Exam 1 Flashcards
1
Q
Define endogenous?
A
A chemical produced from within the body
2
Q
The first recorded physician?
A
Imhotep
3
Q
Coined the “Father of Western Medicine”?
A
Hippocrates
4
Q
Famous quote from the “Father of Toxicology?”
A
“The dose makes the poison”
5
Q
The “Father of Toxicology”?
A
Paracelsus
6
Q
Pharmacokinetics is defined as?
A
What the body does to a drug
7
Q
Pharmacodynamics is defined as?
A
What a drug does to the body
8
Q
Define what an agonist is?
A
Activates a response from a receptor; similar to native ligand.
9
Q
Define what an antagonist is?
A
Blocks an endogenous ligand from eliciting a response / Does not activate a response
10
Q
Define exogenous?
A
A chemical that is produced outside of the body
11
Q
Describe a toxin?
A
A biologic chemical that produces undesirable effcts
12
Q
Describe a poison?
A
A non-biologic chemical that produces undesirable effects
13
Q
What are the three main types of bonding in pharmacology?
A
Covalent, Electrostatic, and Hydrophobic
14
Q
Most drugs are what molecular weight?
A
100-1000 MW (daltons)
> 1000 MW has difficulty due permeability
15
Q
What is the strongest bond?
A
Covalent bonds
16
Q
What is the weakest bond?
A
Hydrophobic bonds
17
Q
Describe the relationship between the type of bond and their receptor specificity?
A
The stronger the bonds, the less specific. The weaker the bonds the more specific. (Inverse relationship)
18
Q
What are racemic mixtures made of?
A
50/50 of each stereoisomer
19
Q
This is the most potent stereoisomer of ketamine?
A
The (S) stereoisomer, named Esketamine
20
Q
Describe an orthosteric receptor interaction?
A
Orthosteric interactions occur at the active site
21
Q
Describe an allosteric receptor interaction?
A
Allosteric interactions occur away from the active site
22
Q
What are the primary components of Pharmacokinetics?
A
Adsorption, Distribution, Metabolism, and Excretion
23
Q
What is the EC50?
A
The concentration of a drug when 50% of the maximal effect (Emax) is achieved
24
Q
What is the distribution coefficient (Kd)?
A
The concentration of a drug when 50% of the maximal binding is achieved
25
Explain why Kd does not have to equal EC50?
Because they are not proportional. You may achieve EC50 when Kd is only at 5%, or you may achieve Kd and not have any effect achieved.
26
Describe the meaning of a low Kd?
A low Kd means that the drug has a high affinity for that receptor. A small amount of drug required to reach 50% receptor binding.
27
Describe a competitive inhibitor?
A drug that stops the agonist from binding at the active site and decreases response.
28
Describe an allosteric activator?
A drug that does not bind to the active site, but improves binding and increases the response.
29
Describe an allosteric inhibitor?
A drug that does not work at the active site that non-competitively blocks binding at the active site and decreases response greatly.
## Footnote
Causes change in conformation at the receptor site.
30
Describe the role of an "agonist mimic" or "indirect agonist"?
They increase the activation or response intracellularly by downstream inhibition. (Ex: Binds to an enzyme that breaks down an intracellular second messenger).
31
What does it mean for an antagonist to be "surmountable"?
A competitive antagonist's inhibiting effects can be countered by increasing the amount of the agonist to activate a receptor
| eventually the same effect as agonist alone
32
What does it mean for a antagonist to be "insurmountable"?
The agonist can never overcome the inhibiting effects of the antagonist. No matter how much agonist given, will not achieve same effect as agonist given alone.
| Due to covalent bonding, which is very stong and wont be broken
33
Describe a non-competitve antagonist?
An allosteric receptor interaction that can never be overcome by the agonist.
34
Describe what this diagram is showing?
Competive Inhibitior (antagonist, propanolol) is overcome by addition of more agonist (Isoproterenol) to achieve the same effect. EC50 is increasing due to higher amounts of the drug being required to overcome the competitive antagonist.
35
Describe what this diagram is showing?
