Pharmacokinetics Flashcards
1
Q
Pharmacokinetics
A
What the Body does to the Medication
Absorption
Distribution
Metabolism
Excretion
2
Q
Absorption
A
Medication moves to blood stream or final action site
3
Q
What does the absorption of medication depend on?
A
- Route of administration
- Ionization of Molecule
- Size of Molecule
- Patient Factors
- Bioavailability
4
Q
Lipophilicty
A
Less Ionized, may move accross lipid bilayer
5
Q
Hydrophilicty
A
More Ionized - More likely to stay in solution and blood
Requires carrier, channel, or energy to go through fat layers
EX: Electrolytes
6
Q
Bioavailability (F)
A
Percentage of medication that reaches systemic circulation
- Dissolution & Absorption Characteristics
- ER Tabs can change F
- F = 100% for IV drugs
- Route of Administration
- Stability in GI Tract
- Metabolism prior to blood stream
New Dose = (FOLD x Current Dose) / FNEW
Useful for converting dosage forms
7
Q
Calculating Bioavailability Examples
A
- Ex: Levothyroxine
- Oral Tablet Bioavailabilitiy Range: 40-80%
- PO dose: 100mcg, then IV dose: ?
- 100mcg x 0.4 = 40 mcg
- 100mcg x 0.8 = 80 mcg
- IV Dose Range 40-80 mcg (may use 60 mcg)
- Phenytoin
- Capsule & Salt S: 0.92
- Suspension & Chew Tabs S: 1
- May require dose adjustment if changing from capsule to suspension, IV to tabs, etc.
- Digoxin Tab F: 0.7
- Digoxin Elixter F: 0.8
- Currently taking 250 mcg tabs. How much elixer is equivalent?
- New Dose = (FOLD x Current Dose) / FNEW
- = (0.7 x 250 mcg) / 0.8 = 219 mcg
- Less of tablet is absorbed than elixir, therefore a higher dose than elixer
8
Q
What are all routes of administration?
A
- Oral
- Topical
- Transdermal - cream, patch
- Eye/Ear drops
- Inhalation
- SL/Buccal
- Injection - IV, IM, SQ, IT
- Peripheral vs. Central
9
Q
What are GI considerations for Oral Adminstration
A
- pH
- Contents
- Surface Area
- Blood Flow
- Motility
- Flora
- Complete GI Tract
10
Q
How does pH of GI Tract affect absorption of medication?
A
Some meds need acidic environment for dissolution and/or absorption
Acid suppressants may reduce absorption
EX: Calcium, Iron, Magnesium, B12
11
Q
How does contents in the GI tract effect absorption of meds?
A
Positively or Negatively depending on medication
12
Q
How does the surface area of the GI tract effect medication absorption?
A
Short bowels, resections, IBD may have reduced oral absorption
13
Q
How does Blood Flow of GI Tract effect med absorption?
A
Meds are absorbed from the small intestine into the blood stream.
Poor blood flow may reduce absorption
14
Q
How does GI Motility effect med absorption?
A
Too Fast: possible reduced contact time and reduced absorption
Too Slow: possible increased absorption
15
Q
How does GI Flora effect med absorption?
A
EX: E. lentum is needed for digoxin metabolism. Erythromycin kills this bacteria leading to digoxin toxicity.
16
Q
Sublingual/Buccal Absorption
A
- Drains directly into vena cava
- Very fast
- No first past metabolism, does not rely on GI tract
- Must be HIGHLY lipid soluble and potent
Should have 100% Bioavailability if done correctly
17
Q
What is First Pass Metabolism
A
Concentration of Oral drugs is greatly reduced before it reaches systemic circulation.
- Nasal: Med absorbs directly into veins
- Venous System: transports blood from nose directly to heart - no liver metabolism
- Heart: pumps out blood to body - no delay
- Liver: 90% of oral meds metabolized and destroyed before it goes to heart
- Portal Circulation: All blood from intestines taken to liver for detoxification
- Oral meds: Sit in stomach for 30-45 minutes.
18
Q
Consideration for Topical Administration
A
- Skin
- Intact - dont give if broken/dry
- Solubility - need to be highly lipophillic
- Temperature - heat increase absorption
- Blood Flow - PVD decrease absorption
- Eye
- May become systemic through nasolacrimal canal
- Inhalation
- Rapid d/t large surface area
- Avoids first pass
- Local site of action
- Hard to control
19
Q
Injection Adminstration
A
- IV: Potentially immediate - Good for large doses
- SQ: Depending on solution, rates may be slow (repository) or fast (aqueous)
- slower onset
- IM: Same as SQ. Be sure not to enter blood stream directly
- Almost as fast as IV
- Simple Diffusion
- Rate limits: amount of capillaries, solubility, molecular size, composition
(Bioavailabilty of these all are pretty much 100%)
20
Q
Volume of Distribution
A
- Assumes the concentration of the medication is the same throughout all compartments
- Average Adult Plasma Vd: 3 L
- Total Body Water: 0.65 L/kg
- Useful for Loading Dose
21
Q
Loading Dose
A
Dose needed to reach desired concentration based on volume of distribution
Loading Dose = Vd x Cd (desired concentration)
EX:
Vancomycin Vd = 0.7 L/kg
Desired concentration ~ 30 mg/L
What is loading dose for 70 kg patient?
