Lecture 4: How Drugs Are Eliminated

Question 1

What are the characteristics of competitive drug?

Answer 1

site targeted: orthosteric

effect on potency: weakens potency of agonist

effect on Emax: no effect

Question 2

What are the characteristics of irreversible competitive drug?

Answer 2

site targeted: orthosteric

effect on potency: weakens potency of agonist

effect on Emax: reduces Emax

Question 3

What are the characteristics of non-competitive drugs?

Answer 3

site targeted: allosteric

effect on potency: no effect

effect on Emax: reduces Emax

Question 4

What are the characteristics of positive modulator drugs?

Answer 4

site targeted: allosteric

effect on potency: normally strengthens potency

effect on Emax: no effect, or increase

Question 5

What happens after you administer a drug?

Answer 5

the drug needs to be absorbed and travel in the body to reach its target issue

over time the effects of the drug “wear off” because the drug is eliminated from the body

Question 6

Why is pharmacokinetics important?

Answer 6

understanding what controls absorption and elimination is extremely important in order to maximize the amount of time that the drug is present in an optimal concentration

these parameters influence important questions: how much drug should be taken? how often? how long will it take for me to perceive an effect of the drug?

usually a medication is taken more than once, so these considerations are important to optimize performance of a medication

Question 7

What are factors that can affect steady state concentration and fluctuations?

Answer 7

dose, time between doses, bioavailability, clearance, half-time

Question 8

What is steady state?

Answer 8

attained after approximately four half-times

time to steady state independent of dosage

Question 9

What are steady-state concentrations?

Answer 9

proportional to dose/dosage interval

proportional to F/CL

Question 10

What are fluctuations?

Answer 10

proportional to dose interval/half-time

blunted by slow absorption

Question 11

What are important considerations about the routes of administration?

Answer 11

convenience - it is easy to take a medication orally (vs. injection/IV, other routes)

bioavailability - different drugs may be absorbed with different efficiency from the gut

processing - Hepatic portal circulation is a major consideration, drugs that are absorbed from the gut first encounter the liver BEFORE entering systemic circulation… so there can be significant processing/breakdown

Question 12

What is first pass metabolism?

Answer 12

if ingested orally, drugs absorbed in the gut then pass through the hepatic circulation before entering the systemic circulation

this is a major site of metabolism that strongly influences the bioavailability of many drugs

Question 13

What is the oral route of drug administration?

Answer 13

most common route of prescription drugs

rate of absorption is slow and affected by intake of food

exposure of drug may be influenced by breakdown in the gut, processing in the liver (variable between individuals)

Question 14

What is the intravenous route of drug administration?

Answer 14

delivery directly into the systemic circulation, so very rapid onset of action

inconvenient and requires expertise

high control over circulation level by controlling the rate of infusion, or amount injected

Question 15

What is the intramuscular/subcutaneous route of drug administration?

Answer 15

injection into muscle, or just below the skin

rate of absorption depends on blood flow to site

common to use “depot” preparations (slowly dissolving) for sustained release

Question 16

What is the inhalation route of drug administration?

Answer 16

absorption is through epithelium in the lungs, and can be very rapid

Question 17

What is the sublingual route of drug administration?

Answer 17

rapid absorption route, also bypasses “first pass” effects despite taking orally, rapid delivery

Question 18

What is the transdermal (ointment or patch) route of drug administration?

Answer 18

convenient, slow absorption and sustained exposure

Question 19

What is bioavailability?

Answer 19

fraction of unprocessed/unaltered drug that reaches the systemic circulation after administration by a particular route

how much of the delivered drug reaches systemic circulation?

Question 20

What is distribution?

Answer 20

in pharmacokinetics, distribution refers to how a drug/substance is partitioned into different body “compartments” after it is absorbed

the distribution of a drug can have a big influence on the effective concentration of a drug in the body, as well as the lifetime of the drug in the body

Question 21

Why is binding to plasma proteins important to the distribution of drugs in the body?

Answer 21

drugs will circulate in an equilibrium between “free” and “bound”

usually only the “free” fraction is considered to be pharmacologically active

some drugs are highly bound (so small effect even if a lot is present in body)

Question 22

Why is drug accumulation in tissues important to the distribution of drugs in the body?

Answer 22

accumulation is favored for drugs that are lipophilic

more highly perfused tissues can accumulate a drug more readily than tissues with poor perfusion

key parameter is “volume of distribution”

Question 23

What is volume of distribution?

Answer 23

this is a “concept”, not meant to represent a real volume

this provides a relative comparison of how well different drugs are distributed into tissues

drugs with a high volume of distribution are well distributed

drugs with a low volume of distribution are poorly distributed

Question 24

What is the formula for volume of distribution?

Answer 24

volume of distribution = (total amount of drug in the body)/[drug]

Question 25

How does single compartment distribution affect elimination?

Answer 25

the drug is contained within a single compartment

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

Question 26

How does multiple compartment distribution affect elimination?

Answer 26

after administration, the drug distributes into multiple compartments (“blood”, “tissue”)

if an elimination pathway is present, 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

drugs have to reach the blood compartment in order to be eliminated by liver or kidney

Question 27

What is Phase 1 of metabolism in the liver?

Answer 27

Mixed Function Oxidase system (CYP family enzymes) generates oxidative modifications of drugs (hydroxylation, dehydrogenation, etc.)

Question 28

What is Phase 2 of metabolism in the liver?

Answer 28

conjugation of parent compound, or Phase 1 product with large polar adducts to make the product prone to excretion (sulfation, glutathionylation, methylation, glucuronidation, acetylation)

Question 29

What are the six steps in the pathway of drug elimination?

Answer 29

1. Phase 1 (pink) and Phase 2 (green) do not need to occur “in order/sequence”; also, unmodified drugs can be excreted
2. these reactions happen in liver
3. multiple CYP enzymes can metabolize a drug, often more than one pathway
4. genetic variation in CYP enzymes leads to individual difference sin how we respond to drugs
5. CYP3A4 is the most widely expressed CYP in lover and (together with glucuronosyltransferase UFT1) metabolize ~75% of therapeutic drugs
6. sometimes toxic/reactive intermediates are formed, which can lead to hepatotoxicity (in this example, toxic byproducts may develop if there is insufficient GSH (glutathione)

Question 30

What is the bile/feces route of drug excretion?

Answer 30

biotransformed drugs in the liver are incorporated into bile, and secreted into the gut

modifications (large polar adducts) make these drugs more polar and less prone to accumulate in tissue or reabsorbed in the digestive tract

Question 31

What is the urine route of drug excretion?

Answer 31

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

overall drug elimination is typically described by a half-life, meaning that the enzymes and systems mediating drug elimination are not saturated; an exponential decay equation can be used to describe elimination

in a few notable cases (especially ethanol) - elimination is capacity limited (i.e., 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; this special case is called capacity-limited elimination