Pharm Lecture 1 Pharmacokinetics

Front 1

The study of the changes in the concentration
of a drug during the processes of absorption,
distribution, metabolism and elimination

Back 1

pharmacokinetics

Front 2

What the body does to the drug

Back 2

What the body does to the drug

Front 3

6 Factors Determining Pharmacologic Effect

Back 3

Dose of drug
Rate and extent of absorption
Distribution
Tissue and receptor binding
Biotransformation
Excretion

Front 4

Major Factors Determining
Pharmacokinetic Activity FYI

Back 4

1 Stereochemistry
2 Movement of Drugs Across Membranes
(Molecular size - Lipid Solubility - Ionization
3 Protein Binding

Front 5

The study of how molecules are structured in 3
dimensions’

Back 5

Stereochemistry

Front 6

molecules with the same chemical formula, but different arrangement of atoms

(Therefore, different chemical properties)

Back 6

Isomers:

Front 7

Body is made of mostly

Back 7

carbon-containing molecules

Front 8

Molecule that
has 2-dimensional
asymmetry

Back 8

Chirality:

Carbon atom that has 4
different bonds
Makes it’s function
unique

Front 9

pair of molecules that are
mirror images of each other
(Cannot be Superimposed)

Back 9

Enantiomers:

Front 10

When 2 enantiomers
are present in equal
amounts

Back 10

Raceimic mixture:

Front 11

Membrane Transport

Aqueous or liquid environment
Most common

Back 11

Passive Diffusion

Front 12

Membrane Transport

Important for some drugs, particularly larger molecules

Back 12

Active Transport

Front 13

LAW OF MEMBRANE TRANSPORT

Back 13

Fick’s Law

J= (C1 – C2) x area x permeability/
Thickness of membrane


 Flux (J): molecules per unit time
 C1 is the higher concentration and C2 is the lower
concentration
 Area: area across which the diffusion occurs
 Permeability coefficient: drug mobility in the
diffusion path
 Thickness: length of the diffusion path

Front 14

Passive Transport
Plasma protein-bound drugs cannot permeate through

Back 14

aqueous pores

Front 15

Transport depends on: 3 components

Back 15

Molecular size
Lipid Solubility
Degree of ionization

Front 16

Membrane Transport
3 points

Back 16

Smaller molecules cross membranes easier

Molecules with molecular weights > 100-200 do not
pass easily

Most drugs have a molecular weight between 10-1000

Front 17

Most important barrier
for drug permeation

Back 17

Lipid Solubility


Most important barrier
for drug permeation due
to many lipid barriers
separating body
compartments

Front 18

Ratio of drug’s lipid solubility to water solubility

Back 18

Oil–Water Partition Coefficient

Front 19

Oil–Water Partition Coefficient expresses the

Back 19

Ratio of drug’s lipid solubility to water solubility
Major determinant of drug mobility
Reflects how easily the drug enters the lipid phase from
the aqueous medium
The greater the lipid: water coefficient, the more rapidly
the drug can diffuse through the lipid components of
cell membranes

Front 20

The greater the lipid: water coefficient,

Back 20

the more rapidly
the drug can diffuse through the lipid components of
cell membranes

Front 21

Oil-Water Partition Coefficient Expresses

Back 21

the lipid solubility of a drug


Morphine 1
Meperidine 32
Fentanyl 955
Sufentanil 1727

Front 22

Most drugs are

Back 22

weak acids and bases that
present in solution as both ionized and nonionized
molecules

Front 23

Charged drugs diffuse through lipid
environments with

Back 23

difficulty

Front 24

2 factors that influence transport

Back 24

pH and drug pKa

Front 25

Drug ionization reduces a drug’s ability

Back 25

to cross a lipid bilayer

Front 26

The pH at which half of a drug is in the non-ionized
form and the other half is ionized

Back 26

pKa Dissociation Constant

Front 27

pKa and the pH of the surrounding fluid determines

Back 27

how much drug is in the non-ionized form

Front 28

Indicates the pH above and below which pH trapping
can affect the ability of the drug to cross biological
membranes

