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Pharmacology > Lecture 2-3: General Principles of Pharmacokinetics > Flashcards

Lecture 2-3: General Principles of Pharmacokinetics Flashcards

1
Q

What is pharmacokinetics

A

Describes the process by which the body handles the drugs presented to it

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2
Q

What are 4 the pharmacokinetic processes

A
  1. Absorption
  2. Distribution
  3. Metabolism
  4. Excretion
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3
Q

What are ways drugs can be absorbed

A
  1. Oral intake
  2. Inhalation
  3. Injection
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4
Q

Drugs enter the bloodstream and interact/bind with ___

A

Proteins

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5
Q

Do bound or free drugs leave bloodstream and go to site of action

A

Free

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6
Q

Size of ____ determines what size of molecules can get in and out of bloostream

A

Fenestrated capillaries

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7
Q

What is the distribution process of drugs

A
  1. Enter liver or other sites of bio transformation
  2. Either enter bile to be eliminated or can be reabsorbed or enter circulation
  3. Free drug when migrates to site of action or inactive tissues
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8
Q

How are drugs eliminated

A
  1. Transported in Bile and eliminated in feces
  2. Air
  3. Urine via kidney
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9
Q

What is the major site of elimination/excretion

A

Kidney—> urine

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10
Q

What are the 3 kinds of passive transported

A
  1. Simple diffusion
  2. Channel mediated
  3. Transporter mediated
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11
Q

What is passive/simple diffusion

A

Water soluble and lipid soluble drugs penetrate membrane

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12
Q

What does carrier mediated transport depend on

A
  1. Structure specifics- # of transporter molecules
  2. Competition for binding
  3. Tmax- # of transporters finite
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13
Q

What are the 2 types of carrier mediated transport

A
  1. Facilitated diffusion
  2. Active transport (ATP)
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14
Q

What is filtration

A

Glomerular filtration in kidney

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15
Q

What is transcytosis (pinocytosis)

A

Drug molecules and fluid get engulfed by vesiculation of cell membrane

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16
Q

Mechanisms of membrane penetration follow ____ gradient

A

Concentration gradient

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17
Q

Are most drugs in clinical use weak or strong acids/bases

A

Weak

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18
Q

The extent of ionization is described by what equation

A

Henderson hasselbachs

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19
Q

In order for a drug to be lipid soluble does it need to be ionized or non-ionized and why

A

Non-ionized, if it is ionized it will bind H20 and become large and charged therefore will not be able to go through membrane and will be eliminated

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20
Q

Do acidic drugs have lower or higher pKa’s

A

Lower

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21
Q

Do basic drugs have lower or higher PKa’s

A

Higher

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22
Q

What is the ionized form of an acid

A

A-

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23
Q

What is the unionized form of an acid

A

HA

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24
Q

What is the ionized and unionized form of basic drug

A

Unionized form: B
Ionized form: BH+

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25
Q

What is the Henderson hassalbach equation

A

PH-pka=log (A-)/(HA)

*B and BH basic

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26
Q

Is a weak acid LESS ionized in an acidic or basic medium

A

Acidic medium and therefore more lipid soluble and readily absorbed

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27
Q

If you have a weak acid and want it to be eliminated and not absorbed what type of medium should be created

A

Basic medium, will ionize acid and therefore no longer lipid soluble

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28
Q

Is a weak basic drug LESS ionized in an acidic or basic medium

A

Basic medium and therefore rapidly absorbed

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29
Q

If you have a weak basic drug that you want to be eliminated and not absorbed should the medium be acidic or basic

A

Acidic- will ionize the drug and therefore no longer lipid soluble and will be eliminated

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30
Q

What is ion trapping

A

When a weak base or acid diffuses into an acidic or basic medium, respectively and becomes ionized and will accumulate in that environment- trapped and will get eliminated

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31
Q

Are strong or weak acids/bases always ionized in the body and therefore not lipid soluble

A

Strong

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32
Q

Are mineral acids and quaternary ammonium compounds like methylnaltrexone and mineral bases strong or weak acids/bases

A

Strong

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33
Q

If a drug is non-ionized what is the concentration of that drug in 2 separate “compartments”

A

Concentration is equal on both sides because the drug is lipid soluble and will therefore diffuse across the membrane via a concentration gradient until equilibrium is reached

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34
Q

What is the concentration of an ionized form dependent on

A

Environmental pH (increase acidity, increase ionized bases and vice versa) and pKa

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35
Q

The total concentration on each side of the compartment is the sum of what

A

Concentrations of the ionized and non-ionized form of the drug

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36
Q

Compartment example: Weak acid
- compartment #1: pH=3, pka=4 nonionized=1, ionized=0.1 and total= 1.1

-compartment #2: pH=7, pka=4

What do you expect the concentration of nonionized and ionized to be in compartment #2?

