Exam Review 1 Flashcards
1
Q
Pharmacology
A
The study of substances that react with living systems through chemical processes.
2
Q
Toxicology
A
The branch of pharmacology concerned with the adverse effects of chemicals on living systems
3
Q
Agonist
A
a substance that binds to a receptor to activate a response (usually the response you would see from the native ligand)
4
Q
Antagonist
A
a drug that binds to a receptor to prevent the binding of native ligand (inhibits receptor)
5
Q
Drug
A
Any substance that brings about a change in biological function through chemical processes
6
Q
Receptor
A
Are proteins where the drug molecule reacts, and plays a regulatory role in the biological system.
(can be: regulatory proteins, enzymes, transport, proteins, structural proteins)
7
Q
Pharmacogenomics
A
Genetic makeup vs response to drug (the future of pharmacology)
8
Q
Endogenous
A
“essentially physiology”
ligands inside the body
9
Q
Exogenous
A
Drugs, toxins, or poisons originating outside the body
10
Q
Pharmacodynamics
A
the way the drug works on the body
11
Q
Pharmacokinetics
A
The way the body works on the drug
(Absorption, distribution, metabolism, elimination)
(occasionally L=liberation)
12
Q
Toxins
A
Biologic
13
Q
Poisons
A
Typically non-organic
14
Q
Characteristics that determine interaction between receptor and drug:
A
Appropriate size
Electrical charge
Shape
Atomic composition
15
Q
Physical nature of drugs
A
solid/liquid/gas
16
Q
Molecular weight of most drugs:
A
100-1,000 kilodalton (MWU)
Drugs >1,000 MWU can’t readily diffuse and may have to be given directly into the location of action
17
Q
3 Bond types:
A
Covalent
Electrostatic
Hydrophobic
(see picture on lecture 1 at 1:09:16)
18
Q
Covalent bonds
A
Drug and receptor are sharing electrons. (Very strong, Less specificity) irreversible
19
Q
Electrostatic bonds (listed from greater bond strength to lesser bond strength)
A
Charged molecules (ionic bonds) Hydrogen bonds (weakly charged bonds) Van der Waals forces
20
Q
Hydrophobic interactions
A
Very weak
High specificity
lipid soluble
no charge
21
Q
Chirality
A
non-superposable on its mirror image
22
Q
Stereoisomerism
A
Drug with exact same chemical components but are mirror images (have a central carbon)
23
Q
Amount of drugs we give that are Stereoisomers
A
More than half
24
Q
Racemic mixture
example
A
a mixture that is equal amounts of left and right hand stereoisomers (R-Ketamine, S-Ketamine)
25
What is more toxic S or R ketamine?
R-Ketamine
26
Allosteric
Bind to a receptor
NOT at active site
Agonist or Antagonist
non-competative
27
Orthosteric
Bind to receptor AT the active site
Agonist or Antagonist
Competitive
28
Drug concentration response curve:
| Bmax
Concentration at which maximum receptors are bound
| lecture 1 at 1:23:25
29
Drug concentration response curve:
| Kd
Concentration at which 1/2 of receptors are bound
| lecture 1 at 1:23:25
30
Drug concentration response curve:
| Emax
Concentration at which the maximum effect the drug is produce (vary depending on drug)
(Acetaminophen will have lesser Emax than Morphine)(lecture 1 at 1:23:25)
31
Drug concentration response curve:
| EC50
Concentration of drug when 50% of effect is seen
| lecture 1 at 1:23:25
32
A low Kd means..
high drug/receptor affinity
33
Indirect agonist (mimic)
inhibits the molecules responsible for terminating the action of endogenous agonist. (has same effects as agonist but doesn't bind to the same receptor)
34
Competitive antagonist
Orthosteric
| Can be countered by increasing amounts of agonist (surmountable)
35
Non-competitive antagonist
Allosteric
| Insurmountable
36
Irreversible antagonist
Can be allosteric or orthosteric
Covalently bind to receptor and do not come off
Not the same as non-competitive
Only way to get rid of it is to get rid of the receptor
37
Partial agonist
Binds to same receptor site as agonist but produces a lower response
Competes with full agonist form binding site
38
Physiologic antagonism
Drugs acting at different receptors to counter effects of each other (example: Epi increases HR at beta1, ACH decreases HR at muscarinic receptor)
39
Inverse agonist
| and example
Greater affinity for inactive state of receptor. (no constitute activity) (example: narcan)
(see lecture 2 at 0:20:00)
40
Factors that determine the duration of a drugs effects:
- As long as the drug stays bound to receptor.