Back 28

pKa Dissociation Constant

Front 29

Henderson-Hasselbach Equation

Back 29

General form: log (protonated)/(unprotonated) =
pKa-pH


The lower the pH relative to the pKa, the greater the
fraction of protonated drug is found


The protonated form of an acid is uncharged; the
protonated form of a base is charged

Front 30

A weak acid at acid pH will be more lipid soluble
because

Back 30

it is uncharged and moves more readily through
a lipid environment

Front 31

A weak base at alkaline pH will be more lipid-soluble
because

Back 31

at alkaline pH a proton will dissociate from
molecules leaving it uncharged and free to move
through lipid membranes

Front 32

When the pKa of a drug and the pH are similar…..
Small changes in the pH

Back 32

can cause a large change in the
degree of ionization!

Front 33

4 Weak Acids

Back 33

Phenobarbital
Pentobarbital
Acetaminophen
Aspirin

Front 34

Weak Bases 4

Back 34

Cocaine
Ephedrine
Librium
Morphine

Front 35

Differences in pH between two different
body compartments can cause

Back 35

Ion Trapping
an accumulation of ionized drug in one
compartment

Front 36

Nearly all drugs are filtered at

Back 36

the glomerulus

Front 37

Most drugs in a lipid soluble form will be reabsorbed by

Back 37

passive diffusion

Front 38

To increase excretion – change

Back 38

the urinary pH

Front 39

Weak acid – excreted faster in

Back 39

an alkaline pH (anion
form favored)

Front 40

Weak base- excreted faster in

Back 40

an acidic pH (cation form

Front 41

6 Body sites where pH differences from blood pH favor
trapping or reabsorption:

Back 41

 stomach contents
 small intestine
 breast milk
 aqueous humor
 vaginal secretions
 prostatic secretions

Front 42

Ion Trapping: Anesthesia Correlation OB 4x

Back 42

 Placental transfer of basic drugs (local anesthetics) from
mother to fetus
 Fetal pH is lower than maternal pH
 Lipid soluble, non-ionized local anesthetic crosses the
placenta and is converted to poorly lipid soluble ionized
drug
 In fetal distress, acidosis contributes to local anesthetic
accumulation

Front 43

Degree of Ionization fyi

Weak Bases- Amines

Back 43

N + 1 carbon and 2 hydrogens = primary amine
(reversible protonation)
 N + 2 carbons and 1 hydrogen = secondary amine
(reversible protonation)
 N + 3 carbons = tertiary amine (reversible protonation)
 N + 4 carbons = quarterary amine (permanently

Front 44

Plasma proteins bind reversibly with

Back 44

drugs in blood

Front 45

The bound fraction of drug is not available to

Back 45

cross cell
membranes

Front 46

Binding of drugs to plasma proteins is

Back 46

nonselective

Front 47

Drugs with a stronger protein affinity can displace
drugs with

Back 47

a weaker affinity

Front 48

The most important binding
agent for weak acids

Back 48

Plasma Albumin

Front 49

IIs the most important
binding agent for weak bases

Back 49

Alpha 1- Acid Glycoprotein

Front 50

Concentration increases
following surgery, MI, and
chronic pain

Back 50

Alpha 1- Acid Glycoprotein

Front 51

The process by which a drug leaves its site of
administration to enter the bloodstream

Back 51

Absorption

Front 52

The fraction of unchanged drug that reaches the
systemic circulation

Back 52

Bioavailability

Front 53

Determined by absorption as well as the duration and
intensity of drug action

Back 53

Bioavailability

Front 54

6 Factors Affecting Absorption

Back 54

Factors Affecting Absorption
Route of administration
Drug solubility
Rate of drug dissolution
Drug concentration
 Blood flow to site of absorption
Area of absorbing surface

Front 55

Routes of Administration
Enteral - Oral points

Back 55

 Most common
 Inexpensive
 Little skill needed
 Low Bioavailability
 First-Pass Hepatic effect