Noncompetitive inhibitors are insurmountable, adding more of the agonist will never reach the same effect as the agonist acting alone. There is no change in EC50 because the maximum effect is now lower.
36
Describe a partial agonist?
Competes with the full agonist and produces a lower response than full agonist when all receptors are bound.
## Footnote
In the prescene of a full agonist, it acts as an antagonist. In the abscence of a full agonist, it acts as an agonist.
37
Describe physiologic antagonism?
Drugs that inhibit the effect of another drug without binding to the same receptor.
| Acetylcholine opposes the effects of epinephrine
## Footnote
Insulin opposes gluccocorticoid hormones
38
Explain active (Ra) and inactive (Ri) receptor congigurations?
Receptors switch between Ra and Ri on their own, even in the abscence of a drug - favors Ri.
| Agonist favors Ra and Inverse Agonist favors Ri
39
Describe an inverse agonist?
An agonist that has a greater affinity for the Ri state, which inactivates the receptor site. Reduces constitutive activity which may producing an opposing physiologic effect.
| In clinical practice it is just an antagonist.
## Footnote
Antagonistic activity (beta blockers, H1/H2 blockers)
40
What is the Materia Medica?
Collection of works describing the preparation and use of botany and medical substances
## Footnote
Precursor to pharamcology
41
Correlate stereoisomerism and differences in drug effects
One enantiomer is typically much more potent than the other, they can elicit differing respones from the receptor.
| one enantiomer fits better into the receptor than the other
42
What is Bmax on a drug response curve?
The drug concentration when the maximum number of receptors are bound.
43
What is Emax on a drug response curve?
The drug concentration when maximal effectiveness is achieved.
44
How can a partial agonist also behave as an antagonist?
Partial agonists compete for the same receptors as the full agonist, preventing the full agonist from binding.
45
Describe a receptor site?
A protien on the cell surface that can bind to specific molecules, which activates a chemical reaction.
| The "lock" to the drug "key"
46
What would a high Kd indicate?
That the drug has a low affinity for the receptor.
47
Describe antagonism with opposite charge?
A drug is given with an opposite charge that will bind and inhibit its effects.
## Footnote
Protamine (+) binds to and inhibits the effects of heparin (-)
48
What is constitutive activity?
The spontaneous activation of receptors without the binding of agonist.
49
What are properties of a "good" receptor?
It is selective and can activate an alteration in function (initiate downstream effects.)
50
What are "bad" receptor properties and some examples?
They bind with drugs but do not cause a change in function. Examples are inert binding sites and drug carriers.
51
Describe a drug carrier's funtion?
A drug carrier can bind to a drug at it's inert binding sites to transport a drug around the body.
52
What are the differences in bound and unbound drugs?
Drugs bound to a drug carrier cannot cross membranes, only the unbound drug can cross.
| Unbound too large to cross membranes
53
What changes in drug administration for drugs that are highly protein bound?
A highly bound drug may require a higher dose to increase free drug concentration.
##Footnote
This is pharmacokinetics
54
Desribe plasma protein and drug effects in malnutrition and liver damage?
In malnutrition/liver damage plasma albumin levels are lower, so there will be more free drug with an equal dose = increased effect and toixc effects.
55
What may be the effect if 2 drugs are given that are both highly bound to proteins?
One drug may displace the other off of the protein it is bound to.
56
What are the most common drug carriers?
Albumin (most important), a1-acid glycoprotein, and lipoproteins.
57
What does albumin mostly bind to?
Acidic drugs
58
What does a1-acid glycoproptein mostly bind to?
Basic drugs
59
What does lipoprotein mostly bind to?
Neutral drugs.
60
What is drug potency?
Potency is the concentration or dose of a drug need to get to 50% of maxmimal effect.
## Footnote
Low does and high effect = more potent
61
What is the drug efficacy?
The maximal response a drug can deliver. Depends on receptor interactions.
## Footnote
More important clinically than potency
62
Compare the efficacy and potency of these drugs.
