Exam 1 Flashcards
Lectures 1 thru 10
1
Q
Pharmacokinetics
A
What the body does to the drug
2
Q
Pharmacodynamics
A
What the drug does to the body
3
Q
ADME
A
Absorption
Distribution
Metabolism
Excretion
4
Q
Prototype Drug
A
A drug that represents a whole drug class
5
Q
Examples of Drug Targets
A
Cell Surface Receptors
Enzymes
Ion Channels
Transporters
6
Q
Endogenous Ligands
A
The substances native to your body that interact with receptors naturally
7
Q
Orthosteric Site
A
When the binding site of a drug is the same binding site as the endogenous ligand
8
Q
Drugs that bind to enzymes and transporters most commonly bind to this site
A
The Active Site
9
Q
Agonist
A
Binds to a receptor and activates it to produce a response
10
Q
Antagonists
A
Binds to a receptor and blocks the action of the receptor agonist
11
Q
Relationship between Antagonists and Inhibitors
A
Antagonists for Receptors
Inhibitors for Enzymes and Transporters
12
Q
Do ligands displace one another
A
NO!
Drugs with different affinities compete for an unoccupied site
13
Q
Saturation
A
Total number of receptors on a cell is finite, so more drug will NOT induce more response after a certain point
14
Q
Rt
A
Total number of receptors
15
Q
Selective Affinity
A
Drugs have affinity for some receptors but not others
16
Q
Affinity
A
The probability that a drug will associate with a target and how long it will stay associated
17
Q
K on
A
Forward rate constant for association
How quickly the complex forms relative to how quickly the drug comes off
18
Q
K off
A
Reverse rate constant for dissociation
How quickly the drug comes off relative to how quickly the complex forms
19
Q
Is association and response linnear
A
NO
More drug equals more response but the relationship is not linnear
20
Q
Equilibrium
A
Rate of association equals rate of dissociation
21
Q
Equilibrium Dissociation Constant Equation
A
Kd=[R][D]/[RD]
22
Q
Dissociation Constant Significance
A
Tells you how much drug you need to achieve any association
23
Q
Fractional Receptor Occupancy
A
The ratio of bound to unbound receptors at equilibrium
24
Q
Fractional Receptor Occupancy Equation
A
FRO=[D]/Kd+[D]
25
Kd+D Term Significance
Affinity
26
[D]=Kd Significance
50% of receptors are occupied
27
Kd Significance
How much drug is required to occupy HALF its receptors
28
Graph Shape of Percent Receptor Occupancy vs Drug Concentration
Hyperbolic for every drug
29
General Relationship Between Kd and Affinity
INVERSE
30
Relationship Between Fractional Response and Receptor Occupancy
NOT 1 to 1
Higher fractional response occurs at lower receptor occupancy than expected
31
Spare Receptors
We have more receptors than needed for a particular response
32
EC 50
Fraction of a drug concentration that produces 50% of possible effect
AGONISTS ONLY
33
EC 50 Equation
E/Emax=[D]/EC50+[D]
34
Relationship between Kd and EC50
EC50 is usually lower than Kd
35
Potency
How much drug is required to get any given effect
36
Relationship between EC50 and Potency
INVERSE
37
Efficacy
Maximum effect that a drug is capable of producing
How well does the drug activate a receptor WHEN IT IS BOUND
38
Is 100% binding required to get 100% response?
NO!