- Longterm downstream effects last until downstream effectors go away. (If a drug initiates the production of a protein, it will take longer to see effects and longer for response to stop)
- Receptor is degraded (in covalent bonding)
- Desensitization
41
Good receptor properties:
Selective
| Alteration
42
Bad receptor properties:
"inert binding sites"
| drug carriers
43
Potency
Concentration (EC50) or Dose (ED50) of a drug required to produce 50% of that drugs maximal effect
44
Maximal efficacy
Greatest possible response a drug can deliver
45
Dose-Response curve:
| ED50
Median Effective Dose
46
Dose-Response curve:
| TD50
Median Toxic Dose
47
Dose-Response curve:
| LD50
Median Lethal Dose
48
Therapeutic Index
Establishes margin of safety (higher the number the better)
ED50 vs TD50
Animals: LD50/ED50
Humans: TD50/ED50
49
Idiosyncratic
Unusual drug response (we don't know why one patient responds differently than another)
50
Possible reasons for idiosyncratic drug response:
- genetic factors
- hyperactive
- hypoactive
51
Tolerance
Response changes over course of therapy
52
Tachyphylaxis
Quick tolerance
53
Chemical Antagonism
| and example
Administration of opposite charge
| example: Protamine (+) and heparin (-
54
4 causes to variation in drug responsiveness:
- Alteration in concentration of drug that actually reaches receptor (age, weight, sex, disease state, rate of absorption/distribution/clearance)
- Variation in concentration of endogenous receptor ligand
- Alteration in number or function of receptors
- Changes in components of response distal to receptor (largest and most important cause)
55
Toxic effects
Extension of therapeutic effects
| Some drugs produce desired and adverse effects at same receptor, others bind to different classes of receptor sites
56
4 ways of permeation:
```
Aqueous diffusion
Lipid diffusion
Special carriers
Endocytosis/Exocytosis
(All depend on drug, charge, size)
```
57
Aqueous diffusion
Diffuse by concentration gradient
Charged drugs through aqueous channels
Molecules can be large (20K-30K MVW)
Larger aqueous compartments (cytosol, Interstitial)
58
Lipid diffusion
Uncharged drugs
| Gets into cells/body easily
59
Special carriers
If drug needs to get from one place to another (pumps or special carrier proteins)
Molecules bind to drug and move across barriers.
Active transport or facilitated diffusion.
60
Endocytosis/Exocytosis
Cell swallowing the drug, pulling it into the cell, and pushing it out the other side. (see lecture 2 at 0:56:50)
61
What will not diffuse through aqueous diffusion?
Highly charged molecules
| Bound to large proteins (carriers)
62
What is the most limiting factor for drug permeation?
Lipid diffusion because there are many lipid barriers to cross
63
The number one thing to consider when a drug is crossing a barrier is..
..the concentration of the drug on either side of the barrier.
64
Fick's Law of Diffusion
Relates concentration to variables of diffusion path (how readily a substance will move down a concentration gradient)
65
pKa and pH
pKa is pH at which ionized and unionized concentrations are equal
66
If pH < pKa, it favors..
| ratio will be..
Protonated form
| ratio will be <1
67
If pH >pKa, if favors..
| ratio will be..
Unprotonated form
| ratio will be >1
68
Henderson Hasselbach Equation
pH = pKa + log([A-]/[HA])
69
What does the Henderson Hasselbach equation tell us?
Ratio of ionized to unionized.
| Relates ionization constant (pKa) to concentration of H+ (pH)
70
If pH=pKa..
..log([A-]/[HA]) = 0
| ionized vs unionized are in equilibrium
71
Weak acids are uncharged when they are..
..protonated.
72
Weak bases are uncharged when they are..
