Chapter 7- Review Exam #2

Front 1

What is Pharmacokinetics?

Back 1

the study of the changes in the concentration of a drug during the processes of absorption, distribution, metabolism or biotransformation, and elimination from the body.
- What the body does to a drug once it has been introduced into a system.

Front 2

What system delivers the drug to various tissues?

Back 2

the vascular system

Front 3

Once in the blood, what does the drug do?

Back 3

it can remain within the vascular system and body water, bound to proteins, or cross membranes into tissues.

Front 4

The unbound drug enters?

Back 4

organs, muscles, fat and, of greatest importance, the site of activity—the receptor.

Front 5

The transfer of drug to different sites depends on? 4

Back 5

LIMP
i. Lipid Solubility
ii. Ionization (degree of ionization)
iii. Molecular Size
iv. Protein Binding

Front 6

Uptake also depends on?

Back 6

the amount of blood flow to the tissue and the concentration gradient of the drug across membranes

Front 7

How does molecular size affect pharmacokinetic activity?

Back 7

The smaller the agent, the better it crosses the lipid barriers and membranes of tissues (molecule MW> 100-200 don’t cross).

Front 8

Transport can be either ?

Back 8

active or passive

Front 9

What is active transport?

Back 9

Generally faster and require energy. Uses carriers that form complexes with drug molecules on the membrane surface. Involves movement against concentration gradients from a low to high concentrations.

Front 10

What is passive transport?

Back 10

Does not require energy. Transfer of drug from high to low concentration

Front 11

Most drugs are ?

Back 11

salts of either weak acids or weak bases

Front 12

Acids and bases exist in what forms?

Back 12

ionized and non-ionized

Front 13

What is ionized?

Back 13

charged form, water soluble, unable to cross cell membranes

Front 14

What is nonionized?

Back 14

uncharged, lipid soluble, diffuse across cell membranes (BBB, gastric, placenta) to reach effect

Front 15

The higher the degree of ionization?

Back 15

the less access the drug has across tissues such as the GI tract, BBB, or liver hepatocytes

Front 16

Ionized drugs not generally taken?

Back 16

orally because they are not absorbed, therefore, not metabolized by the liver, more commonly, they are excreted by the kidneys.

Front 17

The Dissociation Constant (pKa) and its pH gradient across a membrane determines?

Back 17

the degree of ionization of an agent at a particular site.

Front 18

Basic Drugs are proton?

Back 18

ACCEPTORS

Front 19

Acidic Drugs are proton?

Back 19

DONORS

Front 20

pKa for basic drugs =?

Back 20

pKa = pH = log (HA+)/A-

Front 21

pKa for acidic drugs =?

Back 21

pKa = pH = log (A-)/(HA+)

Front 22

When the pH and pKa are equal, they exist in?

Back 22

equal amounts

Front 23

If a drug is a weak acid and if the pH it is placed in is below that of the PK, most of the drug’s protons are associated?

Back 23

with the drug molecule, therefore the uncharged species predominates and is lipid soluble.

Front 24

If pH is below the pK for a weak base, protons exist?

Back 24

in abundance, and most of the drug tends to ionize as protons are donated by the drug molecule, resulting in a highly charged species that is lipid insoluble.

Front 25

For Weak Acids

Back 25

pH > pKa Ionized form
pH < pKa Nonionized form predominates

Front 26

For Weak Bases

Back 26

pH > pKa Non ionized form predominates
pH< pKa Ionized form predominates

Front 27

Drugs are weak acids or weak bases, their state of ionization varies with pH according to the?

Back 27

Henderson-Hasselbach equation.

Front 28

What is Ion Trapping?

Back 28

Degree of ionization for a specific agent can vary across a membrane that separates fluids with different pH values.

Front 29

When may ion trapping occur?

Back 29

LA overdose, high concentrations of a basic LA enter the CNS and cause toxicity. Acidosis traps drug in the brain, resulting in prolonged and a more intense toxicity.

Front 30

What is the Protein Binding Theory?

Back 30

Change protein binding = change drug’s clinical effect

Front 31

What is the most abundant plasma protein? Favors binding what type of drugs?

Back 31

albumin, acidic

Front 32

Alpha-1 acid glycoprotein and Beta-globulin favor binding?

Back 32

basic

Front 33

Protein binding influences how a drug is?

Back 33

distributed because protein-bound drug is not free to act on receptors. High protein binding prevents the drugs from leaving the blood to enter into tissues (resulting in high plasma concentrations).

Front 34

What does extensive protein binding cause?

