Exam 1 Flashcards
Basic Principles of Pharmacology; Receptors (284 cards)
1
Q
Agonist
A
Binds to Receptor & elicits response (Activator)
2
Q
Antagonist
A
Binds to Receptor & blocks response (Inhibitor)
3
Q
Pharmacodynamics
A
What the drug does to the body
4
Q
Pharmacokinetics
A
What the body does to the drug
5
Q
Pharmacogenomics
A
Genetic profile / how an individual responds to a drug
6
Q
Chirality (stereoisomerism)
A
“Mirror Images” optical isomers
7
Q
Orthosteric
A
Binds to active site
8
Q
Allosteric
A
Binds outside of active site
9
Q
EC 50
A
Concentration of drug where 50% of drug has taken affect
10
Q
Kd
A
Drug concentration where 50% of receptors are bound
11
Q
Toxicology
A
Study of undesirable effects of chemicals on living systems
12
Q
Native ligand
A
Produced by body to bind to receptor to elicit response
13
Q
Materia Medica
A
First medical textbook of pharmacology
14
Q
Covalent bonds
A
Very strong & in many cases not reversible. Share electron bonds
15
Q
Electrostatic
A
Charged molecules.
Weaker than covalent.
16
Q
Hydrophobic
A
Lipid Soluble Drugs
Weakest / most numerous
Noncharged, MUST fit perfectly in receptor to elicit response.
“Phobia” to water
17
Q
Poisons
A
drugs that have almost exclusively harmful effects.
Biologic & Nonbiologic
18
Q
Toxins
A
Poisons of biologic origin
19
Q
Constitutive Activity
A
Active even in absence of agonist activity
20
Q
Racemic Mixture
A
50:50 mixture of two enantiomers, chiral molecules (mirror images)
21
Q
Receptor
A
Target molecule that plays a regulatory role in the biologic system (Large Protein)
22
Q
Receptor site
A
Active site on receptor to which ligand/drug binds to
23
Q
B max
A
Point where maximum amount of receptors are bound to
24
Q
E max
A
Point where maximum effect is seen
25
Competitive Inhibitor
Compete with agonist for active site binding, can be surmountable (surplus of agonist) or insurmountable (covalent bond forms)
26
Allosteric Inhibitor
Do not compete with agonist, binds outside of active site, can have inhibitor effects to which the agonist can not over come (Insurmountable)
27
Inverse Agonist
Greater affinity for Ri (Inactive form of receptor), Becomes less receptive, essentially an antagonist
28
Partial Agonist
Produce a reduced response at full receptor occupancy
In presence of full agonist, acts as antagonist
In absence of full agonist, acts as agonist
29
Potency
The concentration of drug required to produce 50% of drugs maximal effect (EC50)
29
Physiological Antagonism
A drug that counters the effects of another by binding to a different receptor and causes an opposite affect
30
Efficacy
The maximum effect a drug can produce regardless of dose (Emax)
31
Stereoisomers
Molecules that have the same molecular formula and differ only in how their atoms are arranged
32
Endogenous
Produced within the body
33
Exogenous
Produced outside the body
34
Imhotep
First recorded physician
35
Hippocrates
Fathers of Western Medicine
36
Caduceus
Symbol of peace and commerce (mistaken for rod of Asclepius) Winged staff intertwined with Two serpents
37
Asclepius
God of medicine staff intertwined by one serpent
38
Paracelsus
Father of Toxicology "The dose makes the poison"
39
Controlled drug trial
Compares drug to placebo to monitor for actual effects
40
Molecular Weight of most drugs
100-1000 Daltons
41
ADME
Absorption, Distribution, Metabolism, Excretion
42
Low Kd
High drug/receptor affinity
43
High Kd
Low drug/receptor affinity
44
Agonist "mimic" or Indirect agonist
Works inside the cell to inhibit the molecules responsible for terminating the action of an agonist
45
A drug must have the proper ___ to interact with a receptor
Shape, Size, Electrical Charge, or Atomic Composition
46
Van der Waals forces
Weak electrostatic forces that attract neutral molecules
47
Bond strength and specificity have an __ relationship
Inverse
48
What is nonspecific binding
when a drug binds somewhere else
Ex. albumin
49
What makes a compound organic?
