Drug Clearance and Elimination Half Life

Question 1

What is the definition of drug absorption?

Answer 1

Drug is absorbed from the site of administration - entry into the plasma.

Question 2

What is the definition of drug distribution?

Answer 2

Drug reversibly leaves the bloodstream and is distributed into interstitial and intracellular fluids.

Question 3

What is the definition of drug metabolism?

Answer 3

Drug transformation by metabolism by the liver and other tissues.

Question 4

What is the definition of excretion (elimination) of drugs?

Answer 4

Drug and/or drug metabolites excreted in urine, faeces or bile.

Question 5

What is the principle organs for drug elimination?

Answer 5

The kidneys

Question 6

What process eliminates most drugs. What is reabsorbed and what is excreted I the urine?

Answer 6

Drug elimination is mostly accomplished by renal filtration of blood plasma.
Water and most electrolytes are reabsorbed into blood circulation in the renal tubules.
Drug metabolites rendered polar (and water soluble) by phase II metabolism are not reabsorbed, thus excreted in the urine.

Question 7

What form of administration occurs during 1st class metabolism?

Answer 7

1st class metabolism normally involves administration of drugs orally but can be through other methods.

Question 8

What does understanding how the drug concentration will change over time help clinicians to do?

Answer 8

Understanding how the drug concentration will change over time helps clinicians maintain drug concentrations at therapeutic levels and avoid the patient experiencing toxic side effects.

Question 9

What is the spectrum of effects from increasing plasma concentration of drug?

Answer 9

From very low drug plasma concentration (probably below the EC50 of the drug) you get sub-therapeutic effects.
Therapeutic effects are normally present around the drug’s EC50.
If you keep increasing the dose this will increase the drug plasma concentration and will result in toxic effects.

Question 10

What happens if you keep increasing the concentration of drugs that are selective?

Answer 10

Drugs are selective. If you keep increasing the concentration of a drug you increase the likelihood that it will bind to an off target, where you get many of the side effects from.

Question 11

Can you describe the plasma concentration-time profile after oral administration of a single dose?

Answer 11

The components relevant to the pharmacokinetics of a drug’s concentration-time profile are the peak or maximum plasma concentration (Cmax) and the time when it occurs (Tmax), the area under the concentration-time curve (represented as shaded area), and the elimination t1/2 (1/2 is subscript) (determined using the blue lines).
If the drug is administered through an IV, it would spike at the Y-axis as it has access much quicker than through oral administration.
As soon as the drug goes into the body, the body works to reduce the concentration o the drug in the body.
The drug is slowly decreased or excreted.
Both absorption and elimination are occurring simultaneously.

Question 12

What is the definition of clearance (CL)?

Answer 12

Broadly, clearance (CL) is an expression of the elimination of a drug from the body.
Specifically, CL is the volume of blood removed (or cleared) of drug per unit of time (e.g. L/hour or mL/minute).

Question 13

Does CL tell you how much drug is removed?

Answer 13

CL is a flow parameter, it does NOT tell you how much drug is removed.

Question 14

What is the CL of a drug broken down into?

Answer 14

CL of a drug can be broken down into renal (CLR (R is subscript)), hepatic (CLH (H is subscript)) or other elimination routes (CLO (O is subscript)) or described as total clearance (CLT (T is subscrip)).

Question 15

Why is CL important?

Answer 15

CL is important as it helps determine the dosage rate needed to maintain a desired (D)plasma (plasma is subscript).
CL is independent of Vd (d is subscript) but both determine the elimination half life of a drug (important pharmacokinetics concept #3).

Question 16

What is the method by which you estimate clearance?

Answer 16

CL = (Rate of Drug Elimination)/(Drug)plasma (plasma is subscript).

Question 17

If the rate of drug elimination = 20mg/hour
(D)Plasma = 2mg/L
How do you estimate clearance (CL)?

Answer 17

CL = (20 mg/hour)/(2mg/L) = 10 L/hour

Question 18

What is first order kinetics?

Answer 18

Rate of drug elimination increases as plasma drug concentration increases.

Question 19

What is zero order kinetics?

Answer 19

Elimination mechanisms become saturated and reach Vmax (max is subscript), the maximal elimination rate. This then becomes zero order kinetics.

Question 20

How does the first order elimination rate follow Michaelis-Menten kinetics. What is the equation and description?