Front 56

Routes of Administration - Sublingual and Buccal

Back 56

Bypass first-pass effect
Directly into superior vena cava

Front 57

Sublingual and Buccal passes into

Back 57

Directly into superior vena cava

Front 58

Routes of Administration - Rectal points

Back 58

Prevention of emesis
 Oral ingestion is difficult
 Proximal rectum- first-pass hepatic effect
 Distal rectum- no first-pass effect
 Higher predictability of circulatory levels

Front 59

Drugs absorbed from the GI tract enter

Back 59

the portal
venous blood and pass through the liver before entering
the systemic circulation

Front 60

the reason for large
differences in the pharmacologic effect between oral and
IV doses

Back 60

Extensive hepatic metabolism

Front 61

Transdermal: Must be

Back 61

water and lipid soluble

Front 62

vessel rich group

Back 62

Brain,
heart,liver,
kidney

Front 63

Brain,
heart,liver,
kidney

body mass vs CO

Back 63

10 % Body
Mass

75% Cardiac
Output

Front 64

Muscle, skin

Body
Mass vs CO

Back 64

50%

19%

Front 65

Distribution
Factors affecting

Back 65

 Tissue blood flow
 Concentration gradient
 Diffusable fraction of the drug
 Protein binding
 Tissue binding

Front 66

First Pass Pulmonary Uptake

> 65% of dose of 6 meds

Back 66

 Lidocaine
 Fentanyl
 Propranolol
 Sufentanil
 Meperidine
 Alfenta

Front 67

Pulmonary Uptake

Back 67

 Affects peak arterial concentration
 May serve as a reservoir, enabling transport of drug into
systemic circulation

 Magnitude is not affected by:
 spontaneous respiration
 controlled ventilation
 apnea

Front 68

Pulmonary Uptake
Magnitude is not affected by:3x

Back 68

 spontaneous respiration
 controlled ventilation
 apnea

Front 69

Blood Brain Barrier

Drugs with limited access:

Back 69

Cerebral capillaries limit the
amount of drug entering the
CNS

Drugs with limited access:
 low lipid solubility
 highly ionized
 large size molecules

Front 70

2 Factors determining the
amount of drug transferred
to the uterus

Back 70

Physiochemical
properties of drugs and
uterine integrity

Duration of exposure of
the fetal circulation

Front 71

2 Compartment Model

Back 71

Central compartment - Intravascular fluid and highly perfused tissues

Peripheral compartment - Muscle, fat and bone

Front 72

Drugs leave the central compartment in 2 phases

Back 72

Distribution

Metabolism

Front 73

Expresses the extent of distribution for a drug

Back 73

volume of distribution

Front 74

Vd = formula

Back 74

Amount of drug in body divided by
Concentration of drug in plasma

Front 75

2 parts of Elimination

Back 75

Biotransformation
Excretion

Front 76

Rate of elimination =

Back 76

Clearance X Drug concentration

Front 77

2 Most important for
Metabolism and
Excretion

Back 77

Liver and Kidneys

Front 78

Renal Clearance
Correlates directly or
indirectly with

Back 78

Correlates directly with creatinine clearance or indirectly
with serum creatinine

Front 79

Tubular secretion is

Back 79

Active process - drug/metabolite selectivity

Front 80

Tubular Reabsorption is

Back 80

Passive Tubular Reabsorption

pH, pKa, rate of renal tubular urine flow

Front 81

most of the drug in the blood is eliminated on

Back 81

the first
pass through the organ Hepatic Clearance

Front 82

Hepatic Clearance
Depends on 3 factors:

Back 82

1) Intrinsic ability of the liver to metabolize a drug
2) Hepatic Blood Flow
3) Extent of Protein Binding

Front 83

A process that converts
lipid-soluble parent drugs to
water soluble metabolites

Back 83

BIOTRANSFORMATION

Front 84

the addition of O2, making the structure
more positive (loss of electron)

Back 84

the addition of O2, making the structure
more positive (loss of electron)