..unprotonated
73
pH of stomach
1-1.5
74
pH of blood
7.35-7.45
75
Where are most drugs filtered?
Glomerulus
76
Weak acids excreted faster in..
..alkaline urine
77
Weak bases excreted faster in..
..acidic urine
78
Receptor affinity..
..determines dose
| if receptor binds to drug with higher affinity you give less of drug; low affinity, more drug
79
Receptor selectivity..
..varies per drug
80
Receptors can be activated or blocked by..
Agonist or antagonist.
81
Orphan receptors
Receptor without a native ligand or we don't know what the native ligand is
82
7 receptor categories by molecular structure:
- Seven-transmembrane receptors (7TM)
- Ligand gated channels
- Ion channels
- Catalytic receptors
- Nuclear receptors
- Transporters
- Enzymes
83
What is cell signaling?
Converting extracellular signals into intracellular responses
84
Steps in cell signaling:
```
Signaling molecule released from ligand-->
Binds to receptor-->
Activates signal transduction protein-->
Production of 2nd messengers-->
Activate effector protein
```
85
Lag period
Ligand binds to a receptor and starts the process of transcription/translation which is a timely process.
(can take 30minutes to several hours)
86
Persistence
How long the drug is going to last.
Protein degradation varies.
(Response can remain for hours to days)
87
Phosphorylation Cascade
```
Drug binds to receptor-->
response is to add Phos to a protein which activates protein-->
repeats-->
eventually elicits cell response
(see lecture 2 at 1:37:16)
```
88
Kinase
Enzymes within the cell that will add a phosphate group to a specific protein using ATP (require energy)
89
Phosphorylase
Enzyme within the cell that will add a phosphate group to a specific protein using inorganic phosphate thats readily available in the cell (don't require energy)
90
Phosphatase
Enzyme that strips Protein-P of its phosphate
91
Signaling Mechanisms are based on..
..Molecular structure (seven superfamilies of receptors)
92
Drug-receptor binding-signaling depends on..
..if its intracellular or intercellular
93
G-Protein Coupled Receptor (GPCR) can activate:
..hundreds of G-proteins when a ligand is bound to the surface of the receptor.
94
GPCR structure:
7 trans-membrane alpha-helices
95
G-protein binding protein:
```
Guanine nucleotide
(GDP=inactive)
(GTP=active)
```
96
GPCR exhibits pleiotropy which means..
..several downstream effects are possible
97
Steps of activating GPCR:
Ligand binds to receptor-->
Activates G-protein which dislodges GDP and binds to GTP-->
G-protein activates 2nd enzyme-->
Activates cellular response-->
G-protein becomes inactive and strips iP off GTP becoming GDP-->
G-protein goes back to receptor
98
GPCR: Fast response
Metabotropic ion channels (G-protein activates and opens ion channel)
(undergoes rapid desensitization)
99
GPCR: Slow response
Transcription factor activation
100
Second messengers:
```
cAMP
cGMP
Calcium
DAG
IP3
```
101
Adenylyl cyclase -->
Increases cAMP
102
Adenylyl cyclase K+ channels-->
Decreases cAMP
| Change in membrane potential
103
Phospholipase C-->
Increases IP3 and DAG
104
cGMP phosphodiesterase-->
Decreases cGMP
105
Catalytic cell-surface receptors:
| location and activation
Membrane bound
| Ligand activated
106
Catalytic cell-surface receptors:
| Examples
Tyrosine Kinase
Tyrosine Phosphatase
Serine/Threonine Kinase
Guanylate cyclase
107
Catalytic cell-surface receptors do not have to activate another enzyme because..
..they are enzymes and have enzymatic activity directly associated with them.
108
Receptor Tyrosine Kinase (RTKs) ligands are..
..Growth factors and adhesions
109
We typically want to activate or inhibit RTK?
Inhibit
110
Dimerization
It takes two molecules (two monomers) to come together to form a dimer, which activates the signal of a RTK
111
How is the dimer of a RTK activated?
The tyrosine has to be phosphorylated by ATP
112
Voltage gated ion channels
Opening depends on the resting membrane potential
| selective for ions
113
Voltage gated ion channels are found in..
