PK/PD 2 Flashcards
1
Q
- Convert the parent drug to a more polar (water-soluble) or more reactive product by unmasking or inserting a polar functional group such as —OH, —SH, or —NH2
- Cytochrome P450 enzyme species (eg, CYP2D and CYP3A4) that are responsible for much of drug metabolism. Many isoforms of CYP have been recognized
A
Phase 1 Reaction (drug metabolism)
2
Q
- increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate, or sulfate
A
Phase 2 Reactions (drug metabolism)
3
Q
- An ATP-dependent transport molecule found in many epithelial and cancer cells. The transporter expels drug molecules from the cytoplasm into the extracellular space.
A
P-glycoprotein, MDR-1 (drug metabolism)
4
Q
- Usually convert the parent drug to a more polar metabolite
- Introduce or mask a functional group
–=OH, -NH₂, –SH
- Usually changed to inactive
- May be modified or even enhanced
- Polar metabolite generally more easily excreted
A
Phase 1 Reactions (drug metabolism) : PK
5
Q
- Generic name for the group of enzymes that are responsible for most drug metabolism oxidation reactions. (Phase I)
- Several P450 isozymes have been identified
–CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4
A
PK: Metabolism—Cytochrome P450 (CYP450)
6
Q
Which 2 pathways are involved in the metabolism of more than 75% of drugs in use?***
A
CYP3A4/5 and UGT
7
Q
- **Drug which is metabolized by one of the CYP450 enzymes***
- Give example
A
Substrate
Ex: Acetaminophen is metabolized by CYP1A2
8
Q
- ***Drug which can increase the activity of a CYP450 enzyme***
- Give example
- Does acetaminophen increase or decrease?
A
- Inducer
- Ex: smoking increases activity of CYP1A2
- Decreases acetaminophen
9
Q
- ***Drug which can decrease the activity of a CYP450 enzyme***
- Give an example
- Does acetaminophen increase or decrease?
A
- Inhibitor
- Ex: Fluvoxamine decreases the activity of CYP1A2
- Increases acetaminophen
10
Q
- Cocaine is metabolized by which enzyme?
- In this situation, what is cocaine considered to be?
A
- CYP3A4 enzyme
- Substrate
11
Q
- You prescribe erythromycin and you look up that this drug is an inhibitor of CYP3A4
- What happens to cocaine?
A
Cocaine will linger
12
Q
- At the next visit you prescribe a glucocorticoid which again you look up and know it is an inducer of CYP 3A4.
- What happens to cocaine?
A
Cocaine will leave
13
Q
What is the subsequent reaction to a phase 1 reaction?
A
Phase 2 reaction
14
Q
- Do phase 1 or phase 2 reactions form a highly polar conjugate?
- Glucuronic acid (glucuronidation UDP)
- Sulfuric acid (sulfation SULTs)
- Acetic acid (Acetylation NAT)
- Amino acid
A
Phase 2 reactions
15
Q
P-gp inhibitors
A
Inhibitors of Intestinal P-glycoprotein
16
Q
2 examples of P-gp inhibitors
A
- Verapamil
- Furanocoumarin components of grapefruit juice
17
Q
- Not all commercially available grapefruit juices are equally potent (the CYP3A4 inactivation potency is dependent on amt of furano extracted into the juice from the areas w/ highest potency)
- Which areas of the grapefruit have the highest potency?
A
- Zest (highest)
- Pith
- Pulp
18
Q
PK : Metabolism
- Important drugs that are normally expelled by P-gp are potentially toxic when given with what?
- What are 3 examples of these drugs?
A
- When given w/ P-gp inhibitor
- Digoxin
- Cyclosporine
- Saquinavir
19
Q
PK : Metabolism
- In which age range is drug metabolism substantially slower?
- Give an example of a drug.
A
- Slower in infants than in older children/adults
- Ex: Compared to adults, premature infants require a higher serum concentration of morphine to achieve efficacy
- Ex: Infants are not able to metabolize morphine adequately to its 6-glucuronide metabolite (20X more active than morphine)
20
Q
PK : Metabolism
- Which pathway is well developed in infants?
-
Which pathway is undeveloped in infants?
- acetaminophen metabolism by _____ is impaired in infants compared with adults
- partly compensated for by increase through the _____ pathway
- balanced to some degree because clearance of morphine quadruples between 27 and 40 weeks of postconceptional age
A
-
Developed: Sulfation
- Undeveloped: Glucuronidation
21
Q
PK : Metabolism
In which persons does hepatic pefusion increase?
(theoretically increases the hepatic extraction of drugs)
A
Pregnancy
22
Q
PK : Metabolism
In which persons do these occur?
- ↓ Hepatic size
- ↓ Hepatic blood flow
- ↓ Phase I (oxidation, reduction, hydrolysis) metabolism (therefore includes the CYP450 enzymes)
A
Geriatric
23
Q
- Condition in which the average total amount of drug in the body does not change over multiple dosing cycles
- Ex: the condition in which the rate of drug elimination equals the rate of _____.