Having Carbohydrates, Lipids, Proteins
50
Desensitization
cell shuts down signaling process; "protective mechanism"
51
Good Receptor Properties
selective - bind only to certain receptors
alteration - binds to ligand & causes change
52
Bound (albumin) drugs
can not cross barriers
53
Unbound Free form Drugs
can cross barriers
54
Bad Receptor Properties
- binds but cause no change (drug carriers)
- not specific
55
Albumin mostly bind to
Acidic drugs
56
Displacement of drugs is
when two drugs compete to bind to albumin (more free form drug)
57
Albumin has how many binding sites?
2
58
Maximal Efficacy
maximal effect; might see side effects at this point
59
Clinical effectiveness of a drug depends on
maximal efficacy
60
Therapeutic Index is
The distance between ED50 & TD50; Established safety margins
61
TD50 is
median toxic dose; point where 50% of toxic affects seen
62
ED50 is
Median effective dose; point where 50% of dose sees desired effects
63
Narrow Therapeutic Index
dangerous; closely monitored (ex. digoxin)
64
Wide Therapeutic Index
relatively safe; larger margin for error; OTC meds (acetaminophen)
65
Variations in drug responsiveness
Tolerance; Tachyphylaxis (quick tolerance); Chemical agonist (drug); Physiologic antagonism (body blocks or heightens response)
66
Four causes of drug responsiveness variations
- Alteration in concentration of drug that reaches receptor;
- Variation in concentration of endogenous receptor or ligand;
- Alteration in number of functioning receptors;
- Changes in downstream effect post-receptor
67
In order to cross barriers
drugs need to be uncharged
68
Most drugs are ___ or ___
"weak acids" or "weak bases"
69
pKa relates to what?
pH
70
If pH < pKa it
favors protonated form (H+ attached)
71
If pH > pKa it
favors unprotonated form (no H+)
72
Acids tend to ___ __ into solution
release H+
73
Bases tend to ___ __ from solution
absorb H+
74
Acids are ___ when protonated (H+ attached)
uncharged
75
Acids are __ when unprotonated (No H+)
charged
76
Bases are __ when protonated (H+)
charged
77
Bases are __ when unprotonated (No H+)
uncharged
78
"Weak acids" in acidic environment
protonated/uncharged
79
"Weak acids" in basic environment
unprotonated/charged
80
An example of a weak acid?
Aspirin
81
"Weak bases" in acidic environment
protonated/charged
82
"Weak bases" in basic environment
unprotonated/uncharged
83
An example of a weak base?
Morphine
84
Monoclonal Antibodies are created by
biologic organisms; clones of a single parent cell
85
monoclonal antibody suffix
- mab
86
Benefit of monoclonal antibodies?
