Apex-Pharmacokinetics Flashcards
1
Q
What measures the relationship between a drug dose and a drugs plasma concentration?
A
Volume of Distribution
2
Q
What is a theoretical measure of how a drug distributes throughout the body?
A
Volume of distribution
3
Q
What does Vd (volume of distribution) assume? (2)
A
- That the drug distributes instantaneously &
- That the drug is not subject to biotransformation or elimination before it’s fully absorbed
4
Q
Do hydrophilic drugs have a low or high Vd?
A
Low > they distribute into some or all of the total body water but don’t distribute into fat
5
Q
Do hydrophilic drugs require higher or lower doses to achieve a given plasma concentration?
A
Lower doses (they are restricted to the ECF and stay there - don’t have to worry about their distribution into fat which would require more drug to get to a certain plasma concentration)
6
Q
Example of high vs low Vd drugs? (1 each)
A
High = propofol (distributes into fat, lipophillic)
Low = neuromuscular blockers (stays in the ECF)
7
Q
Volume of Distribution = (2 calculations)
A
Amount of drug/Desired plasma concentration
Patients weight x Vd of a given drug
8
Q
How to calculate a loading dose
A
Vd x Desired plasma concentration/Bioavailability
9
Q
What is the bioavailability of all IV drugs?
A
1
> bc 100% of it is immediately available in the ECF (doesn’t have to go through 1st pass metabolism in the liver)
10
Q
Total Body Water = ____L or _____L/kg
A
42 L
0.6L/kg
11
Q
(High/low) Vd drugs exceed total body water
A
High (Lipophilic)
12
Q
What makes up total body water?
A
The ECF - 14L & ICF 28L
60%/40%/20% (15%/5%)
T-I-E
70kg always normal reference
40% x 70kg = 28L
20% x 70kg = 14L
13
Q
What makes up ECF?
A
60/40/20 (15/5)
Intesistial = 15% (10.5L)
Plasma = 5% (3.5L)
% of 70kg
14
Q
Define drug clearance
A
The volume of PLASMA that is cleared of the drug over time
15
Q
What are the major clearing organs? How are drugs cleared in the plasma?
A
Liver and Kidney
Hoffmann elimination and ester hydrolysis in the plasma
16
Q
What is the term for when the amount of drug entering the body = the amount of drug leaving the body
A
Steady state
17
Q
How many half-times must elapse to achieve steady state?
A
5
18
Q
Clearance is directly proportional to (3)
A
- Blood flow to the clearing organ
>more blood flow to the kidney = faster the drug can be cleared - Extraction ratio
>more extraction = more cleared - Drug dose
>increased drug = increased clearance
19
Q
Clearance is (indirectly/directly) proportional to:
Half life vs drug concentration in the central compartment
A
Both inversely related
- Half-life
>increased 1/2 life = decreased clearance - Drug concentration in the central compartment
>more drug in the central compartment = less being cleared
20
Q
In multi-compartment models, what do the Alpha and Beta phases represent ?
A
Alpha phase = distribution (plasma concentration decreases)
Beta phase - represents drug elimination from the central compartment
21
Q
Elimination half-life vs half-time
A
Half life = time required for a drugs plasma concentration to decrease 50%
>the time it takes for 50% of the drug to be removed from the body
Half-time = The time it takes for 50% of the drug to be removed from the PLASMA during the elimination phase (think- watch 1/2 TIME show on PLASMA tv)
> this oversimplifies the movement of drug inside the body and is clinically meaningless
22
Q
What is the term for the time required for the plasma concentration to decrease 50% after an infusion has stopped?
A
Context-sensitive half-time
23
Q
When is a drug considered to be cleared from the body?
A
When 96.9% of it has been eliminated from the plasma (5 half-times)
24
Q
Filling out half-time table
A
First row 0-5
%Drug eliminated
%Drug remaining
25
Label the opioids on the context-sensitive half time chart
FASteR
26
A weak acid/base is where the pH of a solution is (>) the pKa of the drug?
Weak acid : pH of solution < pKa of the drug (decreased pH =acidic)
Weak base: pH of solution > pKa of the drug (increased pH = basic)
*more likely to pass through a lipid membrane
27
What is the difference between a weak acid and a weak base?
Weak acids donate a H+
Weak bases donate OH-
28
What happens when the pKa & pH of the drug are the same?