A

Nonionized=1–> will be equal to compartment #1 because non-ionized form is freely diffusible regardless of different pH

Ionized form: greater in compartment 2 because the weak acid will become ionized in the more basic pH of 7 in compartment #2

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37
Q

Acids are accumulated in a ___ environment

A

Basic

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38
Q

Bases are accumulated in a ___ environment

A

Acidic

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39
Q

What can be used to make the urine more acidic and increase the elimination of bases

A

Ammonium chloride

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40
Q

What can be used to make the urine more basic and increase elimination of acids

A

Sodium bicarbonate

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41
Q

Ex: dog eats a lot of phenobarbital which is a barbiturate acid. What can you give in order to excrete the acid to maintain homeostatic pH

A

Sodium bicarbonate- basic which will ionize acid no longer lipid soluble so won’t be absorbed into bloodstream

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42
Q

Are uniports, symports, and antiports forms of active or passive transport

A

Active

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43
Q

What type of active transport is an H+ pump

A

Uniport

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44
Q

What type of active transport does glucose uptake use

A

Symport

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45
Q

What type of active transport does Na+/K+ ATPase use

A

Antiport

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46
Q

What is permeability glycoprotein (P-gp) also known as

A

multi drug resistant protein (MDR1) or ATP binding cassette subfamily B membrane 1 (ABCB1)

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47
Q

What does P-gp do

A

Utilizes ATP as energy to pump out a wide variety of substrates across extra- and intracellular membranes

Utilized to excrete toxins

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48
Q

Where is P-gp distributed in body

A

Widely distributed- found in intestinal mucosa, hepatocytes, renal proximal tubular cells, adrenal gland, and capillary endothelial cells making BBB

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49
Q

What is absorption

A

The process whereby a drug gains entry into body fluids, usually blood that distribute throughout the organism

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50
Q

What factors modify absorption

A
  1. Solubility
  2. Dissolution
  3. Concentration
  4. Blood flow
  5. Absorbing surface
  6. PH
  7. Contact time
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51
Q

How does pH modify absorption

A

Weak Acid drug in basic environment will decrease absorption because ionized Weak acid in acidic environment is lipid soluble

**same concept applies to bases

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52
Q

What is bioavailability

A

Amount of active drug available at the site of action

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53
Q

Which form of drug administration has 100% bioavailability

A

IV- directly into circulation

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54
Q

What is the equation that represents the relationship between IV and oral administration of the same drug

A

Dose-IV= Dose-PO(F)

F=bioavailability

Helps convert IV to PO dose

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55
Q

Bioavailability is the summary result of what 4 things

A
  1. Decomposition /inactivation of drugs in the intestine
  2. Degree of absorption
  3. Metabolism in the wall of the gut or in the liver
  4. Transport of drug by P-gp back to lumen of the gut
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56
Q

What is the first pass effect

A

Initial metabolism of a drug while passing through the wall of the gut and liver

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57
Q

If there is little first pass effect does a small or large amount of the drug get into the system

A

Large (vice versa)

58
Q

Which form of drug administration would have a large first pass effect and therefore a smaller % gets into blood

A

Orally

if unable to increase amount entering blood, drug must be given IV

59
Q

What are the three main routes of administration

A
  1. Oral
  2. Parenteral
  3. Topical
60
Q

What are the 7 forms of parenteral administration

A
  1. IV
  2. IM
  3. SQ
  4. Intraperitoneal
  5. Intraarterial
  6. Intrathecal
  7. Inhalation
61
Q

What are the four forms of topical administration

A
  1. Skin/transdermal
  2. Eye
  3. Buccal/sublingual
  4. Rectal
62
Q

What are some disadvantages of oral administration

A
  1. Emesis
  2. Destruction of drug by enzymes or by low pH
  3. Metabolism by the intestinal flora
  4. Absorbed drug is exposed to the liver
  5. Gastric emptying time
  6. Binding to food
63
Q

What is slow release formulation

A

Designed to produce slow uniform absorption of the drug for several hours

64
Q

What is a negative side effect of slow release formulation

A

Absorption is often irregular and erratic

65
Q

Which form of parenteral route has no absorption phase

A

IV-directly injected into systemic circulation

66
Q

What form of parenteral route is important route of entry for toxic substances

A

Inhalation

67
Q

Topical application of drugs includes to what areas

A

Skin, eye, nose throat (usually for local effects) and systemic absorption

68
Q

Under normal conditions the ___binding capacity is much larger than the drug concentration. Consequently the free fraction of drug is generally ____