The signal is often amplified
Think about GPCR
39
Loss of spare receptors does this to the response curve
Shifts RIGHT then DOWN
40
Increased potency does this to the response curve
Shifts LEFT
41
Causes of Loss of Spare Receptors
Diseases
Chronic Agonist Administration
Irreversible Antagonists
42
Most Common Type of Antagonist
Competitive
43
Competitive Antagonist Binding Site
Same as for the agonist
44
Mechanism to Overcome the Action of a Competitive Antagonist
Raise the concentration of the agonist
45
Kb
Binding Kd for a BLOCKER or antagonist
46
Equation for Binding and Effect With an Antagonist
E/Emax=[A]/EC50(1+[B]/Kb)+[A]
47
This Happens When [B]=Kb
Agonist response curve shifts right by a factor of 2
48
Equation for Magnitude of Rightward Shift of Response Curve With an Antagonist
1+[B]/Kb
49
Full Agonist
Produce a maximal 100% response
50
Partial Agonist
Does not produce a maximal response even when they occupy all receptor binding sites
51
Intrinsic Efficacy Coefficient
e
Expressed as a decimal
52
Relationship Between Partial Agonists and Antagonism
Partial agonists act as antagonists at concentrations above their "e" value
53
Non Competitive Antagonists Binding
Irreversible
54
Allosteric Modulator Binding
Binds to a secondary site
55
Positive Allosteric Modulator
Increase actions of agonist at orthosteric site
56
Negative Allosteric Modulator
Decreases action of agonist at orthosteric site
57
Physiological Antagonists
Agonists that produces OPPOSING PHYSIOLOGICAL EFFECTS
58
Receptor Sensitivity
Changes in receptor response
Too much agonist will downregulate receptors on target cells
59
Receptor Desensitization
Lack of responsiveness that occurs when ION CHANNEL receptor stimulation is prolonged
60
Receptor Subtypes
Different receptor proteins for the SAME endogenous ligand
61
Receptor Families
Intracellular Transcription Factor Receptor
Receptors of Intrinsic Enzyme Activity
Ligand Gated Ion Channels
GPCR
62
Intracellular Transcription Factor Receptor Prototype
Estrogen Receptor
63
Intracellular Transcription Factor Receptor Response
Regulates gene expression
64
Intracellular Transcription Factor Receptor Response Timeframe
Hours to Days
65
Receptors With Intrinsic Enzyme Activity Timeframe
Minutes to hours with long lasting effects
66
Ligand Gated Ion Channel Timeframe
Milliseconds
67
GPCR Timeframe
Second to minutes
68
Xenobiotic
An chemical foreign to a biological system
69
Drug
An chemical foreign to a biological system the induces change in that system
70
Drug Disposition
Qualitative description of how the body handles a drug
71
Absorption
Transport of drug from site of administration to general circulation
72
Distribution
Delivery of the drug from the blood to the tissues
73
Metabolism
Conversion of xenobiotic to metabolites
74
Excretion
Removal of the compounds and metabolites from the body
75
Most Critical Factor for Bioavailability
Absorption
76
Factors that Determine Absorption
Size
Acid Base
Molecular Polarity
Formulation
Route of Administration
77
Route of Administration Influences This
Efficiency of therapeutic effect
78
Advantages of Enteric or Oral Administration
Safe
Economical
Large Surface for Absorption
79
Disadvantages of Enteric or Oral Administration
First Pass Effect
Low rate of absorption
80
Advantages of Buccal or Sublingual Administration
Rapid absorption
Safe from first pass for the first round of circulation
81
Advantages of Rectal Administration
Useful when oral route is precluded
82
Absorption of Rectal Drugs
Proximal 50% of the rectum goes to portal circulation
Distal 50% of rectum goes directly into venous blood
83
Parenteral Route
Beyond the alimentary tract
84
Advantages of SubQ Route
Sustained release
85
Disadvantages of SubQ Route
Small volumes
Slow Release
86
Advantages of IM Route
Prompt absorption
Faster blood flow in deltoid than gluteal
87
Advantages of IV Route
Rapid
Can be delivered as a bolus
88
Disadvantages of IV Route
More prone to toxic effects
89
Advantages of Inhalation Route
Direct action on bronchus
Highly vascularized
90
Advantages of Intranasal Route
Direct action on nasal mucosa
Highly vascularized
91
Advantages of Dermal Route
Direct action upon the skin
Can be absorbed thru the skin in an oily formation
92
Bioavalability