Drug B is the most potent drug, but drugs A,C, and D are more and equally efficacious. Potency of the drugs is such that B>A>C>D.
63
What is TD50?
Median Toxic Dose
64
What is LD50?
Medican Lethal Dose.
65
How can you calculate therapeutic index?
TD50 divided by ED50.
66
What does the therapeutic index indicate?
The safety of a drug. A high Ti means the drug is safer than a low Ti.
67
What are the 4 main causes of drug variation?
1. Variations in concentration of drug that makes it to the receptor (ADME, age, sex, disease).
2. Variation in concentration of endogenous ligands.
3. Variation in number or function of receptors.
4. Variations in downstream responses (most important).
68
What charge must a drug have to cross a barrier?
Uncharged
69
Describe weak acids?
They release a proton (H+) into solution
70
Describe weak bases?
They absorb protons (H+) from a solution.
71
What does pKa tell us?
At what pH there are equal amounts of the protonated and unprotonated drug forms.
## Footnote
50% protonated and 50% unprotonated
72
What does Hendersen Hasselbach equation correlate between pH and pKa?
It correlates that if pH < pKa, it favors the protonated form. If pH > pKa, it favors the unprotonated form.
## Footnote
Remember, the lower pH = more H+ = protonated!
73
What charge will a weak acid with a pKa of 3.5 favor at a pH of 1.5 and 6.5?
At pH 1.5 it will favor the uncharged (protonated) from and at pH 6.5 will favor the charged (unprotonated) form.
74
What is the charge on a weak acid when it become protonated and unprotonated?
When protonated it becomes uncharged, when unprotonated it becomes charged.
## Footnote
Acids have protons to give, so when protonated become neutral.
75
What is the charge on a weak base when it becomes protonated and unprotonated?
When protonated it becomes charged, when unprotonated it becomes uncharged.
## Footnote
Bases readily accept protons, and take on their charge when protonated.
76
What does the henderson hasselbach equation tell us?
The pH at which the protonated and unprotonated forms are in equilibrium (or the pKa)
77
How are monoclonal antibodies produced?
Created by living system after exposure to an antigen. A single antibody (monoclonal) is taken and replicated. Can be extracted from living system or produced by recombinant DNA.
78
What is the structure of a monoclonal antibody?
A human antigen molecule that has the propagated antibody cells attached at the binding sites.
79
Draw the basic structure of a monoclonal antibody.
## Footnote
antibodY, drawn like a Y. Binding sites at the tips.
80
How are all monoclonal antibodies named?
*-mab*
81
Why are MAB good drugs and what are they used for?
They bind to very specific receptors, which improves efficacy and decreases adverse effects.
Useful in cancer treatments (target specific tumors or cells), RSV, in the CV system to prevent clots, in diabetes, and growth hormones.
82
What is the role of the FDA?
To oversee drug development, determine if drugs are both safe and effective, make recommendations, verify claims, and categorize drugs (presription, OTC, herbal).
83
What is the difference in regulation in OTC and prescription drugs?
OTC are available to the general public, lower risk (not safe).
Prescription drugs must be recommended by liscenced health professional, higher concern for misuse.
84
What are the steps to bring a presription to market?
In vitro studies (lead compound isolated and patent submitted), animal testing (investigational new drug submission), Phase 1, Phase 2, Phase 3 human clinical testing (new drug application), and Phase 4.
85
What is orphan receptor?
A receptor that we know exists but do not what endogenous ligand it binds to.
86
What are all receptors?
Proteins
87
What category of receptor structure are GCPR's in?
Seven-transmembrane (7TM) receptors
88
Describe the cell signaling process.
1. Signaling molecule (drug or endogenous ligand)
2. Molecule activates the receptor.
3. Signal transduction proteins and 2nd messengers (cAMP, IP3, DAG)
4. Effector protein (causes the change intracellulary)
89
What is a kinase and what does it do?
An enzyme that activates a protein by phosphorylating another protein
90
Draw the phosphorylation cascasde.
Drug activates the receptor, this causes a conformational change and becomes an activated effector protein and starts a chain of activated second messengers by phosphorylation through kinases.