specificity - bind to a specific site, can target certain protein; can cause apoptosis (cell death - cancer cells)
87
The variable region
region that binds to specific protein
88
The constant region
region that does not change (mediates immune response after binding)
89
4 ways a drug action ceases
1. Drugs stops binding to receptor
2. Downstream effectors go away/run out
3. Receptor degradation (covalent bond)
4. Desensitization
90
Malnourished patients and dosing
Require lower dose of medication; less albumin available = more free/unbound drugs
91
a1 glycoproteins mostly bind to
basic drugs
92
Lipoproteins most bind to
neutral drugs
93
Therapeutic Index can be determined by which equation
TI = TD50/ED50 (human)
TI = LD50/ED50 (animal studies)
94
Unusual/unsuspected response to a drug is termed
idiosyncratic (don't know why it happened)
95
Idiosyncratic responses are often attributed to
genetic factors
96
The largest and most important cause in drug response variation is
changes in components of response (downstream effectors)
97
pKa
dissociation constant
98
Endogenous antibodies have 2 major functions
1. recognize and bind to antigen
2. Induce immune response after binding
99
Monoclonal antibodies do not
elicit immune response
100
Spleen cells fused with myeloma cells are
Immortal; cloned; utilized in monoclonal antibody production
101
Food and Drug Administration (FDA)
federal agency responsible for regulating food and drug products
102
For drugs to be approved by FDA they must be proven to be
"Safe & Effective"
103
FDA regulates the way drugs can be
marketed (what claims can be made by drug/product)
104
FDA famously denied approval for ___ in the 1950s
Thalidomide - teratogenic medication; utilized for morning sickness in Europe
105
In Vitro studies are looking for new drugs identified as
Lead compounds
106
Prior to conducting human studies drugs researchers must first
Ensure safety in animals & be approved for IND (Investigational New Drug)
107
Phase 1 clinical trials
Testing a new drug on small drug of healthy individuals to find out how the body reacts to the drug
108
Phase 2 clinical trials
Drug is tested on target population to determine if is more beneficial than placebo (double blind)
109
Phase 3 clinical trials
Drug is tested on large target population (second double study)
110
Prior to phase 4 drug studies a __ is required
NDA (New Drug Application)
111
Phase 4 clinical trials
Approved and gone into market; after 20 years patent expires and generic meds can be made
112
Receptor
component that interacts with drug/ligand and initiates chain of events
113
Receptors are
Proteins
114
Orphan receptors
receptors whose natural ligands are unknown
115
G-protein coupled receptors (GPCRs)
a signal receptor protein in the plasma membrane that responds to the binding of a signal molecule by activating a G-protein
116
Ligand-gated ion channel
act as "gate"; open channel when something binds to them
117
Ion channels
open because of change in charge on membrane
118
Signaling molecule
drug or endogenous ligand that binds to receptor of GPCR
119
Second messenger
molecule that is activated byeffector proteins
120
Effector proteins
have an effect on the behavior of a cell
121
Most common second messenger
cyclic AMP (cAMP)
122
Lag period
delay in gene expression related to the requirement for transcription/translation
123
Drugs with a greater persistence require ___ dosing
less frequent (they last longer)
124
Conformational change
The receptor binds to a drug & changes in some form
125
Dose response is related to
number of receptors bound (linear) or strength of signal transduction cascade (multiple responses)
126
Kinase
any enzyme that attaches a phosphate group to another protein
127
a phosphorylated protein is
active
128
Steps in Phosphorylation Cascade
1. Drug bind to receptor
2. Drug invokes conformational change
3. Protein Kinase is activated
4. Chain reaction of protein phosphorylation (phosphate attahed)
5. Effector is reached & activated
129
To activate intracellular receptor drug must be
Lipid soluble or uncharged (must cross cell membrane)
130
A Catalytic receptor
activates an enzyme
131
2/3 of all non-antibiotic drugs are activated by
GPCRs
132
G-Protein trimeric (3 subunits); the alpha subunit is
the most important; it initiates a response of an effector protein
133
When inactive, the alpha subunit of the G-protein is bound to
GDP (guanine diphosphate)
134
When active, the alpha subunit of G-protein is bound to
GTP (Guanine triphosphate)
135
G-protein
A GTP binding protein that relays signal from plasma membrane signal receptor (G protein coupled receptor), to signal other transduction proteins inside the cell
136
GPCRs structure:
seven transmembrane a-helices
137
GPCRs are a
seven transmembrane spanning receptor region
138
Desensitization is
utilized when covalent bonds form on receptor by drug/ligand to stop constant signaling
139
What are the two possible outcomes that may occur with desensitization
1. The covalent bond breaks between drug & receptor to which receptor is recycled
2. The covalent bond does not break and a lysosome breaks down receptor
140
What is beta arrestin?
it is a protein that binds to OH groups on receptors to stop them from signaling
141
What is a clathrin pit?