22
Q
Multi-Compartment Models
A
- Redistribution before elimination
- Slow rate of adminstration for secondary redistribution
- Target organ may be in inital or secondary compartment
- Volume distribution assumes concentration of med is same in EVERY tissue
23
Q
How do meds flow through multiple compartments?
A
- Given via any route
- Goes to Compartment 1 - usually general circulation.
- Goes to Other Compartments or straight to elimination
(Normally 2nd Compartment - Major Organs & 3rd Compartment - Fatty Tissue)
24
Q
Protein Binding
A
Some meds bind to proteins to move through circulation
- Unbound/free drugs = active
- Acidic Drugs: albumin
- Basic drugs: alpha 1 acidic glycoprotein
- Generally reversible
- Saturable
- Non-linear - binding plateau
- Competitive
25
How does low albumin effect free drug concentration?
Increases concentration, which can increase toxicity
Ex: Burns, Malnutrtion, Kidney/Liver Disease
26
Tissue Binding
Some meds gravitate to certain tissues
* Fat: Reservoir for lipid soluble drugs
* Bone: Tetracyclines
* Dont give to children who dont have all adult teeth - permanent yellow teeth
* Heart Muscle: Digoxin
27
In order for a drug to enter an organ, what ability must it have?
The ability to permeate all membranes that separate the organ from the site of drug administration.
EX: Benzodiazepines are lipophilic and readily cross gut wall, capillary wall, blood-brain barrier; They get to the brain fast and are useful for anxiety and seizures.
28
Blood Brain Barrier
Super Compact Wrapping of the Blood Vessels
Very protective - only blood, glucose, and electrolytes that can normally pass
29
What occurs in fetal plasma and why?
Ion trappig of basic drugs because fetal plasma is more acidic
30
Placental Transfer
* More likely to absorb in fetal circulation:
* Low molecular weight, high lipid solubility, unbound
* P-glycoproteins limit transport in
* Anything mom takes, baby takes
31
P-Glycoproteins
* Transporter proteins found all over
* Important for med interactions & drug resistance (cancer cells)
* Needs ATP ( ABC = ATP binding cassette)
32
Passive Diffusion
No Energy, No Carrier
Rapid for liphophilic, nonionic, small molecules
33
Facilitated Diffusion
No Energy, Needs Carrier
Drugs bind by noncovalent mechs. Chemically same drugs compete for carrier.
34
Aqueous Channels
No Energy, No Carrier
Smalll, hydrophilic drugs (\<200mw) diffuse along concentration gradient by passing through these channels/pores.
35
Active Transport
Needs Energy & Carrier
Same as facilitated diffusion, but needs ATP to go against concentration gradient
36
Metabolism
* Breakdown for elimination - reduce size, improve hydrophilicity (more ionized)
* Meds may become active (prodrug) or inactive
* Metabolites may be more toxic than parent compound
37
What happens in Phase I Metabolism
1. Induce/Expose functional group
2. Hydrolyzed or ester linked for elimination via kidneys
* increased ionization
38
What happens in Phase II Metabolism?
* Conjugation
* Link Parent compound OR Phase I metabolite w/ functional group via covalent link
* EX:
* Morphine: 6-glucouronide metabolite becomes MORE active than parent compound
39
What are the functional groups in Phase II metabolism that become linked with Phase I metabolites
Glucouronic Acid
Sulfate
Amino Acid
Acetate
40
Enzymes
What drives reactions
* Liver:
* GI tract, kidney, lung
* Endoplasic reticulum
41
Cytochrome P450
* Terminal Oxidase in multicomponent e- transfer chain
* AKA: Mixed function oxidase system
* Phase I Type Reactions
42
Enzyme Inhibition
Enzyme does not work right.
Ability to increase amount of parent compound
43
Enzyme Inducer
Enhance enzyme capability
Ability to quickly metabolize parent compound
44
What happens in CYP Substrate + CYP Inducer
Reduced amount of Substrate d/t increased metabolism
EX: Patient on Carbamezapine (Inducer) + Versed (Substrate). Potential for difficult induction/early awakening
45
What happens in CYP Substrate + CYP Inhibitor
Increased Amount of Substrate d/t reduced metabolism
46
What factors effect Metabolism
Genetics, Liver & Kidney Disease, Age
47
Elimination of Drugs
Either unchanged, metabolite, or mix
48
What compounds are easier to eliminate?
Polar/Hydrophilic compounds easier to eliminate than lipophillic compounds
49
How are drugs eliminated through the kidneys?
