Exam 1 material Flashcards
1
Q
Who is considered to be the father of modern medicine?
A
Hippocrates
2
Q
What Greek god and artifact did the medicine logo come from?
A
the rod of Asclepius
3
Q
What is Materia Medica?
A
It is the precursor to a pharmacology text. It contains a body of knowledge throughout history of botany and medicinal substances.
4
Q
Define pharmacodynamics
A
What the drug does to the body
5
Q
Who is the father of Toxicology?
A
Paracelsus
6
Q
Define pharmacokinetics
A
What the body does to the drug
7
Q
Define pharmacogenomics and give an example
A
How the body responds to the drug given our genetics. Example: HER2 positive breast cancer.
8
Q
What is the difference between a poison and a toxin?
A
Toxins are organic and poisons are inorganic materials
9
Q
What four characteristics contribute to the lock and key mechanism of receptor interactions?
A
Size, shape, electrical charge and atomic composition
10
Q
List 4 different bond types in order of bond strength (strong to weak)
A
Covalent bonds (strongest), ionic bonds, hydrogen bonds, hydrophobic bonds (weakest)
11
Q
What is an isomer and give an example?
A
Two molecules with the same chemical formula. Example fructose and glucose
12
Q
What is an optical isomer?
A
Isomers that are mirror images of one another. They do not behave the same in the body however.
13
Q
What is a racemic mixture and give an example
A
A mix of optical isomers. Example: S and R ketamine. S-ketmaine is the purified form and 4x more potent than R-ketamine, which has the toxic side effects we associate with ketamine
14
Q
What is an orthosteric interaction?
A
When a drug binds to the active site of the receptor
15
Q
What is an allosteric interaction?
A
When the drug or agonist binds a site adjacent to or outside of the active site
16
Q
What is non specific binding and give an example of an endogenous molecule that facilitates this
A
Non-specific binding can occur simultaneously but is outside of receptor-agonist binding (which has a limit when receptor sites are saturated). Albumin can facilitate non-specific binding.
17
Q
What are the 4 things we look at when studying pharmacokinetics?
A
Absorption, Distribution, Metabolism, and Excretion
18
Q
What is Emax?
A
Emax is the maximum effect of the drug. This number can be variable. EC50 is a single point.
19
Q
When looking at the drug concentration response curve, what is EC50?
A
EC50 is the concentration of the drug where it has reached 50% of its maximum effect
20
Q
When looking at the concentration response curve, what is Kd?
A
Kd is the dissociation constant. Kd is the concentration of the drug where 50% of the receptors are bound.
21
Q
What is Bmax?
A
Bmax is where receptors are 100% bound or saturated. Only non specific binding can occur at this point.
22
Q
If a drug has a low Kd what does that mean? A high Kd?
A
A drug with a low Kd is said to have high affinity for the receptor. A high Kd corresponds with a drug that has a low affinity for binding the receptor
23
Q
What is an allosteric activator and give an example of one?
A
An allosteric activator is an agonist that binds to a site outside of the active site and potentiates the the activity of that protein bound active site. Example, both benzos and general anesthesia bind GABA receptors and these regulatory sites produce positive allosteric modulation such that the activity of GABA is potentiated.
24
Q
What is a competitive antagonist? Give an example
A
Antagonists that bind the active site of a receptor. These interactions are surmountable if you increase the amounts of agonist given. Propranolol to isoproterenol.
25
Give an example of how a competitive antagonist interaction can be irreversible...
When an antagonist binds the active site (orthosteric) and forms a covalent bond.
26
What is a non-competitive antagonist? Give an example
Antagonists that bind outside the active site (allosteric). These are irreversible and insurmountable. Phenoxybenzamine to norepinephrine.
27
What is a partial agonist and what problems can they pose to agonists?
A partial agonist produces a lower response at full receptor occupancy. They can out-compete full agonists and can actually act as antagonists in the presence of full agonists.
28
Give an example of antagonism by administration of an opposing charge...
Protamine, which carries a positive charge can be given in the event of an overdose of heparin, which has a negative charge. Protamine binds the heparin and renders it ineffective in the clotting cascade.
29
What is physiologic antagonism and give an example...
When two compounds bind to two different receptors and have opposite effects. Example: Epinephrine can bind beta receptors and increase HR while acetylcholine can bind muscarinic receptors and decrease the HR.
