Lecture slides week 2 Flashcards
What is pharmacotherapeutics?
The study of the therapeutic uses and effects of drugs
Which two concepts are important for clinicians to understand to be safe and effective in their approach to therapeutics?
Kinetics and dynamics
Define absorption
the movement of a drug from its site of administration into the systemic circulation
What are factors that affect drug absorption?
rate of dissolution, surface area, blood flow, lipid solubility, pH
Define bioavailability
The amount of drug that gets to the action site unchanged
What impacts bioavailability?
route of administration, extent of absorption
Define distribution
the movement of drugs from the systemic circulation to the site of drug action
What impacts distribution?
manner in which the drug is introduced (intravascular vrs. extravascular)
blood flow
availability of binding molecules and other carriers or elements (ex. K+) that support distribution
What is the equilibrium constant?
- determines the amount of bound versus unbound drug in each body compartment
- drugs placed in one compartment then move to other compartments, the body creates an equal distribution of drugs in each compartment
- once a drug binds to proteins it stays in that compartment
What are some examples of body compartments?
Fat
Extracellular fluid
intracellular fluid
blood (plasma)
other
What provides the driving force for distribution of the agent to tissues?
Unbound drug
What are some possible outcomes once unbound drug leaves the blood and distributes to the tissues?
Can become tissue bound
Can remain unbound in tissue
can be rendered inactive (if the tissue has the ability to metabolize or eliminate the drug)
can bind to a receptor and cause its pharmacologic or toxic effects
can bind to a non specific binding site that causes no effect
T/F tissue binding is usually reversible
True.
Tissue binding (as well as protein binding) is usually reversible so that unbound and bound can find equilibrium
What is volume of distribution?
a proportionality constant that relates the amount of drug in the body to the plasma concentration at a given time
VD = total amount of drug in the body/conc. of drug in plasma
How can the VD be applied in practice?
The VD is determined by the physiologic volume of blood and tissues and how the drug binds in blood and tissues (typically based on a male of a certain weight)
It can then be used to calculate how much drug needs to be in the body to reach a desired plasma concentration of drug
Can be used to calculate the needed loading dose of a drug
What are some patient factors that would affect volume of distribution?
patient physiologic and disease processes like body size, maturation of organ function, etc.
What is the main factor of a drug that impacts volume of distribution?
the propensity of the drug to remain in the plasma or redistribute to other tissues
Worded another way, the space in the body that is available to contain a drug
What is clearance?
The ability of the body to eliminate the drug
T/F: volume of distribution and clearance are unrelated
False
clearance impacts the volume of distribution
What is the primary organ responsible for clearance ?
The kidneys will clear a given volume of fluid per unit of time
Some drugs will be unable to move out of the compartment they were introduced to due to their molecular composition limiting their movement, what will be the result on their volume of distribution?
These drugs will not be homogeneously distributed and therefore will have a minimal possible volume of distribution equal to the blood component in which they are distributed
Therefore extravascular equilibrium will not be achieved for some drugs and VD outside of the compartment that the drug was introduced will be minimal
What are some organs with enzymes for metabolism of drugs?
Liver, GI tract, lungs
Where Phase I and phase II reactions occur?
In the liver
Differentiate phase I and phase II reactions
Phase I: reactions that make the drug molecule more water soluble and therefore more able to be eliminated by the kidneys
Phase II: reactions that involve conjugation to form inactive metabolites so that they can be eliminated by the kidney.
T/F: the metabolites resulting from metabolism are always rendered inactive for excretion
False
Metabolites can be inactive or can have their own pharmacologic effects
Phase I involves: _______, _______, or ________.
Phase II involves: _________.
Phase I involves hydrolytic reactions, oxidation or reduction
Phase II involves conjugation
Describe first-pass metabolism and its effect on bioavailability
When a drug is given orally, it must be absorbed across the gut wall and delivered to the liver prior to entering the systemic circulation - the drug can be metabolized in the gut wall and/or liver before entering systemic circulation, decreasing bioavailability
What is the primary organ of drug elimination? Which other organs have the ability to excrete drugs or metabolites?
Kidneys
lungs, breast milk, sweat, tears, skin, hair, saliva, feces
Enterohepatic recycling occurs between which organs?
drug travels in bile from liver to intestine and back again
T/F: clearance depends on the body’s ability to eliminate
true
The body’s ability to eliminate drugs is called clearance, it is expressed mathematically as:
CL = rate of elimination/drug concentration
T/F: clearance is a function of only the kidneys
False
The two major sites of drug elimination are the kidneys and liver
Clearance of unchanged drug in the urine represents renal clearance, while clearance via the liver occurs vis biotransformation of the drug into metabolites or excretion of the unchanged drug into bile, or both.
How do you calculate total systemic clearance?
By combining the clearance of all organs involved.
ex. CL systemic = CL kidney + Cl liver + Cl other
Define first order elimination
clearance is constant over the concentration range encountered in clinical settings - elimination is not saturable and the rate of drug elimination is directly proportional to the concentration
Rate of elimination = clearance X concentration
worded another way, a constant proportion of the drug is eliminated over time
Describe capacity limited elimination
most drug elimination pathways can become saturated if the dose/concentration are high enough. Therefore elimination cannot keep up and the concentration continues rising. Clearance varies depending on concentration of drug achieved
Also termed mixed-order, zero order, dose/concentration dependent, nonlinear or Michaelis-Mentin.
So instead of the clearance being proportional to the concentration in first order elimination, the clearance maxes out and cannot keep up with doses at a certain point. Ex. alcohol
Describe flow-dependent elimination
some drugs are cleared very rapidly by the organ of elimination so that at any clinically realistic concentration, most of the drug in the blood perfusing the organ is eliminated on the first pass of the drug through it
Elimination of these drugs depends on the rate of drug delivery to the organ of elimination
These drugs are known as “high extraction” drugs, since they are almost completely extracted from the blood by the organ
What two dosing actions cause drug to accumulate in the body?
repeated drug dosing or continuous infusion
How many half-lives does it take to eliminate one dose of a drug?
4
How do you calculate accumulation ?
Accumulation is inversely proportional to the fraction of dose lost in each dosing interval
Accumulation = 1/fraction lost in one dosing interval
(fraction lost is 1-the fraction remaining just before the next dose)
What is the accumulation factor useful for understanding?
useful to understand how often doses need to be administered to maintain “close to peak” concentration
Regarding extraction ratios, what are some considerations regarding high extraction drugs?
Drugs with high extraction ratios will show marked variations in bioavailability between patients because of differences in hepatic function and blood flow
For drugs that are highly extracted by the liver, the use of routes of administration that bypass the first pass effect will substantially increase bioavailability
Drugs that are poorly extracted by the liver will not have their bioavailability affected as much by first pass.