3 Processes
* Glomerular Filtration - Unbound meds
* Active Tubular Secretion
* P-GP and Other transport Proteins
* Passive Tubular Reabsorption
* Weak Acids & Bases via Concentration Gradient
50
What are routes of elimination other than Kidneys
Bile & Fecal
Sweat, Saliva, Tears
Lungs
51
First Order Kinetics
Pecentage of the Remaining Percentage
52
Zero Order Kinetics
Percentage of the Remaining Med
53
Elimination Rate (k)
k = % of total amt. of drug in body removed per unit of time.
* k = In (ΔC) / time
* t1/2 = ln2/k
* Use medication levels drawn at different times to calc. half-life
EX:
Drug A Level Drawn @ 0630 = 14.7 mcg/mL
Drug A Level Drawn @ 1400 = 3.4 mcg/mL
```
k = 0.32
t1/2 = 2.17
```
54
Purpose of Half Life & Elimination Rate
* Estimate time to steady state
* Estimate time to eliminate med from body
* Predict non-steady state plasma levels
* Predict steady state from non-steady state level
* Determine dosing interverals
55
Steady State
Amt. of drug given over time = amt. of drug eliminated during same time period
Rate in = Rate Out
This is when the the med is at full effect.
56
Dosing Interval & Half Life
Dosing Interval = Half Life
* 1 Half Life: 50%
* 2 Half Lives: 75%
* 3 Half Lives: 87.5%
* 4 Half Lives: 93.75%
* 5 Half Lives: 96.875%
At steady state after 5 Half Lives
57
Does a Loading Dose shorten the time to steady state
No - only brings to therapeutic concentration faster.
Steady state is a kinetic property: rate in = rate out
58
Would you reach steady state faster if the dose was given at one half of the medication's half life
No - it only shortens the time for toxicity.
Rate out still does not equal rate in
59
Questioning Drug Levels
NEVER treat an isolated number - check dosing history
Always treat the patient not the number
1. When was sample obtained w/ respect to the dose?
2. Is the patient at steady state?
3. Is drug serum concentration obtained therapeutic?
60
What level to check for drug efficacy?
Trough Levels
Provide exact draw time in reference to dose given.
61
What level to check for Drug Toxicity
Drug Peak Levels
Provide exact draw time in reference to dose given
62
Context Sensitive Half Time
For Continuous Infusion - the time until med plasma levels reduce by 50% after stopping infusion
* Follows Multi-Comparment Model of Distrubution
* If steady state by d/c: CSHT = t1/2 - even distro throughout tissues
* If not at steady state by d/c: CSHT \< t1/2
* Not clinically useful
63
Creatinine Clearance
CrCl = _[ (IBW) x (140-age)_ X 0.85 female
Cr x 72
* IBW = 45.5 + (2.3 x inches \> 5 ft.)
* IBW 50 + (2.3 x inches \> 5 ft.)
64
Creatinine Clearance Calculation Example
CrCl for Female, 5'6", 140 lbs., 76 y.o. with creatinine of 1.1
CrCl = _[45.5 + (2.3 x 6)] x (140-76) x 0.85]_
1.1 x 72
**CrCl** = **40.73**
65
Modification of Diet in Renal Disease (MDRD) Calculation
* For Excessive Body Weight & Renal Dysfunction
* For chronic, stable kidney disease
* Verified with C-G clinical trials
66
Dosing Weights
* Actual Body Weight (ABW)
* Ideal Body Weight (IBW)
* Adjusted Body Weight
* For Obese (30% + IBW)
* = 0.4(ABW-IBW) + IBW
67
Single Dose Regimen
Reaches peak, then concentration reduces based on t 1/2
68
Continous IV Dosing Regimen
Reaches peak & remains therapeutic until d/c, then concentration reduces based on t 1/2
69
Intermittent Dosing Regimen
Small peaks and troughs until steady state reached
70
Pharmacokinetics In Elderly
* Reduced absorption via carrier proteins
* Reduce first pass metabolism
* Increase fat%, reduced free water
* Poss. reduced albumin concentration
* Increased Alpha-1 Acid Glycoprotein
* Reduced Phase I (CYP450)
* Other disease states, thinning BBB, Gi tract changes
71
Pharmacokinetics in Neonates & Infants
* Higher gastric pH, longer emptying time
* Higher body water:fat ratio
* Reduced/Immature CYP450 enzymes
* Reduced Protein Binding
* Reduced Renal Clearance
72
Dialysis
Diffusion vs. Ultrafiltration
Continous, Intermittent, Peritoneal
Provides an Average CrCl ~ 30 mL/min
73
Will it Be Removed?
Unbound volume \< 3.5 L/kg: TOO BIG to be filtered
Clearance \< 10 mL/min/kg
Dosing Interval Longer than Half Life - Easier to be removed
Molecular weight \< 1000 daltons
