Elementary Pharmacokinetics

Question 1

What do the terms Minimum Effective Concentration and Maximum Tolerated Concentration mean?

Answer 1

Minimum Effective Concentration (MEC) - to achieve an effect, a drug must reach a critical conc. in the plasma

Maximum Tolerated Concentration (MTC) - ideally, drug conc. should be well below that causing significant unwanted effects

Question 2

What is the therapeutic window and ratio?

Answer 2

Between MEC and MTC

Therapeutic ratio (index): TR = MTC / MEC

Question 3

Difference between safe and unsafe drugs?

Answer 3

Safe drugs have a wide therapeutic window (high ratio), e.g: penicillins, benzodiazepines

Unsafe drugs have a narrow therapeutic window (low ratio), e.g: cardiac glycosides, barbiturates

Question 4

Considering the human body in pharmacokinetics?

Answer 4

As a single, well-stirred, compartment of volume (V_d)

Drug is added to compartment by absorption at rate K_abs.

Removed by elimination at rate K_el

Question 5

Considerations to make with absorption in iv injection?

Answer 5

Absorption is by-passed and the:

Initial conc. (C_o) = D / V_d (conc. = mass / volume)

Conc. at a later time (C_t) depends upon K_el

Question 6

Type of kinetics most drugs exhibit?

Answer 6

First order kinetics - rate of elimination is DIRECTLY PROPORTIONAL to drug conc.

Question 7

Changes in drug conc. in first order kinetics?

Answer 7

Drug conc. falls EXPONENTIALLY according to equation

In other words, drug conc. drives rate at which drugs is eliminated,

Higher drug conc. means a greater rate of elimination (higher K_el)

Another way of explaining this is that Kel is INVERSELY related to HALF-LIFE; if Kel is large, half-life is long

Question 8

What is the half-life?

Answer 8

Time taken (t_1/2) for C_t to fall by 50%

Question 9

How does dose affect concentration, rate of elimination of half-life?

Answer 9

For drugs that exhibit first order kinetics, dose administered CHANGES Cp in direct proportion, but DOES NOT EFFECT K_el or t_1/2

If dose is doubled, plasma conc. doubles but no K_el and half-life are the same

Question 10

What is Clearance (Cl)?

Answer 10

Volume of plasma cleared of drug in unit time but only applies to drugs with first order kinetics; it is a constant relating rate of elimination to plasma conc.

Cl determines the maintenace dose rate (dose per unit time required to maintain a given plasma conc.)

Units are l/hr

In most cases, most of the drug will have left the body after 5 half-lives

Question 11

Equation relating to clearance?

Answer 11

Rate of elimination = Cl x C_p

Clearance is the sum of all clearance processes:

Cl (total) = Cl (renal) + Cl (hepatic) + Cl (other)

Question 12

What is steady state?

Answer 12

ss - rate of drug administration = rate of drug elimination

For drugs with first order kinetics, ss plama conc. (Cp_ss) is LINEARLY related to the infusion rate (as infusion rate increases, so does Cp_ss)

Rate of elimination at ss = Cl x Cp_ss

Thus, rate of administration must also = Cl x Cp_ss

Question 13

Equation for maintenane dose rate?

Answer 13

Cp_ss = maintenance dose rate / Cl

Question 14

Time to reach C_ss?

Answer 14

Time to reach Cp_ss is determines by HALF-LIFE, not by the infusion rate

C_ss is reached after APPROX 5 HALF-LIVES

Question 15

Drug dosing orally?

Answer 15

Dosing to steady state with intermittent oral administration involves same principles as continuous infusion, but Cp FLUCTUATES about an AVERAGE STEADY STATE (C_{ss (average)}), where:

Rate of drug entering plasma > rate leaving plasma

Rate of drug entering plasma = rate leaving plasma

Rate of drug entering plasma < rate leaving plasma

After 5 doses, average steady state is achieved and subsequent peaks are higher than pervious ones

Question 16

Factors affecting drug dosing?

Answer 16

Drug doses

Clearance

Dosage interval

Oral bioavailability (F) - fraction of drug administered that enters systemic circulation

Question 17

What is the volume of distribution?

Answer 17

V_d - volume into which a drug APPEARS to be distributed with a conc. equal to that of plasma; it is a proportionality constant relating the plasma conc. (Cp) to amount of drug in the body (Ab):

Ab = V_d x Cp (conc. = mass /volume)

Units of V_d = l or l/kg

Question 18

How to determine V_d?

Answer 18

Plot log of Cp against time; instead of being exponential, it is a LINEAR function

At time zero Ab = dose

then Cp_o = dose / V_d and V_d = dose / Cp_o

Question 19

What is a loading dose?

Answer 19

LD - initial higher dose of a drug given at the beginning of a course of treatment before stepping down to a lower maintenance dose; can be given when therapeutic window must be reached quickly

Employed to decrease time to steady state FOR DRUGS WITH LONG HALF-LIVES, e.g: digoxin, phenytoin

Question 20

Determination of loading dose?

Answer 20

Can be estimated from V_d of drug

For iv administration: LD = V_d x Target Cp

For oral administration: LD = (V_d x Target Cp) / F

Question 21

Changes in V_d in disease?

Answer 21

Vd can change in disease, e.g: heart failure, liver disease, and so adjustment of dosage may be necessary, particularly for drugs with a low therapeutic ratio

Question 22

What does half-life give an index of?

Answer 22

Time course of drug accumulation (5 half-lives to ss)

Time course of drug elimination (often 5 half-lives)

Choice of dose interval

Question 23

What is half-life depend on?

Answer 23

Upon Vd and Cl (these are INDEPENDENT variables

If Vd is large for any Cl, the half-life is long

Question 24

What is zero order kinetics?

Answer 24

Some drugs of clinical significance, e.g: ethanol, phenytoin, are initially eliminated at a CONSTANT RATE, rather than at a rate that is proportional to their conc. ; this can happen when, for example, plasma conc. of a drug is greater than Km of an enzyme than metabolises it

Initally, at high/moderate concentration, elimination constant and is zero order but it converts to first order at low concentration, and Cp drives rate of elimination

Question 25

Cp_ss and dose rate in zero order kinetics?

Answer 25

Cp_ss is not simply linearly related to dose rate, continues to rise as it is zero order