91
What are the 4 transmembrane signaling methods by drug-receptor interations?
1. Lipid soluble molecule crosses and attaches intracellularly.
2. Enzyme activation (catalytic)
3. Ion channels
4. GPCR's
92
What is the GPCR structure?
Receptor = 7TM alpha helices Protein = trimeric (alpha, beta, gamma amino acid strands), and GDP (inactive)/GTP (active)
93
Explain the mechanism of GPCR signaling.
Drug binds to the receptor, this causes a conformational change and GDP leaves the alpha strand and GTP attaches - activating it. The activated G protein activates the effector protein releasing the second messengers like cAMP that activates the effector protein that invokes a response.
##Footnote
The drug does not have to stay attached, it can leave an another can bind - the downstream effects still occur.
94
What is the role of second messengers? What are the 4 most important?
cAMP, Ca, IP3, DAG. Second messengers are what is produced after the effector protein is activated and eventually activate the desired intracellular effect.
95
Draw and describe the GPCR pathway involving adenyl cyclase?
96
Define what desensitization is?
Densitization is when an agoinst is still present but its effect is being blocked by intracellular processes.
The receptor cannot be bound/activated.
97
Describe how GCPRs cause desensitization?
Drug activates GPCR. The carboxyl tail becomes phosphorlated by G protein kinases. This promotes binding of beta arestin and prevents further interactions with G proteins. This complex binds with a clatherin coated pit which internalizes the receptor. Then the drug unbinds form the receptor causing dephosphorylation and detachment of beta arestin. Then either 1. the receptor can be returned to the plasma membrane and bound again or 2. be taken to a lysosome for destruction.
##Footnote
This causes desensitization because the receptor cannot be bound during this period
98
What does phosphatase do?
Removes phosphate group from a protein or molecule.
99
What is the structure of a RTK (receptor tyrosine kinase)? How does it function?
The receptor becomes dimerized when activated (two seperate receptor monomers combine). Each monomer has 3 tyrosine sites. These 6 tyrosine site are phosphorylated by 6 ATP and become active. Once active, can activate an effector proteins and second messengers.
100
Describe voltage gated ion channels and where they’re found?
1.Found in excitable cells like neurons, muscle, and endocrine. 2.They are closed at resting membrane potential and open when the threshold is met.
3.They are selctive based on the ion.
101
Describe ionotropic ligand gated ion channels?
The protein has a ligand binding site and channel. Ligand binding opens the gate and allows ions to cross.
102
Describe metabotropic ligand gated ion channels?
The ligand activates a GPCR which activates and EP that releases second messengers that open the ion channel.
103
What types of ligands can bind to intracellular receptors? Name an example of each?
Gasses (nitric oxide) and lipid soluble agents (steroid hormones).
104
What is Volume of Distubution (Vd)? How is derived?
The space available in the body to contain a drug. The higher the Vd the less it says in the blood and more it disturbutes into the tissues and vice versa.
Vd= dose / initial drug concentration
105
What is drug clearence? How is it derived?
The predicted rate of elimation of a drug, in relation to drug concentration.
Cl = rate of elimination/drug concentration
106
What are the metric system converion factors?
107
How can you calculate the dose when given Vd?
Multiply the Vd by the target concentration.
| The dose needs to be in mg/kg
108
Practice Vd problems
109
Describe first order elimination?
Applies to most drugs, rate of elimination varies with concentration. ***Clearance remains constant. ***
110
What is the rate of elimination? How is it derived?
There is First Order and Zero Order, describes the amount of drug eliminated over a certain time period.
ROE= CL x C (blood)
111
Describe Zero order elimination?
***Rate of elimination is constant.*** Clearance varies with concentration.
| Occurs when ability to eliminate drugs is at max capacity.
## Footnote
All transporters are being used.
112
What are some drugs that experience Zero order elimination (capacity-limited elimination)?
Ethanol, phenytoin, and aspirin.
113
What is Vmax?
The maximum elimination capacity
114
What is Km?