Answer 20

RE (E is subscript) = (Vmax X (Drug)plasma)/(Km + (Drug)plasma)
Where Vmax is the maximum rate of drug elimination, Km is the drug concentration at which the rate of elimination is 1/2 Vmax (Drug)plasma is the drug concentration in plasma.

Question 21

What is the steady state?

Answer 21

The steady state exists when the rate of drug administration (R0 (0 is subscript)) = Rate of Drug Elimination (RE (E is subscript)).
At steady state what goes in is what goes out.

Question 22

What is CL used to calculate and what is the equation?

Answer 22

CL is used to calculate the dosage required to maintain (Drug)plasma at steady state ((Drug)plasmas): Dosage rate = (Drug)plasma X CL

Question 23

If a drug follows the first order kinetics, will it reach the steady state.

Answer 23

If a drug follows the first order kinetics, (most therapeutic drugs do this), it will eventually reach the steady state, where the rate of drug administration = the rate of drug elimination.

Question 24

How does the steady state factor into how we can use clearance to come up with a dose?

Answer 24

This factors into how we can use clearance to come up with a dose.
The clearance is used to calculate the dosage to maintain the blood plasma concentration. Particularly important when administering a drug to a patient through an IV.

Question 25

Clearance and Steady State - clinical example: IV infusion of theophylline.
Patient has COPD and is to be administered IV theophylline.
Recommended (Drug)plasma is 10-20 mg/L.
CL for theophylline is 3L/hour.
Upper plasma limit is recommended for this patient.
What is the dosage rate?
And what would happen if the dosage rate is doubled?

Answer 25

Dosage Rate = (Drug)plasmas X CL
60mg/hour would need to administered (20mg/L X 3L/hour).

(Drug)plasmas = dosage rate/CL
(Drug)plasmas = 120 mg/hour/3L/Hour
(Drug)plasmas = 40mg/L - toxic levels

Question 26

What does the elimination half-life (t1/2 (1/2 is subscript)) depend on?

Answer 26

The elimination half-life (t1/2) depends only on the volume of distribution and clearance
t1/2 = (0.693 X VD (D is subscript))/CL

Question 27

What is the role of elimination half-life (t1/2)?

Answer 27

Elimination t1/2 may place major constraints on the dosage regimen.
Elimination t1/2 determines the time required for (Drug)plasma to achieve (Drug)plasmas.
Elimination t1/2 determines how much time is required for drug to be eliminated from body. This is extremely useful when designing a therapeutic dosing regimen.
Clearance particularly for IV drugs gives us a dosage rate.

Question 28

What happens when the infusion stops?

Answer 28

When the infusion stops the plasma concentration washes out to zero with the same time course observed in approaching steady state.

Question 29

How many half lives are normally required to reach steady state?

Answer 29

5

Question 30

Can you describe the plasma concentration-time profile after oral administration of a single dose?

Answer 30

The components relevant to the pharmacokinetics of a drug’s concentration-time profile are the peak or maximum plasma concentration (Cmax) and the time when it occurs (Tmax), the area under the concentration-time curve (represented as shaded area), and the elimination t1/2(determined using the blue lines).

Question 31

What is the equation to calculate (t1/2 (1/2 is subscript))?

Answer 31

t1/2 = (0.693 X VD (D is subscript))/CL
Therefore is CL increases, t1/2 decreases
CL decreases, t1/2 increases
VD increases, t1/2 increases
VD decreases, t1/2 decreases

Question 32

When determining the elimination of Half-Life what is the relationship between the components?

Answer 32

t1/2 = (0.693 X VD)/CL
CL increases, t1/2 decreases
CL decreases, t1/2 increases
VD increases, t1/2 increases
VD decreases, t1/2 decreases

Question 33

What are the factors affecting Elimination Half-Life (t1/2)?

Answer 33

Effects of Volume of Distribution
- Aging (decrease in muscle mass), decreases t1/2
- Obesity (increase in adipose tissue), increase t1/2
- Pathologic fluid, increase t1/2
Effects on Clearance
- Cytochrome P450 induction, decrease t1/2
- Cytochrome P450 inhibition, increase t1/2
- Cardiac failure, increase t1/2
- Hepatic failure, increase t1/2
- Renal failure, increase t1/2.
If someone is a chronic drinker it will reduce their elimination half-life for many drugs.