Back 34

slow drug elimination

Front 35

Kinetic binding is?

Back 35

a saturable, finite, process in that protein binding can be overcome by adding more agent.

Front 36

The bond between drug and protein is usually?

Back 36

weak

Front 37

Drugs with protein binding > 90% have an?

Back 37

unexpected intensification of their effect if they are displaced from plasma protein (fentanyl, Propofol, propranolol, phenytoin, warfarin, diazepam).

Front 38

Drugs with protein binding < 90% have?

Back 38

little change in free fractions (not a concern)

Front 39

increased unbound drug in plasma = increased?

Back 39

rate of elimination. Therefore, when plasma proteins are lower, total drug concentrations are lowered, but unbound concentrations are not affected

Front 40

After how many half-lives do the unbound concentrations returns to previous steady state?

Back 40

4

Front 41

What determines how much of the drug gets into the systemic circulation?

Back 41

the route of administration

Front 42

When the entire amount is delivered, it is said to have ?

Back 42

100% bioavailability

Front 43

The enteral or oral route tends to have?

Back 43

lower bioavailability due to confounding factors (pH, stress, food). Because of the high acidity (pH 1.5-2.5) in the stomach, drugs that are highly acidic are highly absorbed. Basic drugs tend to be absorbed in the small intestines (pH 7-8).

Front 44

Presystemic Elimination, what three ways can this occur?

Back 44

elimination of drugs by the GI system before the drug reaches systemic circulation. Occurs three ways (1) stomach acids hydrolyze the drug, (2) enzymes in stomach wall deactivate the drug or (3) the liver biotransforms ingested drug before it reaches the effect site.

Front 45

First Pass Elimination

Back 45

Drugs absorbed from the GI tract after oral ingestion enter the portal venous blood and pass through the liver first, with subsequent delivery to the tissue receptors. The drug may undergo extensive hepatic metabolism before the chance to enter the systemic circulation

Front 46

Sublingual and buccal routes of administration bypass the?

Back 46

presystemic, portal first pass and the drug is rapidly delivered to the SVC for transport.

Front 47

Proximal Rectum

Back 47

drugs absorbed into the portal system via the superior hemorrhoidal vein, undergoing significant first pass elimination in the liver before entering systemic circulation.

Front 48

Distal Rectum

Back 48

No presystemic elimination and have more predictable circulatory levels.

Front 49

Parenteral Administration or?

Back 49

Injection. The most rapid and predictable route.

Front 50

Pulmonary

Back 50

Lungs have large SA.

Front 51

Transdermal (topical)

Back 51

chosen for administration of sustained release agent, providing the patient with a steady therapeutic plasma concentration. Usually both lipid and water soluble.

Front 52

Bioavailablity

Back 52

The extent to which a drug reaches it effect site after introduction in the circulatory system.

Front 53

The rate of absorption establishes?

Back 53

a drugs duration of action and intensity

Front 54

What factors affected bioavailability? 5

Back 54

Lipid solubility, pH, pKa, blood flow, MW.

Front 55

What is the pH role in bioavailability?

Back 55

LA (weak base) is injected into an acidic environment, the LA is highly ionized (basic agent in acidic env) therefore cannot enter the lipid nerve membrane to reach the site of action

Front 56

What is the Single compartment model of distribution?

Back 56

entire body, homogeneous distribution occurs. When changes in drug concentration occur in any of these tissues, a corresponding qualitative change occurs in the rest.

Front 57

Two-compartment model of distribution?

Back 57

(1) central, composed of intravascular fluid and the highly perfused tissues such as the heart, lungs, brain, liver and kidney, represents 10% of body mass in adult yet receives 75% of the CO (vessel rich group). (2) peripheral, composed of muscle, fat, bone (vessel poor group) and represents 90% of body mass, yet only receives 25% of the CO.

Front 58

In the 2-compartment model drugs leave the central compartment in what two phases?

Back 58

(1) distribution into the tissues or (2) metabolism or excretion.

Front 59

As blood flows through the tissues, serum concentrations do what?

Back 59

drop because of this distribution, and the fall in plasma concentration is described mathematically via the alpha half-life.

Front 60

When the plasma concentration falls below the tissue concentration, the drug does what?

Back 60

reemerges from the highly perfused tissue, and enters the plasma serum, and is again redistributed.

Front 61

Volume of Distribution (Vd)

Back 61

Vd is a proportional expression that relates the amount of drug in the body to the serum concentration. It is the apparent volume in which the drug is distributed after it has been introduced into the system.