30
Describe receptor configurations in pharmacodynamics
Receptors can be active or inactive. Physiologically the inactive configuration tends to win favor. Agonists will activate the receptors turning them "on"
31
What is an inverse agonist?
These are agonists that "inactivate" receptors or turn them "off" In practice these act as antagonists but in theory they are agonists as they elicit a response by turning "off" the receptor favoring the inactive form.
32
Graphically what effect do antagonists and inverse agonists have on constitutive activity of a receptor?
Competitive antagonists bring the receptor activity back down to constitutive activity. Inverse agonists lower that receptor's activity below the constitutive activity threshold.
33
Take Beta-1 receptors and give an example of an agonist (direct and indirect), partial agonist, antagonist, and inverse agonist...
Agonist: Epinephrine (direct), amphetamines (indirect)
Partial agonist: Pindolol
Antagonist: Propranolol
Inverse agonist: Carvedilol
34
List 3 scenarios that can dictate the duration of drug action...
1. How long the drug binds the receptor
2. How long downstream effectors last (these can be degraded/used up)
3. Desensitization occurs (signals are dampened)
35
What is special about albumin?
It is a large carrier protein. It has two inert binding sites (these do not elicit a response). It binds mostly to acidic drugs
36
What is the difference between potency and efficacy?
Potency is the drug concentration required to produce 50% of that drugs maximal effect. Efficacy describes the maximal response a drug can deliver. Efficacy is more important.
37
What is the therapeutic index?
The TI is a ratio. The median toxic dose (TD50) over the median effective dose (ED50). The larger the ratio, the safer the drug.
38
List a few causes of variations in drug responsiveness
Drug-drug interactions (polypharmacy), genetics, tolerance (tachyphylaxis/quick tolerance), body composition
39
if pH is greater than a drug's pKa what happens?
The drug favors its unprotonated form, donates a H+ to it's basic environment
40
if pH is less than a drug's pKa what happens?
The drug favors it's protonated form as it picks up a H+ from its acidic environment
41
Which form of aspirin (weak acid pKa = 3.5) is favored in the stomach (pH = 1.5), in the intestine (pH = 6.5) and will it be charged or uncharged?
In the stomach it's protonated form, uncharged.
In the intestine it will be unprotonated and charged
42
Which form of morphine (weak base pKa is 7.9) is favored in the stomach (pH = 1.5), in the blood (pH = 7.4) and will it be charged or uncharged?
In the stomach it will be protonated and charged.
In the blood it will be slightly protonated and charged as well or in equilibrium.
43
List a few reasons biologic drugs are in vogue...
They are very targeted (high specificity)
There are less adverse effects associated with these drugs
Increased efficacy
They can be used to cause cell death
44
What are biologics (drugs that use monoclonal antibodies) used to treat?
Asthma, migraines, cancer
45
How are monoclonal antibodies made?
1. isolate a protein from a human
2. inject that protein into another living thing which will generate an immune response and produce antibodies
3. Take a spleen cell (antibody producing cell) and fuse it with a myeloma cell (immortal cancer cell)
46
Describe the process of clinical testing
1. In vitro studies to find a lead compound
2. Animal testing (can take 2 years)
3. Apply for an IND
4. Phase 1: healthy subjects
5. Phase 2: patients as subjects
6. Phase 3: clinical trials and placebos as controls, double blind
7. Apply for NDA (can take a year)
8. Marketing and post-marketing surveillance (phase 4)
47
Describe 4 methods of permeation (absorption) for a drug to cross barriers to the site of action
1. Aqueous diffusion
2. Lipid diffusion
3. Carrier proteins
4. Endocytosis and exocytosis
48
How does aqueous diffusion work?
Compounds are able to traverse a barrier using channels or guided by the concentration gradient. Water can use aquaporins. This is just simple diffusion.
49
How does lipid diffusion work?
if the drug is lipid soluble it can cross the membrane by diffusion. If a drug can go from being charged to noncharged it can cross barriers based on pH of surrounding fluid.
50
How do carrier proteins participate in drug permeation?
Carrier proteins bind to a drug and help move them across barriers. This is by facilitated diffusion or active transport.
51
What binds to GPCR's and what are orphan receptors?
2/3 of all non-antibiotic drugs bind to GPCRs. Orphan receptors are GPCRs that have no known endogenous ligand, these make up 50% of the GPCRs in our body.
52
Describe the structure of a GPCR
They have 7 transmembrane spanning alpha helices. The receptor is coupled with a G protein. Once the drug or ligand binds the receptor this activates the G protein.