Front 85

the addition of electrons, making the
structure more negative

Back 85

Reduction –

Front 86

uses H2O to breakdown compound

Back 86

Hydrolysis –

Front 87

adds a CHO or amino acid

Back 87

Conjugation –

Front 88

Enzymes that catalyze the reactions in the
biotransformation of drugs

Back 88

Hepatic Microsomal Enzymes

Front 89

Lipid solubility is important for a drug to be
metabolized by these enzymes

Back 89

Hepatic Microsomal Enzymes

Front 90

Collective term for a group of related enzymes that are
responsible for the OXIDATION of numerous drugs

Back 90

Cytochrome P-450

Front 91

Primarily located in the hepatic smooth endoplasmic
reticulum.

Back 91

Cytochrome P-450

Front 92

Most phase I reactions are catalyzed by these

Back 92

Cytochrome P-450

Front 93

Drugs or chemicals have the ability to increase enzyme
activity

Back 93

Enzyme Induction

Front 94

4 Drugs or chemicals have the ability to increase enzyme
activity

Back 94

 Tobacco smoke
 Chronic ETOH
 Cruciferous vegatables- brussel sprouts, cabbage,
aculiflower
 Hydrodarbons from charcoal-broiled meats

Front 95

Inducers fyi

Back 95

 Phenytoin
 Carbamazepine
 Barbiturates
 Rifampin
 Ritonavir
 Chronic ethanol toxicity
 Griseofulvin

Front 96

Inhibitors fyi

Back 96

 Omeprazole
 Disulfiram
 Erythromycin
 Valproic Acid
 Isoniazid
 Cimetadine
 Ciprofloxacin
 Acute ethanol toxicity

Front 97

These enzymes are primarily present in the liver and
catalyze certain hydrolysis and conjugation reactions

Back 97

Nonmicrosomal Enzymes

Front 98

2 Factors Affecting Biotransformation

Back 98

Drug concentration
Intrinsic rate of metabolism

Front 99

The constant FRACTION of available drug is metabolized in a given time period

Back 99

First Order Kinetics

Front 100

A constant amount of drug is metabolized over a unit of
time

Back 100

Zero Order Kinetics

Front 101

Determined by intrinsic activity of enzymes

Back 101

Zero Order Kinetics

Front 102

Drugs are excreted either

Back 102

unchanged or as metabolites

Front 103

most important organ for excretion
of drugs and their metabolites

Back 103

The kidney

Front 104

The non-ionized fraction of drug is reabsorbed in

Back 104

the
renal tubules

The ionized fraction is excreted

Front 105

Renal Clearance Determined by:2x

Back 105

Renal Blood Flow
 Rates of Processes

(glomerular filtration
 tubular secretion
 tubular reabsorption)

Front 106

Relatively few drugs depend on biliary excretion. They
are usually reabsorbed in

Back 106

the intestine and then
excreted in the urine.

Front 107

A graphic representation of the change in plasma
levels of a drug over time.

Back 107

Plasma Concentration Curve

Front 108

Y axis =

Back 108

drug concentration in plasma

Front 109

X axis =

Back 109

time

Front 110

corresponds to the
redistribution of drug from the central compartment
to the peripheral compartment

Back 110

Distribution phase or alpha phase

Front 111

is when distribution slows
and drug is eliminated from the central
compartment

Back 111

Elimination or beta phase

Front 112

The time necessary for the plasma
concentration of drug to decline 50%
during the elimination phase

Back 112

Elimination Half-Time

Front 113

The time necessary to eliminate 50% of the drug from
the body

Back 113

elemination half life

Front 114

Time necessary for the
plasma drug
concentration to
decrease by 50% after
discontinuing a
continuous infusion

Back 114

Context Sensitive Half-Time

Front 115

The volume of plasma cleared of drug by renal
excretion and/or metabolism in the liver or other
organs in ml/min

Back 115

Clearance

Front 116

The study of the responsiveness of receptors to a drug
and the mechanisms by which they occur

