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Spring 2020 - Pharmacology 1 > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

Pharmacokinetics

A

What the Body does to the Medication

Absorption

Distribution

Metabolism

Excretion

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2
Q

Absorption

A

Medication moves to blood stream or final action site

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3
Q

What does the absorption of medication depend on?

A
  • Route of administration
  • Ionization of Molecule
  • Size of Molecule
  • Patient Factors
  • Bioavailability
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4
Q

Lipophilicty

A

Less Ionized, may move accross lipid bilayer

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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

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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

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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
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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
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9
Q

What are GI considerations for Oral Adminstration

A
  • pH
  • Contents
  • Surface Area
  • Blood Flow
  • Motility
  • Flora
  • Complete GI Tract
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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

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11
Q

How does contents in the GI tract effect absorption of meds?

A

Positively or Negatively depending on medication

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12
Q

How does the surface area of the GI tract effect medication absorption?

A

Short bowels, resections, IBD may have reduced oral absorption

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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

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14
Q

How does GI Motility effect med absorption?

A

Too Fast: possible reduced contact time and reduced absorption

Too Slow: possible increased absorption

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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.

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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

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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.
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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
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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%)

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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
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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?

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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
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23
Q

How do meds flow through multiple compartments?

A
  1. Given via any route
  2. Goes to Compartment 1 - usually general circulation.
  3. Goes to Other Compartments or straight to elimination

(Normally 2nd Compartment - Major Organs & 3rd Compartment - Fatty Tissue)

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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
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25
Q

How does low albumin effect free drug concentration?

A

Increases concentration, which can increase toxicity

Ex: Burns, Malnutrtion, Kidney/Liver Disease

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26
Q

Tissue Binding

A

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
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27
Q

In order for a drug to enter an organ, what ability must it have?

A

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.

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28
Q

Blood Brain Barrier

A

Super Compact Wrapping of the Blood Vessels

Very protective - only blood, glucose, and electrolytes that can normally pass

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29
Q

What occurs in fetal plasma and why?

A

Ion trappig of basic drugs because fetal plasma is more acidic

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30
Q

Placental Transfer

A
  • 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
Q

P-Glycoproteins

A
  • Transporter proteins found all over
  • Important for med interactions & drug resistance (cancer cells)
  • Needs ATP ( ABC = ATP binding cassette)
32
Q

Passive Diffusion

A

No Energy, No Carrier

Rapid for liphophilic, nonionic, small molecules

33
Q

Facilitated Diffusion

A

No Energy, Needs Carrier

Drugs bind by noncovalent mechs. Chemically same drugs compete for carrier.

34
Q

Aqueous Channels

A

No Energy, No Carrier

Smalll, hydrophilic drugs (<200mw) diffuse along concentration gradient by passing through these channels/pores.

35
Q

Active Transport

A

Needs Energy & Carrier

Same as facilitated diffusion, but needs ATP to go against concentration gradient

36
Q

Metabolism

A
  • 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
Q

What happens in Phase I Metabolism

A
  1. Induce/Expose functional group
  2. Hydrolyzed or ester linked for elimination via kidneys
    • increased ionization
38
Q

What happens in Phase II Metabolism?

A
  • 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
Q

What are the functional groups in Phase II metabolism that become linked with Phase I metabolites

A

Glucouronic Acid

Sulfate

Amino Acid

Acetate

40
Q

Enzymes

A

What drives reactions

  • Liver:
    • GI tract, kidney, lung
    • Endoplasic reticulum
41
Q

Cytochrome P450

A
  • Terminal Oxidase in multicomponent e- transfer chain
    • AKA: Mixed function oxidase system
  • Phase I Type Reactions
42
Q

Enzyme Inhibition

A

Enzyme does not work right.

Ability to increase amount of parent compound

43
Q

Enzyme Inducer

A

Enhance enzyme capability

Ability to quickly metabolize parent compound

44
Q

What happens in CYP Substrate + CYP Inducer

A

Reduced amount of Substrate d/t increased metabolism

EX: Patient on Carbamezapine (Inducer) + Versed (Substrate). Potential for difficult induction/early awakening

45
Q

What happens in CYP Substrate + CYP Inhibitor

A

Increased Amount of Substrate d/t reduced metabolism

46
Q

What factors effect Metabolism

A

Genetics, Liver & Kidney Disease, Age

47
Q

Elimination of Drugs

A

Either unchanged, metabolite, or mix

48
Q

What compounds are easier to eliminate?

A

Polar/Hydrophilic compounds easier to eliminate than lipophillic compounds

49
Q

How are drugs eliminated through the kidneys?

A

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
Q

What are routes of elimination other than Kidneys

A

Bile & Fecal

Sweat, Saliva, Tears

Lungs

51
Q

First Order Kinetics

A

Pecentage of the Remaining Percentage

52
Q

Zero Order Kinetics

A

Percentage of the Remaining Med

53
Q

Elimination Rate (k)

A

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
Q

Purpose of Half Life & Elimination Rate

A
  • 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
Q

Steady State

A

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
Q

Dosing Interval & Half Life

A

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
Q

Does a Loading Dose shorten the time to steady state

A

No - only brings to therapeutic concentration faster.

Steady state is a kinetic property: rate in = rate out

58
Q

Would you reach steady state faster if the dose was given at one half of the medication’s half life

A

No - it only shortens the time for toxicity.

Rate out still does not equal rate in

59
Q

Questioning Drug Levels

A

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
Q

What level to check for drug efficacy?

A

Trough Levels

Provide exact draw time in reference to dose given.

61
Q

What level to check for Drug Toxicity

A

Drug Peak Levels

Provide exact draw time in reference to dose given

62
Q

Context Sensitive Half Time

A

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
Q

Creatinine Clearance

A

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
Q

Creatinine Clearance Calculation Example

A

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
Q

Modification of Diet in Renal Disease (MDRD) Calculation

A
  • For Excessive Body Weight & Renal Dysfunction
  • For chronic, stable kidney disease
  • Verified with C-G clinical trials
66
Q

Dosing Weights

A
  • Actual Body Weight (ABW)
  • Ideal Body Weight (IBW)
  • Adjusted Body Weight
    • For Obese (30% + IBW)
    • = 0.4(ABW-IBW) + IBW
67
Q

Single Dose Regimen

A

Reaches peak, then concentration reduces based on t 1/2

68
Q

Continous IV Dosing Regimen

A

Reaches peak & remains therapeutic until d/c, then concentration reduces based on t 1/2

69
Q

Intermittent Dosing Regimen

A

Small peaks and troughs until steady state reached

70
Q

Pharmacokinetics In Elderly

A
  • 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
Q

Pharmacokinetics in Neonates & Infants

A
  • Higher gastric pH, longer emptying time
  • Higher body water:fat ratio
  • Reduced/Immature CYP450 enzymes
  • Reduced Protein Binding
  • Reduced Renal Clearance
72
Q

Dialysis

A

Diffusion vs. Ultrafiltration

Continous, Intermittent, Peritoneal

Provides an Average CrCl ~ 30 mL/min

73
Q

Will it Be Removed?

A

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

Spring 2020 - Pharmacology 1 (11 decks)

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