Fraction of unchanged drug dose that enters systemic circulation
93
Mechanism of Drug Transport After Administration
Passive
Carrier Mediated
94
Bulk Flow
Passive passage of compounds through intercellular pores
DRUGS MUST BE LESS THAN 300 to 500 da
95
Passive Diffusion
Passive passage through cell membranes
96
Properties of Drugs That Pass Through Passive Diffusion
Uncharged
Sufficiently Lipophilic
97
Most Drugs Belong to This Class
Small molecular weight organic acids or bases that exist as ionized and nonionized forms
98
Amount of Ionic vs Nonionic Drug Species Depends on These Things
Acidity of drug
pKa of drug
pH of the environment
99
Weak Acidic Drugs Accumulate on This Side of the Membrane
The high pH side
100
Weak Basic Drugs Accumulate on This Side of the Membrane
The low pH side
101
Henderson Hasselbalch Equation
pH=pka+log(charged/uncharged)
102
Carrier Mediated Transport
Membrane proteins that bind molecules for transfer
103
How many genes are in the genome
22 to 25 thousand
104
Specificity of Carrier Mediated Transport
Not as specific as receptors
105
Kinetics of Carrier Mediated Transport
Similar to enzyme kinetics
Easily saturated at low concentration
106
Facilitated Diffusion Mechanism
Moves drugs down a concentration gradient in either direction so long as the flow moves from high to low concentration
107
Active Transport Mechanism
Uses ATP to move drugs against a concentration gradient
Continues until inhibition, no more drug, or no more ATP
108
Primary Active Transport Mechanism
Burns ATP within the molecule to power transport
Also called ABC family of transporters
109
Secondary Active Transport Mechanism
Energy sources exist outside the transporter
Often works by coupling favorable ion diffusion
110
Symporters
Transport ions in same direction as the substrate
111
Antiporters
Transport ions in opposite directions from the substrate
112
ABC Transporters
Primary active unidirectional transport
Transport drugs to the outside of the cell
113
OAT Family of Transporters
Antiporters
Prefer organic anions
Live on the blood side of epithelia
114
OCT Family of Transporters
Uniporters
Prefer organic cations
Similar tissue and cells as OAT
115
Neurotransmitter Reuptake Transporter Mechanism
All Sodium Symporters
116
Receptor Mediated Endocytosis Mechanism
Molecule hits specific receptors on cell membrane
Membrane pinches off and the contents enter the cell
Used for larger molecules like peptides
117
Drugs Administered Orally or Rectally Enter This Circulation First
Portal Circulation
118
Preabsorption Metabolism
Breakdown of the drug that happens on the gut wall BEFORE the drug enters circulation
119
This determines pharmacological effect
Concentration at site of action
120
Impact of Blood Flow on Drug Distribution
Faster blood flow means faster drug entrance into tissue and faster effect
121
Impact of Larger Tissue Mass Volume on Drug Distribution
Allows more total drug but takes longer to reach effective concentration
122
Experimental Measurement of Lipid Solubility
Octonal to water partition coefficient
123
Impact of Capillary Permeability on Drug Distribution
Tight junctions between cells prevent bulk flow, so tissues must rely on passive diffusion or active transport
124
Impact of Lipid Solubility on Drug Distribution
Lipophilic drugs accumulate in fatty tissues and are slower to leave the body
125
Impact of Ionization on Drug Distribution
Drug pKa and tissue pH determines where the drug will collect
126
Ion Trapping
When concentration of ion is higher in the tissue than plasma and cannot get out due to different tissue pH
127
Equation of Apparent Volume of Distribution
Vd(L)=Xomg/Cp(mg/L)
128
Relationship Between Concentration in Plasma Cp and Volume of Distribution Vd
Inverse
129
Volume of Fluid in Plasma
3L for a 70kg Male
130
Volume of Fluid in Extracellular Fluid
12L for a 70kg Male
131
Total Body Water Volume
42L for a 70kg Male
132
What does a Vd of 3L Mean
The drug does not leave the blood because 3L is plasma volume
133
What happens if the Vd is more than 3L but less than 15L
Drug is retained in the plasma by binding to plasma proteins
134
Drugs that enter the total body water but bind to the plasma proteins have a Vd of this
Less than 42L
135
Vd of Greater than 42L Means This