..excitable cells (neurons, muscle, endocrine)
114
Closed ion channel
Activation gate closed
| Inactivation gate open
115
Active ion channel
Activation gate open
| Inactivation gate open
116
Inactive ion channel
Activation gate open
| Inactivation gate closed
117
Deactivated ion channel
Activation gate closed
| Inactivation gate closed
118
Ionotropic Ligand-gated ion channels
A ligand binds and the channel opens.
| When a ligand is not bound, the channel is closed.
119
Ionotropic Ligand-gated ion channel: Cys-loop
Excitatory: ACh
Inhibitory: GABA
120
Metabotropic ion channels
Ligand doesn't directly bind to receptor.
Ligand binds to GPCR which sends 2nd messenger to activate Metabotropic channel.
(see lecture 3 at 1:13:35)
121
How do gasses get into cell?
Direct crossing
| see lecture 3 at 1:14:27
122
Goal of rational dosing:
To achieve desired beneficial effect with minimal adverse effects.
123
Volume of Distribution (Vd)
Amount of drug in body to concentration in blood (does it stay in the blood, or leave the blood)
Vd= (amount of drug in body/concentration)
124
Blood volumes:
| Whole blood
0. 08L/kg
| 5. 6L per 70kg person
125
Blood volumes:
| Plasma
0. 04 L/kg
| 2. 8L per 70kg person
126
What is meant by a high Vd?
The drug leaves the blood and goes elsewhere.
127
Clearance
Ability of body to eliminate drug
Predicts rate of elimination in relation to drug concentration.
(Constant)
128
Rate of elimination
RofE = CL x C
129
First-order elimination
Applies to most drugs (low doses)
| Clearance is constant, rate of elimination varies with concentration
130
Zero order of elimination
Occurs when body's ability to eliminate a drug has reached its maximum capability (high doses)
(Rate of elimination is constant, clearance varies with concentration)
131
Capacity-Limited Elimination
Starts as 1st order, turns into zero order
132
Flow dependent elimination
Some drugs are highly sensitive to 1st pass metabolism
"high extraction drugs"
depends on blood flow through the organ
133
Organ clearance
tells us the clearance of a particular organ
| Blood flow x extortion ratio
134
Half-life (T1/2)
Time required to change drug in body to 1/2 of dose
| T1/2= (0.7xVd)/CL
135
How many half lives does it take to get to target concentration in steady state?
4
| it also takes 4 to eliminate it after stopping drug
136
Why will true half life often be greater than calculated?
Because the calculation is based off of healthy test subjects
137
Accumulation
building up levels of drug in the body more than target concentration and will continue until dosing stops
138
Dosing in intervals
If you give a second dose shorter than 4 half lives, then the concentration in the blood will go up
139
Bioavailability (F)
The fraction of unchanged drug reaching systemic circulation (percentage)
*remember if you are calculating using F, convert the % to a decimal
140
Biotransformation
the alteration of a drug before reaching systemic circulation. Some drugs become inactive after altered, some become active after altered.
141
First-pass elimination
Just because there is a high absorption doesn't mean there is a high bioavailability.
Liver can filter out many drugs leaving less to enter systemic circulation
142
Maintenance Dose
Maintain steady state of drug by giving just enough to replace eliminated drug
143
Dosing rate for steady state
```
Dosing rate (SS)= Rate of elimination(ss)
OR
Dosing rate(SS)= CL X Target Concentration
```
144
*Important* Dosing rate for steady state if bioavailability is 100%
```
Dosing rate(SS)= Rate of elimination(ss)
OR
Dosing rate(SS)= CL X Target Concentration
```
145
*Important* Dosing rate if bioavailability is less than 100% (like PO drug)
Dosing rate = (CL X TC)/F
146
*Important* Intermittent maintenance dosing
Maintenance dose = Dosing rate X dosing interval
OR
md=[(CLxTC)/F] x interval
147
when do we give loading dose?
When we need to reach target concentration quickly
148
Loading dose equation
LD = Vd x TC
149
How do you administer loading doses for potentially toxic drugs?
slowly. They need time for distribution into compartments
150
When calculating a dose for a patient, if the drug has a high Vd, do we use actually body weight or ideal body weight?