A

Protein, constant

69
Q

How do storage depots of drugs affect plasma levels and 1/2 lives

A

Decreasing plasma levels and prolongs 1/2 life by accumulating in body

70
Q

What are some storage depots of drugs

A

Fat, tissues, bone

71
Q

What are some common sites of drug exclusion

A
  1. CSF (no fenestrated membranes- only lipid soluble can pass)
  2. Ocular fluid
  3. Endolymph fluid
  4. Fetal fluid
  5. Pleural fluid
72
Q

When drugs enter the body and bloodstream where are they redistributed first

A

1st (most) goes to the brain quickly
Then slowly makes its way to affected tissues

73
Q

What is the initial and secondary redistribution/effect of thiobarbiturates and benzodiazepines)

A

Initial effect: anesthetic
Then goes to fatty tissue

74
Q

What is the apparent volume distribution (Vd) equation

D-IV/C0

A

Vd= Total amount of drug in the body/concentration in plasma

75
Q

What is C0 (mg/L)

A

Plasma concentration of the drug at time zero

76
Q

What is D-IV (mg)

A

Intravenous dose

77
Q

Sample problem: 200mg of drug A is administered IV. Plasma concentration was found to be 5mg/mL at time zero. Calculate Vd

A

Vd= dose of drug administered/plasma concentration

= (200mg)/(5mg/L)= 40L

78
Q

What is the standard value of plasma compartment fluid

A

3L

79
Q

What is the standard value of extracellular fluid compartment

A

12L

80
Q

What is the standard value of total body water

A

41L

81
Q

What is the distribution and binding of drugs that show a large Vd

A

Extensive distribution and bind extensively in peripheral tissues

*vice versa

82
Q

Would Vd be low or high if the drug is mostly present in the plasma

A

Low

83
Q

Drugs with a very high plasma protein binding have low or high Vd

A

Low

84
Q

What is the principal goal of metabolism or biotransformation of drugs and xenobiotics

A

Elimination

85
Q

What are some characteristics of most pharmacologically active drugs

A
  1. Lipid soluble
  2. Unionized or partially ionized
  3. Strongly bound to plasma proteins or other tissues
  4. Not readily excreted by the kidney
  5. Tend to remain in body for a long time
86
Q

What happens during phase I metabolism of drugs

A

Form drug metabolite with modified activity and inactive drug metabolite

Decrease lipid solubility

87
Q

What happens during phase II metabolism

A

Add conjugate- large charged molecule that will promote elimination and form hydrophilic, polar molecules

88
Q

Absorbed drugs are initially lipophilic and transform to ____ to be eliminated

A

Hydrophilic

89
Q

Phase I reactions usually convert lipid soluble parent to more __ metabolites

A

Polar

90
Q

What functional groups are introduced or unmasked during phase I reactions that will decrease lipid solubility

A

OH, SH, NH2

91
Q

What are the two classes of metabolism enzymes in phase I reactions

A
  1. Nonmicrosomal
  2. Microsomal
92
Q

Are nonmicrosomal inducible or non-inducible

A

Non-inducible

93
Q

What are the three nonmicrosomal enzymes

A
  1. Esterases and amidases
  2. Monoamine oxidases
  3. Alcohol and aldehyde dehydrogenases
94
Q

What do esterases and amidases metabolize

A

Pseudocholinesterases- genetic polymorphism

Important for elimination of local anesthetics, succinylcholine

95
Q

What do monoamine oxidases metabolize

A

Endogenous amines- catecholamines, serotonin

96
Q

What does alcohol and aldehyde dehydrogenases

A

Ethylene glycol metabolism (toxicology)

97
Q

Are microsomal reactions inducible or non-inducible

A

Inducible

98
Q

Where do microsomal metabolic enzymes come from and what are they made of

A

Come from endoplasmic reticulum- layers of enzyme and lipid layers- so can metabolize lipid soluble drugs

99
Q

What is the mechanism of drug oxidation for microsomal reactions

A

P450

100
Q

What are the inducers of P450

A
  1. Rifampin
  2. Barbiturates
  3. Phenytoin
  4. Glucocorticoids
  5. St. John’s wort
101
Q

What are the inhibitors of P450 microsomal reactions

A
  1. Cimetidine
  2. Ketoconazole
  3. Diltiazem
  4. Erythromycin
  5. Verapamil
  6. Fluoxetine
102
Q

What is the result of phase II synthetic reactions

A

Large molecular weight, increased polarity, diminished biological activity

103
Q

What is the only phase II reaction that is microsomal and inducible

A

Glucuronidation

104
Q

What are the 7 types of Phase II reaction conjugations

A
  1. Glucuronidation
  2. Acetylation
  3. Glutathione
  4. Glycine
  5. Sulfate on
  6. Methylation
  7. Water
105
Q

What is the process of enterohepatic circulation

A
  1. Drug enters liver, becomes conjugated
  2. Conjugated drug enters bile to small intestines
  3. Drug conjugate is cleaved from drug- smaller, lipophilic and therefore can get reabsorbed back into circulation
106
Q