Drug moves out of the plasma to bind to tissue proteins or get stored in fat
136
Vd Greater than 100L Means This
Drug is stored in fat
137
Drugs with Higher Vd are Eliminated This Way
Hepatic Metabolism
138
Drugs with smaller Vd are eliminated this way
Through the Kidneys
139
Two Plasma Proteins That Bind Drugs
Albumin to Acidic Drugs
Alpha 1 Acidic Glycoprotein to Basic Drug
140
Lung Tissue Has an Affinity for These Drugs
Basic amines with large lipophilic groups and pKa greater than 8
141
Bone Has an Affinity for These Types of Drugs
Drugs that complex with calcium like tetracycline
142
Enzymes do this general thing to xenobiotics
Convert them to more polar compounds to be more readily excreted into the kidneys and incorporated into the bile
143
Phase 1 Metabolism Reaction Function
Catalyzes drug to yield a functional group
Inactivates the drug
144
Consequences of Phase 1 Reactions
Inactive Metabolite
Active Metabolite
Toxic Metabolite
Reactive Intermediate
Prodrug Bioactivation
145
Purpose of Phase 2 Reactions
Covalently conjugates endogenous compounds to functional groups catalyzed by Phase 1 metabolism
146
Purpose of Phase 3 Reactions
Mostly transporter mechanisms of drug efflux
147
Biological Protein Drugs are Metabolized This Way
Degradation by serum and tissue proteases
148
Most drug metabolism happens here
The liver
149
Drugs enter the space of Disse thru this mechanism
Bulk flow
150
Drugs enter hepatocytes thru this mechanism
Passive diffusion thru Phase III OAT, OCT, and NTCP transporters
151
Drugs enter the hepatic vein circulation thru this mechanism
Passive diffusion thru transport protein
152
Site of Phase I Enzymes in the Hepatocytes
Lipid bilayer of smooth ER
153
Major Enzyme of Phase I Metabolism
Cytochrome P450 Complex, or CYP
154
CYP Drug Oxidation Equation
Drug + O2 + NADPH + H+ —> DrugOH + H20 + NADP+
155
CYP Isoform Nomenclature
Greater than 40% Homology Means Family
Greater than 60% Homology Means Subfamily
156
Relationship Between CYP Type and Drug Metabolism
Each drug may be metabolized by several different enzymes
157
Other Important Phase 1 Enzymes
Amine Oxidases for Catecholamine Neurotransmitters
Dehydrogenases for Alcohols and Aldehydes
Flavin Monooxygenases for Oxidizing N, S, or P Moieties
Reductases for Azo, Nitro, and Carbonyl Groups
Carboxyesterase for Hydrolizing Ester Bonds
Amidases for Hydrolyzing Amide Bonds
Epoxide Hydrolase for Aromatic Rings
158
General Reaction of Phase II Enzymes
Use reactive functional groups on drugs to bond them to endogenous molecules
This INACTIVATES the drug
159
Phase II Enzyme Location
Cytosol
160
UGT Enzyme Location
Only Phase II Enzyme in Smooth ER
161
UGT Enzyme General Function
Enables enterohepatic recirculation to increase half life and process things like vitamins
162
SULTS Enzyme Function
Attaches sulfur groups to acceptor sites
Important for metabolism of Heparin and Acetaminophen
163
GST Enzyme General Function
Attaches acetate to aromatic amine and hydrazine substrates
164
NAT Enzyme Functions
Attaches acetate to aromatic amine and hydrazine substrates
Important for Isoniazid and Hydralazine Metabolism
165
Methyltransferase Enzyme Function
Methylates functional groups
166
Main Phase III Enzymes
ATP Binding Cassette ABC Transporters
Solute Carrier SLC Transporters
167
Enzyme Induction
Increase transcription and protein expression
SLOW time course
168
Enzyme Expression Mechanism
Lipophilic inducers that accumulate and activate xenobiotic sensing receptors
169
Three Xenobiotic Sensing Receptors
Pregnane X
CAR
Aryl Hydrocarbon Receptor
170
Long Term Exposure to Enzyme Inducer Consequence
Induced enzyme levels may never return to normal even after cessation of exposure to inducer
171
Enzyme Inhibition Timecourse
Acute
172
Enzyme Inhibition Consequence
Drug drug interaction
173
Effect of Multiple CYP Genes
Atypically rapid metabolism
174
General Rule for Drug Therapy in the Elderly
Start Low. Go Slow
175
Impact of Protein Deficiency on Drug Metabolism
Decreased CYP activity
Impaired phase I metabolism
176
Impact of Fat Free Diet on Drug Metabolism
Decreased fatty acid in ER lipid bilayer, which impairs CYP phospholipid anchor
177
Impact of Pregnancy on Drug Metabolism
Increases rate of metabolism
178