Actual body weight because the drug mostly leaves the blood and goes into the fatty tissue.
151
Why do we have to use Ideal Body Weight (IBW) when dosing an obese patient with a drug that is not lipid soluble?
Because if you use actual body weight then you are giving a higher amount of drug and this drug will not diffuse into fatty tissue, therefore the dose will stay in circulation and you can reach toxic side effects faster.
152
IBW for men
52 + (1.9kg x inches over 5ft)
153
IBW for women
49 + (1.7kg x inches over 5ft)
154
Hepatic Clearance
Product of blood flow (Q) and Extraction (E)
| extraction is drug specific
155
3 primary considerations of hepatic clearance:
1) Hepatic blood flow
2) Plasma-drug binding (albumin)
3) Biotransformation mechanisms
156
Hepatic blood flow (if drug was give PO)
GI--> Local veins--> hepatic portal vein--> sinusoids--> hepatic vein--> vena cava--> systemic circulation
157
Hepatic artery flow (If drug was give IV)
Systemic circulation--> hepatic artery--> sinusoids--> hepatic vein--> vena cava--> systemic circulation
158
Two different types of reactions in the liver:
Phase 1 and Phase 2
159
Phase 1 reactions:
Convert drug to more polar metabolite. (usually to make it more water soluble)
More readily excreted, less likely to cross barriers.
Lipophilic becomes hydrophilic.
160
Phase 1 reactions include:
Oxidation, reduction, dehydrogenation, hydrolysis
161
Most drugs are usually activated or inactivated by Phase 1:
Inactivated
162
What do Phase 2 reactions do?
Add larger conjugate to endogenous substrate.
163
Phase 1:
| Oxidation enzyme:
Cytochrome P450
164
Phase 1:
| Hydrolysis enzymes:
Esters and Amides
165
Cytochrome P450
Enzyme in Oxidation.
Responsible for the metabolism of 2/3 of non-antibiotic drugs.
Mostly in Liver
166
How does oxidation with Cytochrome P450 work?
The lipophilic drug binds to Cytochrome P450--> through a series of oxidation reduction reactions the drug becomes oxidized--> an -OH group is added to the drug and the enzyme is recycled
167
Specificity of Cytochrome P450:
Very low
168
Important types of Cytochrome P450s:
CYP3A4 (metabolizes 50% of drugs)
CYP2D6
CYP2B6
169
P450 Induction
some drugs enhance synthesis of P450 and inhibit degradation
(Decreases drug effect if metabolism deactivates drug)
(Increases drug effect if metabolism activates drug)
170
P450 Inhibition
Decreases or inhibits P450
171
Hydrolysis
Phase 1
means "break water"
occurs throughout body
172
Carboxylesterases
Phase 1
| Hydrolysis of both esters and amides
173
Carboxylesterase
| 2 main isoforms:
hCE1 and hCE2
174
Example of drugs effected by carboxylesterase
Cocaine, meperidine (demerol), heroin
175
Cholinesterase
Phase 1
Acetylcholinesterase (enzyme at NMJ)
Hydrolysis of Succinylcholine
176
Types of Phase 2 reactions:
```
Glucuronidation
Acetylation
Glutathione conjugation
Glycine conjugation
Sulfation
Methylation
Water conjugation
```
177
Glucuronidation (UGTs)
Phase 2
Attaches a glucuronic acid to a Phenol, alcohol, carboxyl, or sulfhydryl group.
Increases aqueous solubility
Increases urine excretion
178
Where does glucuronidation happen?
Primarily in the liver
179
Propofol undergoes phase 2 reaction with what enzyme?
UGT1A9
180
Opioids undergo phase 2 reaction with what enzyme?
UGT2B7
181
Glucuronidate does what to morphine?
Makes it more potent
182
Glutathione-S-transferase (GST)
Phase 2
Important in Detoxification like tylenol
(can Increase toxicity)
Increases water solubility
183
Glutathione-S-transferase (GST) is located?
All over the body
184
Example of drug broken down by GST?
Sevoflurane
| Toxic metabolite- compound A
185
Acetaminophen is inactivated by..