Front 62

Vd=

Back 62

Dose of drug/Plasma concentration of drug

Front 63

Vd is used to calculate what?

Back 63

the loading dose of a drug to achieve a steady state.

Front 64

A drug with a large Vd has _____ concentrations in the plasma. What about elimination?

Back 64

very low concentrations in the plasma
-very little drug would be available to the organs for elimination.

Front 65

Vd is affected by? 3

Back 65

lipid solubility, plasma protein binding, and molecular size.

Front 66

Large Vd means a drug is? 3 Distribution is _____. Elimination is_______.

Back 66

free, unbound, lipid soluble. Distribution is rapid, but elimination is slow.

Front 67

Structure-Activity Relationship

Back 67

Minor modifications in the drug structure can result in major changes in pharmacologic properties.

Front 68

Stereochemistry

Back 68

A carbon-containing compound usually exists as stereoisomer-molecules with the same chemical bonds but different configurations in their fixed spatial arrangements.

Front 69

Enantiomers

Back 69

stereoisomers that are non-superimposable mirror images of each other

Front 70

Plasma Concentration Curve

Back 70

A schematic depiction of the decline in plasma concentrations of a drug with time after rapid intravenous injection in the central compartment plotted on a logarithmic graph.

Front 71

y-axis=
x-axis=

Back 71

plasma concentration
time after dose was injected

Front 72

Alpha phase

Back 72

the distribution phase, the first phase of the curve which represents the initial dispersal of drug into the tissue compartments from the central compartment

Front 73

What does the slope look like in the alpha phase for highly lipid soluble drugs?

Back 73

steep, which demonstrates the ability of these agents to cross lipid membranes and be distributed into the peripheral compartment rapidly, leading to the fall in plasma levels.

Front 74

Beta phase

Back 74

elimination, the second slower phase of elimination. Once equilibration has been reached, the concentration falls exponentially. Gradual process. Flatter line.

Front 75

Biexponential curve

Back 75

steep slope = distribution
flatter slope = elimination.

Front 76

The elimination phase of the plot is used to determine?

Back 76

the elimination half-life of drugs for dosing intervals.

Front 77

Steady State

Back 77

Stable concentration of a drug is acheived.
-At this point, drug elimination is equal to the rate at which the drug is made available, so the amount of drug being added to the system is equal to the amount being eliminated.

Front 78

Metabolism is synomonous with ?

Back 78

biotransformation

Front 79

Metabolism is?

Back 79

An enzyme-catalyzed change in the chemical structure of agents, usually involves more than one pathway.

Front 80

What is the major organ for metabolism?

Back 80

the liver

Front 81

What is the goal of metabolism?

Back 81

change lipid soluble agents into more soluble water soluble forms so the kidneys can eliminated them from the body.

Front 82

For most drugs, metabolism occurs as a?

Back 82

first order process, meaning the drugs is cleared at a rate proportional to to the amount of drug present in the plasma. A constant fraction of total drug is metabolized in a set time period. The greatest amount of drug eliminated per unit time occurs when the concentration of drug is the highest.

Front 83

Zero order kinetics

Back 83

Even at therapeutic levels, they exceed the body’s ability to excrete or metabolize the drug (ie alcohol). A constant amount of drug is cleared regardless of the plasma concentration. The amount of drug cleared is independent of its plasma concentration.

Front 84

Oxidation

Back 84

(adding oxygen to molecule): Loss of electrons

Front 85

Oxidation is catalyzed by?

Back 85

enzymes of CYP-450 system

Front 86

Reduction

Back 86

gaining of electrons, also uses P450 enzymes

Front 87

Hydrolysis

Back 87

addition of water to an ester or amide to break the bond and form two smaller molecules.

Front 88

The end result of phase I reactions is typically a?

Back 88

more polar compound that is easily excreted by the kidneys

Front 89

Phase II Reactions

Back 89

Referred to as synthetic reactions because the body actually synthesizes a new compound. Conjugation

Front 90

The product of Phase II reactions usually ?

Back 90

have little to no biologic activity

Front 91

What does conjugation lead to?

Back 91

a more polar compound that is more highly ionized at physiologic pH and therefore more easily extractable by the kidneys by glomerular filtration

Front 92

The CYP-450 is also called the ?

Back 92

mixed function system because it involves both oxidation and reduction steps and has low substance specificity.

Front 93

Elimination Half-times

Back 93

the time necessary for the plasma content of the drug to drop to half of its prevailing concentration after a rapid bolus injection.

Front 94

A drug is considered fully eliminated when ?

