Answer 29

pH trapping, plasma protein binding, hydrophilic charge state.

Question 30

What does a VoD of 0.1 L/kg represent?

Answer 30

Most of the drug is in the plasma

Question 31

What does a VoD of 1 L/kg represent?

Answer 31

The drug has been preferentially pulled out of the plasma.

Question 32

What factors decrease water content of the body?

Answer 32

Fat content in the body and age are huge players. As you age your % water decreases significantly (it’s crazy high in babies and quite low in elderly patients). As you gain fat (less water in fat) your relative amount of water per unit kg decreases.

Question 33

Why does total water content in the body matter for drug administration?

Answer 33

less drug should be used in people who have less water, because you want to conserve overall drug concentration between patients.

Question 34

What are the major families of enzymes involved in drug metabolism?

Answer 34

Cytochrome p450 enzymes are heavily used in phase 1 (functionalization) modifications of drugs (occurs in the liver).
UDP-glucouronosyltransferase enzymes are key in phase 2 (conjugation) modifications.

Question 35

What are the primary site(s) of drug metabolism?

Answer 35

Most of it occurs in the liver, but it can occur in other tissues. Some bacteria or enzymes in the gut digest drugs. In some cases enzymes in lung mucus modifies drugs.

Question 36

What is the purpose of drug modification in the body?

Answer 36

Usually to deactivate the drugs! Sometimes tricky drugs can be made that activate after being modified by phase 1 enzymes, but it’s almost always a deactivating step.

Question 37

What are the major steps in drug modification?

Answer 37

Phase 1 - functionalization is basically a preparatory step for phase 2. Almost always reduction, oxidation, or hydrolysis.
Phase 2 - conjugation. This phase usually adds a very polar and chunky molecule to the drug. A polar, chunky molecule is easier to get rid of in the kidneys and often interrupts the drug’s function.

Question 38

What are the general metabolic pathways for a drug as it enters the body?

Answer 38

The drug can be pushed directly to the kidney and urinated out. It can be pushed to the liver and undergo phase 1 modifications and then be peed or excreted (as part of bile). It can go through phase 1 and phase 2 modifications and be excreted in bile or peed out. It can go straight to phase 2, or it can go straight to bile and be excreted.

Question 39

Do all drugs have a specific pathway for metabolism?

Answer 39

It depends! There are definitely specific protein channels for each drug, but they can be metabolized through many pathways. A single drug could be put through both phases of liver metabolism and also have some of it shunted to the bile right away.

Question 40

What are zero-order kinetics? When do they show up with respect to drug metabolism?

Answer 40

Zero order kinetics is what you see when concentration of substrate does not effect the rate of reaction. You have an excess of substrate, and it is the amount of enzyme that determines overall reaction rate. This would happen in the body when you have a huge amount of drug and not enough enzymes to work with all the drug. This doesn’t happen often in drug metabolism but is seen commonly after a night of drinking. This graph would be linear.

Question 41

What are first-order kinetics? When do they show up with respect to drug metabolism?

Answer 41

First order kinetics define enzymatic reactions where the enzyme is in excess. The enzyme binds any substrate it can find. The reaction rate decreases as substrate is used up because it’s harder to find. This graph would be an exponential decay. This is what most medicinal drug metabolism looks like. Enzymes are in excess, drug is limited.

Question 42

What portion of the michaelis menten graph represents zero order kinetics? Which part represents first-order kinetics?

Answer 42

The early part of the graph is first-order. As the rate reaches the asymptotic Vmax you begin to see zero-order kinetics.

Question 43

What does zero order metabolism look like on a graph? What are the axes?

Answer 43

x axis is time. y axis is concentration of drug. zero order metabolism is a linear decay. Constant speed of reaction.

Question 44

What is enterohepatic circulation?

Answer 44

Drug recycling: bacteria in gut unmodifies and put back into the tissue to do their thing. This increases total tissue exposure to drug (increases halflife)

Question 45

What are the two major forms of drug clearance in the body?

Answer 45

Excrete in feces/bile or pee out. We’re covering excretion here more because pee happens in the urinary block.

Question 46

What effect can antibiotics have on the potency of other drugs?

Answer 46

By killing the natural bacteria in our gut, antibiotics can either reduce or increase our exposure to other drugs. Bacteria in the stomach are often key in breaking down drugs before they get to our systems (this isn’t really a good or bad thing, it just happens so the applied dose is increased). Bacteria in our lower GI tracts often reactive drugs and allow them to recirculate through target tissues. Antibiotics would stop either of these pathways, and could cause trouble.

Question 47

What are some complications that arise when a patient is on multiple drugs?

Answer 47

Some drugs actively compete through the same mechanisms. Other drugs may use similar pathways to get through the blood (binding to the same plasma protein), and will thus increase each other’s free drug concentrations in the blood. Other drugs may inhibit or activate digestive/metabolic enzymes.

Question 48

What is a common plasma protein?

Answer 48

Albumin! It is used to bind multiple drugs for transport through the body.

Question 49

How can multiple simultaneous drugs impact drug clearance?

Answer 49

One drug may inhibit the carrier protein of another, which would sustain the latter’s higher concentration in the body.

Question 50

Where does clearance occur?

Answer 50

In the nephrons of the kidney. Across nephron epithelial cells.

Question 51

What major factors effect drug pharmacokinetics in an individual?

Answer 51

Age, Body composition, Overall health status (immune suppressed) genetic profile (mutations in cytochrome p450 or other enzymes could cause trouble)

Question 52

How does age affect the different aspects of pharmacokinetics?

Answer 52

Age decreases absorption by slowing GI function, reduced surface area of intestines, increased stomach pH.
Age increases distribution efficiency, because there’s less water in the body to get through.
Age decreases metabolic efficiency, because the liver’s function is reduced.
Age decreases renal function, which decreases speed of clearance.
Overall you need to decrease dose in old people.

Question 53

What is Beers criteria for potentially inappropriate medication use in older adults?

Answer 53

A guideline, put forward by the geriatric society of doctors, with instructions on which drugs are known to have altered pharmacokinetics/dynamics in the elderly. It provides a suggested change in dosage, along with some data on the strength of their recommendation and the breadth of research supporting the recommendation.

Question 54

How do genetics influence pharmacokinetics?

Answer 54

A lot of drug absorption, distribution, metabolism, and clearance is dictated by various proteins. Proteins are made by RNA, which is made by DNA. DNA can be altered in genetic mutations, usually to decrease efficacy of protein.

Question 55

What is p-glycoprotein?

Answer 55

A protein involved in drug absorption/clearance in the body. It pumps drugs out of cells. p-glycoprotein has dozens of polymorphic sites (locations in gene where mutations can occur), each of which can mess with function.