a protein involved in endocytosis (engulfs receptor with beta-arrestin attached and brings it into cell)
142
Phosphatase
strips phosphate group from protein
143
With RTKs you have _____ that join to form a ___
two monomers; dimer
143
How many ATPs are utilized during phosphorylation of RTKs
6
143
Receptor Tyrosine Kinase ligands typically are
Growth factors or Adhesion factors
143
Ligand binding stimulates what on RTKs
Dimerization & Phosphorylation of tyrosine (makes it act like a kinase)
143
Four types of Catalytic Cell Surface Receptors
- Tyrosine Kinase
- Tyrosine Phosphatase
- Serine/Threonine Kinase
- Guanylate Cyclase
143
Steps in the RTK process
1. Two RTK are bound by ligands (requires 2)
2. Both monomers join to form Dimer
3. The dimer becomes phosphorylated utilizing 6 ATPs
4. The receptor begins to interact with effector protein
144
Ion channels
pores that allow charged molecules to go from one side of membrane to the other
145
Ion channels can be opened by
A ligand or voltage
146
Voltage gated channels are found in
Excitable cells (Neuron, muscles, endocrine cells)
147
Membrane potential is called
Threshold
148
Inotropic-gated Ion channel
Ligand binds to it & opens channel on same protein
149
Describe GPCR activating Ion channel
1. Ligand binds to GPCR
2. G protein is activated
3. G protein activates effector protein
4. Effector protein produces 2nd messenger
5. 2nd messenger binds to ion channel & Ion channel opens
149
Ligands that bind to receptors inside the cell
- Gases (nitric-oxide)
- Lipid soluble (steroid hormone)
149
Metabotropic-gated Ion channel
Ligand activates GPCR & second messenger activity opens channel
149
Four ways a drug can cross a membrane
- aqueous diffusion
- lipid diffusion
- special carriers
- Endocytosis & exocytosis
150
water channels are
Aquaporin channels; pores that allow water into cell
151
Aquaporin channels allow drugs into cell if they are ___ ___ by process of ___
water soluble; simple diffusion (high concentration to low)
151
Aqueous diffusion will not be allowed if drug is
Highly charged or Bound to large proteins (carriers)
152
Lipid Diffusion allows ___ ___ drugs to cross membrane
lipid soluble
152
Special carriers
Bind to drug & move it across barriers (by active transport or facilitated diffusion)
153
Endocytosis
membrane engulfment
154
Exocytosis
releasement out of membrane
155
Volume distribution (Vd)
relates amount of drug in body to concentration in blood (how much we gave vs. how much is in the blood)
155
Clearance is
ability of body to eliminate drug; given in percentage of how much drug is eliminated/hr
156
Elimination does not equal
clearance
157
Elimination changes based on
clearance (in first order)
158
The higher the volume distribution
the less amount there is in the blood
159
Equation for volume distribution (Vd)
dose/drug concentration = Vd
ex. (10mg/Kg / 125mg/L = 0.08L/kg)
160
Target concentration can be calculated from
volume distribution
161
Clearance predicts
the rate of elimination in relation to drug concentration
162
Equation for clearance
CL = rate of elimination/C
163
Clearance for almost every drug will remain
constant
164
Equation for Rate of Elimination
ROE = CL x C
165
First order elimination is
Clearance is constant; rate of elimination varies with concentration
166
Zero order elimination is
Rate of elimination is constant; clearance varies with concentration (so much drug in body, elimination mechanism saturated)
Ex. Ethanol, phenytoin, ASA
167
Vmax
Maximum rate you can eliminate drug
168
Three main drugs Zero order applies to
Ethanol; Phenytoin; Aspirin
169
Sodium channels are considered to be
Fast
170
Calcium channels are considered to be
Slow
171
Four stages of gated channels
1. Channel closed; internal gate 1st closed & 2nd (innermost) gate open
2. Channel activated & both gates open
3. Channel is inactivated; 2nd gate closes to prevent too many ions; 1st gate remains open
4. Channel is deactivated & both gates closed
172
Rational Dosing
goal is to achieve desired beneficial effect with minimal adverse effects
173
Whole blood constant is
0.08 L/Kg
174
Plasma volume constant is
0.04 L/Kg
175
How many nanograms in a mg
1,000,000
176
How to calculate dose given Vd
Vd x Target conc. = dose
177
To get dose, divide ___ by ___
Target concentration; percent in blood
178
Rate of elimination is
Mass of drug eliminated per unit time. (mg/hr)
179
What is half life (T 1/2)?