Impact of Depleted Intestinal Flora on Drug Metabolism
Diminished metabolic enzymes increases drug in circulation
Diminished B glucoronidases decrease reabsorption of drug and diminished pharmacological effect
179
Routes of Drug Elimination
Kidney
Liver
Lungs
Sweat and Saliva
Breast Milk
180
Location of Renal Elimination Processes
Bulk flow in glomerulus
Passive diffusion in distal tubule
Carrier mediated transport in proximal tubule
Water reabsorption in Loop of Henle
181
Drug Types Filtered by the Glomerulus
All unbound drugs of small size and shape
182
Impact of Decreased Renal Blood Flow on Renal Elemination
Impairs renal elimination and increases plasma concentration of drug
183
Impacted of Renal Inflammation on Renal Elimination
Increased capillary permeability increases elimination and decreases plasma concentration of drug
184
These Factors Determine Passive Drug Diffusion in the Kidneys
Lipid solubility
PKa of Drug
Acidity or Alkalinity of Drug
PH of urine
185
Location of Carrier Mediated Transport in Kidney
Proximal Tubule for both uptake and efflux renal transporters
186
Drugs That Favor Carrier Mediated Transport
Larger, hydrophilic, ionized drugs
Phase II Metabolites
187
Renal Transport Favors This Process
Secretion to the tubule
188
Formula for Total Amount Excreted in the Urine
Glomerular filtration+passive secretion-passive reabsorption+tubular secretion-tubular reabsorption
189
Main Mechanism of Biliary Excretion
Transporter mediated
Tight junctions make bulk flow unlikely
190
Biliary Transporters Prefer This Drug Type
Large, polar, ionic
191
Pulmonary Excretion Prefers This Drug Type
Volatile Substances
192
Method of Transport into Breastmilk
Passive Diffusion
193
Breastmilk Excretion Prefers This Type of Drug
High Lipid Solubility
Basic Drugs
Drugs That Chelate Calcium
Drugs That Do Not Bind Strongly to Albumin
194
Most Important Question in Clinical Pharmacokinetics
At what drug level do we induce the desired effect
195
Time of Onset
Time for drug to reach minimal effective level
196
Duration of Action
Time from time of onset to when the drug drops slow minimum effective level
197
Irreversible Receptor Binding Effect on Duration of Action
Effect of the drug will continue even after plasma concentration drops below minimum effective level
198
Cutoff for Narrow Therapeutic Range
2 to 4 fold window
199
Parts of A Rate of Elimination Graph
Initial Slope=1st order kinetics
Asymptote of maximum elimination=zero order kinetics
Inflection point=Michaelis Menten Kinetics
200
First Order Elimination Kinetics Behavior
A constant fraction of drug is eliminated per unit time
201
Zero Order Elimination Kinetics Behavior
A constant amount of drug is eliminated per unit time
202
Half Life
The time required for half the drug to be eliminated from the body
203
How many half lives does it take to eliminate the drug from the body
Under first order kinetics, it takes 4 to 5 half lives
204
Half Life Equation
t=0.693/B
B is the elimination rate constant
205
Clearance
Rate of drug elimination
Note it is idiosyncratic for each drug
206
Clearance Equation
CL=dose/area under curve
207
Relationship Between Half Life, volume of distribution, and clearance
t=0.7(Vd/CL)
Vd is Volume of Distribution
CL is Clearance
208
Conceptual Relationship Between Half Life and Volume of Distribution
Half life directly affects half life
209
Conceptual Relationship Between Half Life and Clearance
Inverse
210
Bioavailability Equation
F=AUCo/AUCiv
F is Bioavailability
AUCo is Area Under the Curve for Oral Administration
AUCiv is Area Under the Curve for IV Administration
211
FDA Bioavailability Regulation
Bioavailability of generics must be 80% to 125% of proprietary drug
212
Mean Drug Concentration at Steady State
Drug intake=drug elimination
213
Time Required to Achieve Therapeutic Window Steady State Concentration
4 to 5 half lives
214
Maintenance Dose Rate Equation
Dose Rate=Css(CL)/F
CL is Clearance
F is Bioavailability
215
Loading Dose Equation
Loading Dose=(Css)(Vd)/F
CL is Clearance
F is Bioavailability
216
Oral Dose Formula
[(Css)(CL)(dose interval)]/F
F is bioavailability
217
Does Patient Weight Effect Half Life
NO!
218
Is Vd Effected by Drug Metabolism
NO!
It’s only effected by things like weight and total body water
