Pharmacokinetics II

Question 1

What terminates drug action?

Answer 1

Drug redistribution

Question 2

Drug redistribution is usually a factor for:

Answer 2

1. highly lipid soluble drugs
2. site of action in brain or cardiovascular system
3. administered by IV injection or inhalation

Question 3

What is thiopental used for?

Answer 3

anesthesia

Question 4

Describe how and why drug redistribution affects thiopental:

Answer 4

1. Lipophilic and brain blood flow is very high:
   
   • drug reaches a high concentration in the brain shortly after administration
2. After the administration:
   
   • blood concentration of thiopental falls
   • drug comes out of the brain back into the blood
3. Redistribution to other tissues
4. Results in a fast onset and fast offset of action
   
   • leads to hangover because of slow loss from the fat

Question 5

What kind of transport do CNS drugs depend on?

Answer 5

Transcellular transport:

• Brain capillary endothelial cells have continuous, tight junctions
  
  • BBB
• Same is true at the choroid plexus
  
  • Blood-CSF barrier
• Can also enter via specific uptake transport

Question 6

What type of drugs usually enter the brain?

Answer 6

• Lipophilic
• Unionized
• Not bound to plasma proteins

Question 7

What limits drug entry?

Answer 7

Expression by the capillary endothelial cells of efflux transporters that remove the drug from the endothelial cell back into the blood:

• P-glycoprotein
• organic-anion transporting polypeptide (OATP)
  
  • Example: Act to reduce the brain distribution of the HIV protease inhibitors

Question 8

What can increase local permeability of the BBB?

Answer 8

Meningeal and encephalic inflammation:

• Intentional disruption of the BBB has emerged as a way to enhance delivery of chemotherapy to brain tumors

Question 9

Briefly describe the transfer of drugs to the placenta:

Answer 9

1. Lipid solubility, amount of unionized drug and protein binding are important determinants
2. Fetal plasma is slightly more acidic (pH 7-7.2) than maternal plasma
   
   • ion trapping of basic drugs can occur
3. Influx and efflux carriers are expressed
4. Safest course:
   
   • assume that the fetus is exposed to some extent to all of the drugs taken by the mother

Question 10

How are drugs excreted?

Answer 10

1. Renal excretion
2. Biliary and fecal excretion
3. Other routes of excretion:
   
   • Sweat, saliva, tears, hair, skin
     
     • mostly used for drug detection
   • Breast milk

Question 11

Renal excretion: Glomerular filtration

Answer 11

• Determines the amount of drug that enters the tubular lumen
• Only unbound drug is filtered

Question 12

Renal Excretion: Active tubular secretion

Answer 12

• Carrier mediated and energy requiring:
  
  • moves drug from blood ⇒ lumen in the proximal tubule
• Can move drug against its concentration gradient
• Various types of transport proteins:
  
  • P-glycoprotein
  • multidrug-resistance-associated protein type 2 (MRP2)
• There is a small amount of active reabsorption of drug:
  
  • lumen ⇒ blood
  • mediated by carriers in the distal renal tubule

Question 13

Renal Excretion: Passive tubular reabsorption

Answer 13

• Occurs in the proximal and distal tubules
• Unionized forms of the drug can be reabsorbed from the lumen ⇒ blood:
  
  • must follow the drug concentration gradient
  • concentration in the lumen > concentration in the blood
• Concentration gradient is created because of the reabsorption of water
  
  • Leaves drug at a higher concentration in the lumen than in the blood

Question 14

How is the amount of reabsorption determined for weak acids and weak bases?

Answer 14

pH of the urine

Question 15

When tubular urine is more ________ , weak acids will be ionized (in the ____ form), will ________ and be
________.

Answer 15

alkaline; A^-; remain in the urine; excreted

Question 16

When tubular urine is more _______, weak bases will be ionized (in the ____ form) will ____________ and be _________.

Answer 16

acid; BH⁺; remain in the urine; excreted

Question 17

What can be done to treat poisoning or drug overdose?

Answer 17

Intentionally changing urine pH:

• depends upon:
  
  • extent and persistence of the pH change
  • contribution of passive reabsorption to the elimination of the particular drug
• effect is greatest when the pKa of the drug is in the range of urinary pH
  
  • 5 to 8

Question 18

Biliary and fecal excretion:

Answer 18

1. Protein carriers are present in the canalicular membrane of the hepatocyte:
   
   • actively transport drugs into the bile
   • P-glycoprotein transports amphipathic lipid-soluble drugs
   • MRP2 transports conjugated metabolites of drugs
2. Drugs and metabolites present in the bile are released into the GI tract during the digestive process
3. Protein carriers are also present on the apical membrane of enterocytes:
   
   • transport drugs from the blood ⇒ intestinal lumen
4. In addition, drugs and metabolites can be reabsorbed back out of the lumen of the GI tract into the blood
   
   • This is called “enterohepatic recycling”: prolong the presence of the drug in the body
   • Can counteract by administering a resin or other substance that will bind to the drug in the intestine and prevent reabsorption

Question 19

Describe how drugs are excreted in breast milk:

Answer 19

• Lipophilic drugs such as ethanol, will readily enter milk
• milk is slightly acidic compared to plasma, so the concentration of weak bases
  can be higher in breast milk than plasma

Question 20

Goal is drug therapy:

Answer 20

To maintain a concentration of a drug in the body that is high enough to produce the desired effect with a minimum of toxicity: therapeutic window

Question 21

Volume of distribution (V_d):

Answer 21

• Measure of the apparent space in the body available to contain the drug
• Assumption that the concentration of drug throughout the body is the same as its concentration in the plasma or serum

Question 22

Equation: Amount of drug in the body

Answer 22

Amount of drug in the body = V_d * C

Question 23

A drug that does not leave the plasma compartment will have a _______________.