Drug concentration where elimimination is at 1/2 Vmax.
115
How are rate of elimination and clearance effected by drug concentration?
At inital drug concentrations, rate of clearence remains the same and elimination changes based upon drug concentration (First order). Then as drug concentration increases, the body switches to zero order and rate of elimination remains the same and clearance changes based upon drug concentration.
116
Describe how flow dependent elimation relates to extraction ratio?
Blood flow x extraction ratio = clearance
The only time you have a high clearance is when you have high extraction and high blood flow.
117
What is half life (T1/2)?
The time it takes to get drug in body to 1/2 of its concentration.
118
How many half lives does it take to acheive full drug effect and full drug elimination?
4 1/2 lives to reach both full effect and full elimination.
119
What is target concentration?
The dose required to acheive desired effect without having toxic effects.
120
How can you calculate T 1/2?
0.7 x Vd/ CL
121
What is bioavalibility (F)?
The fraction of unchanged drug that reaches the systemic circulation.
122
What are the 7 routes of drug administration?
1. IV
2. IM
3. SC
4. PO
5. Rectal
6. Inhalational
7. Transdermal
123
Describe first pass elimination?
Drugs that are PO will be metablized by the liver and either activated or inactivated before getting to the systemic circulation.
124
What is steady state dosing?
Dosing the drug in a way that replaces the eliminated amount and still keeps therapetic effects.
125
What is loading dose?
A bolus given if needed to reach steady state quickly.
LD = Vd x TC
## Footnote
Rate of administration is important. Needs to be given slowly so drug can disdribute into compartments
126
How can you calculate dosing for steady state for IV drugs?
Dosing (ss) = CL x drug concentration
127
How do you calculate dosing rate for oral drugs?
Dosing rate (oral) = dosing rate (calc.) / F(oral)
128
How can you calculate maintenance dose?
dosing rate x dosing interval
129
How do calculate the dose for a patient who is not 70 kg?
Use the ratio of the differences in weights, then multiply the dosing rate by that.
(patient's weight kg/70 kg) x dosing rate
130
Describe therapeutic drug monitoring?
Drawing of blood at certain intervals to assess an individuals pharmokinetics as compared to standard (Vd, TC, CL).
**Peak** - 5-10 mins after IV admin.
**Trough** - 30 mins before next dose
**Random** - any time
131
What is the most important variable in therapeutic drug monitoring?
Clearance
132
How can you calculate Vd for patients who do not weigh 70 kg?
Use IBW calculations.
**Men**: 52 + (1.9kg x in. over 5 ft)
**Women**: 49 + (1.7kg x in. over 5 ft.)
133
What test is used to determine kidney function?
Creatinine clearance.
134
What is drug biotransformation?
How a drug can be metabolically converted in the body. Drug can be decreased or activated.
135
What is a prodrug and an active drug?
A prodrug requires metabolism in the body before it is active. It is inactive when initally given. An active drug is ready to work as soon as it is given.
| Codeine is a prodrug that becomes morphine
136
Describe the first pass effect?
Oral drugs go to the liver prior to reaching systemic circulation. In the liver significant biotransformation can occur. Some drugs become inactive and others become active.
| Even IV drugs eventually pass through the liver and will be effected.
137
What is the route of blood through the liver?
**Oral**: GI - local veins - hepatic portal vein - Sinusoids - Hepatic vein - vena cava - systemic circulation
**All drugs**: Systemic circulation - hepatic artery - Sinusoids - hepatic vein - vena cava - systemic circulation
138
What are the role of sinusoids?
They are the "leaky" vessels where deoxygenated blood can interact with hepatocytes and be biotransformed.
139
What is a phase 1 reaction?
Converts the drug to a more polar metabolite (hydrophilic, can't cross membranes) so that it can be more readily excreted. Occurs by adding or unmasking a functional group.
140
What are phase II reactions?
Adding an endogenous substrate to a drug by conjugation to make drug more hydrophlic. Also causes drug to be heavier which is detoxifying.
141
What are the major phase 1 reactions?