50% will be ionized and 50% will be unionized
29
What is ionization?
The process where a molecule gains a positive or negative charge, affecting it’s ability to diffuse through lipid membranes
30
Amount of ionization a drug undergoes depends on what 2 factors?
The solutions pH and the pKa of the drug
31
Another name for pKa
Disassociation constant
32
Ionized vs un-ionized:
Water/lipid soluble
Pharmacologically active/inactive
Hepatic biotransformation vs renal elimination more likely
Diffuse across lipid bilayers - yes/no
Ionized = water soluble , pharmacologically inactive, renal elimination more likely, does not diffuse across lipid bilayers (likes the water and stays there)
Un-ionized = lipid soluble, pharmacologically active, hepatic biotransformation more likely, yes diffuses across lipid bilayers (BBB, GI tract, Placenta)
33
Does albumin carry a positive or negative charge?
Will it primarily bind acidic or basic drugs?
Negative charge
-will primarily bind acidic drugs (+/-)
34
Does alpha-1 acid glycoprotein primary bind basic or acidic drugs?
Basic drugs
35
Does beta-globulin bind acid or basic drugs?
Basic
(Beta, Basic)
36
5 circumstances where albumin will be decreased (increased risk of toxicity)
1. Liver disease (liver makes albumin)
2. Renal disease (albumin passes through diseased kidneys)
3. Old age
4. Malnutrition (ETOH)
5. Pregnancy (altered distribution)
37
5 circumstances where alpha-1 acid glycoprotein would be increased and 2 for decreased states
Increased = surgical stress, MI, chronic pain, RA, old age
Decreased = neonates and pregnancy
38
If a drug is 98% bound and the bound fraction decreases to 96%, how much has the unbound or free-fraction of the drug increased by?
100%
(2% free increases to 4% free)
(4-2)/2 x 100 = 100%
39
Zero order kinetics vs First-order kinetics
Zero order = a constant AMOUNT of a drug is metabolized over time
First- order = a constant FRACTION (F/F) of a drug is metabolized over time
40
The majority of our drugs follow first-order kinetics, which drug follows zero-order kinetics? (6)
WAP HAT
Warfarin
Alcohol
Phenotoin
Heparin
Aspirin
Theophylline
41
What is the enzymatic process of altering the chemical structure of a molecule?
Biotransformation/Metabolism
42
What are the 3 phases of metabolism/biotransformation?
1. Modification
2. Conjugation
3. Elimination
43
What is the primary goal of metabolism?
To change a lipid-soluble, pharmacologically active compound into a water-soluble, pharmacologically inactive byproduct so it can be excreted
44
What is a prodrug? Example?
When the body converts and inactive molecule into a pharmacologically active one
(The body is a Pro at making drugs)
Fospropofol is metabolized by alkaline phosphatases to it’s active metabolite > propofol
45
Jeopardy-style: When you administer the drug, how much of it will end up in the bloodstream?
What is Bioavailability
46
In order for a drug to diffuse across the lipid bilayer of cells, does it have to be ionized or unionized?
Un-ionized (the cell membrane is negatively charged and if an ionized (+) drug tries to cross, it can't. It will just stick to it.
47
Is morphine sulfate an acid or a base and why?
Morphine is a base, it is combined with sulfuric acid to be a stable compound (which can be stored)
(acid + base = salt > water)
(add water(what our body is made of)) to the salt and acid and base will dissociate into it's two seperate parts) i think
Demerol hydrocholide - hydrochloronic acid = acid, so demorol is a base.
48
What is the pKa of a drug?
A pH in which that drug would be 50% ionized and 50%unionized
49
pH of CSF?
7.3 (slightly more acidic than blood)
50
Which equation is used to determine the pKa of a drug?
Henderson-Hasselbalch
51
Phase I, II, & III reactions are associated with which terms?
I- modification
II- conjugation
III- elimination
52
Which type of reaction results in small, molecular changes that increase the polarity (water solubility) of a molecule?
Phase I
>it does this to prepare it for phase II reactions (Conjugation)
53
Most Phase I reactions are carried out by what?
The P450 system
54
What are 3 elements of phase I reactions and what do they mean?
1. Oxidation - removes electrons from a compound
2. Reduction- adds electrons to a compound
3. Hydrolysis- adds water to a compound to split it apart (usually an ester)
55
What phase reaction results in a water-soluble, biologically inactive molecule ready for excretion?