Answer 23

small volume of distribution

Question 24

A drug that moves out of the circulation into tissues and achieves an equal distribution among the blood and tissues will have _______________________.

Answer 24

a volume of distribution equal to the volume of the body

Question 25

A drug that is sequestered in tissues (that is, has a higher concentration in one or another tissue than in the plasma) will have __________________________.

Answer 25

a volume of distribution even larger than the volume of the body

Question 26

_______________ can alter the volume of distribution

Answer 26

Disease states

Question 27

Bioavailability (F):

Answer 27

fraction of an oral dose that reaches the systemic circulation

Question 28

Equation: Dose

Answer 28

Dose = V_d x C₀/F

Question 29

Clearance (CL) of the drug from the body:

Answer 29

Clearance (CL) = rate of elimination/concentration (L/min)

CL_renal = rate of elimination by the kidney/concentration
CL_liver = rate of elimination (metabolism) by the
liver/concentration

CL_total = CL_renal + CL_liver

Question 30

Renal clearance occurs by:

Answer 30

removal from the unchanged drug from the blood into the urine

Question 31

Liver clearance occurs:

Answer 31

• biotransformation of the drug into one or more metabolites

&/or

• excretion of the unchanged drug into the bile

Question 32

Most drugs are elimated via _________ kinetics

Answer 32

1st order

Question 33

Elimination via 1st-order kinetics:

Answer 33

• Clearance is a constant
  
  • k_el
• rate of elimination:
  
  • directly proportional to the drug concentration
• change in drug concentration over time:
  
  • log:linear plot
  • slope of the line = –k_el/2.3

Question 34

Equation: Volume of Distribution

Answer 34

**V_d = Dose x F/C₀ **

Question 35

Half-life (T_1/2):

Answer 35

• Time required to decrease the concentration of the drug by one half
  
  • More useful to think of the half-life (T_1/2) of the drug in the body rather than its elimination rate constant
• T_1/2 = 0.69/k_el .
  
  • constant for drugs that are eliminated by first order kinetics

Question 36

Distribution phases:

Answer 36

• alpha (α) phase:
  
  • distribution of the drug out of the circulation into the tissues
• beta (β) phase:
  
  • elimination
• sum of two lines

Question 37

Zero-order: Michaelis-Menton Elimination

Answer 37

• Drugs saturate their elimination pathways at clinically useful doses
• Rate of elimination = V_max x C/(K_m + C)
  
  • maximum elimination capacity corresponds to Vmax

Question 38

When concentrations of drug (C) >> Km:

Answer 38

Elimination rate becomes independent of drug concentration

Question 39

If the dosing rate exceeds elimination capacity:

Answer 39

Then the concentration of drug will increase as long as the dosing continues

Question 40

Equation: CL & Half-life (T_1/2)

Answer 40

CL = V_d∗ K_{<strong>el</strong>} & T_1/2 = 0.69/K_el

Thus,

CL = (0.69 x V_d)/ T_1/2 ⇒ T_1/2 = (0.69 x V_d)/CL

Question 41

Drug accumulation with repeated dosing:

Answer 41

1. When drug doses are repeated, the drug will accumulate in the body
2. Drugs that are eliminated by first order kinetics:
   
   • amount of drug in the body will reach a steady state concentration

Question 42

Steady-state:

Answer 42

• dosing rate (“rate in”) = rate of elimination (“rate out”)
• F x Dose/Interval = rate of elimination
  
  • rate of elimination = CL x Concentration
• Thus,
  
  • F x Dose/Interval = CL x C_ss, C_ss = concentration at steady state
• Used to calculate the dose and dose interval needed to achieve a therapeutic steady state concentration
  
  • Dose/Interval = (C_ss x CL)/ F

Question 43

Therapeutic window

Answer 43

• Concentrations above the therapeutic window can be toxic
• Concentrations below are ineffective

Question 44

Multiple Dosing:

Answer 44

• Saw-toothed pattern at steady state:
  
  • Ideally, the maximum and minimum concentrations are within the therapeutic window
• Steady state reached after 4-5 half-lives of the drug have passed
  
  • 1 half-life, 50%
  • after 2, 75%
  • after 3, 87.5%
  • after 4, 93.75
  • after 5, 97%
• Any change in dosing or clearance will alter steady state concentrations of the drug
  
  • Will take another 4-5 half-lives until the new steady state is reached
• iii. When the drug is discontinued:
  
  • 4-5 half-lives for the drug to disappear from the body as well

Question 45

Multiple Dosing (Graph):

Answer 45

Saw-toothed pattern at steady state

Question 46

How to reach steady state faster:

Answer 46

1. Use a loading dose:
   
   • Larger dose ⇒ therapeutic levels to be achieved immediately
2. The loading dose can be calculated from this equation:
   
   • Loading Dose = Vd x C₀/F, where C₀ is the desired therapeutic concentration.
3. When a loading dose is used, it is generally given once:
   
   • Followed by maintenance dosing to keep the steady state concentration in the therapeutic window
4. Loading doses are useful for:
   
   • very long half-life drugs
   • therapeutic goals that must be reached quickly
   • antibiotic therapy