53
What is the purpose of coupling in the case of G proteins.
The receptors can activate numerous G proteins (pleiotropy) which can then go on to activate effector proteins and produce secondary messengers which set up a signaling cascade. G proteins help amplify the dose response.
54
Describe the structure of the G protein.
The G protein is trimeric and has alpha, beta, and gamma subunits. The alpha subunit has a GDP in its inactive form. When its activated by the GPCR the GDP is exchanged for a GTP on the alpha subunit, which allows the alpha subunit to break away and activate an effector protein.
55
GPCRs participate in two main signaling pathways what are these (the names of the effector proteins and the second messengers)
1. Adenylyl cyclase and protein kinase A; cAMP
2. Phospholipase C; Diacylglycerol (DAG), IP3, and Calcium
56
What is desensitization?
the rapid attenuation in response of the receptor to the binding of the agonist. This is usually due to a conformational change.
57
Describe one scenario of how desensitization occurs
Drug binds GPCR and forms a covalent bond, holding in its open conformation. This exposes the -OH groups, which get phosphorylated. This attracts beta-arestin, which binds to the -OH groups and arrests any further activity. Beta-arestin also drags the entire receptor/drug compound to a clatherin coated pit which then engulfs the compound (endocytosis). The covalent bond breaks and then the receptor can then be recycled.
58
Describe another scenario for the receptor's fate in desensitization.
If the covalent bond is too strong between the drug and the receptor, after it is engulfed by the clatherin coating pit, then a lysosome comes along and merges with the endosome and degrades the receptor and the drug using proteases.
59
Describe the structure and function of receptor tyrosine kinases (RTKs). Do they use ATP? If so, how much?
RTKs are catalytic cell surface receptors that begin as two monomer receptors, which dimerize when two drugs or ligands bind. This dimerization allows the RTKs to phosphorylate the tyrosine residues on one another (with the help of 6 ATP), which activates the docking site for numerous downstream signals.
60
What are a couple key differences between a GPCR and a RTK.
1. RTK's do not need a G protein and can phosphorylate itself
2. RTK docking sites can interact with over 200 different proteins (GPCRs only interact with 2 effector proteins)
61
List the 4 methods of transmembrane signaling
1. intracellular receptors, drug must be lipid soluble (steroid hormones)
2. Ion channel (voltage gated or ligand gated)
3. Catalytic receptor, a receptor that activates an enzyme inside the cell (RTKs)
4. GPCRs
62
How do voltage gated channels work? And which cells have lots of them?
These channels are found in neurons, muscle cells and endocrine cells. The M gates are closed at resting membrane potential (H are open). When activated the M gates open and Na floods in. When inactivated H gates close. When deactivated M gates also close.
63
How do ligand gated ion channels work? And what are the two types?
The ligand, or chemical binds to open the channel. These can be ionotropic or metabotropic.
64
How do ionotropic ligand gated channels work and give an example?
The ligand binds to a site on the channel and which activates it or opens the gates. These are the more common type of ligand gated channels. Example; nicotinic ACh receptors.
65
How do metabotropic ligand gated ion channels work and give an example?
These channels are located near a GPCR, whose second messenger activity opens the channel. Example: olfactory nerve in recognizing a specific odorant.
66
How do steroids get inside the cell? Inside the nucleus?
Steroids have a receptor inside the cell. This steroid receptor complex then is able to bind to chromatin a protein inside the cell nucleus and activate mRNA transcription.
67
Give an example of how an endogenous gas is able to decrease blood pressure
Blood pressure is elevated, this creates a shearing force on the outside of an endothelial cell producing nitric oxide (NO) which can cross the cell membrane into a smooth muscle cell. Here the NO activates guanyl cyclase which cyclates a GMP. GMP causes smooth muscle relaxation and thus dilates the blood vessel.
68
How does endocytosis work? And exocytosis?
Endocytosis is receptor mediated via clatherin coated pits which engulf the membrane and whatever binds the receptors. Exocytosis involves the merging of the vesicle with the membrane.
69
What is the volume of distribution? What units?
The space in the body that is able to contain the drug. This can be the blood, plasma, water, fat, or bone. The Vd is an apparent volume (much greater than the physical body can contain). It is expressed in liters.
70
What is meant by a high volume of distribution? A low Vd?
A high Vd means less of the drug stays in the blood. A low Vd, it stays in the blood.
