elimination

Question 1

elimination definition

Answer 1

Transfer of drugs to the external environment

Question 2

main organs, and secondary, involved in elimination

Answer 2

*Kidney
*Liver
Lungs (volatile drugs)
Intestinal tract
Other (milk, sweat, tears etc.)

Question 3

why is the kidney an important organ for elimination? what are the properties that make it good at this? What drugs are most easily eliminated here and why?

Answer 3

• Kidneys receive ~20% of cardiac output
• Glomerular capillaries highly porous & permeable
  > filtration of drug molecules that are not bound to plasma proteins is a non-saturable and non-selective process
• Polar drugs & drug conjugates are most easily eliminated because they can’t diffuse back out of renal tubules

Question 4

what is renal active tubular secretion, and what is the mechanism? Is it limited?

Answer 4

Active tubular secretion also occurs
* Transporters in proximal tubules actively
pump some types of drug into urine
* Saturable

Question 5

what is renal tubular reabsorption, and how is this relevant to drug elimination? What is the mechanism?

Answer 5

Tubular reabsorption can occur
* Active transporters present in distal tubules reabsorb some filtered drugs from provisional urine
* Lipid-soluble un-ionized drugs are reabsorbed passively (diffuse out of tubule back into bloodstream)

Question 6

what sort of process is elimination? That is, how much of the drug is eliminated in a given timeframe?

Answer 6

Elimination is usually a 1-step, first-order process
> i.e., a constant fraction of the drug in the body is eliminated per unit time
* Half-life (T1/2) can be used to describe elimination Half-life = time required for serum drug concentration to decrease by 50%

Question 7

how many half lives must pass for a drug to fall below clinically relevant concentrations? How many for virtually all of the drug to be eliminated?

Answer 7

-Drug falls below clinically relevant concentrations after 4-5 half-lives
-99.9% of dose is eliminated after 10 half-lives

Question 8

The duration of drug action following a single dose is often insufficient for therapeutic purposes
To prolong the duration of effect, we could give a larger dose, but this can cause certain issues. How do we get around this?

Answer 8

-In many cases, large dose would cause drug concentration to exceed the MEC for adverse effects
-Instead, a longer duration of action is normally achieved by administering multiple small doses of drug

Question 9

what is a steady-state for drug concentration, and how do we acheive this?

Answer 9

When plasma drug concentration varies between two levels (i.e., no further accumulation is occurring), we call this ‘steady-state’
>Steady-state is achieved within ~5 half-lives for any regular dosing regimen
>ie. Peak [drug] is higher after each successive dose for the first 5 half-lives, then a plateau is reached

Question 10

Why doesn’t the concentration keep rising after successive doses of drug? ie. why is a steady state concentration possible?

Answer 10

Remember that the kidneys clear a constant fraction of drug per unit time

1. At low concentrations, that fraction is a relatively small quantity of drug, and is smaller than the dose
2. At higher concentrations, clearing the same fraction of drug means removing a larger quantity, and as plasma drug concentration rises with each dose, a situation is eventually reached (after 5 half-lives) where the amount cleared during each dosing interval is equivalent to the amount administered per dose, and levels stabilize

Question 11

what do we want our steady state concentration to be between?

Answer 11

In most cases, steady- state concentrations should remain above the MEC for the desired effect but below the MEC for any adverse effect

Question 12

how can we minimize fluctuations in drug concentration? What do we have to balance?

Answer 12

Fluctuations in drug concentration can be minimized by giving small doses frequently
Clinically, it will be a balance between convenience and safety

Question 13

what is Css? What does the time to acheive Css not depend on? What is it directly proprtional to, with chronic dosing?

Answer 13

Css = steady state conc.
-The time taken to achieve steady-state plasma drug concentration (Css) does not depend on the rate at which the drug is administered
-With chronic dosing, the steady-state drug concentration (CSS) is directly proportional to the rate of drug administration

Question 14

Css magnitude rises with what?

Answer 14

-rises with rate of admin.

Question 15

if rate of administration is doubled, how does Css change?

Answer 15

Css will also double

Question 16

what is a loading dose, and what is its use? how does it relate to Css?

Answer 16

CSS can be reached essentially instantly with a loading dose I.e., the initial dose is larger than subsequent doses
-1st dose is large enough to reach the desired peak concentration

Question 17

to achieve steady state immediately, how large should the loading dose be?