Back 116

pharmacodynamics

Front 117

Protein or other substance that binds to an
endogenous chemical or a drug

Back 117

Receptors

Front 118

3 properties of Receptors

Back 118

 Sensitivity
 Selectivity
 specificity

Front 119

Interact with specific G proteins in the plasma membrane which
activates enzymes or ion channels

Back 119

G-protein coupled receptors

Front 120

Receptors for homones, neurotransmitters and neuropeptides

Back 120

G-protein coupled receptors

Front 121

Receptors for neurotransmitters

Back 121

Ion Channels

Front 122

Mediate fast synaptic transmission
 Ion channel is an integral part of a larger and more complex
transmember protein
 Important targets for drugs

Back 122

Ligand gated ion channels

Front 123

Enzyme-linked Cell Surface Receptors fyi

Back 123

 Receptor guanylyl cyclases
 Receptor serine/threonine kinases
 Receptor tyrosine kinases
 Tyrosine kinase-associated
 Receptor tyrosine phosphates

Front 124

Interact selectively with extracellular compounds
Initiate a cascade of biochemical changes that lead to a
response
Able to bind hydrophilic ligands in extracellular space

Back 124

Transmembrane Receptors

Front 125

process that
modulates cell physiology

Back 125

Signal Transduction

Front 126

an increase in the number of receptors.

Back 126

Up regulation

Front 127

a decrease in the number of receptors.

Back 127

Down
regulation

Front 128

Increasing concentrations of antagonists act
to progressively inhibit responses to
unchanging concentrations of an agonist.

Back 128

Competitive Antagonism

Front 129

A drug, hormone, or neurotransmitter that binds
weakly to receptors and produces a minimal
pharmacologic effect.

Back 129

partial agonist

Front 130

how much drug
is required to produce
desired response

Back 130

Potency –

Front 131

related to the
number of receptors that
must be occupied to
achieve the effect.

Back 131

Slope –

Front 132

the maximum
pharmacologic effect that
the drug can produce.

Back 132

Efficacy –

Front 133

factors influencing
patient’s response to drugs.

Back 133

Individual Variability –

Front 134

Ratio of the median lethal dose to the median effective
dose.

Back 134

Therapeutic Index

Front 135

Drug produces usual
effect at unusually low
doses

Back 135

Hyper-reactive

Front 136

Drug produces usual
effect at unusually high
doses

Back 136

Hypo-reactive

Front 137

Reserved for people who
all allergic (sensitive)

Back 137

Hyper-sensitive

Front 138

Hypo-reactivity from
chronic exposure to a
drug

Back 138

Tolerance

Front 139

Tolerance that develops
rapidly after
administration of only a
few doses

Back 139

Tachyphylaxis

Front 140

Effect is = to algebraic
equation

Back 140

Additive

Front 141

2 drugs effect <
algebraic equation

Back 141

Antagonism

Front 142

2 drugs effect >
algebraic equation

Back 142

Synergistic

Front 143

D enantimoers rotate to

Back 143

rotate right

Front 144

L enantiomers rotate

Back 144

rotate to the left

Front 145

high oil water coefficient means that

Back 145

drug is more lipid soluable, occurs faster

Front 146

Enzymes that catalyze the reactions in the
biotransformation of drugs
Lipid solubility is important for a drug to be metabolized by these enzymes

Back 146

Hepatic Microsomal Enzymes

Front 147

6 Signal Transductions – process that
modulates cell physiology

Back 147

1. Drug crosses cell membrane- activates intracellular receptor
2. Transmembrane receptor protein – drug binding influences
intracellular enzyme activity
3. Drug- transmembrane receptor protein complex binds and
stimulates a second protein
4. Drug binding to a transmembrane ion channel affects membrane
potential
5. Agonist drug binding can stimulate a G protein leading to increased
second messenger responses

Front 148

What are Intracellular Receptors

Back 148

Small lipophylic molecules (ie. Steroids) bind to
intracellular transcription factors
By activating or inhibiting transcription, this impacts
cell function