Phase 2 reactions
186
What happens in Acetaminophen overdose?
If you give too much Acetaminophen you overwhelm phase 2 reactions, therefore phase 1 reactions (CYP450)can further detoxify them. Phase 1 reactions will still build up toxic metabolites which are degrade by glutathione. Glutathione get used up rapidly so if you don't give them more, then liver cell death occurs.
187
Antidote for Acetaminophen
N-acetylcysteine
| It replenishes glutathione if given within 8 hours of overdose
188
Other factors that can effect metabolism:
Diet, Environment (smoking), Age, Sex (males metabolize faster), Disease state, genetics
189
Pro-drug
Needs metabolism to work
190
Pro-drug given to poor metabolizer
Poor efficacy
| Possible accumulation of pro-drug
191
Active drug given to poor metabolizer
Good efficacy
Accumulation of drug can produce adverse reactions
May need lower dose
192
Pro-drug given to ultra-rapid metabolizer
good efficacy, rapid effect
193
Active drug given to ultra-rapid metabolizer
Poor efficacy
| Need greater dose or slow release formulation
194
Genetic analysis allows:
- More rapid determination of stable therapeutic dose.
- Better prediction of dose than clinical methods alone.
- Genetic testing now recommended/required by FDA
195
TPMT mutation
6-MP is an active drug that is detoxified by TPMT. If there is a TPMT deficiency or mutation it will result in toxic metabolites more quickly (my way to remember: Troubled People Make Toxins)
196
Warfarin is metabolized by:
CYP2C9 (Carol Your Patient in room 2's Coumadin level is 9)
197
To get Herceptin treatment for breast cancer you must be positive for what protein?
HER2 over expression
198
Parameters affecting Passive diffusion:
- Molecular weight (larger it is, harder to cross barrier)
- pKa (Charged vs uncharged due to pH)
- lipid solubility
- plasma protein
199
Solute Carrier Proteins (SLC)
15-30% of all membrane proteins
| High specificity
200
Drug Efflux transporters
Proteins that pump drugs out of cells.
It is a cell survival mechanism.
Broad substrate specificity.
201
ATP-Binding Cassette
ABC transporters
| Multidrug resistant protein
202
ABC gene families
A-G and over 50 genes
203
ABC A1
Cholesterol efflux
204
ABC B1
(Broadest substrate specificity)
Antineoplastics, HIV protease inhibitor, antibiotics, antidepressants, antieplileptics, and opioids.
(Wide distribution)
GI, Kidney, Liver, testes
Critical in maintenance of Blood-brain barrier
205
ABC B1 Loperamid effects
Antidiarrheal
| no CNS effects because it is bound to ABC B1 in GI and not absorbed into the blood
206
ABC B1 Fentanyl effects
Koreans have significantly altered efflux therefore fentanyl will not work as well
207
ABCC
Largest class
ubiquitous
Antineoplastic efflux
208
ABCG2
Breast cancer resistant protein
Antineoplastic, toxins, food-borne carcinogens
Folate transport
209
Non-ABC drug efflux transporters
SLC21
(OATPs)
passive transport gradients
some function for drug Influx
210
Blood brain barrier is made up of:
Physical barrier and transport barrier
211
In the blood brain barrier, transporters are mainly pumping..
..into blood.
212
Blood-CSF barrier
Fewer effluxes
| some drugs can get into brain easier from CSF than from blood except antineoplastics
213
GI tract transporter pump..
..into intestine cell, then into blood.
214
Liver transporter pump..
..into hepatocyte, then into bile.
215
Placenta transporters pump..
..back into maternal circulation.
216
IND
Investigational New Drug
217
NDA
New Drug Applicaiton
218
Phase 1 clinical testing:
20-100 healthy volunteers
Dosing, Safety, ADME
Can be in patients if high risk
219
Phase 2 clinical testing:
100-200 patients
Double-blind
efficacy
220
Phase 4 clinical testing:
1000s patients
Market formulation
route
221
GRASE
Generally Recognized As Safe and Effective
222
St. John's Wort
Claims: Depression
Issues: induce CYPs
others: MAOI (serotonin syndrome, malignant hyperthermia)