**Oxidation (CYP450)**, Reduction, Dehydrogenation, and Hydrolysis.
142
What is the generic pathway of CYP450 metabolism?
## Footnote
Note: Flavoprotein is oxidized by reducing PY450 and then is reduced by use of NADPH so the reaction and happen again.
143
What is the most prevalent CYP450 isoform?
CYP3A4/5 is responsible for 50% of phase I reactions, 2D6 20%, 2B6 8%.
144
What are wild type CYP enzymes? How are they denoted?
Wild type means it occurs most often in the population. Denoted by *1
| Star 1
145
Describe PY450 induction?
A drug may induce CYP450, increasing its activity. If a drug becomes inactive by P450 then it will be inactivated faster.
If a drug is activated by P450 (prodrug), it will taken to its active form faster.
146
Describe P450 inhibition?
A drug may inhibit P450, decreasing its activity. For a drug that is inactivated by P450 it may be active longer or have less inactivation.
For a drug that is activated by P450 (Prodrug), much less of the the drug will be activated.
147
What are the major phase II reactions?
Glucoronidation (most prevalent) and glutathione conjugation (GST)
Others: glycine-conjugation, **sulfation**, methylation, acetylation, water conjugation
| Remember, sulfation and glucoronidation are normal pathways for tylenol metabolism.
148
Describe glucoronidation?
Adds glucuronic acid to a drug via UGT's (uridine diphosphate glucuronyltransferases) to make a drug more hydrophilic (more water soluble) which increases urinary excretion.
149
Describe glutathione-S-transferase reactions? (glutathione-conjugation)
Glutathione is added to a drug by GST to increase water solubility.
| Ubiqutious; many in RBC to aid in detoxification.
150
Describe the pathways that acetaminophen is metabolized to harmless products? What happens if you are low on glutathione?
Normally, acetaminophen will undergo Phase II reactions of glucorondiation and Sulfation and be excreted as nontoxic byproducts.
You can give N-acetylcistine which causes recycling of glutathione.
151
Describe the pathway that acetaminophen is metabolized to hepatotoxic products during an overdose?
In and overdose acetaminophen will be metabloized in Phase I reactions (CYP2E1/CYP3A4) that creates a toxic intermediate. This will undergo GSH conjugation to mercapturic acid and be excreted (backup plan) but, when glutathione runs out the intermediate will bind to cell macromolecules (proteins), inactivate them, and lead to liver cell death.
152
What other factors affect drug metabolism?
1. Diet (charcoal broiling, grapefruit juice)
2. Environment (cigarette smoke)
3. Age and Sex
4. Disease state (liver diseases)
5. Genetics
153
What is an example of a CYP450 inducer?
Charcoal broiled food and brussel sprouts (CYP1A2)
## Footnote
1A2 inactivates warfarin
154
What is an example of CYP450 inhibitor?
Grapefruit juice.
155
What is pharmacogenomics? How is important to personalized medicine?
Pharmacogenomics looks at an individuals genome to understand how they will respond to a drug prior to giving it. It helps predict, explain, and treat.
Personalized medicine is giving the right dose of the right drug for the right indication for the right patient at the right time.
156
What is a SNP? What are the types?
Single Nucleotide Polymorphism: single base pair variants with a frequency of at least 1%.
Wild type: highest frequency
Synonomous: "silent", doesn't change protein
Non-synonomous: changes amino acid
157
Describe how codeine may require dosage adjustments in certain genetic populations?
Codeine is metabolized by CYP2D6 to become activated to moprhine. Poor metabolizers will have poor efficacy and accumulation of prodrug, may need higher dose. Ultra-rapid metabolizers will have good, rapid effect and may need lower dose.
158
Describe how omeprazole may require dosage adjustments in certain genetic populations?
Omeprazole becomes inactivated by CYP2D6. In poor metabolizers, they will have good efficacy and may need a lower dose to prevent adverse effects. In ultra rapid metabolizers they will have poor efficacy and higher drug inactivation. May require a greater dose or slow release formulation.
159
Describe how 6-meracptopurine may require dosage adjustments in certain genetic populations?