Answer 17

Calculation: Loading dose = Vd x target concentration/F

Question 18

if rate of excretion decreases, what happens to drug half life? What is a consequence of this? What must we do to compensate?

Answer 18

half life increases > increased drug accumulation
-to avoid accumulation, we must decrease dose, or increase dosing interval

Question 19

what measurement can we use to adjust the dosing regimen?

Answer 19

Can adjust dosage regimen based on serum creatinine:
e.g., adjust dosing interval:
New interval = usual interval x (patient’s creatinine)/ (normal creatinine)

Example: Renal failure
Medication usually given every 8 h Creatinine = 200 uM/L (high normal = 160)
New dosing interval: (8h)x(200)/160 =8x1.25=10h
(160)
In other words, if creatinine levels increase by 25%, one option is to increase the dosing interval by 25%

Question 20

what is the liver’s role in excretion? What is the mechanism?

Answer 20

-Drug molecules that are not bound to carrier proteins as blood passes through the liver may diffuse into hepatocytes

-A fraction of the drug entering the liver may, therefore, undergo metabolism (depends on drug)

-Metabolites may then re-enter circulation > renal excretion

-Some drugs, however, are excreted entirely or in part by undergoing Phase II metabolism (conjugation) followed by active secretion into bile > into gut
> eliminated in feces

Question 21

what is enterohepatic recycling? does it depend on route of administration?

Answer 21

1. Drug enters liver, where it becomes conjugated and is actively transported into bile
2. Bile enters intestine and some drug is excreted in feces
3. A fraction of the conjugated drug molecules may become de-conjugated in the gut (e.g., by bacteria) and reabsorbed > returned to the liver > re- enter systemic circulation
   A given drug molecule may undergo a number of cycles prior to excretion

ie. Any drug that is excreted into the bile may be reabsorbed in the small intestine > returned to liver in portal blood > returned to systemic circulation

Enterohepatic recycling does not depend on route of administration, it simply requires that drug is secreted into the bile

For example, gut microbes may de- conjugate opioids (e.g., morphine) and various other drugs such as chloramphenicol (an antibacterial)
> reabsorbed > 2nd peak of drug effect
-Can be clinically important (e.g., accumulation of digoxin)

Question 22

What is drug response proportional to? what is the therapeutic margin? what cause adverse effects?

Answer 22

-Drug response is essentially proportional to the concentration of free drug at the target organ
-All drugs have more than one effect on the body

=>Too much drug > toxicity

-Adverse effects can be due to excessive stimulation of target receptors (i.e. an overdose), or stimulation of non-target receptors

-Range that is both safe and effective is called the therapeutic margin / therapeutic window

Question 23

what is drug clearance? how do we express it and why?

Answer 23

Clearance (CL) is a term indicating the rate of elimination of a drug from the body

We can refer to the clearance associated with a specific organ (e.g., renal clearance), but most often we think in terms of elimination via all routes (total systemic clearance)

Clearance is expressed as a volume rather than a quantity of drug, because the quantity of drug eliminated per unit time varies with concentration, but the fraction of the drug that is eliminated does not change

Question 24

why do we express the amount of drug cleared per unit time as a volume instead of a quantity?

Answer 24

Because the kidneys clear a constant fraction of drug per unit time, they appear to completely clear drug from a constant volume of blood per unit time, regardless of concentration

e.g., If the plasma concentration of a drug falls by 10% per hour, that is the theoretical equivalent to the complete clearance of drug from 10% of the dog’s blood volume per hour, with no drop in drug concentration in the remaining 90% of the blood volume

Since the volume cleared is constant for a given drug, we express the amount of drug cleared per unit time as a volume instead of a quantity

Question 25

who determines a drugs clearance?

Answer 25

manufacturer

Question 26

how is the amount of drug lost per hour calculated? how does this relate to the maintenance dosing rate?

Answer 26

The amount of drug lost per hour is the volume cleared per hour multiplied by the concentration that was cleared from that volume, which is CL x TC

Let’s assume that clearance of the drug in dogs is 7
mL/h/kg BW

To calculate the dosing rate for a dog, you simply multiply CL x TC:
0.007 L/kg BW x 15 mg/L = 0.1 mg/kg BW
So the amount to give our 27 kg dog is 2.7 mg per hour