Back 94

95% of the drug has been eliminated.

Front 95

How many half-lifes are usually required?

Back 95

4-5

Front 96

In first order kinetics, half life is?

Back 96

constant

Front 97

Context Sensitive Half-time.

Back 97

Time to halving the blood concentration after termination of drug administration by infusion.

Front 98

Clearance is directly proportional to? inversely proportional to?

Back 98

-Directly proportional to the dose
-Inversely related to the agent’s half-life as well as its concentration in the central compartment.

Front 99

Two main organs for clearance

Back 99

Liver and Kidneys

Front 100

Clearance=

Back 100

blood flow x extraction ratio

Front 101

Clearance by liver depends on what two things?

Back 101

the hepatic enzymes and the degree of protein binding.

Front 102

Clearance by the kidney excretion includes? 3

Back 102

glomerular filtration, active tubular secretion and some reabsorbtion.

Front 103

What else can affect the elimination of drugs?

Back 103

the urine, Weak acids are better excreted in alkaline urine, and weak bases are more readily excreted in acid urine

Front 104

List four other things that influence pharmacokinetics?

Back 104

age, gender, temperature, and disease comorbidities

Front 105

How does age affect pharmacokinetics?

Back 105

Elderly
-decreased renal function, resulting in impaired excretion of agents that are eliminated in the urine.
- Cr is an indicator of renal fx, and parallels the kidneys ability to excrete drugs and is useful in predicting renal pharmacokinetics in patients.
-decreased liver blood flow, decreasing the metabolism of agents with high extraction ratios.

Front 106

What is different about babies that affect pharmacokinetics?

Back 106

poor renal function in the first year of life and have an immature liver so they cant metabolize certain agents.

Front 107

Are males or females more sensitive to muscle relaxants?

Back 107

females

Front 108

M or F more sensitive to propofol?

Back 108

males

Front 109

Who is more likely to experience recall?

Back 109

females

Front 110

Pharmacogentics

Back 110

the study of variations in human genes that are responsible for different responses to drug therapy.

Front 111

Polymorphisms

Back 111

variations in the DNA sequences that occur in at least 1% of the population

Front 112

Do genetic polymorphisms occur in most if not all of CYP-450 enzymes?

Back 112

YES

Front 113

Ion trapping also occurs in?

Back 113

mother and fetus, fetus is more acidic than mother

Front 114

List 6 drugs that go through substantial first-pass elimination?

Back 114

1. ASA
2. Levodopa
3. Metoprolol
4. Morphine
5. Propranolol
6. Verapamil

Front 115

What is absorption dependent on with IM or subq injection? 2

Back 115

the capillary flow to the area and the lipid solubility of the agent

Front 116

The degree of protein binding for a drug is proportional to its?

Back 116

lipid solubility

Front 117

Lipoproteins bind?

Back 117

cyclosporine

Front 118

Transcortin binds?

Back 118

corticosteroids

Front 119

The drug enters what compartment for clearance from the body?

Back 119

central

Front 120

Adding water to an ester gives you?

Back 120

an acid and alcohol

Front 121

Adding water to an amide gives you?

Back 121

an acid and amine

Front 122

Why are phase II reactions called synthetic reactions?

Back 122

because the body actually synthesizes a new compound by donating a functional group usually dervied from an endogenous acid

Front 123

Where do microsomal enzymes which are responsible for biotransformation of numerous agents reside?

Back 123

in the hepatic smooth ER

Front 124

What is enzyme induction?

Back 124

increasing enzyme activity by stimulating enzymes over a period of time (ex.alcohol)
-breaks down agents that use same enzymatic system for biotransformation

Front 125

What drugs cause enzyme induction? 10

Back 125

alcohol
phenobarbital
phenytoin
rifampin
carbamazepine
nicotine
isoniazid
rifabutin
ritonavir
st. johns wart

Front 126

If a drug has an extraction ratio of 0.7 what does it heavily rely on?

Back 126

perfusion of the liver to be cleared- called high-clearance drug

Front 127

If extraction ratio is less than 0.3?

Back 127

capacity-dependent elimination, clearance of these drugs depends on hepatic enzymes and the degree of protein binding

Front 128

What is SNPs?

Back 128

single nucleotide polymorphisms- one nucleotide is exchanged for another in a given position

Front 129

Where do most variations in the human genome occur?

Back 129

in drug-metabolizing enzyme genes

Front 130

What 4 CYP enzymes account for 40% of all drug metabolism?

Back 130

CYP2A6, CYP2C9, CYP2C19, CYP2D6