Drug Excretion/Elimination week 1

Question 1

What are the two types of drug elimination?

Answer 1

Drug elimination is defined as the removal of the parent drug from the body. There are two types of elimination:

a) Excretion – physical removal of a drug from the body (KIDNEY)
b) Metabolism – conversion of parent drug to metabolite (LIVER)

Termination of drug activity can also occur through redistribution away from site of action (e.g., redistribution of thiopental into fat.)

Note that once a parent drug is metabolized, the resultant metabolite(s) are excreted. Excretion is only considered a type of elimination if the parent drug is excreted unchanged.

Question 2

enterohepatic recylcing

Answer 2

Some conjugates such as glucuronides (formed by phase II Metabolism) and amino acid conjugates are principally excreted into bile. From the bile these compounds pass into the GI tract where they are exposed to bacteria. The bacteria can act on these drugs, sometimes resulting in recovery of parent drug which can be reabsorbed to again exert its effect. This is known as enterohepatic recycling and is thought to be responsible for the prolongation of action of drugs such as ethinyl estradiol and digoxin.

Question 3

How is urinary excretion calcualted?

Answer 3

Urinary excretion = filtration + active secretion – reabsorption

E= F + S -R

Question 4

Explain the effect of urine pH on urinary excretion.

Answer 4

Ionization increases renal clearance of drugs:

1. Both ionized and unionized drugs are filtered.
2. Passive reabsorption is only associated with unionized drugs.
3. Ionized portion of a drug is water soluble, can be filtered, but cannot be reabsorbed. It is, therefore, trapped in the filtrate. This trapping increases removal of drug from the body. For example, in acute toxicity from overdoses of aspirin, alkalinization of the urine will increase the ionization of salicylic acid in the filtrate and thus eliminate it faster by decreasing reabsorption.

Question 5

Calculation for extraction

Answer 5

The rate of presentation of a drug to an organ is the product of the blood flow to that organ and the concentration of the drug in the blood. The rate of the drug leaving the organ is the product of the rate of blood flow and the drug concentration in the blood exiting the organ. The difference between presentation and leaving is the rate of drug extraction.

Question 6

Calculation for clearance

Answer 6

Clearance is proportional to extraction ratio. Since clearance is the theoretical volume of drug cleared of blood per unit time, it is equal to the rate of blood flow to the organ (volumetric flow rate, Q) times the fraction of drug presented to the organ that is extracted (extraction ratio, E)

CL_organ = Q x E

Question 7

T or F: Clearances are additive.

Explain the impact of blood flow on clearance and under what circumstances blood flow to an organ can change.

Answer 7

True. Clearances are ADDITIVE. Total body clearance is the sum of all the different clearances that are present in the body. Usually for convenience, clearance is divided into renal clearance (Cl_R) and non-renal clearance (Cl_NR). The non-renal clearance is the sum of all the other clearances such as hepatic, lung, extrahepatic metabolism, etc.

Cl = Cl_R + Cl_NR

3. Impact of changes to blood flow to the kidney on renal clearance vs. total clearance. Blood flow (Q) to an organ can be reduced by disease or age.

TAKE HOME MESSAGE: the larger the extraction ratio for an organ, the more impact that changes in blood flow to that organ will have on the total clearance. This is clinically relevant since dosing is based on clearance.

Question 8

Calculation for renal clearance

Answer 8

The mechanics of the nephron applied to renal clearance

Previously we noted the following: (amount of drug excreted by the kidney) = filtration + active secretion – reabsorption.

Recasting renal elimination in terms of rates instead of amounts,

Cl_R = (GFR)α + (active secretion rate) – (reabsorption rate)

Where Cl_R = renal clearance

GFR = glomerular filtration rate

α = free fraction of drug

If there is no active secretion or reabsorption, this simplifies to

Cl_R = (GFR)α

Free fraction of drug = 1 – (fraction of drug bound to protein)

If the drug has no protein binding, then Cl_R would equal GFR.

On the other hand if the drug is 100% protein bound then Cl_R = 0.