II
56
What does conjugation mean?
(what phase reaction)
Phase II - it adds on an endogenous, highly polar, water-soluble substrate to the molecule to inactivate it so it can be excreted.
57
What drug works via enterohepatic circulation and what does that mean?
Diazepam - some conjugated compounds are excreted in the bile, reactivated in the intestine, and reabsorbed into systemic circulation
58
What phase of metabolism involves ATP-dependent carrier proteins that transport drugs across all cell membranes that are present in the kidney, liver, and GI tract?
Phase III - elimination
59
Hepatic clearance is a product of what 2 things?
1. Liver blood flow - how much blood is delivered to the liver
2. Hepatic extraction ratio- how much drug is removed by the liver
60
Hepatic extraction ratio - what is it?
A measure of how much drug is delivered to a clearing organ vs how much is removed by that organ.
61
How is the extraction ratio calculated?
Arterial concentration - venous concentration
/arterial concentration
62
What do extraction ratios of 1.0 and 0.5 mean?
1.0 = 100% of the drug delivered to the clearing organ is removed
0.5 = 50% is removed
63
Extraction ratios of flow limited elimination and capacity limited elimination
flow limited = ER > 0.7
(clearance is dependent on liver blood flow)
(increased blood flow = increased clearance)
capacity limited = ER < 0.3
(clearance is dependent on the ability of the liver to extract the drug from the blood)
& since only a small amount of drug is removed per unit of time, alterations in blood flow minimally effect the clearence
64
Does enzyme induction result in increased or decreased clearance from the liver?
induction = INcreased
65
Does enzyme inhibition result in increased or decreased clearance from the liver?
inhibition = decreased
66
6 drugs with low ER's (liver depedent)
PTT, MLD (PTT and MELD score) LOW ER
Phenytoin
Theophylline
Thiopentyl
Methadone
Lorazepam
Diazepam
67
15 drugs with high ER's (blood flow dependent)
(5 groups of drugs)
Opioids (5)
1. Fentanyl
2. Sufentanil
3. Morphine
4. Meperidine
5. Naloxone
(fent and su, M&M, and the reversal)
Induction drugs (2)
6-7. Propofol & Ketamine
Locals (2)
8-9. Lidocaine & BPV
Beta-blockers (3) MAP (blood blow)
10. Metoprolol
11. Alprenolol
12. Propanolol
CCBs (3)
13. Nifideipine
14. Diltiazem
15. Verapamil
68
4 intermediate ER drugs
eating M&M's in Virginia (VA)
1. Midazolam
2. Methohexital
3. Vecuronium
4. Alfentanyl
69
2 other names for P450 isoenzymes
Where are they located?
1. Mixed-function oxidase system
2. Monooxygenases
In the smooth ER of the hepatocyte
(also in lungs, kidney, skin, adrenals, GI tract)
70
What is the most important cytochrome P450 enzyme?
What's the second most important?
-CYP 3A4 (3 Ashleys, how about 4)
(metabolizes nearly 50% of drugs we administer)
-CYP 2D6 (2 dicks sux)
71
What do enzyme inducers do?
Stimulates the synthesis of additional enzymes
-increased clearance
-decreased drug plasma level (t1/2 life)
72
What do enzyme inhibitors do?