6-MP is metabolized by TPMT (thiopurine methyltransferase). In the population, people have variations in this gene that alters response. Most people have 2 normal TPMT genes and metabolize quickly so they need a large dose. Some people have 1 normal and 1 abnormal TPMT gene and need a lower dose to avoid toxic side effects. Others have 2 abnormal TPMT genes (TPMT defiecent) and should not take 6-MP due to high risk of toxicity/fatality. A TPMT genotype can be completed to assess enzymatic activity.
160
Describe how warfarin may require dosage adjustments in certain genetic populations?
Warfarin is metabolized by CYP2C9. People who carry the CYP2C9^2 and CYP2C9^3 variants have reduced metabolism, leading to higher warfarin concentrations. These people require a lower daily dose than wild type allele carriers.
CYP2C9 and VKORC1 genotyping is recommended.
161
Describe the role of drug transporters in the cell?
Drug transporters are molecules that bind to a drug to move it across barriers (BBB, intestine, liver, kidney). They do this by active and facilitated diffusion.
Examples: SGLT, NCX, ion channels, Na+/K+/ATPase pump.
162
Desribe the role of drug efflux transporters?
They pump drugs out of the cell. Most are ATP Binding Cassette (ABC) transporters.
163
Describe the ABCB1 transporter? What drugs is this transporter relevant for?
It has the broadest substrate specificity with a wide distrubution: GI, kidney, liver, testes, BBB. They have increased expression in certain cancers.
## Footnote
Digoxin and Loperamide are transported by ABCB1, inhibitors of ABC1 (quinidine) decrease intestinal removal and increase plasma levels.
164
Describe ABCC transporter?
Largest class and ubiquitous. Mainly are involved in antineoplastic efflux.
165
Describe the ABCG2 transporter?
Transport antineoplastics, toxins, food-borne carcinogens, and folate. Example is Breast Cancer Resistance Protein (BCRP).
166
Describe drug transporters in the intestine?
Most transporters are positioned on the apical membrane (micrvilli) allowing transport of drugs from the intestine to the blood stream. There are a few that efflux some drugs (which prevents them from being taken orally, like glucoronidation).
167
Describe drug transporters in the placenta?
Most transporters are positioned to efflux drugs from the placental membrane back into the mother's blood stream. The placental barrier is the only pathway for fetal nutrients.
168
Describe drug transporters in the liver?
Most transporters move drugs into the liver for metabolism.
169
Describe drug transporters in the blood-CSF barrier?
Has less efflux than the BBB, drugs like bupivicaine work here.
170
Describe drug transporters in the BBB?
The vascular epithelium is primary site of exclusion due to tight junctions and multiple transporters. Most transporters efflux drugs back into the blood.
171
Describe drug transporters in the kidneys?
Primarily located on the apical side that leads to excretion in the renal tuble from the glomerulus.
172
What are the components of an intact brain barrier?
Vascular space, vascular epithelium (tight junctions), astrocyte, podocyte.
173
Describe the pathway of tylenol in the gut before and after biotransformation?
Tylenol is absorbed into the blood by transporters in the microvilli. It then travels to the liver where it undergoes First Pass Effect and becomes a non-toxic glucoronide (Phase II; glucoronidation). Then it is effluxed back into the intestine for excretion by ABCC that are specialized for glucuronides.
174
What is the normal blood volume in an adult?
5.6 L/ 70 Kg or .08 L/Kg
.04 kg/L for plasma
175
What is tachyphylaxis?
Rapid tolerance to a drug, making it less effective.
176
Describe how pharmacogenomics plays a role in the drug Herceptin?
In 15-25% of breast cancers HER 2 is amplified 2-20x. These tumors that express HER2 are responsive to Herceptin. Pharmacogenomics are important here because herceptin is only useful for HER 2 + breast cancers. Genomic testing is imperative to properly treat this disease.
177
What are the 4 ways drugs cross barriers?
1. Lipid diffusion
2. Special carriers
3. Endocytosis/exocytosis
4. Aqueous diffusion
