Lecture 4- Intro to Pharmacokinetics

Question 1

What happens after you administer a drug?

Answer 1

• The drug needs to be absorbed and travel in the body to reach its target tissue
• Overtime the effects of the drug wears off because the drug is eliminated from the body

Question 2

What is a theraputic window?

Answer 2

a concentration range where the drug will have it’s desired effects

Question 3

What are the 3 important considerations in terms of routes of administration?

Answer 3

• Convenience (route of adminstration)
• Bioavailability (different drugs may be absorbed with different efficiency from the gut)
• Processing in the hepatic portal circulation (drugs absorbed from the gut first encounter the liver before entering systemic circulation for significant breakdown)

Question 4

The higher the bioavailability, the ____ the steady state concentration

Answer 4

higher

Question 5

The higher the clearane, the ____ the steady state concentration

Answer 5

lower

Question 6

What is first pass metabolism?

Answer 6

• Refers to the amount of a drug that is processed or eliminated during its first pass through the liver before being distributed to the circulatory system
• The liver strongly influences the bioavailabilty of many drugs

Question 7

What is the extraction ratio?

Answer 7

clearance (liver)/blood flow

Question 8

• The more that’s cleared from the blood going through the liver, the ____ the extraction ratio
• The more weakly a drug is cleared from the blood going through the liver, the ____ the extraction ratio

Answer 8

higher; lower

Question 9

Are statins (prodrugs) high or low extraction ratio drugs?

Answer 9

high extraction

Question 10

What is the rate of absorption for oral administration of a drug?

Answer 10

• it is slow and affected by intake of food and pH
• most common

Question 11

What is the rate of absorption for intravenous administration of a drug?

Answer 11

• very rapid onset action as it is directly delivered into systemic circulation
• high control over circulating level by controlling the amount injected and the rate of infusion

Question 12

What is the rate of absorption for intramuscular/subcutaneous adminstration of a drug?

Answer 12

• depends on the blood flow to site as it is injected into muscle or jsut below the skin

Question 13

What is the rate of absorption for inhalation admistration of a drug?

Answer 13

• absorption is through the epithelium in the lungs and is rapid

Question 14

What is the rate of absorption in sublingual admistration of a drug?

Answer 14

• rapid absorption
• also bypasses the “first pass” metabolism effect

Question 15

What is the rate of absorption for a transdermal adminstration of a drug?

Answer 15

• ointment or patch
• slow absorption and is sustained exposure

Question 16

What does bioavailability mean?

Answer 16

• it is a fraction of unprocessed/unalterted drug that reaches the systemic circulation after administration by a particular route.

Question 17

Which 2 methods of drug administration fluctuate the most when it comes to bioavailability?

Answer 17

inhaled and oral

Question 18

What are the 2 key factors in influencing the effective concentration and the lifetime of a drug in the body?

Answer 18

Binding to plasma proteins
* drugs will circulate in an equilibrium between “free” and bound
* usually only the free fraction is considered to be pharmacologically active

Drug accumulation in tissues
* accumulation is favored for drugs that are lipophillic (these drugs can accumulate in fat and have a long lifetime in fat)
* more highly perfused tissues can accumulate a drug more readily than tissues with poor perfusion

Question 19

What is volume of distribution?

Answer 19

• is the total amount of drug in your body divided by the concentration of the drug in your plasma.

Question 20

Does this refer to large or small distribution of volume?
* some drugs find their way to all parts of your body, so you will have a lot of the drug in your body but just a small amount in your blood

Answer 20

large volume distribution

Question 21

Des this refer to large or small volume of distribution?
* Some drugs don’t escape your bloodstream, so the amount of drug in your body is proportional to the amount of the drug that’s in your bloodstream

Answer 21

smaller volume of distribution

Question 22

How will the VOD of drugs that are restricted to the circulation/plasma compare to blood volume?

Answer 22

• drugs that are restrictred to the circulation/plasma (often because of high propensity to bind plasma proteins) will have a VOD close to the blood/plasma volume (i.e., heparin)

Question 23

How can drugs that are poorly lipid soluble be distributed?

Answer 23

they can be distributed through the extracellular fluid; high VOD

Question 24

Drugs that distribute throughout the entire body water will have a ____ VOD (i.e., ehtal and phenytoin)

Answer 24

large

Question 25

Drugs with a large VOD (ie, ____) is usually because the drug is highly ____ and accumulates in fat tissue.

Answer 25

chloroquine (common anti-malarial drug); lipophillic

Question 26

What is single compartent distribution?

Answer 26

* if an elimination pathway is present (B), the drug concentration decreases with exponential decay kinetics (the rate of elimination depends on the concentration of drug)

Question 27

What is single compartent distribution?

Answer 27

* if an elimination pathway is present (B), the drug concentration decreases with exponential decay kinetics (the rate of elimination depends on the concentration of drug)

Question 28

What is multiple compartment distribution?

Answer 28

* after adminstration, the drug distributes into multiple compartments (such as blood and tissue) * if an elimination pathway is present (D), the drug concentration in the blood determines the rate of elimination but the reservoir of drug in the tissues can prolong the lifetime of the drug in the body

Question 29

What is biotransformation?

Answer 29

mechanisms for metabolism in the liver

Question 30

How many phases does metabolism in the liver involve?

Answer 30

2

Question 31

What is phase 1 of the metabolism in the liver?

Answer 31

* mixed function oxidase system (CYP enzymes) which generates oxidative modification of drugs through hydroxylation, dehydrogenation, etc

Question 32

What is phase 2 of the metabolism in the liver?

Answer 32

conjugation of parent compound or phase 1 product with large polar adducts to make the product more prone to excretion

Question 33

What is CYP and which 2 enzymes metabolize most drugs?

Answer 33

* CYP is cytochrome P.450 oxidase enzyme * 2 most common ones are CYP3A4 and CYP2D6

Question 34

Phase 1 and phase 2 ____ need to occur in order/sequence

Answer 34

do not

Question 35

Where does phase 1 and phase 2 happen in the body?

Answer 35

liver

Question 36

Can multiple CYP enzyme metabolize a drug, often more than one pathway?

Answer 36

yes

Question 37

____ variation in CYP enzymes leads to individual differences in how we respond to drugs

Answer 37

genetic

Question 38

____ is the most widely expressed CYP in liver and metabolize ~75% of theraputic drugs

Answer 38

CYP3A4

Question 39

The formation of toxic/reactive intermediates is known as ____

Answer 39

hepatotoxicity.

Question 40

What are the 2 main routes of drug excretion?

Answer 40

* Bile/feces * urine

Question 41

How are drugs excreted through bile/feces?

Answer 41

* biotransformed drugs in the liver are incorporated into bile and secreted into the gut. * modifications which are large polar adducts,make the drugs more polar and less prone to accumulate in tissue or reabsorbed in the digestive tract.

Question 42

How are drugs excreted through urine?

Answer 42

* drug passes from the blood through glomerular filtration or is actively secreted into the renal tubule and excreted in urine

Question 43

Drug elimination is typically described by a half-life, what does this mean?

Answer 43

It means that the enzymes and systems mediating drug elimination are not saturated and an exponential decay equation can be used to describe elimination.

Question 44

What is the following description known as? * elimination is capacity limited meaning that enzymes involved in elimination are saturated and rate-limiting. This is because ethanol concentrations are much higher than the affinity of a key enzyme involved in their elimination

Answer 44

Capacity-limited elimination