How does enterohepatic circulation effect the 1/2 of a drug

A

Increases

107
Q

How do antibiotics effect enterohepatic circulation

A

Get rid of bacteria/enzymes that cleave drug conjugate therefore drug remains large and doesn’t get reabsorbed- is eliminated

108
Q

What are some common enterohepatic circulation drugs

A

Opioids, benzodiazepines

109
Q

What are the three ways in which the renal system excretes drugs and drug metabolites

A
  1. Glomerular filtration
  2. Active tubular secretion or reabsorption (especially in PT)
  3. Passive diffusion across tubular epithelium
110
Q

How does the proximal tubule affect drug concentration

A

Increases it because 65% of Na+ and H20 are reabsorbed

111
Q

How does the proximal tubule reabsorption of Na+ and H2O effect the concentration gradient for the drug

A

Will generate strong concentration gradient if the drug is capable of diffusion and it will go back into blood stream

112
Q

If we want to eliminate of a weak acid drug via the tubular system what can we do the tubular fluid

A

Can make tubular fluid more basic by adding sodium bicarbonate to ionize the weak acid therefore making it not lipophilic and can’t be reabsorbed

113
Q

If we have a weak base drug that we want to eliminate via the tubular system what can we do to tubular fluid

A

Make tubular fluid more acidic by adding ammonium chloride therefore ionizing the drug and making it less lipophilic so its not absorbed

114
Q

Are the following drugs acid or base drugs: Penicillin, ampicillin, cephalosporins, furosemide, thiazide diuretics, probenecid, salicylate, phenylbutazone

A

Acid

115
Q

Are the following drugs acid or base drugs: histamine, amiloride, cimetidine, procainamide, neostigmine, trimpethoprim, atropine

A

Basic

116
Q

What is clearance

A

Measure of the capacity to remove the drug

Proportionality constant that relates the rate of drug elimination to its plasma concentration

117
Q

What is the equation for systemic clearance

A

CL=CL(renal) +CL (hepatic) +CL (lung) + CL (others)

118
Q

What is the rate of elimination equation

A

Rate of elimination= CL(c)

119
Q

What is the equation for 1/2 life

A

T 1/2= ln2(Vd)/CL

120
Q

what is the equation for elimination rate constant

A

Kel=CL/Vd

121
Q

Describe the two compartment model

A

Dose is administered and enters central compartment then travels to peripheral compartments. It must then travel back to central compartment where it is excreted into Bowmans’ capsule

122
Q

What is first order elimination

A

Constant proportion of the drug is eliminated in a unit time

123
Q

First order elimination follows ___ kinetics

A

Exponential

124
Q

First order elimination example: 100mg unit of drug is given. 50% of the drug is eliminated at each 1/2 life . How many units are eliminated in first half life and then second half life

A

1st 1/2 life eliminate 50 units
2nd 1/2 life= 25 units

125
Q

First order elimination gets ride of drugs at ___proportion but ____ rate

A

Same proportion but different rate

126
Q

What is half life

A

Time required to change the amount of the drug in the body by 1/2 of 50%

127
Q

What are the assumptions regarding 1/2 life

A

Body is a single compartment, size is the volume distribution (Vd), the drug is distributed equally, the drug in the plasma is in equilibrium with total volume

128
Q

What is zero order elimination

A

Elimination process gets saturated after a high dose and only a constant amount is eliminated in urine

129
Q

What are some examples of drugs that follow zero order elimination

A

Aspirin, fentanyl, and phenytoin

130
Q

What order of elimination is followed when >Vmax

A

Zero order

131
Q

What is repeated administration

A

Same doses at the same dosing intervals

132
Q

Which order of elimination is repeated administration for

A

1st order

133
Q

How many half lives must a drug go through to develop a steady state

A

5

134
Q

Plasma concentration at a steady state is directly proportional to the ___ and indirectly proportional to ___

A

Directly proportional to dose and inversely proportional to clearance

135
Q

Would you want to shorten or lengthen the dosing interval to result in a higher steady state concentration

A

Shorten

136
Q

What would have to the steady state if you lengthen dose interval

A

Gradual decrease of the plasma level and a new lower steady state

137
Q

What is the purpose of a loading dose

A

To reach immediate therapeutic concentration, immediate biological effect

138
Q

What is the loading dose equation

A

Loading dose= Vd(TC)

139
Q

What is the loading dose dependent on

A

Volume distribution and target concentration

140
Q

What is the loading dose not dependent on

A

1/2 life and clearance of the drug

141
Q

Dosing rate= elimination rate- what is the equation

A

CL (TC)/F

142
Q

What is the equation for maintenance dose

A

Maintenance dose= CL(TC)/(F) x dosing interval

Pharmacology (13 decks)

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