Time it takes for the body to get rid of half the concentration of drug
180
What is the formula for half life?
T 1/2 = (0.7 x Vd)/CL
181
High extraction drugs are
Drugs that are eliminated in large portions during "first pass effect"
182
Extraction ratio categories & percentages
- High extraction ratio > 70%
- Intermediate extraction ratio 30-70%
- Low extraction ratio < 30%
183
The only time we have a high clearance is when we have both
A high extraction ratio & high (normal) blood flow
184
How many half lives does it take to reach steady state (No bolus)?
4 half lives
185
How many half lives does it take to eliminate the drug from the body when the dose is stopped?
4 half lives
186
If dosing interval is shorter than four half lives __ will develop
Accumulation (toxic levels can be reached)
187
What is Bioavailability?
Fraction of unchanged drug reaching systemic circulation
188
Giving a drug IV will make the bioavailability
100%
189
Factors that affect bioavailability (6)
- Physical properties (pKa, Hydrophilicity, solubility)
- Formulation/route
- GI - diet, gastric emptying
- Overall heath/disease state
- Interactions with other drugs
- Circadian
190
Absorption does not equal concentration because
once absorbed in gut medication must undergo "First pass effect" in liver
191
Routes that bypass First Pass Effect
- IV, IM, SC
- Inhalation (has own metabolism/first pass effect)
- Sublingual or transdermal
- Rectal suppositories
192
Target concentration
concentration that will produce desired effect without adverse effects
193
Target concentration is ____
Therapeutically determined (what is the end goal?)
Ex. Digoxin
- 2ng/mL: controls a fib
- 1ng/mL: manages HF
194
Formula for Dosing rate
Dosing rate = CL x TC
195
Formula for Dosing rate with less than 100% Bioavailability
Dosing rate = (CL x TC) / Foral (bioavailability)
196
Maintenance dose formula
Dosing rate/ Foral (bioavailability) x Dosing interval
197
Why is a loading dose given?
To reach steady state quickly
198
Formula for Loading dose?
LD= Vd x TC
199
A loading dose must be given
Slowly, needs time to distribute
200
The most important factor in Therapeutic drug monitoring is?
Clearance
201
Drugs that do not penetrate fat (stay in bloodstream) utilize ___ when drug dosing
Ideal Body Weight (IBW)
202
Creatine clearance give us
overall idea of health/function of kidneys
203
Where does Biotransformation primarily occur?
Liver
204
What is Biotransformation?
changing or bio modifying a drug to make it more or less active
205
First pass effect is
passing through the liver prior to reaching systemic circulation
206
Oral Hepatic portal system of drug
GI --> Local veins --> Hepatic portal Vein --> Sinusoids (Leaky capillaries) --> Hepatic vein --> Vena Cava --> Systemic circulation
207
Biotransformation takes place in liver by which cells?
Hepatocytes
208
Where is a drug bio-transformed?
