Pharmacology Pharmacokinetics Flashcards
What’s Volume of distribution?
describes the relationship between a drug plasma concentration following a specific dose. VD= Amount of drug/Desire plasma concentration VD that exceeds total body of water >0.6 L/kg or >42L =lipophilic Distribute into body of water as well as into the fat VD that’s less that total body of water <0.6L/kg or <42L =hydrophilic Distributes to some or all the body of water, but it does not distribute to fat.
Volume of distribution is inversevely related to the degree of plasma protein binding.
What is the formula for loading dose?
Loading dose = VD x Desired plasma concentration / Bio-availability For IV bio-availability =1
What is volume of distribution affected by? Drugs characteristics, Patient characteristics
Drug 1. molecular size 2.ionization 3.protein binding Patient 1. Burn 2. pregnancy
What is clearance?
Clearance is the volume of plasma that is cleared of drug per unit time
What is clearance directly proportional to?
- extraction ratio 2.Blood flow to clearance organ 3. Drug dose
What is clearance indirectly proportional to?
- half-time 2. Drug concentration in the central compartment
What is steady state? When is it achieved?
Steady state occurs when the amount of drug entering the body is equivalent to the amount of drug being eliminated by the body SS Rate of administration = Rate of Elimination Steady state is achieved after 5 half-life
Describe the Two Compartment Model with the Plasma concentration curve.
The plasma concentration curve describes the biphasic decrease of a drug plasma concentration following a rapid IV bolus.
A= Distribution- drugs are not confined in the plasma, instead they distribute into multiple theoretical compartments in the body. When we give a rapid IV bolus, the drug follows its concentration gradient from the central compartment ( the plasma) to the peripheral compartments ( the tissue).
- This quickly reduces the plasma concentration which reflects by the steep slope of line A
- The slope of line A is influenced by a drug’s colume of distribution. As a general rule, the more lipohilic the drug the larger the VD, and the steeper(epinado) the slope
Line B represents elimination
- As soon as the drug enters the plasma, parts of ot redistributes based on the concentration gradient, between the plasma and the tissues.
- At the same time, some of the drug in the plasma is already undergoing elimination.
- As plasma concentration continues to decline as a result of continued elimination, the concentration gradient reverses and the drug redistribues from the peripheral compartments and re-enters the central compartment.
- The relatively flatter slope (beta Phase) represents grud elimination from the central compartment
A+B Represent plasma concentration over time; it is summation of A nad B
- the alpha portion of the curve represents distribution. it’s also called t1/2a.
- The beta portion of the curve represents elimination. It is also called t1/2b.
What is the rate Constant?
The rate constant comunicate the speed at which a reaction occurs ( or how fast a molecule moves between compartments)
- k12- rate constatn for drug transfer from central to peripheral compartment
- k21- rate constant for drug transfer from perioheral to central compartment
- ke- rate constatn for drug eliminatin from body
Afeter administering an IV drug that distributes into 1 compartment model, the patients serum contains 6.25% of original dose? How many halflife have elapsed?
4
The elimination half-life is the time required for a drug of plasma concentration to decline by 50%.
After 4 half-life have elapsed, the patient serum wil contain 6.25% of the original dose,
What’s the difference between elimination half-life and half-time?
When are they different?
Elimination half-life is the time it takes for 50% of the drug to be removed from the body after a rapid IV injection
Elimination Halt-time is the time it takes for 50% of the drug to be removed from the plasma during the elimination phase.
When the rate of drug removal from the plasma is not the same as the rate of drug removal from the body, the elimination half-life and half-time will be different.
How long until the drug is eliminated?
A drug has been cleared from the body when 96.9% of the dose has been eliminated from the plasma. This occurs at 5 half-time.
The half-time measures the constant fraction no the constant amount. It takes the same period fo time for the plasma concentration of a drug to fall from 200mg/l to 100mg/l as it does for the same drug fall from 50mg/L to 25mg/L
Constant fraction- The two quantities may change, but their ratio (porcion) remains constant. As I drink my beer, the amount of liquid in the bottle changes, but the amount of alcohol left in the bottle is a constant fraction of the amount of liquid left in the bottle
What is the Context sensitive- Half-life?
The context sensitive half-time takes the duration of the drug administration into account.
It is the time required for the plasma concentration to decline by 50% after the inffusuion is stopped. The context is “time”
Fentanyl(260min) >Alfentanil(60 min) >sufentanyl(30 min) >remifentanil (4 min)
Volume of Distribution
- Fentanyl -335
- Sufentanyl- 123
- Alfentanyl-27
Remifentanyl-30
Context sensitive half time for fentanyl infusion increases as a function of how long it was infused. A longer infusion had more time to fill up the peripheral compartments, therefore more fentanyl has to be eliminated and it will have a longer elimination half-time, this is also true for alfentanil and sufentanil. Remifentani is the exception. Eve though it is highly lipophilic, it is quickly metabolized by plasma esterasa and has similar context sensitive half time regardless of how long it is infused.
