Pharmacokinetics 5: Time Course of Drug Responses

You have just started an IV infusion of drug X at 8 mL/min. The concentration of the drug is 1 mg/mL. The T1/2 of the drug is 2 hours. How long will it take your patient to reach the Css?

10 hours Steady-state blood drug concentration levels are reached in approximately five half-lives for both oral and IV administration.

The order for the infusion rate of drug X above has been doubled to 16 mL/min. Now how long will it take your patient to reach the Css?

10 hours The Css level will be higher when the rate is doubled, but it will still take 10 hours to reach this steady-state level.

Baby Sally was given a sulfa drug for an ear infection. She broke out in hives, and her mother stopped giving her the drug. The half-life of the drug is 12 hours. How long might Sally be expected to experience hives?

4.5 more days It takes approximately nine half-lives for the body to rid itself of every molecule of a given drug. In this case, the sulfa drug may elicit an allergic response for another 4.5 days (9 x 12 = 108 hr = 4.5 days).

What is the half-life of Digoxin?

50 Hours

Which is true of drugs with a narrow therapeutic range?

All of these statements are true Drugs with a narrow therapeutic range are more likely to cause adverse effects when free levels rise in the blood. Bioavailability is more likely to vary with formulation and between patients. Differences in patient responses are also more likely with drugs that have a narrow therapeutic range.

Which of the following formulations provide a zero-order delivery without peak and trough concentrations?

An extended-release capsule given twice daily Extended-release capsules contain drug particles with different rates of absorption and are intended to produce constant plasma drug concentrations without peaks and troughs.

What can be used to stop the action of Digoxin?

Digoxin levels can be rapidly lowered by administering IV Fab antibody fragments (Digibind) to bind digoxin and prevent it from acting

Ashley G has taken oral phenytoin for 4 years to control her seizure disorder. She has just been hospitalized for anorexia nervosa. Her total phenytoin level is subtherapeutic at 4 mcg/mL. She continues to be free of seizures. What should be done?

Her free phenytoin level should be checked; it is probably in the therapeutic range. It is likely that Ashley has reduced plasma albumin synthesis as a result of anorexia nervosa. With less plasma albumin available for binding, extra free phenytoin will be cleared and a lower total steady-state phenytoin level will result. The amount of bound phenytoin will be less but the amount of free drug in the blood will be relatively unchanged. The free phenytoin levels will remain in the therapeutic range.

How many half-lives does it take for the body to eliminate the last dose of a drug after the Css has been reached?

It takes five half-lives for the body to eliminate the last dose of a drug after the steady-state level has been reached.

How many half-lives does it take to reach 97% of the Css?

It takes five half-lives to reach 97% [chart] of the steady state level.

How many half-lives does it take to rid the body of every drug molecule?

It takes nine half-lives to rid the body of every drug molecule.

How many half-lives does it take for the plasma drug concentration to be reduced by 50% after a drug is discontinued?

It takes one half-life for the plasma drug concentration to be reduced by 50% after a drug is discontinued

What is zero order delivery?

Nearly constant plasma drug concentration.

Two 60-year-old sisters are planning to have plastic surgery. Sue weighs 150 lb, and Sara weighs 270 lb. Which sister will take longer to rid her body of diazepam before surgery? Both report taking diazepam (Valium) for many years for anxiety. (Hint: Diazepam is distributed into adipose tissue.)

Sara, because she has a higher volume of distribution Drugs such as diazepam (Valium) that are distributed into fat have a relatively large volume of distribution. The more body fat a person has, the larger the volume of distribution and the longer the drug half-life. Sara may have significant postsurgical sedation if she undergoes surgery before the diazepam has been cleared from her body.

Css stands for

Steady state concentration

Why is T1/2 not a good indicator of rate of clearance of an oral drug?

T1/2 is a poor indicator of the rate of clearance of an oral drug. An older person could have a decreased renal clearance of digoxin and a decreased digoxin Vd (because of loss of muscle mass), and the T1/2 might not change.

What can T1/2 help predict?

T1/2 is important for predicting how long it will take for a drug level to reach a plateau and how long it will take for drug levels to go below the MEC after the drug is stopped.

How is T1/2 related to total body clearance (Cl)?

T1/2 is inversely proportional to the total body clearance (Cl) of the drug by the liver, kidney, or other route. A person with renal or hepatic impairment will have a slower drug clearance and a longer T1/2.

How is T1/2 (half-life) related to Vd (Volume of Distribution)

T1/2 is proportional to the volume of distribution (Vd). A person with more body fat will have a large Vd for drugs that are distributed into fat (e.g., diazepam [Valium]) and a longer T1/2.

Drug 1/2 Life (T1/2)

The time it takes for the plasma drug concentration to decrease by 50%

Why are loading doses used for some reason?

To help drugs with long half-lives reach Css quickly Because it takes approximately five half-lives for a drug to reach steady-state concentrations in the blood, one might need to wait days for the Css to be reached. Administration of a loading dose (equal to the total amount of drug in the body at steady state) shortens the time to the onset of therapeutic action.

The duration of pharmacologic effect is:

how long the plasma drug concentration is above the MEC The plasma drug concentration must be above the minimal effective concentration for the drug to exert a therapeutic effect. Just how long the plasma drug level exceeds the MEC is known as the duration of pharmacologic effect.

Half-life is likely to be shortest for a drug with a:

large clearance and a small volume of distribution Half-life is related to the ratio of the volume of distribution to the total body clearance (liver + renal + other) (T1/2 ~ Vd/Cl). A large volume of distribution and/or a small clearance will cause the half-life to be large relative to drugs with a small volume of distribution, a large clearance, or both.

A formulation of a PO drug that has a slow rate of absorption:

may not reach the MEC and therefore may not be clinically effective. When drug absorption is slowed, the liver is able to more efficiently biotransform the drug on the first pass through the liver. As a result, bioavailability is reduced and plasma drug levels may not reach the minimal effective concentration.

George G, age 78, has been told that he has a 40% reduction in kidney function. He has lost a significant amount of lean body mass (muscle) over the past 5 years. Compared with the reported T1/2 in your drug handbook, you expect his T1/2 for digoxin to perhaps be:

unchanges because of both decreased volume of distribution and renal clearance. Lean body (muscle) mass and renal function typically decrease with the aging process. A reduced lean body mass results in a reduced volume of distribution for digoxin. Reduced renal clearance will reduce the total body clearance of digoxin. Simultaneously, these changes may not alter digoxin T1/2. However, digoxin levels will accumulate, and "dig toxicity" is a likely result.

Signs of Digoxin toxicity include ... ?

• GI: Nausea/vomiting, anorexia, abdominal pain • Cardiac: Ectopic (ventricular) beats, AV block, A. Fib *MS: muscle cramps • CNS: Visual disturbances (halos), disorientation, weakness, confusion, fatigue --- Note: Amiodarone, Verapamil and Quinidine: -Increase Digoxin (so need to decrease Digoxin by 25-50% when taking these other drugs simultaneously).