Sinusoids
209
Hepatic Artery route (all IV drugs take)
Systemic circulation --> Hepatic artery --> Sinusoids --> Hepatic Vein --> Vena Cava --> Systemic circulation
210
Phase 1 Reactions
utilization of an enzyme to add or unmask a functional group (convert drug to more polar metabolite)
211
Phase 1 reaction types:
- Oxidation (most important) (Lose electrons)
- Reduction (Gain electrons)
- Dehydrogenation (Remove OH group)
- Hydrolysis (add OH group)
212
Most drugs are modified by which oxidation reaction in phase 1
Cytochrome P450
213
Cytochrome P450 enzymes have
- low substrate specificity (Bind to multiple drugs)
- Multiple different types (CYP-***)
- Mixed-function oxidases (oxidizes & makes drug hydrophilic)
214
CYP3A4
cytochrome P450 subtype that metabolisms 50% of drugs undergoing phase 1 reactions
215
The Cytochrome P450 that occurs most often in blood types is (wild type)
CYP3A4*1
216
P450 Induction
Enhance synthesis or inhibit degradation (increased levels of P450)
217
P450 Inhibition
Decrease or irreversibly inhibit P450
218
Competitive inhibition is
co-administration of drugs metabolized by same P450 (cant metabolize 2 drugs at once)
219
The effects of inhibition or induction of CYP450 depend on
if metabolism by P450 activates or deactivates the drug
220
Three CYP subtypes & percentages of phase 1 reactions they are involved in
- CYP2B6 (8%)
- CYP2D6 (20%)
- CYP3A4 (50%)
221
Phase 2 reactions
Conjugation reactions - attaches a molecule making it larger & more hydrophilic (less likely to cross barrier)
222
Types of phase 2 conjugations (7):
- Glucuronidation
- Acetylation
- Glutathione conjugation
- Glycine conjugation
- Sulfation
- Methylation
- Water conjugation
223
Glucuronidation
- uridine diphosphate glucuronosyltransferases (UGTs) enzyme - carrier molecules - add glucuronic acid making it easily excreted in urine
224
Glutathione-S-Transferase (GST) enzymes attach
- Glutathione to xenobiotic (foreign body) making it more likely to be excreted in urine
- Ubiquitous - found everywhere (High in RBCs)
225
When a patient ODs we see toxics byproducts because we have ___
overwhelmed normal pathways & alternative pathways that are activated can have toxic by-products
226
What is the importance of pharmacogenetics?
The specific testing to help predict, explain, & treat
227
Warfarin is a __ mixture
Racemic mixture (R &S)
- S is 7-10x more potent than R
228
15-25% of breast cancers are caused by ___
HER2
229
What is the drug that targets breast cancers that are HER2 positive
Trastuzumab (Herceptin)
230
What is the Purine analogs MOA
blocks rapidly dividing cell from dividing
231
What is the role of drug transporters in the cell?
To transport endogenous & xenobiotic substances across barriers (membranes)
232
Role of Drug efflux transporters
Pump drug out of cell
233
Most of drug efflux transporters are
ATP - binding cassette transporters (ABC)
234
What are the three important ABC transporters?
ACBB1, ABCC, & ABCG2
235
Which ABC transporter has the broadest substrate specificity?
ABCB1
236
Which ACB transporter is the largest?
ABCC
237
Which way do transporters typically move in the Intestine?
Into cell (INFLUX)
238
Which way do transporters typically move in the Placenta?
Out of cell (EFFLUX) (alcohol can pass)
239
Which way do transporters typically move in the Liver?
Into cell (INFLUX) ; liver metabolizes most drugs; Liver --> bile
240
Which way do transporters typically move in the Kidneys?
Into cell (INFLUX) ; into glomerulus out through tubule excreted via urine
241
Which way do transporters typically move in the Blood Brain Barrier?
Out of cell (EFFLUX)
242
Which way do transporters typically move in the CSF?
Out of CSF (Efflux)
243
What are the components that protect the BBB?
- ABC transporters
- Vascular epithelium cells (tight junction)
- Cells that regulate what enters neuron (Astrocytes & Podocytes)
244
Barrier properties mediated by specific transporters in BBB are
- Active Efflux transporters (allows small lipophilic molecules - O2, CO2, Ethanol)
- Carrier Protein (allows glucose, amino acid nucleotides in)
- Receptor mediated (Insulin)
- Adsorption endocytosis (Albumin)
245
Delineate pathway of Tylenol in gut before & after bio-transformation
Tylenol absorbed through gut --> "First pass" goes to liver --> Phase 2 metabolism (glucuronidation adds glucose to it becomes nontoxic glucuronide) --> gets sent to bile --> Bile dumps it into intestine (ABC transporters) --> out through feces
246
What are parameters Affecting Passive diffusion?
