test 2 Flashcards
Distribution
- After absorption, drugs must be distributed throughout the body
- Accomplished through circulation via the bloodstream
Factors That Affect Distribution Dependent on
- Blood flow (CO)
- Capillary permeability
- Protein binding
- Lipophilicity
- Tissue volume
Blood Flow affecting distribution
•Organs that receive higher flow receive higher drug concentrations
•High flow organs
-Heart, brain, kidneys, liver, skeletal muscles
•Low flow organs
- Adipose tissue
- Skin
Capillary Permeability affecting distribution
•Determined by capillary structure
-Varies in how much of the basement membrane is exposed by slit junctions between endothelial cells
Lipid solubility affecting distribution
•Move readily across most cell membranes
•Hydrophilic drugs do not penetrate the cell membrane
-Need slit junctions
Plasma Protein Binding affecting distribution
•Reversible binding of drug to plasma proteins
- Sequesters drug
- Nondiffusible form
- Slows transfer out of the vascular compartment
when does protein binding occur
•Occurs when a portion of drug is bound to protein and is therefore not able to be free to bind to active sites and produce an effect
Albumin in the plasma
- Major drug binding protein
- Acts as a drug reservoir
- Concentration of free drug decreases due to elimination, bound drug will dissociate from protein
less albumin leads to
-more free drug in the plasma that can cause an effect
Competing drug in the plasma
- the competing drug takes up binding sites on the proteins allowing more free drug to cause more of an effect
Tissue Protein Binding affecting distribution
•Higher concentration of drug in tissues than in the extracellular fluid and blood
-Due to drug binding to lipids, proteins, and nucleic acids
-Due to active transportation of drug
•Drugs sequestered in the tissues
- Prolong drug action
- Cause local toxicity
what is Volume of Distribution (Vd)
•Fluid volume required to contain the entire drug in the body at the same concentration measured in the plasma
Volume of Distribution equation
Volume of Distribution = [amount of drug in the body] / [serum concentration]
OR
volume (L) = dose (mg) / [plasma drug] (mg/L)
what makes up the extracellular fluid
- intravascular fluid
- interstitial fluid
what compartments do the drugs tend to be in
- intracellular fluid
- intravascular fluid
- interstitial fluid
Plasma Compartment
•4% of body weight •High MW drugs •Extensive protein bound drugs •Drugs with a low Vd are confined in plasma (intravascular fluid)
Extracellular Fluid Compartment
•20% of body weight
•Low MW drugs
•Hydrophilic drugs
-Confine in extracellular fluid (interstitial and plasma)
•Drugs confined to interstitial fluid have high Vd
Volume of Distribution based on compartments
- Drugs that are mostly confined to the intravascular space have a smaller volume of distribution
- Drugs that have extensive distribution outside the plasma have a larger volume of distribution
Calculating Vd:
500 mg of drug was added to a beaker with ? L of water. After mixing, measured drug concentration was 5mg/L.
What is the volume of distribution?
Vd = 500mg / 5 mg/L = 100 L
Calculating Vd:
Patient weighing 70kg is given 1000mg of Drug A. Measured plasma concentration is 2mg/L.
What is the volume of distribution?
Vd (L)= 1000 mg / 2 mg/L = 500 L
500 L / 70 kg = 7.1 L/Kg
- a high Vd = low plasma concentration which means mainly extracellular
- you would need to put in 1000 mg of drug into a container that contains 500 L of water in order to get the measured concentration of 2 mg/L
Calculating Vd:
Patient weighing 70kg is given 350mg of Drug B. Measured plasma concentration is 25mg/L.
What is the volume of distribution?
Vd = 350 mg / 25 mg/L = 14 L
14 L / 70 kg = 0.2 L/Kg OR 200 mL/Kg
- low Vd = high concentration in plasma which means mainly intravascular
Affect of Vd on Drug Half-life
•High Vd increases drug half-life
•Drug bound to tissue (low plasma concentration) so not available to excretory organs
•Factors than increase Vd
increase half-life
Half-life (t1/2)
- Time it takes for the drug concentration to decrease by ½ (once administered)
- Used to determine drug dosing frequency
- Depends on how quickly a drug is eliminated from plasma
- Determines length of drug effect
•If a drug has a plasma concentration of 1000mg/L and the drug has a half-life of one hour. How much of the drug is present after:
- One hour?