Competes for binding sites on the enzyme --> fewer binding sites to clear the drug
-decreased clearance
-increased drug plasma level (t 1/2 life)
73
6 Enzyme inducers
1. Alcohol (ethanol)
2. Tobacco
Smokers (love) A Cold PBR
Smokers (love)
Alcohol
Carbamazepine
Phenytoin
Barbituates
Rifampin
*may require increased doses)
74
7 Enzyme inhibitors
(I [love] Geckos)
Isoniazid (TB)
Grapefruit juice
Erythromycin
Cimetidine
Ketoconazole (antifungal)
Omeprazole
SSRIs
75
3 categories of CYP 3A4 substrates and the (4-3-2) drugs in each category
1. Opioids
>Fent, Su, Al ,
>Methadone
2. Locals
>Lido, BPV, Ropi
3. Benzos
>midaz, diazepam
76
Inducers of CYP 3A4 (6)
(ERS has TB - see! (C))
Ethanol
Rifampin
St. Johns Wart *
Tamoxifen*
Barbituates
Carbamazepine
77
Inhibitors of CYP 3A4 (5)
(CAGES)
Cimetidine
"A"-zole antifungals
Grapefruit Juice
Erythromycin
SSRIs
78
Substrates of CYP 2D6 (4)
Codeine --> Morphine
Oxycodone
Hydrocodone
79
Inducers of CYP 2D6 (3)
(Pat Casey likes dexamethasone)
Phenytoin
Carbamazepine
Dexamethasone
80
Inhibitors of CYP 2D6 (3)
(SIsQo)
SSRIs
Isoniazid
Quinidine*
81
Substrate of CYP 1A2 (1)
it's inducers (3) and inhibitors (2)
Theophylline (small therapeutic index)
> tobacco, cannabis, ethanol
>erythromycin, ciprofloxacin
82
What is the primary function of the kidney
To eliminate metabolic waste into the urine
83
What happens to lipophilic drugs that have not undergone biotransformation?
They will be re-absorbed into the peri-tubular fluid by diffusion
84
What are the 2 processes that deliver drug into the urine?
-Glomeular filtration & Organic ion transporters
85
Where are organic anion and cation transporters located and what do they do?
They are transport proteins located in the proximal renal tubules
>secrete organic acid and bases into the urine
86
Organic anion transporter drugs (3)
Organic Cation transporter drugs (3)
Anion transporter - furosemide, thiazides, PCN
Cation transporters - Morphine, meperidine, dopamine
87
What influences whether drugs are excreted in the urine or reabsorbed into the peritubular capillaries?
The urine pH (like dissolves like)
88
Acid urine favors reabsorption of (acid/basic) drugs and excretion of (acid/basic) drugs
reabsorption of acidic drugs
excretion of basic drugs
***AAA: Acid drugs are better Absorbed in an Acidic environment
89
Basic urine favors reabsorption of (acid/basic) drugs and excretion of (acid/basic) drugs
reabsorption of basic drugs
excretion of acidic drugs
***BBB: Basic drugs are Better absorbed in a Basic medium
90
What will help acidify the urine to help eliminate basic drugs? (2)
-Ammonium chloride (A)
-Cranberry juice
91
What will help alkalize the urine to help eliminate acidic drugs? (2)
1. sodium Bicarb (B)
2. Acetazolamide (Diamox)
92
All metabolic pathways involve enzymes for metabolism except what?
Hoffmans elimination (pH and temp)
93
Do plasma enzymes undergo enzyme induction?
No
94
Pseudocholinesterase deficiency extends the duration of action of what 3 drugs?
1. Sux
2. Mivacurium
3. Ester local anesthetics (one i)
95
What are the 3 groups of esterases?
1. Pseudocholinesterase
(Sux, mivacurium, ester local anesthetics)
2. Nonspeicfici esterases
(Esmolol, Remifent, etomidate, atricurium)
3. Alkaline Phosphatase
(Fospropofol) > prodrug concerted to propofol by alkaline phosphatase
96
What 2 drugs are eliminated by Hoffman elimination?
1. Cisatracurium (Chuck Norris)
2. AHHHHtracurium (+nonspecific esterases)
97
Scenario:
You ran propofol gtt and waited too long to shut it off bc u were nervous they were gonna move too soon.....
what can you do to try and facilitate them clearing the drug?
Increase their blood pressure!
- propofol has a high extraction ratio meaning it's depedent on blood flow to the liver to be cleared; increase blood flow to the liver, more drug will be cleared and well-a! (i'ma try this)
and if someone gives pushback saying your giving another drug.... well i'm giving a drug with a relatively safe profile that will clear the anesthetic from their body faster - they will be able to breathe more effectively, eat sooner, and leave the hospital sooner; decrease LOS and increased production time
98
Do you need to reduce the amount of propofol in someone with hepatic failure?
Probably not- it has a high ER - meaning it's clearence is depedent on blood flow to the liver
99
You think you gave too much narcotic, pt is VERY comfortable and doesn't want to breathe; what can you try doing before giving narcan?
Increasing their BP
-fentanyl has a high ER meaning it is depedent on blood flow to the liver for elimation
-more blood flow to the liver = more drug able to be eliminated
(no idea if this is clinically significant but it sounds like a good idea)