- Molecular weight
- pKa
- Lipid solubility
- Plasma protein binding
247
Describe the pathways Acetaminophen can take upon metabolism
Normal pathways
- Glucuronidation --> non-toxic glucuronide (main pathway)
- Sulfation --> nontoxic sulfate
Alternative pathways
- GSH conjugation --> adds glutathione
- Nucleophilic cell macromolecules --> Liver cell death
248
If Drug1 is metabolized by CYP3A4; and CYP3A4 is induced, what affect would that have on drug1?
Drug1 would be inactivated much quicker
249
If a Prodrug is activated by CYP3A4; and CYP3A4 is induced, what affect would that have on the Prodrug?
The Prodrug would become active much quicker
250
If Drug1 is metabolized by CYP3A4; and CYP3A4 is inhibited, what affect would that have on drug1?
Drug1 would be more active (can lead to toxic levels)
251
If a Prodrug is activated by CYP3A4; and CYP3A4 is inhibited, what affect would that have on the Prodrug?
The Prodrug would remain inactive having no effect
252
What is a Prodrug?
A drug that has no biologic affect until it is metabolized
253
What drugs interact with ABCB1 transporters & what affect do they have on ABCB1?
Cyclosporine A, Quinidine, Ritonavir all inhibit ABCB1
254
What is Loperamide? & what effects does it have when combined with quinidine?
Loperamide - opioid, antidiarrheal no CNS effect BUT when combined with quinidine; quinidine inhibits ABCB1 --> Loperamide then has CNS effects (respiratory suppression)
255
Describe ABCG2 transporters
- breast cancer resistance proteins (BCRP)
- Antineoplastic, toxins, food borne carcinogens
- folate transport
256
Describe ABCB1 transporters
- broadest specificity (HIV protease inhibitors, ABX, antidepressants, antiepileptics & opioids)
- Wide distribution (GI, Kidneys, Liver & testes - Critical in BBB)
257
Describe ABCC transporters
- Largest class
- Mainly antineoplastic efflux
258
What is the enzyme that metabolizes Warfarin?
CYP2C9
259
If TPMT is mutated or missing, how will this affect the metabolism of 6-MP?
6-Mercaptopurine (6-MP) will increase & become toxic (TMPT is the main pathway for 6-MP metabolism)
260
What is an Allele?
alternative form of a gene which occurs at the same locus
261
Purine analogs are used to treat cancers & autoimmune disease but are toxic, why?
They suppress immune (myelosuppression) - narrow therapeutic index
262
If a patient has 2 copies of the TMPT gene, how does this affect how they take 6-MP?
It does not, they can take normal doses
263
If a patient has 1copy of the TMPT gene, how does this affect how they take 6-MP?
They need to take a reduced dose of drug
264
If a patient has 0 copies of the TMPT gene, how does this affect how they take 6-MP?
They will require another drug as they can not metabolism drug
265
What is the function of Solute Carrier (SLC) proteins?
Transport 15-30% of all membrane proteins
- High substrate specificity (Na, Glucose, Amino acids)
266
What is the function of SLC21
- Organic anion transporter proteins (OATPs)
- Primarily passive (gradients)
- some function for drug Influx
267
What affect would a poor metabolizer phenotype have on a Prodrug?
Prodrug would be inactive as it needs to be metabolized to work, poor efficacy --> possible accumulation of drug
268
What affect would a poor metabolizer phenotype have on an Active drug?
Active drug would stay active longer, good efficacy, can lead to toxic effects; may require lower dose
269
What affect would an Ultra-rapid metabolizer phenotype have on a Prodrug?
Prodrug would be active faster, good efficacy
270
What affect would an Ultra-rapid metabolizer phenotype have on an Active drug?
Active drug would become inactive rapidly, poor efficacy, will need greater dose
271
Describe the metabolism process involved in Cytochrome P450
Drug binds to P450 (contain iron) --> oxidation occurs --> electrons go to Flavoproteins (FMN) & becomes reduced & oxidized --> FMN is recycled by NADPH --> P450 & the drug are combined with hydrogen & oxygen to form H20 & an OH group attached to drug --> drug leaves HYDROPHILIC
272
60-70% of breast cancers express which type of receptors?
Estrogen receptors & Progesterone Receptors