- Two hours
- Three hours
- Four hours
1 hour: 500
2 hours: 250
3 hours: 125
4 hours: 62.5
Three major routes of elimination
- Hepatic metabolism
- Biliary elimination
- Urinary elimination
Most drugs are eliminated according to
- Firstorder kinetics
- A constant fraction of drug is eliminated in a given unit of time
- Drug half-life is used to measure drug clearance
Clearance equation
CL = (0.639 x Vd) / t½
Clearance Example:
A 100kg patient is taking Lisinopril which exhibits first order elimination kinetics with a half-life of 12 hours and its distribution appears to be limited to the intravascular space. What is the clearance rate for Lisinopril in this patient?
CL = (0.639 x (4% of 100)) / 12 hr = 0.213 L/1 hr
First-order kinetics
- increase the plasma concentration of the drug = increase in rate of elimination
- rate of elimination is proportional to drug concentration
- constant proportion being eliminated
- dependent on initial drug concentration
- half life is constant
- 95% of the drug follow first order kinetics
Zero-order kinetics
- increase plasma concentration of the drug = no increase in rate of metabolism
- rate of elimination becomes independent of concentration
- a constant rate being eliminated
- 5% of the drug follow zero-order kinetics
A patient was given 100mg of Drug A orally. Assume that the drug metabolism follows first-order kinetics at a rate of 10% per minute
- dose given
- proportion being metabolized
- drug metabolized in the first min?
- 2nd
- 3rd
- 4th
- 100 mg
- 10%/min
- 10 mg
- 9 mg
- 8.1 mg
- 7.29 mg
A patient was given 100mg of Drug B orally. Assume that the drug metabolism follows zero-order kinetics at a rate of 10mg/min
- How much drug is metabolized every minute?
- drug is metabolized after 5 minutes?
- 8 minutes
- How long will it take for all of the drug to be metabolized?
- How long will it take for 200mg of drug to be metabolized?
- 10 mg
- 50 mg
- 80 mg
- 10 minutes
- 20 minutes
Drug Metabolism
- Breaks drug down into metabolites
- more water-soluble components
- Aids in excretion of drug
- Occurs by chemical reactions
- Oxidation
- Conjugation
- Acetylation
- Glucuronidation
- Liver is the major organ for drug metabolism
Liver Drug Metabolism
•Contains a microsomal drug oxidation system called the cytochrome P-450 system (CYP-450)
- enzyme system
•Induced
•Increased activity
•Inhibited
•Decreased activityPhase I Biotransformations (breaks down the metabolites)
- Converts lipophilic drugs into more water soluble molecules
- Introducing or unmasking polar groups
- OH or NH2
- Chemical reactions involved:
- Reduction
- Oxidation
- Hydrolysis
- Metabolites often still too lipophilic
Phase II Biotransformations (breaks down the metabolites)
- Consists of conjugation reactions
- Linking an acid (glucuronic, acetic, amino, sulfuric) to phase I metabolite
- Resulting in a more water-soluble compound
- Often therapeutically inactive
Inducers of cytochrome P-450
- Increase activity of CYP 450 enzymes
- Increased biotransformation
- Decreases plasma drug concentration and loss of therapeutic effect
Inhibitors of cytochrome P-450
- Decrease CYP 450 enzymes
- Can lead to adverse side effects
- Prolongs therapeutic drug effect
- Decreases elimination
- Lead to toxicity
Drug Clearance by the Kidneys
- Most important route of drug elimination
- Renal elimination involves
- Glomerular filtration
- Tubular secretion
- Tubular reabsorption
Renal Elimination
Urine excretion = filtration + secretion - reabsorption