What is the difference between a strong and a weak acid or base?
If you put a strong acid and a strong base in water, it will be ionized completely.
If you put a weak acid or a weak base in water. a fraction of it will be ionized and the remaining fraction will be unionized.
In which circumstance is a drug more likely to pass through a lipid membrane ? ph and pka
What is Ionization? What is dependent of?
- A weak acid where the ph of a solution is < the pka of the drug
- Aweak base where the ph of a solution >the pka of the drug
Ionization describes the process where a molecule gains a positive or negative charge.
Is dependent of two things:
- the ph of the solution
- the pka of the solution ( another nake for pka is dissociation constant)
When the pka and ph are the same, 50% of the drug will be ionized and 50% will be unionized
What happens when we put weak acids and weak bases in a solution?
Remember that likes dissolves like
When does the unionized fraction of a drug predominates?
when does the ionized fraction of a drug predominates?
- An acid in a Basic Solution
- An acid drug will be highly ionized in a basic ph.
- The acidic drug wants to donate protons and the basic soution wants to accept protons.
- The acidic drug happily donates its protons and will become ionized.
2.An acid in an acid solution
- and acidic drug wil be highly unionized in an acidic ph
- The acidic drug wants to donate protons and the acidic solution wants to do the same.
- Since there are no proton acceptors, the acidic drugs retain its proton and will re3main unionized.
3.A base in an Acidic solution
- a basic drug will be highly ionized in an acidic ph.
- the basic drug wants to accept protons and the acidic solution wants to donate protons.
- The basic drug happily accepts the protons and will becone ionized.
- A base in a basic solution
- a basic drug will be higly unionized in a basic ph.
- the basic drug wants to accept protons and the basic solution wants to do the same.
- Since there are no proton donors, the basic drug will remain unprotonated and will remain unionized.
unionized fraction of a drug predominates
- the molecule is a weak base and the ph of the solution>than the pka of the drug ( base dissolves in base)
- the molecule is weak acid and the ph of the solution < the pka of the drug(an acid dissolves an acid)
ionized fraction of a drug predominates
- the molecule is a weak base and the ph of the solution < the pka of the drug ( a based dissolves in an acis)
- the molecule is weak acid and the ph is > the pka of the drug ( an acid dissolved in a base)
Which circumstances creates the strongest gradient for passage of Local anesthetics from the mother to the fetus?
Explain Ion trapping , and Fetal IOn trapping
Mother alkalosis and fetal acidosis.
Imagine two different solutions separeted by a lipid bilayer. The solution on the left has a ph of 7.4 and the right a ph of 5.4.
Only the lipophilic, unionized fraction of a drug will freely diffuse across the cell membrane. After it does, it will ionize according to its pka and the ph of the solution on this side of the membrane. Therefore, the drug concentration, as well as the degree of ionization, will be different on each side of the membrane.
Fetal Ion trapping
- if a mother receives an IV injection of lidocaine (pka=7.9), the unionized fraction freely diffuses across the placenta.
- Fetal oh is normally a little lower than the maternal ph.
- Since a weak base has entered a more acidic environment, there will be greater degree of ionization inside the ferus.
- Since the ionized lidocaine cannot freely cross the placenta back to the mother, ir becomes trapped inside the fetus.
- Furthermore the concentration gradient for unionized lidocain favors the passage of even more unionized lidocaine into the fetus.
- As the fetus becomes distressed, it becomes more acidic, which traps even more lidocaine within it.
Maternal alkalosis increases the unionized fraction in the maternal circulation, more lidocaine is available to diffuse across the placenta. Fetal acidosis increases the ionized fraction inside the fetus. Therefore, the combination of maternal alkalosis and fetal acidosis creates the strongest diffusion gradien.
What is zero order kinetics?
Zero order kinetics (linear)- constant amount per unit time
- describes the situation where there is more drug than enzyme.
- The biotransformation process becomes saturated
- Not enough enzyme is available to metabolize all of the drug that is delivered to it.
- The enzyme will metabolize a constant amount per unit time
- Think of a bus (enzyme) and people at the bus stop ( drug molecule). The bus has only 10 seats, so it can only pick 10 people at a time. No matter how many are stanfing in line, only 10 passengers can ride the bus
- Examples: aspirin, alcohol, phenytoin
What is First Order Kinetics?
Non linear - constant Fraction pero unit time
- describes the situation where there is less drug than enzyme
- no saturation ocurrs
- the enzyme will metabolize a constatn fraction per unit time
- Just about all drugs we administer follows it.
What is Flow limited hepatic elimination?
ER >0.7 Clearance is dependent on the liver blood flow.
Hepatic blood flow greatly exceeds enzymatic activity, so alterationsin hepatic enzyme activity has little effect.
- increase liver blood flow increases clearance
- Decreased liver blood flow decreases clearance
Drug example:Fentanyl, lidocaine, Propofol
