Pharmacokinetics II Flashcards
What terminates drug action?
Drug redistribution
Drug redistribution is usually a factor for:
- highly lipid soluble drugs
- site of action in brain or cardiovascular system
- administered by IV injection or inhalation
What is thiopental used for?
anesthesia
Describe how and why drug redistribution affects thiopental:
- Lipophilic and brain blood flow is very high:
- drug reaches a high concentration in the brain shortly after administration
- After the administration:
- blood concentration of thiopental falls
- drug comes out of the brain back into the blood
- Redistribution to other tissues
- Results in a fast onset and fast offset of action
- leads to hangover because of slow loss from the fat
What kind of transport do CNS drugs depend on?
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
What type of drugs usually enter the brain?
- Lipophilic
- Unionized
- Not bound to plasma proteins
What limits drug entry?
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
What can increase local permeability of the BBB?
Meningeal and encephalic inflammation:
- Intentional disruption of the BBB has emerged as a way to enhance delivery of chemotherapy to brain tumors
Briefly describe the transfer of drugs to the placenta:
- Lipid solubility, amount of unionized drug and protein binding are important determinants
- Fetal plasma is slightly more acidic (pH 7-7.2) than maternal plasma
- ion trapping of basic drugs can occur
- Influx and efflux carriers are expressed
-
Safest course:
- assume that the fetus is exposed to some extent to all of the drugs taken by the mother
How are drugs excreted?
- Renal excretion
- Biliary and fecal excretion
- Other routes of excretion:
- Sweat, saliva, tears, hair, skin
- mostly used for drug detection
- Breast milk
- Sweat, saliva, tears, hair, skin
Renal excretion: Glomerular filtration
- Determines the amount of drug that enters the tubular lumen
- Only unbound drug is filtered
Renal Excretion: Active tubular secretion
-
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
Renal Excretion: Passive tubular reabsorption
- 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
How is the amount of reabsorption determined for weak acids and weak bases?
pH of the urine
When tubular urine is more ________ , weak acids will be ionized (in the ____ form), will ________ and be
________.
alkaline; A-; remain in the urine; excreted
When tubular urine is more _______, weak bases will be ionized (in the ____ form) will ____________ and be _________.
acid; BH+; remain in the urine; excreted
What can be done to treat poisoning or drug overdose?
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
Biliary and fecal excretion:
-
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
- Drugs and metabolites present in the bile are released into the GI tract during the digestive process
- Protein carriers are also present on the apical membrane of enterocytes:
- transport drugs from the blood ⇒ intestinal lumen
- 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
Describe how drugs are excreted in breast milk:
- 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
Goal is drug therapy:
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
Volume of distribution (Vd):
- 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
Equation: Amount of drug in the body
Amount of drug in the body = Vd * C
A drug that does not leave the plasma compartment will have a _______________.
small volume of distribution
A drug that moves out of the circulation into tissues and achieves an equal distribution among the blood and tissues will have _______________________.
a volume of distribution equal to the volume of the body
A drug that is sequestered in tissues (that is, has a higher concentration in one or another tissue than in the plasma) will have __________________________.
a volume of distribution even larger than the volume of the body
_______________ can alter the volume of distribution
Disease states
Bioavailability (F):
fraction of an oral dose that reaches the systemic circulation
Equation: Dose
Dose = Vd x C0/F
Clearance (CL) of the drug from the body:
Clearance (CL) = rate of elimination/concentration (L/min)
CLrenal = rate of elimination by the kidney/concentration
CLliver = rate of elimination (metabolism) by the
liver/concentration
CLtotal = CLrenal + CLliver
Renal clearance occurs by:
removal from the unchanged drug from the blood into the urine
Liver clearance occurs:
- biotransformation of the drug into one or more metabolites
&/or
- excretion of the unchanged drug into the bile
Most drugs are elimated via _________ kinetics
1st order
Elimination via 1st-order kinetics:
- Clearance is a constant
- kel
-
rate of elimination:
- directly proportional to the drug concentration
-
change in drug concentration over time:
- log:linear plot
- slope of the line = –kel/2.3
Equation: Volume of Distribution
**Vd = Dose x F/C0 **
Half-life (T1/2):
-
Time required to decrease the concentration of the drug by one half
- More useful to think of the half-life (T1/2) of the drug in the body rather than its elimination rate constant
-
T1/2 = 0.69/kel .
- constant for drugs that are eliminated by first order kinetics
Distribution phases:
- alpha (α) phase:
- distribution of the drug out of the circulation into the tissues
- beta (β) phase:
- elimination
- sum of two lines
Zero-order: Michaelis-Menton Elimination
- Drugs saturate their elimination pathways at clinically useful doses
-
Rate of elimination = Vmax x C/(Km + C)
- maximum elimination capacity corresponds to Vmax
When concentrations of drug (C) >> Km:
Elimination rate becomes independent of drug concentration
If the dosing rate exceeds elimination capacity:
Then the concentration of drug will increase as long as the dosing continues
Equation: CL & Half-life (T1/2)
CL = Vd∗ K<strong>el</strong> & T1/2 = 0.69/Kel
Thus,
CL = (0.69 x Vd)/ T1/2 ⇒ T1/2 = (0.69 x Vd)/CL
Drug accumulation with repeated dosing:
- When drug doses are repeated, the drug will accumulate in the body
- Drugs that are eliminated by first order kinetics:
- amount of drug in the body will reach a steady state concentration
Steady-state:
- 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 Css, Css = concentration at steady state
- Used to calculate the dose and dose interval needed to achieve a therapeutic steady state concentration
- Dose/Interval = (Css x CL)/ F
Therapeutic window
- Concentrations above the therapeutic window can be toxic
- Concentrations below are ineffective
Multiple Dosing:
-
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
Multiple Dosing (Graph):
Saw-toothed pattern at steady state
How to reach steady state faster:
- Use a loading dose:
- Larger dose ⇒ therapeutic levels to be achieved immediately
- The loading dose can be calculated from this equation:
- Loading Dose = Vd x C0/F, where C0 is the desired therapeutic concentration.
- 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
- Loading doses are useful for:
- very long half-life drugs
- therapeutic goals that must be reached quickly
- antibiotic therapy