A
- PK : Steady State
- Administration
24
Q
PK : Steady State
- Most drugs follow _______, whereby steady-state serum drug concentrations ________ with long-term daily dosing.
A
- Follow linear pharmacokinetics
- Concentrations change proportionally w/ long term daily dosing
25
**PK : Steady State**
* Drugs which _do not follow rules of linear pharmacokinetics_ (meaning the concentration does not change proportionally w/ dose)
* The serum concentratios changes _more or less_ than expected
* What do these drugs follow?
Nonlinear pharmokinetics
26
Time required for serum concentrations to decrease by 1/2 after absorption and distribution are complete
Half-life (t1/2)
27
What determines the time required to reach steady state and the \_\_\_\_\_?
* **Half-life (t1/2)**
* and the **Dosage Interval**
28
Half-life is dependent on kinetic variable because its value depends on the values of \_\_\_\_\_\_.
Clearance and volume of distribution
29
What usually alters the clearance of a drug much more than they alter its Vd?
* Disease
* Age
* Other variables
(half-life)
30
* Most important pharmacokinetic parameter
* Determines the steady-state concentration for a given dosage rate
PK
## Footnote
**Clearance**
31
* Determined by blood flow to the organ that metabolizes or eliminates the drug
* Efficiency of the organ in extracting the drug from the bloodstream.
PK
## Footnote
**Clearance**
32
* What is the main organ involved in elimination of drugs?
* Others?
* Kidney #1
* Lungs, skin, GI
* Biliary, salivary, mammary
33
What conditions would require adjustment of dosage when elimination is altered by disease?
_These reduce clearance of drugs that depend on renal function:_
* Renal disease
* Reduced cardiac output
_Less common, but may occur:_
* Liver disease
_Impairment of hepatic clearance (for high extraction drugs) when liver blood flow is reduced_
* Heart Failure
* Severe cirrhosis
* Other forms of liver failure
34
* Total filtration rates of functioning nephrons of kidney
* Cannot be measured directly
* Used for the detection, severity, and treatment of kidney disease
Glomerular Filtration Rate (GFR)
35
What 4 variables affect GFR?
* Gender
* Age
* Weight
* Race
36
* Efficiency of renal excretion is determined by which 3 things?
* The processes of renal excretion may not develop fully in infants until when?
* Glomerular filtration
* Tubular secretion
* Tubular reabsorption
Several weeks to 1 year (after birth)
37
**PK : Excretion**
* What 3 things increase by 30 to 50% or higher in pregnancy?
* What do they do (potentially)?
* Maternal plasma volume
* Cardiac output
* Glomerular filtration
Potentially lowering the concentration of renally cleared drugs
38
**PK : Excretion**
* Higher levels of estrogen and progesterone in pregnant women alter what?
* What does this cause?
* Alters liver enzyme activity
* Increases the elimination of some drugs, but results in accumulation of others
39
**PK : Excretion**
What decreases and increases in Geriatric patients?
* ↓ GFR
* ↓ Renal blood flow
* ↓ Filtration fraction
* ↓ Tubular secretory function
* ↓ Renal mass
40
* Estimates GFR adjusted for BSA
* More accurate than Cockroft-Gault
* Used by most laboratories as eGFR
Modification of Diet in Renal Disease (MDRD) equation
41
* Uses body weight
* Is the standard for drug dosing
Cockroft-Gault equation
42
IBW
ABW
LBW
Ideal Body Weight
Actual Body Weight
Lean Body Weight
43
What 6 factors should be taken into consideration when deciding on best drug dose for patient?
1. Age
2. Gender
3. Weight
4. Ethnic background
5. Concurrent disease states
6. Other drug therapy
44
Deals with the effects of drugs on biologic systems
Pharmacodynamics
45
Denotes the amount of drug needed to produce a given effect
Potency
46
\_\_\_ is the greatest effect (Emax) an agonist can produce if the dose is taken to the highest tolerated level
Efficacy
47
(Efficacy)
\_\_\_\_\_ have lower maximal efficacy than full agonists.
Partial agonists
48
Measure of dose required to produce a response
Potency
49
2 factors that influence the relationship between prescribed dosage and drug effects
* Medication errors
* Patient compliance
50
**PK : Distribution**
The fraction of unbound can be altered by which 3 variables?
* concentration of drug in the body
* amount and quality of plasma protein
* other drugs that bind to plasma proteins
51
**PK : Distribution**
* What would lead to a higher fraction unbound?
* Why?
* Higher drug concentrations
* Because the plasma protein would be saturated with drug and any excess drug would be unbound
52
**PK : Distribution**
What would lead to a higher fraction unbound in cases such as:
* catabolism
* malnutrition
* liver disease
* renal disease
If the amount of plasma protein is decreased
53
PK : Distribution
* Generally speaking, does clearance usually increase or decrease?
* Why?
* Clearnace increases
* Often because the displacing drug is an inhibitor of clearance
54
* What is a low clearance drug?
* What does it interact with?
**Low clearance:** Warfarin
**Interacts w/** ASA