71
How do you calculate a dose given volume of distribution and target concentration?
Vd x TC = dose of drug
72
What is the Target Concentration?
TC is the concentration of a drug in the body that produces the target desired effect of that drug.
73
What is clearance (CL)?
It predicts the rate of elimination in relation to drug concentration in the body. It is expressed in as a fraction. Clearance is additive, it includes clearance that is happening in the blood, plasma, by the kidneys, the liver, etc.
74
How do you calculate clearance (CL)?
Rate of elimination x concentration
(ROE) x (C)
75
What is the rate of elimination (ROE)?
The amount of a drug that is eliminated from the body in a given unit of time, usually per hour.
76
What does capacity-limited elimination mean?
It describes the fact that elimination is not always linear. Clearance varies and is concentration dependent. Example, an overdose of a particular drug undergoes zero order elimination.
77
With first order elimination what is constant and what varies?
Clearance is constant
Rate of elimination varies
78
With zero order elimination what is constant and what varies? Give three examples of drugs that commonly undergo zero order elimination
Rate of elimination is constant
Clearance varies.
Ethanol, salicylates, and phenytoin.
79
Say someone accidentally overdoses on their anti-seizure medication, as their body clears the medication what order will it be in at first and ultimately which order will it eliminate the drug?
Zero order elimination and then first order elimination.
80
What is a half life?
The time it takes for the drug in the body to be at half its initial concentration.
81
how many half-lifes does it take to achieve the target concentration of a drug in the body?
4
82
What is bioavailability and which route has the highest bioavailability, second, third. Which is the least bioavailable route?
The fraction of unchanged drug reaching systemic circulation. IV, IM, SQ (highest) Oral and inhalation (least).
83
What route has first pass elimination and what causes it?
Oral medications experience a first pass effect. The drug needs to be absorbed by the gut and then go through the liver. Some of the drug may be transformed by the portal system in the liver.
84
What is the purpose of a maintenance dose?
to maintain steady state of the drug by giving just enough to replace the eliminated drug.
85
What is the purpose of a loading dose?
You can give a loading dose if you need to reach steady state quickly.
86
When do you use ideal body weight to dose a drug?
When the drug you are dosing preferentially stays in the blood. Need the patient's height to calculate this.
87
List 3 labs you can monitor to ensure therapeutic drug monitoring...
1. Peaks and Troughs
2. Creatinine clearance
3. albumin in the blood
88
What is biotransformation?
The drug gets metabolized mainly by the liver to convert it into something that can get excreted. Some of these metabolites become active after biotransformation, but lots are destined for excretion.
89
Describe the path of the drug from the bloodstream into the hepatic portal system and back out in the first pass effect.
Take the drug orally, goes from the GI tract to the intestinal vein. Then to the portal vein and the sinusoids. From the sinusoids back out to the hepatic vein, the vena cava and into systemic circulation.
90
Where is most of the drug being bio transformed within the liver?
The sinusoids
91
What do phase 1 reactions do?
They are responsible for converting the drug to a more polar metabolite. This makes the drug more hydrophilic.
92
What do phase II reactions do?
These usually add an endogenous compound to the drug, like a sugar group. This results in a much larger molecule which keeps it from getting back into the blood and gets excreted.
93
Do all drugs go through both phase I and phase II reactions?
No. Drugs can go straight to phase II and do not always go through phase I as well.
94
What type of reaction occurs in the enzyme cytochrome P450?
oxidation reaction.
95
50% of phase I oxidation reactions occur in which variant of cytochrome P450? What are the two other common ones mentioned in class?
CYP3A4. CYP2D6 and CYP2B6.
96
Where is cytochrome P450 found?
Primarily in the sarcoplasmic reticulum in the cytosol.
97
If a drug induces CYP450 what results?
Increased drug effect if metabolism activates the prodrug. Decreased effect if metabolism deactivates the drug.
98
What happens with inhibition of the CYP450 enzyme?
Increase in the active drug if metabolism inactivates the drug. Decreased drug effect if metabolism transforms a prodrug.
99
Give three examples of phase II reactions we mentioned in class
Glucuronidation (attaching a sugar group), and glutathione-S-transferase (good at removing toxic metabolites). Also, sulfation (which adds sulfonic acid)
100
How is acetaminophen normally metabolized and how does an overdose lead to liver cell death?
