Intro to Pharmacokinetics Flashcards
Define pharmacology
The study of the effects of drugs on the function of living systems
Pharmacokinetics
What body does to drug
Pharmacodynamics
What the drug does to the body
What are the pharmacokinetic parameters that influence the amount of drug in the blood?
Absorption Distribution Metabolism Excretion
Define absorption
Drug is absorbed from site of administration into blood stream
Define distribution
Drug leaves bloodstream and distributes to interstitial and intracellular fluids
Define metabolism (in context of ADME)
Drug may be biotransformed by metabolism in liver and other tissues b/c body wants to break down compound for excretion once it enters body
Define excretion
Drug and metabolites are excreted from the body in urine, bile or feces
What is meant by volume of distribution?
That a high enough dose needs to be given to account for the fact that the drug will distribute through whole body not just end organ of interest
What is the onset of action?
Time it takes for drug to reach plasma following oral administration
What two things determine how fast a drug will work?
Pharmaceutic phase (formulation of drug, liquid, powder, etc.) Pharmacodynamic phase (ADME)
How is the volume of distribution calculated? (Vd)
Vd = Dose / initial concentration, Co
What does a lower Vd mean?
Lower initial concentration has what effect on Vd (if dose kept constant)?
The drug tends to stay in the plasma and not distrubute to other tissues
Lower Co = Higher Vd
What does it mean if the Vd exceeds the total body water amount for a person?
That the drug has distributed into the body’s tissues. Fat can act as a drug depot and store drug within its tissue. Drugs can also distrubtue into muscle.
Some drugs can bind to albumin (plasma protein in the blood). What effect does this have on ADME?
Proteins bound to plasma proteins have a predictable and restricted volume of distribution and the binding allows them to exert their effects over a longer period of time (increased half life) because they aren’t being metabolized by the body right away. When the concentration of the drug in the body decreases, this concentration gradient will drive more drug to dissociate from albumin and absorb into the body.
Imagine that drug A is administered to a person and is bound to albumin in the plasma. Now imagine that drug B is given to that person and drug B competes with drug A to bind to albumin. What effect will this have on the Vd of drug A?
If Drug B competes with Drug A for albumin binding, then the concentration of Drug A in the plasma will increase. An increase in concentration leads to a subsequent decrease in Vd for that drug. Thus, this drug will be more confined to the plasma.
What two bodily factors can contribute to changes in the pattern of drug distribution?
Accumulation of fat (drug depot for lipophilic drugs)
Accumulation of fluids (drug depot for water soluble drugs)
Describe how the polarity of drugs changes during metabolism and elimination.
Drugs go from more lipophilic –> slightly more soluble in water –> very soluble in water
What are Phase I and Phase II reactions wrt metabolism and elimination?
Phase I: oxidation reactions typically, not much change in drug’s solubility but large change in biological properties which inactivates drug
Phase II: Increase in water solubility via attachment of polar groups or conjugation with another molecule, mass of drug is also increased to facilitate elimination
What effect does conjugation have on the Vd and half life of a drug?
Conjugation leads to a decrease in Vd and thus makes a drug have higher clearance in the urine or stool and as a result shorter half life.
____ substances are not eliminated efficiently by the kidneys.
A) Hydrophilic
B) Neutral
C) High Molecular Weight
D) Lipophilic
D
What is enterohepatic recycling?
When drugs are taken orally, they first enter the gut. Once absorbed in the gut, they travel via the portal system to the liver where they can be processed (First Pass Metabolism, Phase 1 reaction) or left unchanged. The liver then secretes the drugs into the bile, which empties back into the gut where they can be reabsorbed.
What is a Phase 1 reaction with respect to drug metabolism? Give 1 example.
The drug is modified slightly to make it more hydrophilic, but really this type of reaction just sets the drug up for further modification later in Phase 2 reaction.
Example: Hydroxylation
What is a Phase 2 reaction with respect to drug metabolism?
A reaction that makes drugs much more hydrophilic and often increases their molecular weight by attaching bulky hydrophilic groups.
Example: Glucuronidation
In what organ do phase 1 reactions take place (mostly)?
Where in the cell do these reactions occur?
Liver
ER, mitochondria, cytosol, plasma membrane, lysosomes
The Cytochrome P450 family of enzymes are monooxygenases that catalyze phase 1 reactions. What are the types of reactions they produce?
Oxidation
Hydroxylation
Dealkylation
Deamination
Hydrolysis
Where in the cell do phase 2 reactions occur?
Cytosol
What is the equation for clearance?
CL = (Metabolism + Excretion) / Plasma drug concentration
Describe how you would know that a drug is eliminated by first order kinetics.
First order kinetics is a process by which a constant fraction or percentage of drug is metabolized per unit time.
Describe how you would know that a drug is metabolized by saturation kinetics.
Saturation kinetics is a process by which a constant amount of drug is metabolized per unit time regardless of the concentration.
The half life of a reaction that follows first order kinetics is variable.
A) True
B) False
B) False - it is constant
The half life of a reaction that follows saturation kinetics is variable.
A) True
B) False
A) True - half life depends on starting plasma concentration
Clearance is defined as the rate of elimination / plasma concentration. However, it is also affected by the amount of blood flow to each organ that is responsible for excretion. The extent to which an organ contributes to clearance is determined by the extraction ratio. What is the extraction ratio?
Cin - Cout / Cin
What is the equation for the elimination rate?
How does this equation simplify in clinical situations?
How would this equation simplify if the drug was given at a very high dose?
- Most drug dosages are administered at concentrations that are much smaller than the Km of the enzymes that eliminate the drugs. As such, the drug plasma concentration does not need to be considered in the denominator only.
- If given at a very high dose, the [C] drug in plasma is likely to be much higher than the Km, so the opposite would be true and the denominator would simplify simply [C]
What is the equation to determine half life?
t1/2 = (0.693 * VD) / CL
**make sure units of VD and CL match**
What is steady state concentration (Css)?
When drug doses are given repeatedly, the drug will accumulate in the body until Css occurs or dosing stops
50% of Css is achieved in __ half life
75% of Css is achieved in __ half life
90% of Css is achieved in __ half life
100% of Css is achieved in __ half life
1
2
3.3
4-5
What is a maintenance dose of drug?
How is this calculated?
- Administration of a drug to maintain a steady state concentration within the therapeutic window and is given to replace the drug that was eliminated since the previous dose
- Dosing rate * dosing interval –> ((Css * CL) / F)*dosing interval
What is the dosing rate?
(Css * CL) / F
What is a loading dose?
How is this parameter calculated?
- A larger dose injected initially to achieve plasma concentration within therapeutic window more quickly. Without loading dose, would require 4-5 half lives for drug to reach Css.
- (Css * VD) / F
Drugs that are highly absorbed generally require a __ dose than pooly absorbed drugs.
A) Higher
B) Lower
C) Longer
D) Shorter
B) Lower
Poorly distributed drugs require a ___ dose; highly distributed drugs require a ___ dose.
A) Higher, higher
B) Lower, higher
C) Lower, Lower
D) Higher, Lower
B) Lower, higher
Drugs with high elimination rates have shorter half lives and require ___ frequent dosing to maintain therapeutic windows.
Drugs with low elimination rates have longer half lives and require ___ frequent dosing to maintain therapeutic windows.
A) Less, more
B) Less, less
C) More, less
D) More, more
C) More, less