Acetaminophen normally goes through phase II reactions: glucuronidation and sulfation and gets excreted. If one overdoses on acetaminophen, a positively charged reactive toxic intermediate is created and binds to intracellular proteins and disrupts the cell, leading to liver cell death.
101
What other phase II reaction can occur to help get rid of some of the toxic intermediates of Tylenol if there is too much in the system. What drug helps replenish this?
Glutathione can bind to the intermediates and direct them towards excretion. With extreme overdoses, glutathione is all tied up. N-acetyl cysteine can replenish glutathione.
102
What other factors can impact drug metabolism?
Diet (charcoal grilling, grapefruit juice, cruciferous vegetables). Cigarette smoking. Age (pre versus post pubescent).
103
Why is pharmacogenomics important to study?
Because individuals react differently to different drugs. (Some have a hyporeactive response and some a hyperreactive response). It helps us predict and target treatment better and limit toxic side effects.
104
What are SNP's?
Single nucleotide polymorphisms. These can be "silent" and code for the same amino acid, or they can code for a different amino acid and create an allele.
105
Give an example of genetic polymorphisms effecting the CYP450 enzyme.
CYP2D6 is absent in 7% of Caucasians and hyperreactive in 30% of East Africans. This enzyme is responsible for catalyzing the metabolism of the following drugs: beta blockers, analgesics, and various antidepressants and antipsychotics.
106
How is 6-mercaptopurine (6-MP) metabolism effected by pharmacogenetics?
This drug is a purine analog and is used to treat leukemia. It gets metabolized into 6-methyl-MP normally but if someone is TPMT (enzyme) deficient 6-MP gets oxidized into a reactive metabolite (these people require a much smaller dose). Genetic test for this is easy and necessary.
107
What impact dose pharmacogenetics have on warfarin?
Warfarin is metabolized by CYP2C9. Some people have CYP2C9 polymorphisms that make them clear the drug much faster (rapid metabolizers) and some clear it much slower. 50% of people on warfarin need less than the therapeutic dose (slow metabolizers) and 33% need more (rapid metabolizes). That is why this medication is the #1 drug causing death from adverse effects (bleeding). Genetic test is recommended but not required so insurance does not cover it.
108
What impact does pharmacogenetics have on breast cancer?
60-70% of breast cancers express either estrogen receptors or progesterone receptors. Can use drugs to block these receptors.
109
What impact does pharmacogenetics have on HER2 breast cancers specifically?
15-25% of breast cancers have the HER2 gene which can be amplified by 2-20x. This can generate up to 100x more human epidermal growth factor receptors which dictates the spread of the cancer. If someone is HER2 positive they will respond to the Herceptin drug, but if they do not have this gene Herceptin wont work for them and is incredibly expensive.
110
Why do CYP2D6 poor metabolizers get less pain control with codeine?
Codeine can be metabolized to (is a prodrug for) morphine. If you are a poor metabolizer, most codeine will become norcodeine and not get converted to morphine.
111
What are drug efflux transporters and how did we discover them?
These pump drugs into or out of the cell. We didn't know these existed until oncologists noticed patients over time stopped responding to different chemotherapies. They called these multi drug resistant cancers, but these were just patients developing more of these drug efflux pumps.
112
Why do cell make more drug efflux pumps?
It is a survival mechanism. For example, if given a chemo drug that's aim is to kill a cancer cell, the cell upregulates these efflux pumps to get rid of the drug.
113
What are ABC transporters?
These are drug efflux transporters. ATP Binding Cassette Transporters. There are 7 families. They span the membrane and have nucleotide binding domains. Their orientation on the cell membrane and their location in the body dictates where they send the drug.
114
Give a few example of ABC gene families and what they transport
1. ABCA1: cholesterol efflux
2. ABCB1: broadest substrate specificity (see next slide)
3. ABCC: Largest class, mainly antineoplastics
4. ABCG: Antineoplastics and folate transport
115
What drugs are transported by ABCB1 and where are these transporters found?
Antineoplastics, HIV protease inhibitors, antibiotics, antidepressants, antiepileptics and opioids. These are found in the GI tract, kidney liver and testes. Critical in maintenance of the BBB.
116
Which drugs inhibits ABCB1? What increases ABCB1?
Cyclosporine, quinidine and ritonavir inhibit ABCB1. Cancers can increase ABCB1 expression.
117
List three reasons it is difficult to cross the BBB?
1. ABC transporters
2. Vascular epithelium has tight junctions
3. Astrocytes and podocytes that wrap around the vasculature in the brain
